Sos1 inhibitors and uses thereof

Abstract

The present disclosure provides a compound of Formula (I') (I'), a pharmaceutically acceptable salt or stereoisomer thereof, and its use in, for example, the treatment of a condition, disease or disorder in which inhibition of the interaction of SOS1 with a RAS family protein or RAC1 is of therapeutic benefit, in particular in the treatment of neoplastic diseases. The present disclosure is also characterized by compositions containing the compounds and methods of using and making the compounds.

Description

[0001] Related applications

[0002] This application claims priority to International Application No. PCT / CN2023 / 141248, filed on December 22, 2023. The entire contents of the aforementioned application are expressly incorporated herein by reference. Technical Field Background Technology

[0004] RAS family proteins include KRAS (V-Ki-ras2 Kirsten rat sarcoma virus oncogene homolog), NRAS (neuroblastoma virus oncogene homolog), and HRAS (Harvey mouse sarcoma virus oncogene), as well as any of their mutants. They are small GTPases, existing in cells in a GTP-bound or GDP-bound state (McCormick et al., J. Mol. Med. (Berl)., 2016, 94(3):253-8; Nimnual et al., Sci. STKE., 2002, 2002(145):pe36). The intrinsic GTPase activity of RAS family proteins is weak and the nucleotide exchange rate is slow (Hunter et al., Mol. Cancer Res., 2015, 13(9): 1325-35). The binding of GTPase activating proteins (GAPs) such as NF1 increases the GTPase activity of RAS family proteins. The binding of guanine nucleotide exchange factors (GEFs) such as SOS1 (Son of Sevenless 1) promotes the release of GDP from RAS family proteins, thereby achieving GTP binding (Chardin et al., Science, 1993, 260(5112):1338-43). When in a GTP-bound state, RAS family proteins are active and bind to effector proteins (including C-RAF and phosphoinositide 3-kinase (PI3K)) to promote the RAF / mitogen or extracellular signal-regulated kinase (MEK / ERK) pathway, the PI3K / AKT / mammalian target of rapamycin (mTOR) pathway, and the RaIGDS (Ral guanine nucleotide dissociation stimulator) pathway (McCormick et al., J. Mol. Med. (Berl)., 2016, 94(3):253-8; Rodriguez-Viciana et al., Cancer Cell. 2005, 7(3):205-6).These pathways affect a variety of cellular processes, such as proliferation, survival, metabolism, movement, angiogenesis, immunity, and growth (Young et al., Adv. CancerRes., 2009, 102:1-17; Rodriguez-Viciana et al., Cancer Cell. 2005, 7(3):205-6).

[0005] Cancer-associated mutations in RAS family proteins suppress their intrinsic and GAP-induced GTPase activity, leading to an increase in the number of GTP-binding / active RAS family proteins (McCormick et al., Expert Opin. Ther. Targets., 2015, 19(4):451-4; Hunter et al., Mol. Cancer Res., 2015, 13(9): 1325-35). This, in turn, leads to the sustained activation of downstream effector pathways of RAS family proteins (e.g., MEK / ERK, PI3K / AKT / mTOR, RaIGDS pathway). KRAS mutations (e.g., amino acids G12, G13, Q61, A146) are found in various human cancers, including lung cancer, colorectal cancer, and pancreatic cancer (Cox et al., Nat. Rev. Drug Discov., 2014, 13(11):828-51). Mutations in HRAS (e.g., amino acids G12, G13, Q61) and NRAS (e.g., amino acids G12, G13, Q61, A146) are also found in a variety of human cancer types, but they usually occur at a lower frequency compared to KRAS mutations (Cox et al., Nat. Rev. Drug Discov., 2014, 13(11):828-51). Alterations in RAS family proteins (e.g., mutations, overexpression, gene amplification) have also been described as mechanisms of resistance to cancer drugs such as the EGFR antibodies cetuximab and panitumumab (Leto et al., J. Mol. Med. (Berl). 2014 July; 92(7):709-22) and the EGFR tyrosine kinase inhibitor osimertinib / AZD9291 (Ortiz-Cuaran et al., Clin. Cancer Res., 2016, 22(19):4837-47; Eberlein et al., Cancer Res., 2015, 75(12):2489-500).

[0006] SOS1 (non-heptakinase homolog 1) is the human homolog of the first identified Drosophila protein non-heptakinase homolog (Pierre et al., Biochem. Pharmacol., 2011, 82(9): 1049-56; Chardin et al., Cytogenet. Cell. Genet., 1994, 66(1):68-9). The SOS1 protein consists of 1333 amino acids (150 kDa). SOS1 is a multidomain protein with two tandem N-terminal histone domains (HD), followed by a Dbl homologous domain (DH), a Pleckstrin homologous domain (PH), a helical linker (HL), a RAS exchange motif (REM), a CDC25 homologous domain, and a C-terminal proline-rich domain (PR). SOS1 possesses two binding sites for RAS family proteins: a catalytic site that binds to GDP-binding RAS family proteins to facilitate guanine nucleotide exchange; and an allosteric site that binds to GTP-binding RAS family proteins, leading to a further increase in SOS1's catalytic GEF function (Freedman et al., Proc. Natl. Acad. Sci. US A., 2006, 103(45): 16692-7; Pierre et al., Biochem. Pharmacol., 2011, 82(9): 1049-56). Publicly available data suggest that SOS1 plays a crucial role in mutant KRAS activation and oncogenic signaling in cancer (Jeng et al., Nat. Commun., 2012, 3:1168). Depletion of SOS1 levels reduces the proliferation rate and survival of tumor cells carrying KRAS mutations, while no effect was observed in KRAS wild-type cell lines. The effects of SOS1 loss cannot be salvaged by introducing SOS1 with catalytic site mutations, indicating the important role of SOS1 GEF activity in KRAS mutant cancer cells.

[0007] SOS1 plays a key role in the activation of RAS family protein signaling in cancer through mechanisms other than those of RAS family proteins. SOS1 interacts with the adaptor protein Grb2, and the resulting SOS1 / Grb2 complex binds to activated / phosphorylated receptor tyrosine kinases (e.g., EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A / B, FGFR1 / 2 / 3, IGF1 R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1 / 2 / 3, AXL) (Pierre et al., Biochem. Pharmacol., 2011, 82(9): 1049-56). SOS1 is also recruited to other phosphorylated cell surface receptors, such as the T-cell receptor (TCR), B-cell receptor (BCR), and monocyte colony-stimulating factor receptor (Salojin et al., J. Biol. Chem. 2000, 275(8):5966-75). This SOS1 is located on the plasma membrane, adjacent to RAS family proteins, enabling it to promote RAS family protein activation. SOS1 activation of RAS family proteins can also be mediated through the interaction of SOS1 / Grb2 with BCR-ABL oncogenes commonly found in chronic myeloid leukemia (Kardinal et al., 2001, Blood, 98:1773-81; Sini et al., Nat. Cell Biol., 2004, 6(3):268-74). Furthermore, alterations to SOS1 have been shown to be associated with cancer. SOS1 mutations have been found in embryonal rhabdomyosarcoma, sedocoli cell testis tumor, cutaneous granulosa cell tumor (Denayer et al., Genes Chromosomes Cancer, 2010, 49(3):242-52), and lung adenocarcinoma (Cancer Genome Atlas Research Network., Nature. 2014, 511 (7511):543-50). Meanwhile, studies have described SOS1 overexpression in bladder cancer (Watanabe et al., IUBMB Life., 2000, 49(4):317-20) and prostate cancer (Timofeeva et al., Int. J. Oncol., 2009, 35(4):751-60).In addition to cancer, hereditary SOS1 mutations have also been shown to be associated with the pathogenesis of RAS lesions such as Noonan syndrome (NS), cardiofacio-cutaneous syndrome (CFC), and hereditary gingival fibroma type 1 (Pierre et al., Biochem. Pharmacol., 2011, 82(9): 1049-56).

[0008] SOS1 is also a GEF used for the activation of the GTPase RAC1 (Ras-related C3 botulinum toxin substrate 1) (Innocenti et al., J. Cell Biol., 2002, 156(1): 125-36). RAC1, like other RAS family proteins, has been shown to be associated with the pathogenesis of various human cancers and other diseases (Bid et al., Mol. Cancer Ther. 2013, 12(10):1925-34).

[0009] Non-heptakinase homolog 2 (SOS2) is a homolog of SOS1 in mammalian cells and also acts as a GEF for the activation of RAS family proteins (Pierre et al., Biochem. Pharmacol., 2011, 82(9): 1049-56; Busay et al., Biochim. Biophys. Acta., 2008, 1786(2):178-87). Publicly available data from gene knockout mouse models suggest redundant roles of SOS1 and SOS2 in the in vivo constitutive model of adult mice. Although germline knockout of SOS1 in mice leads to death during mid-pregnancy embryonic development (Qian et al., EMBO J., 2000, 19(4):642-54), systemic conditional SOS1 knockout in adult mice is viable (Baltanas et al., Mol. Cell. Biol., 2013, 33(22):4562-78). Targeting the SOS2 gene did not result in any dominant phenotype in mice (Esteban et al., Mol. Cell. Biol., 2000, 20(17):6410-3). In contrast, dual knockout of the SOS1 and SOS2 genes led to rapid death in adult mice (Baltanas et al., Mol. Cell. Biol., 2013, 33(22):4562-78). These publicly available data suggest that selective targeting of individual SOS isotypes (e.g., selective SOS1 targeting) can be adequately tolerable, thereby achieving a therapeutic index between SOS1 / RAS family protein-driven cancers (or other SOS1 / RAS family protein lesions) and normal cells and tissues.

[0010] Selective pharmacological inhibition of the binding of SOS1 to RAS family proteins at their catalytic sites is expected to prevent SOS1-mediated activation of RAS family proteins into their GTP-bound forms. These SOS1 inhibitors are therefore expected to inhibit downstream cellular signaling pathways associated with RAS family proteins (e.g., ERK phosphorylation). In cancer cells associated with RAS family protein dependence (e.g., KRAS mutant cancer cell lines), SOS1 inhibitors are expected to exert anticancer effects (e.g., inhibition of proliferation, survival, metastasis, etc.). For SOS1:RAS family protein binding inhibition (nanomolar IC50 level...) 50 (value) and ERK phosphorylation in cells (nanomolar level IC50) 50High potency (SOS1 value) is an ideal characteristic of SOS1 inhibitor compounds. Furthermore, an ideal characteristic of SOS1 inhibitor compounds would be selective inhibition of SOS1 relative to SOS2. This conclusion is based on the viability phenotype of SOS1 knockout mice and the mortality of SOS1 / SOS2 dual knockout mice, as described above.

[0011] These features have not been fully realized in previously described SOS1 inhibitor compounds. The interaction between RAS family proteins and SOS1 proteins has become increasingly recognized in recent decades. To date, numerous studies have been conducted to identify and optimize binders targeting RAS effector binding sites or SOS1 catalytic binding sites (see Lu et al., ChemMedChem. 2016, 11(8):814-21 for a selected review), but with limited success.

[0012] Recently, small activating molecules have been identified that bind to the lipophilic pocket of SOS1 adjacent to the RAS binding site (Bums et al., Proc. Natl. Acad. Sci. 2014, 111 (9):3401-6). However, the binding of these molecules appears to lead to increased nucleotide exchange, resulting in activation of RAS rather than inactivation.

[0013] In efforts to stabilize the protein-protein interaction between RAS family proteins and SOS1 and to prevent RAS family proteins from reloading GTP, several different fragments have been identified (Winter et al., J. Med. Chem. 2015, 58(5):2265-74). However, the reversible binding of these fragments to SOS1 has not translated into a measurable effect on nucleotide exchange, and only a weak effect has been observed for fragments covalently bound to RAS.

[0014] Recent studies have also been conducted to combine well-designed screening platforms to identify small molecule inhibitors of SOS1 (Evelyn et al., Chem. Biol. 2014, 21 (12):1618-28; Evelyn et al., J. Biol. Chem. 2015, 290(20):12879-98; Zheng et al., WO 2016 / 077793), namely compounds that bind to SOS1 and inhibit protein-protein interactions with RAS family proteins. Although compounds with mild inhibitory effects on SOS1 have been identified, their effects on guanine nucleotide exchange and regulation of cell signal transduction (e.g., ERK phosphorylation) are weak. WO2018 / 115380 and WO2018 / 172250 disclose quinazoline-based SOS inhibitors.

[0015] Therefore, there is a need to develop new compounds that regulate SOS1 activity for the treatment of diseases and conditions, such as cancer. Summary of the Invention

[0016] This disclosure provides SOS1 inhibitors, such as compounds of structural formula (I'), pharmaceutically acceptable salts thereof, tautomers, stereoisomers, and pharmaceutical compositions thereof.

[0017] (I')

[0018] This disclosure also provides methods for inhibiting the activity of SOS1 using compounds disclosed herein (e.g., compounds of structural formula (I'), their pharmaceutically acceptable salts, tautomers, stereoisomers, or pharmaceutical compositions.

[0019] This disclosure also provides methods for treating conditions, diseases, or ailments in which the interaction of SOS1 with RAS family proteins or RAC1 has therapeutic benefit, particularly for treating neoplastic diseases, using compounds disclosed herein (e.g., compounds of structural formula (I'), their pharmaceutically acceptable salts, tautomers, stereoisomers, or pharmaceutical compositions.

[0020] In one aspect, this disclosure provides compounds of any of the formulas described herein (e.g., structural formula (I')), their pharmaceutically acceptable salts, tautomers, or stereoisomers.

[0021] In one aspect, this disclosure provides a pharmaceutical composition comprising a compound of any of the formulas described herein (e.g., structural formula (I')), a pharmaceutically acceptable salt thereof, a tautomer or stereoisomer (as defined in any of the embodiments described herein), and a mixture of at least one pharmaceutically acceptable carrier.

[0022] On the other hand, this disclosure provides compounds of any of the formulas described herein (e.g., structural formula (I')), their pharmaceutically acceptable salts, tautomers, or stereoisomers (as defined in any of the embodiments described herein) for use as pharmaceuticals.

[0023] On the other hand, this disclosure provides compounds of any of the formulas described herein (e.g., structural formula (I')), pharmaceutically acceptable salts thereof, tautomers or stereoisomers (as defined in any of the embodiments described herein), for the treatment of conditions, diseases or ailments in which inhibition of the interaction between SOS1 and RAS family proteins or RAC1 has therapeutic benefit, specifically for the treatment of oncological diseases.

[0024] On the other hand, this disclosure provides the use of compounds of any of the formulas described herein (e.g., structural formula (I')), their pharmaceutically acceptable salts, tautomers, or stereoisomers (as defined in any of the embodiments described herein) in the manufacture of medicaments for treating conditions, diseases, or ailments in which inhibiting the interaction of SOS1 with RAS family proteins or RAC1 has therapeutic benefit, specifically for treating oncological diseases. Detailed Implementation

[0025] 1. Compound

[0026] In a first embodiment, this disclosure provides a compound of formula (I'): (I'), Its pharmaceutically acceptable salts, tautomers, or stereoisomers, among which: Expressed by formula (A') or (B'): (A') or (B'), R 9 R 9' and R 9'' Each of the elements is independently H, halogen, or C. 1-6 alkyl; R 10 R 10' and R 10'' The elements in the formula are independently H, halogen, and C. 1-6 Alkyl groups (optionally surrounded by one or more OH groups, halogens, or C atoms) 1-6 alkoxy substitution), C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 Alkylene C 1-4 Alkoxy, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne, 3 to 8-membered carbocyclic, 3 to 8-membered heterocyclic, 6 to 10-membered aryl, phenyl, or 5 to 10-membered heteroaryl; or R 9 R 9' R 9'' R 10 R 10' and R 10'' Any two of them together with the carbon atoms they are attached to form a 3- to 8-membered carbon cyclic group or a 4- to 8-membered heterocyclic group; in R represents 1 The connection point; Indicates the connection point of the C=O group; Y is CR y Or N; where R y H, halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, 3 to 6-membered carbocyclic, 3 to 12-membered (e.g., 4 to 12-membered) heterocyclic, 6 to 10-membered aryl, or 5 to 10-membered heteroaryl, wherein R y The carbocyclic, heterocyclic, aryl, or heteroaryl group represented is optionally surrounded by one to three groups selected from -OH, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Alkoxy and C 1-6 Substitution of haloalkoxy groups; Ring A is a 6- to 10-membered aryl, phenyl, or 5- to 10-membered heteroaryl group; R 7 Each occurrence is independently of halogen, -CN, or C. 1-6 Alkyl, C 1-4 Halogenated groups (optionally substituted with -OH), -OH, or NR 7a R 7b ; R 7a and R 7b Each of them is independently H or C 1-4 alkyl, or Two adjacent R 7 The group, together with the atoms it is attached to, forms a 4- to 6-membered carbon ring or a 4- to 6-membered heterocycle; wherein the 4- to 6-membered carbon ring or 4- to 6-membered heterocycle is optionally bonded by one or more halogens or C. 1-4 Alkyl substitution; n is 0, 1, 2, 3 or 4; R 1 Halogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3 to 12-membered carbocyclic, -O-3 to 12-membered carbocyclic, -NH-3 to 12-membered carbocyclic, 3 to 12-membered (e.g., 4 to 12-membered) heterocyclic, -C(=O)-3 to 12-membered heterocyclic, -O-3 to 12-membered (e.g., 4 to 12-membered) heterocyclic, -NH-3 to 12-membered (e.g., 4 to 12-membered) heterocyclic, 6 to 10-membered aryl, -O-6 to 10-membered aryl, -NH-6 to 10-membered aryl, 5 to 10-membered heteroaryl, -O-5 to 10-membered heteroaryl or -NH-5 to 10-membered heteroaryl, wherein R 1 Represented or by R 1The alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, aryl, or heteroaryl groups represented are optionally surrounded by one or more R groups. 11 Replace; among them R 11 Each time it appears, it is independently selected from halogen, -CN, oxo (where appropriate), =NH (where appropriate), C. 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group (optionally C 1-4 hydroxyalkyl substitution), C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene C 1-4 Alkoxy, OR 1a -CHO, -COOH, -C(O)R 1a -C(O)OR 1a -(CH2) 0或1 C(O)NR 1a R 1b -C(O)CH2NR 1a R 1b -OC(O)NR 1a R 1b -NO2, -(CH2) 0或1 NR 1a R 1b -NR 1a C(O)R 1a -P(O)R 1a R 1b -(CH2) 0或 1SO2R 1a -(CH2) 0或1 SO2NR 1a R 1b -(CH2) 0或1 -3 to 6-membered carbocyclic groups, 3 to 12-membered (e.g., 4 to 12-membered) heterocyclic groups, and 5 to 10-membered heteroaryl groups, Among them, R 11 Represented or by R 11 The C in the group represented 1-6 Alkyl groups are optionally surrounded by one or more deuterium, CN, OH, =NOH, C 1-6 Alkyl or C 1-6 Alkoxy substitution, By R 11 Represented or by R 11 The C in the group represented 1-6 The alkoxy group may optionally be replaced by one or more deuterium or halogens; By R 11 Represented or by R 11 The 3- to 6-membered carbocyclic group, 3- to 12-membered (e.g., 4- to 12-membered) heterocyclic group, or 5- to 10-membered heteroaryl group in the indicated group is optionally surrounded by one or more CN, -OH, oxo (where appropriate), C 1-6 Alkyl or C 1-6 Alkyl substitution; R 1a and R 1b Independently select H and C 1-6 Alkyl, C 2-6 The group consisting of alkenyl, 3- to 6-membered carbocyclic, 4- to 6-membered heterocyclic and 5- to 6-membered heteroaryl groups, wherein R 1a Or R 1b The alkyl, carbocyclic, heterocyclic, or heteroaryl groups represented are optionally surrounded by one or more halogens, CN, OH, C 1-6 Alkyl or C 1-6 Alkoxy substitution; or R 1a and R 1b Together with the N or P atoms to which they are attached, they form a group optionally bonded by C. 1-6 Alkyl-substituted 4- to 6-membered heterocyclic groups; The heterocyclic group comprises 1 to 3 heteroatoms selected from oxygen, nitrogen, phosphorus and sulfur; and the heteroaryl group comprises 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur.

[0027] In a second embodiment, this disclosure provides a compound according to the first embodiment, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the compound is represented by formula (IIA') or (IIB'): (IIA') or (IIB'); Where Y is CR y Or N; R y H, halogen, -CN, C 1-4 Alkyl or C 1-4 Alkoxy groups. The definition of the remaining variables is provided in the first embodiment.

[0028] In a third embodiment, this disclosure provides compounds according to the second embodiment, pharmaceutically acceptable salts thereof, or stereoisomers thereof, wherein the compounds are represented by formula (IIIA'-1), (IIIA'-2), (IIIB'-1), or (IIIB'-2): (IIIA'-1) (IIIA'-2) (IIIB'-1) or (IIIB'-2).

[0029] The definition of the residual variables is provided in the second implementation scheme. Alternatively, the definition of the residual variables is provided in the first implementation scheme.

[0030] In a fourth embodiment, this disclosure provides compounds according to a third embodiment, pharmaceutically acceptable salts thereof, or stereoisomers thereof, wherein the compounds are represented by formula (VA') or (VB'): (VA') (VB').

[0031] The definition of the residual variables is provided in the third embodiment. Alternatively, the definition of the residual variables is provided in the first or second embodiment.

[0032] In a fifth embodiment, this disclosure provides compounds according to a third embodiment, pharmaceutically acceptable salts thereof, or stereoisomers thereof, wherein the compounds are represented by formula (VC') or (VD'): (VC') or (VD').

[0033] The definition of the residual variables is provided in the third embodiment. Alternatively, the definition of the residual variables is provided in the first or second embodiment.

[0034] In the sixth embodiment, this disclosure provides compounds, pharmaceutically acceptable salts or stereoisomers thereof, according to any one of the first to fifth embodiments, wherein...

[0035] R 9 R 9' and R 9'' Each of them is independently H or C 1-2 alkyl; R 10 R 10' and R 10'' Each of them is independently H and C. 1-4 Alkyl, C 1-4 Halogenated, C 1-4 Hydroxyalkyl, C 1-4 Alkylene C 1-4 Alkoxy, C 1-4 alkoxy, 3- to 6-membered cycloalkyl or phenyl; or R 9 and R 10 R 9' and R 10' R 9'' and R 10'' R 10 and R 10' and R10' and R 10'' Any one of the groups, together with the carbon atoms to which it is attached, forms a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocyclic group. The definitions of the remaining variables are provided in any of the first to fifth embodiments.

[0036] In the seventh embodiment, this disclosure provides compounds according to the sixth embodiment, their pharmaceutically acceptable salts or stereoisomers, wherein

[0037] R 9 R 9' and R 9'' Each of them is independently H or -CH3; R 10 R 10' and R 10'' Each of the following can be independently H, -CH3, ethyl, isopropyl, tert-butyl, isobutyl, -CH2F, -CH2OH, -CH2OCH3, cyclohexyl, tetrahydro-2H-pyranyl, or phenyl; or R 9 and R 10 R 9' and R 10' R 9'' and R 10'' R 10 and R 10' and R 10' and R 10'' Any group thereof, together with the carbon atom to which it is attached, forms cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, or tetrahydro-2H-pyranyl. The definitions of the remaining variables are provided in any of the first to sixth embodiments.

[0038] In the eighth embodiment, this disclosure provides compounds according to the sixth embodiment, their pharmaceutically acceptable salts or stereoisomers, wherein

[0039] (i) R 9 and R 10 Independently H or -CH3; R 9' and R 10' Each of them is independently H; or

[0040] (ii) R 9' and R 10' Each of them is independently H or -CH3; R 9 and R 10 Each of them is independently H; or (iii) R 9'' and R 10'' Each of them is independently H or -CH3; R 9 R 10 R 9' and R10' Each of these is independently represented by H. The definitions of the remaining variables are provided in any of the first to sixth implementation schemes.

[0041] In the ninth embodiment, this disclosure provides a compound, a pharmaceutically acceptable salt or stereoisomer thereof, according to any one of the first to eighth embodiments, wherein...

[0042] R 7 Each time it appears, it is independently a halogen, -CN, -OH, -NH2, or C. 1-2 Alkyl or C 1-2 Halogenated groups (optionally substituted with -OH); or

[0043] Two adjacent R 7 The group, together with the atoms it is attached to, forms a 4- to 6-membered heterocycle optionally substituted with one or two halogens; and

[0044] n can be 0, 1, 2, or 3. The definition of the remaining variables is provided in any of the first to eighth embodiments.

[0045] In the tenth embodiment, this disclosure provides compounds according to the ninth embodiment, their pharmaceutically acceptable salts or stereoisomers, wherein R 7 Each time it appears, it is independently a halogen, -CN, -OH, -NH2, or C. 1-2 Alkyl groups or C groups optionally substituted with -OH 1-2 Alkyl halide; and n is 0, 1, or 2. The definitions of the remaining variables are provided in any of the first to ninth embodiments.

[0046] In the eleventh embodiment, this disclosure provides a compound according to the ninth embodiment, its pharmaceutically acceptable salt or stereoisomer, wherein for , , , , , , , , , , , , , , , or .

[0047] The definition of the remaining variables is provided in any of the first to ninth implementation schemes.

[0048] In the twelfth embodiment, this disclosure provides a compound, a pharmaceutically acceptable salt thereof, or a stereoisomer of any one of the first to eleventh embodiments, wherein: R 1 Halogen, -CN, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, 3- to 6-membered carbocyclic, 4- to 10-membered heterocyclic, -O-4- to 10-membered heterocyclic, -NH-4- to 10-membered heterocyclic, phenyl, -C(=O)-4- to 10-membered heterocyclic or 5- to 10-membered heteroaryl, wherein R 1 Represented or by R 1 The alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, phenyl, or heteroaryl groups represented are optionally surrounded by one to four R groups. 11 Replace; among them R 11 Each time it appears, it is independently selected from halogen, -CN, oxo (where appropriate), =NH (where appropriate), C. 1-4 Alkyl, C 1-4 Halogenated, C 1-4 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group (optionally C 1-4 hydroxyalkyl substitution), C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Alkylene C 1-4 Alkoxy, -OR 1a -(CH2) 0或1 NR 1a R 1b -CHO, -COOH, -C(O)R 1a -C(O)OR 1a -(CH2) 0或1 C(O)NR 1a R 1b -C(O)CH2NR 1a R 1b -OC(O)NR 1a R 1b -NO2, NR 1a C(O)R 1a -(CH2) 0或1 SO2R 1a -(CH2) 0或1 SO2NR 1a R 1b -P(O)R 1a R1b -(CH2) 0或1 -3 to 6-membered carbon cyclic groups, 4 to 6-membered heterocyclic groups, and 5 to 6-membered heteroaryl groups. Among them, R 11 Represented or by R 11 The C in the group represented 1-4 Alkyl groups are optionally surrounded by a CN, OH, =NOH, or C atom. 1-4 Alkyl or one to three deuterium substitutions; By R 11 Represented or by R 11 The C in the group represented 1-4 The alkoxy group is optionally substituted by one to three groups selected from deuterium and halogens; By R 11 Represented or by R 11 The 3- to 6-membered carbocyclic group, 4- to 6-membered heterocyclic group, or 5- to 6-membered heteroaryl group in the indicated group is optionally surrounded by one to three CN, -OH, oxo (where appropriate), C 1-6 Alkyl or C 1-6 Alkyl substitution; R 1a and R 1b Independently select H and C 1-4 Alkyl, C 2-4 The group consisting of alkenyl, 3- to 6-membered carbocyclic, 4- to 6-membered heterocyclic and 5- to 6-membered heteroaryl groups, wherein R 1a Or R 1b The alkyl, carbocyclic, heterocyclic, or heteroaryl groups represented are optionally surrounded by one to three halogens, CN, OH, C 1-4 Alkyl or C 1-4 Alkoxy substitution; or R 1a and R 1b Together with the N or P atoms to which they are attached, they form a group optionally bonded by C. 1-4 Alkyl-substituted 4- to 6-membered heterocyclic groups.

[0049] The definition of the remaining variables is provided in any of the first to eleventh implementation schemes.

[0050] In the thirteenth embodiment, this disclosure provides a compound, a pharmaceutically acceptable salt or stereoisomer thereof, according to any one of the first to eleventh embodiments, wherein

[0051] R 1 It is a 4- to 6-membered monocyclic carbocyclic group, a 4- to 6-membered monocyclic heterocyclic group, a phenyl group, or a 5- to 6-membered heteroaryl group, wherein R 1 The 4- to 6-membered monocyclic carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, phenyl group, or 5- to 6-membered heteroaryl group is optionally surrounded by one to four R groups. 11 replace; R11 Each time it appears, it is independently of halogen, -CN, -OH, oxo (where appropriate), C. 1-4 Alkyl, C 1-4 Halogenated, C 1-4 Alkoxy groups, -COOH, -C(O)C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, -C(O)NR 1a R 1b -OC(O)NR 1a R 1b -NO2, -(CH2) 0或 1NR 1a R 1b -NR 1a C(O)C 1-4 Alkyl, -SO2C 1-4 Alkyl group, -(CH2) 0或1 -3 to 6-membered carbocyclic groups, 4 to 6-membered monocyclic heterocyclic groups, or 5 to 6-membered heteroaryl groups; among which By R 11 Represented or by R 11 The C in the group represented 1-4 The alkyl group is optionally separated by a group selected from -CN, -OH and C. 1-4 The alkoxy group or one to three groups selected from deuterium are substituted; By R 11 Represented or by R 11 The C in the group represented 1-4 The alkoxy group is optionally substituted by one to three groups selected from deuterium and halogens; By R 11 Represented or by R 11 The 3- to 6-membered carbocyclic group, 4- to 6-membered heterocyclic group, or 5- to 6-membered heteroaryl group in the indicated group is optionally surrounded by one or two groups selected from -CN, -OH, oxo (where appropriate), and C. 1-4 Alkyl group substitution; R 1a and R 1b Independently select H and C 1-4 The group consisting of alkyl groups and 3 to 6-membered carbon cycloyl groups, wherein R 1a Or R 1b The alkyl or carbocyclic group represented is optionally surrounded by one to three halogens, -CN, -OH, C 1-4 Alkyl or C 1-4 Alkoxy substitution. The definitions of the remaining variables are provided in any of the first through eleventh embodiments.

[0052] In the fourteenth embodiment, this disclosure provides a compound, a pharmaceutically acceptable salt or stereoisomer thereof, according to any one of the first to eleventh embodiments, wherein

[0053] R 1 It is cyclohexyl, cyclohexenyl, a 6-membered monocyclic heterocyclic group, phenyl, or a 5- to 6-membered heteroaryl group, wherein R 1 The cyclohexyl, cyclohexenyl, 6-membered monocyclic heterocyclic, phenyl, or 5- to 6-membered heteroaryl groups are optionally surrounded by one or two R groups. 11 replace; R 11 Each time it appears, it is independently of halogen, -CN, -OH, oxo (where appropriate), C. 1-4 Alkyl, C 1-4 Halogenated, C 1-4 Hydroxyalkyl, -C(O)C 1-4 Alkyl, -C(O)NR 1a R 1b -NR 1a C(O)C 1-4 Alkyl, -SO2C 1-4 Alkyl or 4- to 6-membered monocyclic heterocyclic groups; By R 11 Represented or by R 11 The C in the group represented 1-4 The alkyl group may optionally be substituted with -OH or -CN; By R 11 The 4- to 6-membered heterocyclic groups are optionally surrounded by one or two groups selected from -OH, oxo (where appropriate), and C. 1-6 Alkyl group substitution; R 1a and R 1b Each of them is independently H or C 1-4 Alkyl group. The definitions of the remaining variables are provided in any of the first to eleventh embodiments.

[0054] In the fifteenth embodiment, this disclosure provides a compound, a pharmaceutically acceptable salt or stereoisomer thereof, according to any one of the first to fourteenth embodiments, wherein

[0055] R 1CN, vinyl, ethynyl, ethoxy, isopropyl, cyclopropyl, cyclohexyl, cyclohexenyl, aziridine, -NH-tetrahydrofuranyl, furanyl, thiophene, pyrroleyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, morpholinyl, thiomorpholinyl, -NH-morpholinyl, -C(O)-morpholinyl, piperazinyl, piperidinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyranyl, tetrahydropyranyl, -NH-tetrahydropyranyl, -O-tetrahydrofuran, di Hydrothionyl, isoindolone, hexahydro-1H-furano[3,4-c]pyrrole, 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazolyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 3-oxa-6-azabicyclo[3.1.1]heptyl, 3-oxabicyclo[4.1.0]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 6-oxa-2-azaspiro[3.4]octyl 2-oxa-5-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl, bicyclo[1.1.1]pentyl, 2,5-dihydrofuranyl, 2-oxaspiro[3.5]non-6-enyl, 2-oxa-6-azaspiro[3.3]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 3-oxa-9-azabicyclo[3.3.1] Nonyl, 7-azaspiro[3.5]nonyl, 1-oxa-7-azaspiro[3.5]nonyl, 2-oxa-7-azaspiro[3.5]nonyl, 1,8-diazaspiro[4.5]decyl, 1-azaspiro[4.5]dec-7-enyl, 1,4-dioxaspiro[4.5]dec-7-enyl, 1,4-dioxa-8-azaspiro[4.5]decyl, pyrrolo[2,3-b]pyridyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-b]pyridyl, indazole or quinolinyl; Among them, R 1The following groups are represented: ethynyl, ethoxy, isopropyl, cyclopropyl, cyclohexyl, cyclohexenyl, aziroxybutyl, -NH-tetrahydrofuranyl, furanyl, thiophene, pyrroleyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, morpholinyl, thiomorpholinyl, -NH-morpholinyl, -C(O)-morpholinyl, piperazinyl, piperidinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyranyl, tetrahydropyranyl, -NH-tetrahydropyranyl, -O-tetrahydrofuran, dihydrothiaranyl, isopropyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, thiomorpholinyl, -NH-tetrahydropyranyl, -O-tetrahydrofuran, dihydrothiaranyl, pyrid ... Indolone, hexahydro-1H-furano[3,4-c]pyrrole, 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazolyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 3-oxa-6-azabicyclo[3.1.1]heptyl, 3-oxabicyclo[4.1.0]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 6-oxa-2-azaspiro[3.4]octyl, 2-oxa- 5-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl, bicyclo[1.1.1]pentyl, 2,5-dihydrofuranyl, 2-oxaspiro[3.5]non-6-enyl, 2-oxa-6-azaspiro[3.3]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 3-oxa-9-azabicyclo[3.3.1]nonyl, 7-azabicyclo[3.2.1]heptyl, 2-oxa-6-enyl, 2-oxa-6-azaspiro[3.3.1]nonyl, 2-oxa-6-enyl, 2-oxa-8-azabicyclo[3.2.1]octyl, 2-oxa-8-azabicyclo[3.2.1]octyl, 2-oxa-8-azabicyclo[3.2.1]non ... Spiro[3.5]nonyl, 1-oxa-7-azaspiro[3.5]nonyl, 2-oxa-7-azaspiro[3.5]nonyl, 1,8-diazaspiro[4.5]decyl, 1-azaspiro[4.5]dec-7-enyl, 1,4-dioxaspiro[4.5]dec-7-enyl, 1,4-dioxa-8-azaspiro[4.5]decyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-b]pyridinyl, indazole or quinolinyl optionally surrounded by one to four R 11 replace; R 11Each time it appears, it is independently selected from F, Cl, -CN, -OH, -NO2, -CH3, CH2F, -CHF2, -CF3, oxo (where appropriate), =NH (where appropriate), -CH2CH3, -CH2CN, -CH2CH2CN, -CH2OH, CH2CH2OH, CH2CH2OCH3, -CH2NHCH3, -CH2CH2F, -CH2CHF2, -CH(CH3)2, -C(CH3)3, -CH2CF3, -C(CN)(CH3)2, -CH2CH(OH)CH3, -C(OH)(CH3)2, -C(CH3)2CH2OH, -CH2C(CH 3) 2OH, -CH2OCH3, -OCH3, -OCD3, -OCH2CH3, -OCHF2, -OCF3, -OCH(CH3)2, -OCH2CF3, -O-cyclopropyl, -OC(O)NHCH3, -OC(O)N(CH3)2, -OC(O)NH-cyclopropyl, cyclopropyl, aziridine, oxacyclobutyl, -CHO, -COOH, -C(O)OCH3, -C(O)CH3, -C(O)C(CH3)3, -C (O)CH2F, -C(O)CH2CH3, -C(O)CH2OH, -C(O)CH2CF3, -C(O)cyclopropyl, -C(O)cyclopentyl, -C(O)-oxacyclobutyl, -C(O)-morpholinyl, -C(O)CH2OCH3, -COCH2N(CH3)2, -C(O)NHCH3, -C(O)NHC(CH3)3, -C(O)N(CH3)2, -C(O)N(CH3)CH2CH2OCH3, -CH2 CON(CH3)2, -NH2, -NHCH3, -NHCH2CF3, -N(CH3)2, NHC(O)CH3, -NHC(O)CH2F, -NHC(O)CH2CN, -NHC(O)CH2OCH3, -N(CH3)C(O)CH3, N(CH3)C(O)CH2CN, -NH cyclopropyl, -P(O)(CH3)2, -CH2SO2CH3, -SO2CH3, -SO2NH2, morpholinyl, pyridyl, , , , , , , , , , , , , , , , , , , , , , , and The definition of the remaining variables is provided in any of the first to eleventh implementation schemes.

[0056] In a sixteenth embodiment, this disclosure provides a compound according to a first embodiment, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the compound is represented by formula (VII'): (VII'), in: Y is either CH or N; R 9 It is H or -CH3; R 10 For H or C 1-4 alkyl; R 1 It is a 4- to 6-membered monocyclic carbocyclic group, a 5- to 6-membered monocyclic heterocyclic group, a phenyl group, or a 5- to 6-membered heteroaryl group, wherein R 1 The 4- to 6-membered monocyclic carbocyclic group, 5- to 6-membered monocyclic heterocyclic group, phenyl group, or 5- to 6-membered heteroaryl group is optionally surrounded by one to three R groups. 11 replace; R 11 Each time it appears, it is independently of halogen, -CN, -OH, oxo (where appropriate), C. 1-4 Alkyl, C 1-4 Halogenated, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -C(O)R 1a -C(O)OR 1a -C(O)NR 1a R 1b -OC(O)NR 1a R 1b -(CH2) 0或1 NR 1a R 1b -NR 1a C(O)R 1a -SO2R 1a 4 to 6-membered monocyclic heterocyclic groups or 5 to 6-membered heteroaryl groups; By R 11 Represented or in R 11 C in the group 1-4 Alkyl groups are optionally prefixed with -CN, -OH, or -C. 1-4 Alkyl substitution; By R 11The 4- to 6-membered heterocyclic group or the 5- to 6-membered heteroaryl group is optionally surrounded by one or two groups selected from -CN, -OH, oxo (where appropriate), and C. 1-4 Alkyl group substitution; R 1a and R 1b Independently select H and C 1-4 The group consisting of alkyl groups and 3 to 6-membered carbon cycloyl groups, wherein R 1a Or R 1b The alkyl or carbocyclic group represented is optionally surrounded by one to three halogens, CN, OH, C 1-4 Alkyl or C 1-4 Alkyl substitution; R 7 Each time it appears, it is independently a halogen, -CN, -NH2, or C. 1-2 Alkyl groups or C groups optionally substituted with -OH 1-2 Halogenated alkyl groups; and n can be 0, 1, 2, or 3.

[0057] The definition of the remaining variables is provided in the first implementation scheme.

[0058] In the seventeenth embodiment, this disclosure provides the compound according to the sixteenth embodiment, its pharmaceutically acceptable salt or stereoisomer, wherein

[0059] R 1 It is a 5- to 6-membered monocyclic carbocyclic group, a 5- to 6-membered monocyclic heterocyclic group, a phenyl group, or a 5- to 6-membered heteroaryl group, wherein R 1 The 5- to 6-membered monocyclic carbocyclic group, 5- to 6-membered monocyclic heterocyclic group, phenyl group, or 5- to 6-membered heteroaryl group is optionally surrounded by one or two R groups. 11 replace; R 11 Each time it appears, it is independently of halogen, -CN, -OH, oxo (where appropriate), C. 1-4 Alkyl, C 1-4 Halogenated, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -C(O)C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, -C(O)NR 1a R 1b -OC(O)NR 1a R 1b -(CH2) 0或1 NR 1a R 1b -NR 1a C(O)C 1-4 Alkyl, -SO2C 1-4 Alkyl, 4- to 6-membered monocyclic heterocyclic or 5- to 6-membered heteroaryl; By R 11 Represented or in R 11 C in the group 1-4 Alkyl groups may optionally be substituted with -CN or -OH; By R 11 The 4- to 6-membered heterocyclic group or the 5- to 6-membered heteroaryl group is optionally surrounded by one or two groups selected from -CN, -OH, oxo (where appropriate), and C. 1-4 Alkyl group substitution; R 1a and R 1b Independently choose H or C 1-4 The group consisting of alkyl groups, wherein R 1a Or R 1b The alkyl group is optionally surrounded by one to three halogens, CN, C 1-4 Alkyl or C 1-4 Alkyl-substituted.

[0060] The definition of the residual variable is provided in the sixteenth embodiment. Alternatively, the definition of the residual variable is provided in the first embodiment.

[0061] In the eighteenth embodiment, this disclosure provides the compound according to the seventeenth embodiment, its pharmaceutically acceptable salt or stereoisomer, wherein R 1 The derivatives are cyclohexenyl, dihydropyranyl, dihydropyridyl, dihydrothiaranyl, morpholinyl, oxazolyl, phenyl, piperidinyl, pyrazolyl, pyridyl, pyrrolidinyl, tetrahydropyranyl, tetrahydropyridyl, or thiazolyl; each optionally marked with one or two R... 11 Replace; and R 11 Each occurrence is independently selected from F, oxo (where appropriate), -OH, CN, -CH3, -CH2F, -CH2OH, -CH2CHF2, -CH2CH2CN, -CH2C(CH3)2OH, -C(O)CH3, -C(O)CH2OH, -CONHCH3, -NHCOCH3, -NHCOCH2CN, -SO2CH3, oxocyclic butyl, or morpholino. Definitions of the remaining variables are provided in the first, sixteenth, or seventeenth embodiments.

[0062] In the nineteenth embodiment, this disclosure provides a compound, a pharmaceutically acceptable salt or stereoisomer thereof, according to any one of the sixteenth to eighteenth embodiments, wherein R 7 Each time it appears, it is independently -F, -Cl, -CN, -NH2, -CH3, -CHF2, -CF3, -CF2CH3, or -CF2CH2OH; R 9 It is H or -CH3; and R 10 It is -CH3; and n is 0, 1 or 2.

[0063] The definition of the remaining variables is provided in any of the first, sixteenth to eighteenth embodiments.

[0064] In the twentieth embodiment, this disclosure provides compounds selected from the examples and compounds disclosed in Table 1, their pharmaceutically acceptable salts or stereoisomers.

[0065] Table 1

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096] 2. Definition

[0097] As used in this article, the terms “halogen” or “halo” refer to fluorine, chlorine, bromine, or iodine.

[0098] The term "alkyl" used alone or as part of a larger category such as "alkoxy" or "haloalkyl" refers to the formula -C n H (2n+1) Alkyl groups are saturated aliphatic straight-chain or branched monovalent hydrocarbon groups. Unless otherwise specified, alkyl groups typically have 1 to 6 carbon atoms, i.e., C64-C ... 1-6 Alkyl group. As used herein, "C 1-6 An "alkyl" group refers to a group having 1 to 6 carbon atoms arranged in a straight or branched chain. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl, etc.

[0099] The term "alkenyl" refers to an alkyl group in which one or more carbon / carbon single bonds are replaced by double bonds.

[0100] The term "alkynyl" refers to an alkyl group in which one or more carbon / carbon single bonds are replaced by triple bonds.

[0101] The term "alkoxy" refers to an alkyl group linked by an oxygen atom and is represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0102] The term "haloalkyl" refers to an alkyl group that is substituted with one or more halogen atoms, depending on the specific case.

[0103] The term "haloalkoxy" refers to an alkoxy group that is replaced by one or more halogen atoms, depending on the specific case.

[0104] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, depending on the specific case.

[0105] The term "alkylene" on its own or as part of another substituent refers to a divalent group derived from an alkane, such as -CH2CH2CH2CH2-.

[0106] The term "carbocyclic" refers to any non-aromatic hydrocarbon ring having a 3- to 12-membered carbocyclic group. In one embodiment, the carbocyclic group is a 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic ring, or a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated or partially unsaturated. Any substituted ring atom may be substituted (e.g., one or more substituents). Examples of such carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. In one embodiment, the carbocyclic group is intended to include bridged rings, fused rings, and spirocyclic groups. In a spirocyclic carbocyclic group, one atom is shared by two different rings. An example of a spirocyclic carbocyclic group is spiropentyl. In a bridged carbocyclic group, the rings share at least two shared non-adjacent atoms. Examples of bridging carbocyclic groups include bicyclic [2.2.1]heptyl, bicyclic [2.2.1]hept-2-enyl, and adamantyl. In fused-ring carbocyclic systems, two or more rings can be fused together, whereby the two rings share a common bond. Examples of bicyclic or tricyclic fused-ring carbocyclic groups include naphthyl, tetrahydronaphthyl (naphthyl), indenyl, indenyl (dihydroindenyl), anthraceneyl, phenanthryl, and decahydronaphthyl.

[0107] The term "cycloalkyl" refers to a cyclic, bicyclic, tricyclic, or polycyclic saturated hydrocarbon group having 3 to 12 ring carbons. In one embodiment, the cycloalkyl group may have 3 to 7 ring carbons. Any substituted ring atom may be substituted (e.g., one or more substituents). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups may include multiple fused rings and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl groups include: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.0]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, etc. Cycloalkyl groups also include spirocyclic (e.g., spirobicyclic, where the two rings are connected by only one atom). Non-limiting examples of spirocycloalkyl groups include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, etc.

[0108] The term "heterocyclic group" or "heterocycle" refers to a group having a 3- to 12-membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from phosphorus, nitrogen, quaternary nitrogen, nitrogen oxides (e.g., NO), oxygen, and sulfur, including sulfoxides and sulfones ("3- to 12-membered heterocyclic groups"). In some embodiments, the heterocyclic group comprises 1 to 3 heteroatoms selected from oxygen, nitrogen, phosphorus, and sulfur. In some embodiments, the heterocyclic group comprises 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, the heterocyclic group may be saturated or partially unsaturated. In some embodiments, the heterocyclic group is a 3- to 7-membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3- to 7-membered heterocyclic groups"). In heterocyclic groups containing one or more nitrogen atoms, the linking point may be a carbon or nitrogen atom, where the valence allows. Heterocyclic groups can be monocyclic (“monocyclic heterocyclic groups”) or polycyclic (e.g., bicyclic systems (“bicyclic heterocyclic groups”) or tricyclic systems (“tricyclic heterocyclic groups”); polycyclic systems include fused rings, bridged rings, or spirocyclic systems). Exemplary monocyclic heterocyclic groups include azirrobutyl, oxoheterobutyl, thioheterobutyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azirroheptyl, oxoheptyl, thioheptyl, tetrahydropyridinyl, etc. Heterocyclic polycyclic systems can include heteroatoms in one or more rings of the polycyclic system. Substituents can be present on one or more rings of the polycyclic system.

[0109] Spiroheterocyclic groups refer to 5- to 12-membered polycyclic heterocyclic groups in which rings are linked by a shared carbon atom (called the spiro atom). The rings have one or more heteroatoms selected from nitrogen, quaternary nitrogen, nitrogen oxides (e.g., NO), oxygen, and sulfur (including sulfoxides and sulfones), with the remaining ring atoms being carbon atoms. One or more rings may contain one or more double bonds, but all rings are not aromatic rings. Representative examples of spiroheterocyclic groups include, but are not limited to, the following groups: .

[0110] Fused heterocyclic groups refer to 5- to 12-membered polycyclic heterocyclic groups, wherein each ring in the group shares an adjacent pair of ring atoms with another ring in the group, wherein one or more rings may contain one or more double bonds, but at least one ring is not an aromatic ring, and wherein the ring has one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxides (e.g., NO), oxygen, and sulfur (including sulfoxides and sulfones), and the remaining ring atoms are carbon. Representative examples of fused heterocyclic groups include, but are not limited to, the following groups: .

[0111] A bridging heterocyclic group refers to a 5- to 12-membered polycyclic heterocyclic group, wherein any two rings in the group share two unconnected atoms, the rings may have one or more double bonds but not a fully conjugated π-electron system, and the rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxides (e.g., NO), oxygen, and sulfur (including sulfoxides and sulfones) as ring atoms, and the remaining ring atoms are carbon. Representative examples of bridging heterocyclic groups include, but are not limited to, the following groups: .

[0112] Generally, the carbocyclic, cycloalkyl, or heterocyclic groups may be unsubstituted or substituted with one or more substituents, where the valence allows, wherein the substituents may be independently selected from a number of groups such as oxo, -CN, halogen, alkyl, and alkoxy groups, and optionally, the alkyl substitution may be further substituted.

[0113] The term "aryl" refers to a 6- to 10-membered all-carbon monocyclic or polycyclic fused-ring group with a fully conjugated π-electron system. Representative examples of aryl groups are phenyl and naphthyl.

[0114] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic aromatic hydrocarbon in which at least one ring carbon atom has been independently replaced by a heteroatom selected from oxygen, nitrogen, and sulfur. Preferably, a heteroaryl is based on a C14 group in which one or more ring carbon atoms have been replaced by heteroatoms. 5-10Aryl. Heteroaryl groups can be linked by a ring carbon atom or, where the valence allows, by a ring nitrogen atom. Generally, heteroaryl groups can be unsubstituted or, where the valence allows, substituted by one or more substituents, wherein the substituents are independently selected from halogens, OH, alkyl, alkoxy, and amino (e.g., NH2, NHalkyl, N(alkyl)2), and optionally, the alkyl group can be further substituted.

[0115] As used in this article, the term "treatment" includes any effect that improves or alleviates the symptoms of a condition, disease, ailment, etc., such as reducing, decreasing, moderating, relieving, or eliminating them.

[0116] The term “therapeutic effective amount” refers to the amount of a drug (such as the compounds described herein) that is effective in treating at least one symptom of a patient’s or individual’s disease or condition. The “therapeutic effective amount” of a drug to be administered may be based on variations of: desired activity, the disease state of the patient or individual being treated, dosage form, method of administration, patient factors (e.g., patient sex, genotype, weight, and age), the underlying cause of the condition or disease to be treated, route of administration and bioavailability, persistence of the administered drug in the body, evidence of urinary sodium and / or diuresis, type of formulation, and potency of the drug.

[0117] Pharmaceutically acceptable salts

[0118] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt that, within reasonable medical judgment, is suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, or allergic reactions, and whose benefits / risks are proportionate to a reasonable ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

[0119] Pharmaceutically acceptable salts of compounds of any of the formulas described above include acid addition salts and base salts.

[0120] This document teaches pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having a basic group can form pharmaceutically acceptable salts with pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid) and organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, ethanesulfonic acid, methanesulfonic acid, and succinic acid). Compounds taught herein having an acidic group (such as carboxylic acid) can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts (such as sodium and potassium salts), and alkaline earth metal salts (such as magnesium and calcium salts).

[0121] Pharmaceutically acceptable salts of any of the compounds described above can be prepared by one or more of the following three methods: (i) To react a compound of any of the formulas described above with a desired acid or base; (ii) Using the desired acid or base, remove the acid- or base-insecure protecting group from a suitable precursor of any of the formulas described above, or open the ring of a suitable cyclic precursor (e.g., a lactone or lactam); or (iii) By reacting with a suitable acid or base or by means of a suitable ion exchange column, one salt of a compound of any of the formulas described above is converted into another salt.

[0122] All three reactions typically occur in solution. The resulting salt can precipitate and be collected by filtration, or it can be recovered by evaporating the solvent. The degree of ionization of the resulting salt can vary from fully ionized to almost unionized.

[0123] Compounds of any of the formulas described above and their pharmaceutically acceptable salts may exist in both non-solventized and solvated forms.

[0124] Stereoisomers and other variants

[0125] Compounds of any of the formulas described above may exhibit one or more isomerisms (e.g., optical, geometric, or tautomerisms). These variations are implied by compounds of any of the formulas described above and therefore fall within the scope of this disclosure, which is defined with reference to its structural features.

[0126] Compounds having one or more chiral centers may exist in various stereoisomers, meaning each chiral center can have... R or S Configurations can be either a combination of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomers and enantiomers of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers that have two or more distinct chiral centers that are not mirror images of each other.

[0127] When indicated by a chemical name that can identify a single enantiomer (e.g., the chemical name using " R "or" SWhen a compound is represented by an "indicator configuration" or its structure (e.g., by a "wedge" bond), unless otherwise indicated, the compound has an optical purity of at least 60%, 70%, 80%, 90%, 99%, or 99.9% (also known as "enantiomerically pure"). Optical purity is the weight of the named or described enantiomer in the mixture divided by the total weight of the two enantiomers in the mixture.

[0128] When the stereochemistry of a disclosed compound is named or described by structure, and the named or described structure covers more than one stereoisomer (e.g., in diastereomer pair form), it should be understood that one of the covered stereoisomers or any mixture of the covered stereoisomers is included. It should be further understood that the stereoisomer purity of the named or described stereoisomers is at least 60 wt%, 70 wt%, 80 wt%, 90 wt%, 99 wt%, or 99.9 wt%. In this case, the stereoisomer purity is determined by dividing the total weight of the stereoisomers covered by the stated name or structure in the mixture by the total weight of all stated stereoisomers in the mixture.

[0129] When two stereoisomers are described by their chemical names or structures, and the chemical names or structures are connected by "and", it means a mixture of the two stereoisomers.

[0130] When two stereoisomers are described by chemical name or structure, and the name or structure is connected by "or", it means one or the other of the two stereoisomers, not both.

[0131] When a disclosed compound with a chiral center is described structurally without showing the configuration at the chiral center, it means that the structure encompasses a configuration at the chiral center. S Compounds with the configuration having at the chiral center R The compound with the configuration or having at the chiral center R and S Compounds with mixed configurations. When a compound is described by its chemical name as having a chiral center without using " S "or" R "When referring to the configuration at the chiral center, it means that the name covers the configuration at the chiral center." S Compounds with the configuration having at the chiral center R The compound with the configuration or having at the chiral center R and S Compounds with mixed configurations.

[0132] A racemic mixture means 50% of one enantiomer and 50% of the corresponding enantiomers. When naming or describing a compound having one chiral center without indicating the stereochemistry of the chiral center, it should be understood that the name or structure covers two possible enantiomers of the compound (e.g., two enantiomerically pure, enantiomerically enriched, or racemic). When naming or describing a compound having two or more chiral centers without indicating the stereochemistry of the chiral centers, it should be understood that the name or structure covers all possible diastereomers of the compound (e.g., diastereomerically pure, diastereomerically enriched, and an equimolar mixture of one or more diastereomers (e.g., a racemic mixture)).

[0133] The term "geometric isomer" refers to a compound having at least one double bond, wherein the double bond may be in the cis (also known as iso-side) or iso-side (...). E )) or trans (also known as anti- or ipsilateral) Z It exists in the form of )) and its mixtures.

[0134] Tautomeric isomerism can occur when structural isomers interconvert through a low-energy barrier. This can manifest as proton tautomerism in compounds containing, for example, imino, ketone, or oxime groups, or as valence tautomerism in compounds containing aromatic moieties. Thus, a single compound can exhibit more than one type of isomerism.

[0135] In some embodiments, tautomeric forms of the disclosed compound exist, such as the tautomeric structures shown below:

[0136] When a geometric isomer is described by name or structure, it should be understood that the named or described isomer is present to a greater extent than another isomer, i.e., the geometric isomer purity of the named or described geometric isomer is greater than 50% by weight, for example, at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. Geometric isomer purity is determined by dividing the weight of the named or described geometric isomer in the mixture by the total weight of all geometric isomers in the mixture.

[0137] Cis / Reverse Isomers can be separated using conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0138] Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from a suitable optically pure precursor or analysis of the racemic mixture (or racemic mixture of salt or derivative) using, for example, chiral high-performance liquid chromatography (HPLC). Alternatively, the racemic mixture (or racemic precursor) can be reacted with a suitable optically active compound (e.g., an alcohol), or, if the compound of any of the formulas described above contains an acidic or basic moiety, with an acid or base (e.g., 1-phenylethylamine or tartaric acid). The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereomeric mixtures can be converted to their corresponding pure enantiomers by means well known to those skilled in the art. Chiral compounds (and their chiral precursors) of any of the formulas described above can be obtained enantiomerically enriched using chromatographic methods (typically HPLC) on an asymmetric resin with a mobile phase consisting of a hydrocarbon (typically heptane or hexane) containing 0% to 50% (typically 2% to 20%) isopropanol and 0% to 5% (typically 0.1% diethylamine). The eluent is concentrated to obtain an enriched mixture. Chiral chromatography using subcritical and supercritical fluids can be employed. Chiral chromatographic methods suitable for some embodiments of this disclosure are known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns)), pages 223 to 249, and references cited therein). Columns are available from Chiral Technologies, Inc., West Chester, Pa., USA, and are manufactured by Daicel. ® A subsidiary of Chemical Industries, Ltd., Tokyo, Japan.

[0139] It must be emphasized that compounds of any of the formulas described above are drawn in this document as a single tautomer, but all possible tautomers are included within the scope of this disclosure.

[0140] 3. Application and administration

[0141] Typically, the compounds of this disclosure are administered in an amount effective in treating the conditions described herein. The compounds of this disclosure may be administered on their own or alternatively as pharmaceutically acceptable salts. For purposes of administration and dosing, the compounds themselves or their pharmaceutically acceptable salts will be referred to simply as the compounds of this disclosure.

[0142] The compounds of this disclosure are administered via any suitable route in the form of a pharmaceutical composition suitable for such route and at a dose effective for the intended treatment. The compounds of this disclosure can be administered orally, rectally, vaginally, parenterally, or topically.

[0143] The compounds disclosed herein can be administered orally. Oral administration may involve swallowing, allowing the compound to enter the gastrointestinal tract, or it may be administered orally or sublingually, thereby allowing the compound to enter the bloodstream directly from the mouth.

[0144] In another embodiment, the compounds of this disclosure can also be administered directly into the bloodstream, muscles, or internal organs. Suitable means of parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous administration. Suitable parenteral administration devices include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0145] In another embodiment, the compounds of this disclosure can also be applied topically to the skin or mucous membranes, i.e., transdermal or percutaneous. In another embodiment, the compounds of this disclosure can also be administered intranasally or by inhalation. In another embodiment, the compounds of this disclosure can be administered rectally or vaginally. In another embodiment, the compounds of this disclosure can also be applied directly to the eyes or ears.

[0146] Dosing regimens for the compounds of this disclosure and / or compositions containing said compounds are based on a variety of factors, including patient type, age, weight, sex, and medical condition; severity of the condition; route of administration; and the activity of the specific compound used. Therefore, dosing regimens can vary considerably. In one embodiment, for the treatment of the specified condition discussed herein, the total daily dose of the compounds of this disclosure is typically from about 0.001 to about 100 mg / kg (i.e., milligrams of the compounds of this disclosure per kilogram of body weight).

[0147] For oral administration, the composition may be provided in tablet form containing 0.1-500 mg of the active ingredient for symptomatic dose adjustment to the patient. The drug typically contains about 0.01 mg to about 500 mg of the active ingredient. For intravenous administration, the dose range can be about 0.01 to about 10 mg / kg / min during constant-rate infusion.

[0148] Suitable individuals according to this disclosure include mammalian individuals, including non-human mammals such as primates, rodents (mice, rats, hamsters, rabbits, etc.). In one embodiment, a human is a suitable individual. A human individual can be of any sex and at any developmental stage.

[0149] 4. Pharmaceutical Composition

[0150] In another embodiment, this disclosure comprises pharmaceutical compositions. These pharmaceutical compositions comprise compounds of this disclosure presented together with a pharmaceutically acceptable carrier or excipient. Other pharmacologically active substances may also be present.

[0151] As used herein, "pharmaceutically acceptable carriers or excipients" include any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents. Examples of pharmaceutically acceptable carriers include water, saline, phosphate-buffered saline, dextran, glycerol, ethanol, and one or more combinations thereof, and may include isotonic agents in the composition, such as sugars, sodium chloride, or polyols, such as mannitol or sorbitol. Pharmaceutically acceptable substances (e.g., wetting agents) or small amounts of excipients (e.g., wetting agents or emulsifiers, preservatives, or buffers) enhance the shelf life or efficacy of antibodies or antibody moieties.

[0152] The compositions disclosed herein can be in a variety of forms. These forms include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusionable solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The form depends on the intended administration method and therapeutic application.

[0153] Typical compositions are in the form of injectable or infusionable solutions, such as compositions commonly used for passive antibody immunization in humans. One administration method is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the antibody is administered via intravenous infusion or injection. In yet another embodiment, the antibody is administered via intramuscular or subcutaneous injection.

[0154] Oral administration of solid dosage forms can be, for example, presented in discrete units, such as hard or soft capsules, pills, sachets, lozenges, or tablets, each containing a predetermined amount of at least one compound disclosed herein. In another embodiment, oral administration can be in powder or granule form. In another embodiment, the oral dosage form is a sublingual dosage form, such as lozenges. In these solid dosage forms, the compound of any of the formulas described above is typically combined with one or more adjuvants. These capsules or tablets may contain controlled-release formulations. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer or may be prepared with an enteric coating.

[0155] In another embodiment, oral administration may be in the form of a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing an inert diluent (e.g., water) commonly used in the art. These compositions may also contain adjuvants such as wetting agents, emulsifiers, suspending agents, flavoring agents (e.g., sweeteners), and / or fragrances.

[0156] In another embodiment, this disclosure includes parenteral dosage forms.

[0157] "Parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. Injectable formulations (i.e., sterile injectable aqueous or oily suspensions) can be formulated using suitable dispersants, wetting agents, and / or suspending agents according to known techniques.

[0158] In another embodiment, this disclosure includes topical dosage forms.

[0159] "Topical application" includes, for example, transdermal application, such as via transdermal patches or iontophoresis devices, intraocular application, or intranasal or inhalation application. Compositions for topical application also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of this disclosure are applied via a transdermal device, application is accomplished using a reservoir layer and a porous membrane type or a solid matrix type patch. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohols, water, mineral oils, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Permeation enhancers may be incorporated, see, for example, Finnin and Morgan. J. Pharm. Sci. , 88:955-958, 1999.

[0160] Formulations suitable for topical application to the eye include, for example, eye drops, wherein the compounds of this disclosure are dissolved or suspended in a suitable carrier. Typical formulations suitable for ocular or ear application may be in the form of drops, which are micronized suspensions or solutions in pH-adjusted isotonic sterile saline. Other formulations suitable for ocular and ear application include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, patches, lenses, and microparticle or vesicle systems (e.g., vesicles or liposomes). Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methylcellulose) or heteropolysaccharide polymers (e.g., gellan gum) may be incorporated with preservatives (e.g., benzalkonium chloride). These formulations may also be delivered via iontophoresis.

[0161] For intranasal or inhalation administration, the compounds of this disclosure are conveniently delivered in solution or suspension form from a pump-operated spray container squeezed or pumped by a patient, or in aerosol spray form from a pressurized container or nebulizer, with the use of a suitable propellant. Formulations suitable for intranasal administration are typically administered as a dry powder (alone; as a mixture, e.g., a dry blend with lactose; or as mixed component particles, e.g., mixed with phospholipids such as lecithin) from a dry powder inhaler, or in aerosol spray form from a pressurized container, pump, spray, nebulizer (preferably using an electrohydraulic nebulizer to generate a fine mist), with or without a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may contain a bioadhesive (e.g., chitosan or cyclodextrin).

[0162] In another embodiment, this disclosure includes a rectal dosage form. This rectal dosage form may be in the form of, for example, suppositories. Cocoa butter is a conventional suppository base, but various alternatives may be used as appropriate.

[0163] Other carrier materials and administration methods known in the pharmaceutical field can also be used. The pharmaceutical compositions disclosed herein can be prepared using any of the well-known pharmaceutical techniques, such as efficient formulation and administration procedures.

[0164] The above considerations regarding effective preparation and administration procedures are well known in the art and described in standard textbooks. The preparation of drugs is discussed, for example, by Hoover, John E. Remington's Pharmaceutical Sciences Mack Publishing Co., Easton, Pa., 1975; edited by Liberman et al. Pharmaceutical Dosage Forms Marcel Decker, New York, NY, 1980; and Kibbe et al., eds. Handbook of Pharmaceutical Excipients (3rd Edition), American Pharmaceutical Association, Washington, 1999.

[0165] 5. Treatment

[0166] This disclosure relates to SOS1 inhibitor compounds, particularly compounds of formula (I'), (IIA'), (IIB'), (IIIA'-1), (IIIA'-2), (IIIB'-1), (IIIB'-2), (IV'), (IVA'), (IVB'), (VA'), (VB'), (VC'), (VD'), (VIA'), (VIB'), or (VII') (including all embodiments thereof), which are suitable for the treatment and / or prevention of diseases and / or conditions associated with or regulated by SOS1, particularly diseases and / or conditions in which inhibition of the interaction of SOS1 with RAS family proteins and / or RAC1 has a therapeutic benefit, including but not limited to the treatment and / or prevention of cancer.

[0167] In one embodiment, this disclosure relates to compounds of formula (I'), (IIA'), (IIB'), (IIIA'-1), (IIIA'-2), (IIIB'-1), (IIIB'-2), (IV'), (IVA'), (IVB'), (VA'), (VB'), (VC'), (VD'), (VIA'), (VIB'), or (VII'), pharmaceutically acceptable salts or stereoisomers thereof, used as pharmaceuticals.

[0168] In one embodiment, this disclosure relates to compounds of formula (I'), (IIA'), (IIB'), (IIIA'-1), (IIIA'-2), (IIIB'-1), (IIIB'-2), (IV'), (IVA'), (IVB'), (VA'), (VB'), (VC'), (VD'), (VIA'), (VIB'), or (VII'), pharmaceutically acceptable salts or stereoisomers thereof, in methods of using them to treat human or animal bodies.

[0169] In one embodiment, this disclosure relates to SOS1 inhibitor compounds, particularly compounds of formula (I'), (IIA'), (IIB'), (IIIA'-1), (IIIA'-2), (IIIB'-1), (IIIB'-2), (IV'), (IVA'), (IVB'), (VA'), (VB'), (VC'), (VD'), (VIA'), (VIB'), or (VII'), pharmaceutically acceptable salts or stereoisomers thereof, for the treatment and / or prevention of diseases and / or conditions in which inhibition of the interaction of SOS1 with RAS family proteins and / or RAC1 has a therapeutic benefit, including but not limited to the treatment and / or prevention of cancer.

[0170] In one embodiment, this disclosure relates to SOS1 inhibitor compounds, particularly compounds of formula (I'), (IIA'), (IIB'), (IIIA'-1), (IIIA'-2), (IIIB'-1), (IIIB'-2), (IV'), (IVA'), (IVB'), (VA'), (VB'), (VC'), (VD'), (VIA'), (VIB'), or (VII'), pharmaceutically acceptable salts or stereoisomers thereof, for the treatment and / or prevention of cancer.

[0171] In one embodiment, this disclosure relates to SOS1 inhibitor compounds, particularly compounds of formula (I'), (IIA'), (IIB'), (IIIA'-1), (IIIA'-2), (IIIB'-1), (IIIB'-2), (IV'), (IVA'), (IVB'), (VA'), (VB'), (VC'), (VD'), (VIA'), (VIB'), or (VII'), pharmaceutically acceptable salts or stereoisomers thereof, and methods of using them for treating and / or preventing cancer in humans or animals.

[0172] In one embodiment, this disclosure relates to SOS1 inhibitor compounds, particularly compounds of formula (I'), (IIA'), (IIB'), (IIIA'-1), (IIIA'-2), (IIIB'-1), (IIIB'-2), (IV'), (IVA'), (IVB'), (VA'), (VB'), (VC'), (VD'), (VIA'), (VIB'), or (VII'), pharmaceutically acceptable salts or stereoisomers thereof, used as defined above, wherein the SOS1 inhibitor compound is administered before, after, or together with at least one other pharmacologically active substance.

[0173] In one embodiment, this disclosure relates to an SOS1 inhibitor compound or a pharmaceutically acceptable salt thereof, used as defined above, wherein the SOS1 inhibitor compound is administered in combination with at least one other pharmacologically active substance.

[0174] In one embodiment, this disclosure relates to compounds of formula (I'), (IIA'), (IIB'), (IIIA'-1), (IIIA'-2), (IIIB'-1), (IIIB'-2), (IV'), (IVA'), (IVB'), (VA'), (VB'), (VC'), (VD'), (VIA'), (VIB'), or (VII'), their pharmaceutically acceptable salts or stereoisomers, used as defined above, wherein the compound is administered in combination with at least one other pharmacologically active substance.

[0175] In one embodiment, this disclosure relates to a pharmacologically active substance prepared for administration before, after, or together with an SOS1 inhibitor compound or a pharmaceutically acceptable salt thereof, as defined above with respect to the use of compounds of formula (I'), (IIA'), (IIB'), (IIIA'-1), (IIIA'-2), (IIIB'-1), (IIIB'-2), (IV'), (IVA'), (IVB'), (VA'), (VB'), (VC'), (VD'), (VIA'), (VIB'), or (VII'), their pharmaceutically acceptable salts, or stereoisomers.

[0176] In one embodiment, this disclosure relates to a pharmacologically active substance prepared for use before, after, or together with a compound of formula (I'), (IIA'), (IIB'), (IIIA'-1), (IIIA'-2), (IIIB'-1), (IIIB'-2), (IV'), (IVA'), (IVB'), (VA'), (VB'), (VC'), (VD'), (VIA'), (VIB'), or (VII'), its pharmaceutically acceptable salts or stereoisomers, as defined above with respect to the use of a compound of formula (I'), (IIA'), (IIB'), (IIIA'-1), (IIIA'-2), (IIIB'-1), (IIIB'-2), (IV'), (IVA'), (IVB'), (VA'), (VB'), (VC'), (VD'), (VIA'), (VIB'), or (VII'), its pharmaceutically acceptable salts or stereoisomers.

[0177] In one embodiment, this disclosure relates to SOS1 inhibitor compounds, particularly compounds of formula (I'), (IIA'), (IIB'), (IIIA'-1), (IIIA'-2), (IIIB'-1), (IIIB'-2), (IV'), (IVA'), (IVB'), (VA'), (VB'), (VC'), (VD'), (VIA'), (VIB'), or (VII'), pharmaceutically acceptable salts or stereoisomers thereof, used in the treatments or methods defined above.

[0178] In one embodiment, this disclosure relates to the use of SOS1 inhibitor compounds, particularly compounds of formula (I'), (IIA'), (IIB'), (IIIA'-1), (IIIA'-2), (IIIB'-1), (IIIB'-2), (IV'), (IVA'), (IVB'), (VA'), (VB'), (VC'), (VD'), (VIA'), (VIB'), or (VII'), their pharmaceutically acceptable salts or stereoisomers, for the preparation of pharmaceutical compositions for the treatment and / or prevention of cancer.

[0179] In one embodiment, this disclosure relates to the use of an SOS1 inhibitor compound or a pharmaceutically acceptable salt thereof as defined above, wherein the SOS1 inhibitor compound is administered before, after, or together with at least one other pharmacologically active substance.

[0180] In one embodiment, this disclosure relates to the use of compounds of formula (I'), (IIA'), (IIB'), (IIIA'-1), (IIIA'-2), (IIIB'-1), (IIIB'-2), (IV'), (IVA'), (IVB'), (VA'), (VB'), (VC'), (VD'), (VIA'), (VIB'), or (VII') as defined above, their pharmaceutically acceptable salts or stereoisomers, wherein the compounds are administered before, after, or together with at least one other pharmacologically active substance.

[0181] In one embodiment, this disclosure relates to the use of SOS1 inhibitor compounds as defined above, particularly compounds of formula (I'), (IIA'), (IIB'), (IIIA'-1), (IIIA'-2), (IIIB'-1), (IIIB'-2), (IV'), (IVA'), (IVB'), (VA'), (VB'), (VC'), (VD'), (VIA'), (VIB'), or (VII'), their pharmaceutically acceptable salts or stereoisomers, for the purpose of treatment.

[0182] In one embodiment, this disclosure relates to a method of treating and / or preventing diseases and / or conditions in which inhibiting the interaction of SOS1 with RAS family proteins or RAC1 has a therapeutic benefit, comprising administering a therapeutically effective amount of an SOS1 inhibitor compound, particularly compounds of formula (I'), (IIA'), (IIB'), (IIIA'-1), (IIIA'-2), (IIIB'-1), (IIIB'-2), (IV'), (IVA'), (IVB'), (VA'), (VB'), (VC'), (VD'), (VIA'), (VIB'), or (VII'), a pharmaceutically acceptable salt or stereoisomer thereof, to a human.

[0183] In one embodiment, this disclosure relates to a method of treating and / or preventing cancer, comprising administering a therapeutically effective amount of an SOS1 inhibitor compound, particularly a compound of formula (I'), (IIA'), (IIB'), (IIIA'-1), (IIIA'-2), (IIIB'-1), (IIIB'-2), (IV'), (IVA'), (IVB'), (VA'), (VB'), (VC'), (VD'), (VIA'), (VIB'), or (VII'), a pharmaceutically acceptable salt or stereoisomer thereof, to a human.

[0184] In one embodiment, this disclosure relates to a method as defined above, wherein an SOS1 inhibitor compound or a pharmaceutically acceptable salt thereof is administered before, after, or together with at least one other pharmacologically active substance.

[0185] In one embodiment, this disclosure relates to a method as defined above, wherein a compound of formula (I'), (IIA'), (IIB'), (IIIA'-1), (IIIA'-2), (IIIB'-1), (IIIB'-2), (IV'), (IVA'), (IVB'), (VA'), (VB'), (VC'), (VD'), (VIA'), (VIB'), or (VII'), a pharmaceutically acceptable salt or stereoisomer thereof, is administered before, after, or together with at least one other pharmacologically active substance.

[0186] In one embodiment, this disclosure relates to a method as defined above, wherein an SOS1 inhibitor compound or a pharmaceutically acceptable salt thereof is administered in combination with a therapeutically effective amount of at least one other pharmacologically active substance.

[0187] In one embodiment, this disclosure relates to a method as defined above, wherein a compound of formula (I'), (IIA'), (IIB'), (IIIA'-1), (IIIA'-2), (IIIB'-1), (IIIB'-2), (IV'), (IVA'), (IVB'), (VA'), (VB'), (VC'), (VD'), (VIA'), (VIB'), or (VII'), a pharmaceutically acceptable salt or stereoisomer thereof, is administered in combination with a therapeutically effective amount of at least one other pharmacologically active substance.

[0188] In one implementation, this disclosure relates to a treatment method as defined above.

[0189] In one implementation, the SOS1 inhibitor compound as defined herein (above and below), the SOS1 inhibitor compound for use, the compound of formula (I'), the compound of formula (I') for use, the preparation purpose, and the treatment and / or prevention method for the disease / condition / cancer treated / prevented are selected from the group consisting of: pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, squamous cell carcinoma of the head and neck, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma.

[0190] In one embodiment, the SOS1 inhibitor compound as defined herein (above and below), the SOS1 inhibitor compound for use, the compound of formula (I'), the compound of formula (I') for use, the preparation purpose, and the treatment and / or prevention method for the disease / condition / cancer to be treated / prevented are selected from the group consisting of: pancreatic cancer, lung cancer (preferably non-small cell lung cancer (NSCLC)), cholangiocarcinoma, and colorectal cancer.

[0191] In one embodiment, the SOS1 inhibitor compound, the SOS1 inhibitor compound for use, the compound of formula (I'), the compound of formula (I') for use, the preparation purpose, and the treatment and / or prevention method for treating / preventing the disease / condition are defined herein as RAS lesions (RASopathy). In one embodiment, it is selected from the group consisting of: neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML) (also known as leopard syndrome), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardiofacial-dermal syndrome (CFC), Legius syndrome (also known as NF1-like syndrome), and hereditary gingival fibromatosis.

[0192] In one embodiment, the pharmacologically active substance as defined herein (above and below) used together or in combination with SOS1 inhibitor compounds, especially compounds of formula (I'), (IIA'), (IIB'), (IIIA'-1), (IIIA'-2), (IIIB'-1), (IIIB'-2), (IV'), (IVA'), (IVB'), (VA'), (VB'), (VC'), (VD'), (VIA'), (VIB'), or (VII'), their pharmaceutically acceptable salts or stereoisomers, or used in medical purposes, uses, treatments, and / or preventive methods, may be selected from any one or more of the following: 1. Inhibitors of EGFR and / or its mutants a. For example, afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, osimertinib, olmutinib, and EGF-816. b. Afatinib, osimertinib, and cetuximab; or c. Afatinib; 2. Inhibitors of ErbB2 (Her2) and / or its mutants a. For example, afatinib, lapatinib, trastuzumab, and pertuzumab; b. Afatinib and trastuzumab; c. Trastuzumab; 3. Inhibitors of ALK and / or its mutants a. For example, crizotinib, alectinib, entrectinib, and brigatinib; b. Crizotinib and alectinib; c. Crizotinib; 4. Inhibitors of MEK and / or its mutants a. For example, trametinib, cobimetinib, binimetinib, selumetinib, and refamatetinib; b. Trametinib and Cobimetinib; c. Trametinib; 5. Inhibitors of GDP-binding KRAS and / or its mutants a. Irreversible inhibitors of KRAS G12C i. For example, ARS-853 (compound V-64 in WO 2014 / 152588), example I-272 in WO 2016 / 044772; b. Reversible inhibitors of GDP-binding KRAS and / or its mutants; 6. Inhibitors of BCR-ABL and / or its mutants a. For example, imatinib, dasatinib, and nilotinib; b. Imatinib and nilotinib; c. Imatinib; 7. Inhibitors of FGFR1 and / or FGFR2 and / or FGFR3 and / or their mutants a. For example, nintedanib; 8. Inhibitors of ROS1 and / or its mutants a. For example, crizotinib, entrectinib, lorlatinib, ceritinib, and merestinib; b. Crizotinib and entrectinib; c. Crizotinib; 9. Inhibitors of c-MET and / or its mutants 10. Inhibitors of AXL and / or its mutants 11. Inhibitors of NTRK1 and / or its mutants 12. Inhibitors of RET and / or its mutants 13. Taxane a. For example, paclitaxel, albumin-bound paclitaxel, and docetaxel; b. Pacific paclitaxel; 14. Platinum-containing compounds a. For example, cisplatin, carboplatin, and oxaliplatin; 15. Antimetabolites a. For example, combinations of 5-fluorouracil, capecitabine, fluxuridine, cytarabine, gemcitabine, trifluridine, and tipiracil (= TAS102); b. Gescitabine; 16. Mitotic kinase inhibitors a. For example, CDK4 / 6 inhibitors i. For example, palbociclib, ribociclib, abemaciclib; ii. Pabosigli and Abesigli; iii. Abesil; 17. Immunotherapy agents a. For example, immune checkpoint inhibitors i. For example, anti-CTLA4 mAb, anti-PD1 mAb, anti-PD-L1 mAb, anti-PD-L2 mAb, anti-LAG3 mAb, and anti-TIM3 mAb; ii. Anti-PD1 mAb; iii. For example, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, pidilizumab, and PDR-001 (=spartalizumab); iv. Nivolumab, pembrolizumab, and PDR-001 (=Spartilizumab); v. Pembrolizumab; 18. Anti-angiogenic drugs a. For example, bevacizumab and nintedanib; b. Bevacizumab; 19. Topoisomerase inhibitors a. For example, irinotecan, liposomal irinotecan, and topotecan; b. Irinotecan; 20. Inhibitors of A-Raf and / or B-Raf and / or C-Raf and / or their mutants a. For example, RAF-709 (= Instance 131 in WO 2014 / 151616), LY-3009120 (= Instance 1 in WO 2013 / 134243); 21. Inhibitors of ERK and / or its mutants a. For example, ulixertinib; 22. Apoptosis regulators a. For example, inhibitors of the interaction between p53 (functional p53, wt p53) and MDM2 (“MDM2 inhibitors”); i. For example, HDM-201, NVP-CGM097, RG-7112, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-1 15; ii. HDM-201, RG-7388 and AMG-232 b. For example, PARP inhibitors; c. For example, MCL-1 inhibitors; 23. mTOR inhibitors a. For example, rapamycin, temsirolimus, everolimus, and ridaforolimus; 24. Epigenetic regulators a. For example, BET inhibitors i. For example, JQ-1, GSK 525762, OTX 015 (= MK8628), CPI 0610, TEN-010 (=R06870810); b. For example, CDK9 inhibitors; 25. Inhibitors of IGF1 / 2 and / or IGF1-R a. For example, xentuzumab (antibody 60833 in WO 2010 / 066868) and MEDI-573 (=dusigitumab); 26. Inhibitors of RAS GEF and / or its mutants a. Inhibitors of SOS2 and / or its mutants, for example. 27. Inhibitors of PI3K and / or its mutants.

[0193] 28. Inhibitors of SHP2 and / or its mutants.

[0194] In one implementation, the nonpharmacological therapy may be used with or in combination with SOS1 inhibitor compounds, particularly compounds of formula (I'), (IIA'), (IIB'), (IIIA'-1), (IIIA'-2), (IIIB'-1), (IIIB'-2), (IV'), (IVA'), (IVB'), (VA'), (VB'), (VC'), (VD'), (VIA'), (VIB'), or (VII'), their pharmaceutically acceptable salts or stereoisomers, or for medical purposes, uses, treatments, and / or preventative methods, as described herein (above and below). Examples of nonpharmacological therapies include, but are not limited to, radiotherapy, cryotherapy, hyperthermia, surgery (e.g., surgical resection of tumor tissue), and T-cell adoptive transfer (ACT) therapy.

[0195] In one embodiment, the compounds of this disclosure can be used as adjuvant therapy after surgery. In some embodiments, the compounds of this disclosure can be used as neoadjuvant therapy before surgery.

[0196] Radiation therapy can be used to suppress abnormal cell growth in an individual (e.g., a mammal (e.g., a human)) or to treat their hyperproliferative conditions, such as cancer. Techniques for administering radiation therapy are known in the art. Radiation therapy can be administered by one or a combination of several methods, including but not limited to external beam radiation therapy, internal body radiation therapy, implant radiation, stereotactic radiosurgery, whole-body radiation therapy, radiotherapy, and permanent or temporary interstitial brachytherapy. As used herein, the term "brachytherapy" refers to radiation therapy delivered by inserting a space-constrained radioactive material into or near a tumor or other site of proliferative tissue disease. The term is intended to include, but is not limited to, exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and Lu). Suitable radiation sources used as cell modulators of this disclosure include both solid and liquid forms. As a non-limiting example, the radioactive source can be a radionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be a fluid made from any solution of the radionuclide (e.g., a solution of I-125 or I-131), or the radioactive fluid can be generated using a slurry of a suitable fluid containing small particles of a solid radionuclide (e.g., Au-198 or Y-90). Furthermore, the radionuclide can be embodied in a gel or radioactive microspheres.

[0197] In one embodiment, the compounds of this disclosure can make abnormal cells more sensitive to radiation therapy used to kill such cells or inhibit the growth of said cells. Therefore, this disclosure further relates to a method for sensitizing abnormal cells in mammals to radiation therapy, comprising applying an amount of the disclosed compound to the mammal, said amount effectively sensitizing the abnormal cells to radiation therapy. The amount of the compound in the method can be determined according to means used to confirm the effective amount of such compounds described herein. In some embodiments, the compounds of this disclosure can be used as adjuvant therapy after radiation therapy or neoadjuvant therapy before radiation therapy.

[0198] In one embodiment, the non-pharmacological treatment is adoptive T-cell transfer (ACT) therapy. In some embodiments, the T cells are activated T cells. The T cells may be modified to express a chimeric antigen receptor (CAR). CAR-modified T (CAR-T) cells can be generated by any method known in the art. For example, CAR-T cells can be generated by introducing a suitable expression vector encoding a CAR into T cells. The T cell source is obtained from an individual prior to T cell expansion and genetic modification. T cells can be obtained from a variety of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from sites of infection, ascites, pleural effusion, spleen tissue, and tumors. In some embodiments of this disclosure, any number of T cell lines available in the art may be used. In some embodiments, the T cells are autologous T cells. Whether before or after T cells are genetically modified to express a desired protein (e.g., CAR), T cells can typically be activated and expanded using methods described, for example, in U.S. Patents 6,352,694, 6,534,055, 6,905,680, 6,692,964, 5,858,358, 6,887,466, 6,905,681, 7,144,575, 7,067,318, 7,172,869, 7,232,566, 7,175,843, 7,572,631, 5,883,223, 6,905,874, 6,797,514, and 6,867,041.

[0199] In one embodiment, the additional therapeutic agent may be used together with or in combination with SOS1 inhibitor compounds, especially compounds of formula (I'), (IIA'), (IIB'), (IIIA'-1), (IIIA'-2), (IIIB'-1), (IIIB'-2), (IV'), (IVA'), (IVB'), (VA'), (VB'), (VC'), (VD'), (VIA'), (VIB'), or (VII'), their pharmaceutically acceptable salts or stereoisomers, or for medical purposes, uses, treatments, and / or preventative methods, as described herein (above and below).

[0200] In one implementation, the additional therapeutic agent may be a steroid. Therefore, in some implementations, one or more additional therapies include steroids. Suitable steroids may include, but are not limited to, 21-acetoxygestrinone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, and cotetrazodone. Cortivazol, Deflazacort, Desonide, Desoximetasone, Dexamethasone, Diflorasone, Diflucortolone, Difuprednate, Enoxolone, Fluazacort, Flucloronide, Flumethasone, Flunisolide, Fluocinolone Acetate Acetone, Fluocinonide, Fluocortin butyl, Fluocortolone, Flumetholone, Fluperolone acetate, Fluprednidene acetate, Fluprednisolone, Flurandrenolide, Fluticasone propionate, Formocortal, Halcinonide, Halobetasol propionate, Halometasone, Hydrocortisone, Lopeprednoletabonate), mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and their salts or derivatives.

[0201] Other examples of therapeutic agents that can be used in combination therapies of the compounds disclosed herein include compounds described in the following patents: U.S. Patents 6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764, and 8,623,885, and International Patents. Patent applications WO01 / 37820, WO01 / 32651, WO02 / 68406, WO02 / 66470, WO02 / 55501, WO04 / 05279, WO04 / 07481, WO04 / 07458, WO04 / 09784, WO02 / 59110, WO99 / 45009, WO00 / 59509, WO99 / 61422, WO00 / 12089 and WO00 / 02871.

[0202] Therapeutic agents can be biologics (e.g., cytokines such as interferons or interleukins like IL-2) used to treat cancer or related symptoms. In some embodiments, the biologic is an immunoglobulin-based biologic, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof), which stimulates a target to elicit an anticancer response or antagonizes antigens that are important for cancer. Antibody-drug conjugates are also included.

[0203] The therapeutic agent may be a checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody, such as a monoclonal antibody). The antibody may be, for example, a humanized antibody or a fully human antibody. In some embodiments, the checkpoint inhibitor is a fusion protein, such as an Fc-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent that interacts with a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is an agent that interacts with a ligand of a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is an inhibitor of CTLA-4 (e.g., an inhibitory antibody or a small molecule inhibitor) (e.g., an anti-CTLA-4 antibody or a fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist of PD-1 (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist of PDL-1 (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist of PDL-2 (e.g., a PDL-2 / Ig fusion protein) (e.g., an inhibitory antibody or an Fc fusion or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist of the following (e.g., an inhibitory antibody or small molecule inhibitor): B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof. In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), PD-L1 antibodies (e.g., avelumab, durvalumab, atezolizumab, pildizumab), JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene), or Preusser, M. et al., (2015) Nat. Rev. Checkpoint inhibitors disclosed in Neurol. include, but are not limited to, ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MED14736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW-6002.

[0204] Therapeutic agents can be drugs used to treat cancer or related symptoms (e.g., cytotoxic agents, non-peptide small molecules, or other compounds that can be used to treat cancer or related symptoms, collectively referred to as "anticancer agents"). Anticancer agents can be, for example, chemotherapy agents or targeted therapy agents.

[0205] Anticancer agents include mitosis inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxin, antibiotics, L-asparaginase, topoisomerase inhibitors, interferon, platinum coordination complexes, anthraquinone-substituted ureas, methylhydrazine derivatives, adrenocortical inhibitors, adrenocortical steroids, progesterone, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Other anticancer agents include leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel. In some embodiments, one or more additional therapies comprise two or more anticancer agents. Two or more anticancer agents may be administered in combination in a mixture or separately. Suitable dosing regimens for combination anticancer agents are known in the art and described, for example, in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999) and Douillard et al., Lancet 355(9209):1041-1047 (2000).

[0206] Other non-limiting examples of anticancer agents include Gleevec® (imatinib mesylate); Kyprolis® (carfilzomib); Velcade® (bortezomib); Casodex (bicalutamide); and Iressa®. Gefitinib; alkylating agents, such as thiotepa and cyclosphosphamide; alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimine and methylmelamine, including altretamine, triethylenemelamine, triethylenephosphoramide, triethiylenethiophosphoramide, and trimethylolmelamine; acetogenin (especially bulbatacin and bulbatacinone); camptothecin. (Including synthetic analogs topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogs adozelesin, carzelesin, and bizelesin); cryptophycin (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin A; spongistatin;Nitrogen mustards, such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novombhichin, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicin, calicheamicin γ-II and calicheamicin ω-II (see also Agnew, etc.) Chem. Intl. Ed Engl. 33:183-186 (1994)); dynemicin, such as dynemicin A; bisphosphonate, such as clodronate; esperamicin;Neocarzinostatin chromophore and related chromogenic proteins (ene diyne antibiotic chromophores), aclacinomysin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin C, kazimycin, carabicin, caminomycin / carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-leucine, adriamycin. Doxorubicin, N-morpholino-doxorubicin, cyano-N-morpholino-doxorubicin, 2-pyrrololino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin (e.g., mitomycin C), mycophenolic acid The following are listed as potential drug derivatives: nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as denopterin, pteropterin, and trimetrexate; and purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine.Pyrimidine analogues, such as ancitabine, azacitidine, 6-azouridine, carmofur, cytarabine, doxifluridine, enocitabine, and fluxuridine; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testosterone; antiadrenergic drugs, such as aminoglutethimide, mitotane, and trilostane; folic acid supplements, such as folinic acid; aceglatone; aldophosphamide glycoside; and aminolevulinic acid. acid); eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate); epothilone, such as epothilone B; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids, such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-acetylhydrazine; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran;Spirogermanium; tenuazonicacid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecene (e.g., T-2 toxin, verracurin A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactalol; piperobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, such as Taxol® (Pacific paclitaxel) and Abraxane®. (A protein-engineered nanoparticle formulation of Pacific paclitaxel without castor oil polyoxyethylene ether) and Taxotere® (docetaxel); chlorambucil; tamoxifen (Nolvadex™); raloxifene; 4(5)-imidazole for aromatase inhibition; 4-hydroxytamoxifen; trioxifene; raloxifene hydrochloride; LY 117018; onapristone; toremifene (Fareston®); flutamide, nilutamide, bicalutamide, leuprolide, goserelin; chlorambucil; Gemzar® gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes, such as cisplatin, oxaliplatin, and carboplatin; vincristine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Navelbine® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; esperapycin; capecitabine (e.g., Xeloda®); and pharmaceutically acceptable salts of any of the above.

[0207] Other non-limiting examples of anticancer agents include trastuzumab (Herceptin®), bevacizumab (Avastin®), cetuximab (Erbitux®), and rituximab. (Rituxan®), Taxol®, Arimidex®, ABVD, avicine, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygerdomyl, alpharadin, alvocidib, 3-aminopyridine-2-carboxaldehyde thiourea, amonafide, anthraquinone, anti-CD22 immunotoxin, antitumor agents (e.g., cell cycle nonspecific antitumor agents and other antitumor agents described herein), antitumor herbs, apaziquone, atipremod, azathioprine, belotecone, bendamustine, BIBW 2992, biricodar, brostallicin, bryostatin, buthionine sulfoximine, CBV(Chemotherapy), Calyculin, Dichloroacetic Acid, Discodermolide, Elsamitrucin, Enocitalbine, Eribulin, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICE Chemotherapy Regimen, IT-101, Imexon, Imiquimod, Indomethacin, Irofulven, Laniquidar, Larontazone larotaxel, lenalidomide, lucanthone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, papaya, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A A) Sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatinum tetranitrate, tri(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, and zosuquidar.

[0208] Other non-limiting examples of anticancer agents include natural products such as vinca alkaloids (e.g., vincristine, vinorelbine, and vinorelbine), epipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., styracin (actinomycin D), daunorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), mitomycin, enzymes (e.g., L-asparaginase, which systematically metabolizes L-asparagine and deprives cells incapable of synthesizing their own asparagine), antiplatelet agents, antiproliferative / antimitotic alkylating agents (e.g., nitrogen mustard (e.g., methylmuscarin, cyclophosphamide, and analogues), melphalan, and chlorambucil), ethyleneimine and methylmelamine (e.g., hexamethylmelamine and thiotepa), and CDK inhibitors (e.g., CDK inhibitors). 4 / 6 inhibitors, such as ribociclib, abecilib, or pebocillib; seliciclib; UCN-01, P1446A-05, PD-0332991; dinaciclib; P27-00; AT-7519; RGB286638; and SCH727965; alkyl sulfonates (e.g., busulfan); nitrosoureas (e.g., carmustine (BCNU) and analogues, as well as streptozotocin); trazenes—dacarbazine. (DTIC), antiproliferative / antimitotic antimetabolites (e.g., folic acid analogs, pyrimidine analogs (e.g., fluorouracil, fluorouracil, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole) and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, aspirin, suberoylanilide hydroxamic acid, vorinostat, LBH) 589. Romidesin, ACY-1215, and panobinostat; mTOR inhibitors (e.g., vistusertib, tesirobolimus, everolimus, fosfolimus, and sirolimus); KSP (Eg5) inhibitors (e.g., Array 520); DNA binding agents (e.g., Zalypsis®); PI3K inhibitors (e.g., PI3Kδ inhibitors (e.g., GS-1101 and TGR-1202), PI3K δ and γ inhibitors (e.g., CAL-130), copanlisib, alpelisib, and idelalisib; multi-kinase inhibitors (e.g., TG02 and sorafenib), hormones (e.g., estrogens) and hormone agonists (e.g., luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprorelin, and triptorelin)), BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GRN 163L), aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CS1) (e.g., elotuzumab), HSP90 inhibitors (e.g., 17AAG and KOS 953), P13K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Zarnestra™), anti-CD138 (e.g., BT062), Torcl / 2 specific kinase inhibitors (e.g., INK128), ER / UPR targets (e.g., MKC-3946), cFMS inhibitors (e.g., ARRY-382), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib and veliparib (ABT-888)), and BCL-2 antagonists.

[0209] In some implementations, the anticancer agent is selected from methicillin, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine®, sorafenib, or any analogue or derivative variant of the foregoing.

[0210] In some implementations, the anticancer agent is an ALK inhibitor. Non-limiting examples of ALK inhibitors include ceritinib, TAE-684 (NVP-TAE694), PF02341066 (crizotinib or 1066), alectinib, brigatinib, entrectinib, ensartinib (X-396), lorlatinib, ASP3026, CEP-37440, 4SC-203, TL-398, PLB1003, TSR-011, CT-707, TPX-0005, and AP26113. Other examples of ALK kinase inhibitors are described in Examples 3-39 of WO05016894.

[0211] In some embodiments, the anticancer agent is an inhibitor of a downstream member of a receptor tyrosine kinase (RTK) / growth factor receptor (e.g., SHP2 inhibitors (e.g., SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068), another SOS1 inhibitor (e.g., BI-1701963), a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, or an mTOR inhibitor (e.g., an mTORC1 inhibitor or an mTORC2 inhibitor)). In some embodiments, the anticancer agent is JAB-3312. In some embodiments, the anticancer agent is a Ras inhibitor (e.g., AMG 510, MRTX1257, LY349946, MRTX849, ARS-3248 (JNJ-74699157) or ARS-1620) or a Ras vaccine, or another therapeutic modality designed to directly or indirectly reduce the oncogenic activity of Ras.

[0212] In some embodiments, the Ras protein is wild-type. In some embodiments, the cancer contains a Ras mutation. In some embodiments, the mutation is selected from: (a) The following K-Ras mutants: G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L or G13V, and combinations thereof; (b) The following H-Ras mutants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N or G12R, and combinations thereof; and (c) The following N-Ras mutants: Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T, and combinations thereof; Or any combination of the foregoing (e.g., both K-Ras G12C and K-Ras G13C). In some embodiments, the cancer contains Ras mutations selected from the group consisting of: G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V.

[0213] In some embodiments, the therapeutic agents that can be combined with the compounds of this disclosure are inhibitors of the MAP kinase (MAPK) pathway (or "MAPK inhibitors"). MAPK inhibitors include, but are not limited to, one or more MAPK inhibitors described in Cancer (Basel) Sep 2015; 7(3): 1758-1784. For example, MAPK inhibitors may be selected from one or more of the following: trametinib, bemetinib, sulmetinib, cobimetinib, LERafAON (NeoPharm), ISIS 5132, vemurafenib, pimasetib, TAK733, RO4987655 (CH4987655), CI-1040, PD-0325901, CH5126766, MAP855, AZD6244, refatinib (RDEA 119 / BAY 86-9766), GDC-0973 / XL581, AZD8330 (ARRY-424704 / ARRY-704), RO5126766 (Roche, described in PLoS One. 25 November 2014; 9(11)) and GSK1120212. (or JTP-74057, described in Clin Cancer Res. 2011 Mar 1;17(5):989-1000).

[0214] In some implementations, the anticancer agent is a disruptor or inhibitor of the RAS-RAF-ERK, PI3K-AKT-TOR, or PI3K-AKT signaling pathway. PI3K / AKT inhibitors may include, but are not limited to, one or more PI3K / AKT inhibitors described in Cancer (Basel) September 2015; 7(3): 1758-1784. For example, PI3K / AKT inhibitors may be selected from one or more of the following: NVP-BEZ235, BGT226, XL765 / SAR245409, SF1126, GDC-0980, PI-103, PF-04691502, PKI-587, and GSK2126458.

[0215] In some implementations, the anticancer agent is a PD-1 or PD-L1 antagonist.

[0216] In some implementations, other therapeutic agents include EGFR inhibitors, IGF-1R inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immunotherapeutic agents.

[0217] IGF-1R inhibitors include linsitinib or its pharmaceutically acceptable salts.

[0218] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNAs. Suitable antibody inhibitors for EGFR include cetuximab (Erbitux®), panitumumab (Vectibix®), zalutumumab, nimotuzumab, and matuzumab. Other antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block the activation of EGFR by its natural ligands. Non-limiting examples of antibody-based EGFR inhibitors include those described in the following: Modjtahedi et al., Br. J. Cancer 1993, 67:247-253; Teramoto et al., Cancer 1996, 77:639-645; Goldstein et al., Clin. Cancer Res. 1995, 1:1311-1318; Huang et al., 1999, Cancer Res. 15:59(8):1935-40; and Yang et al., Cancer Res. 1999, 59:1236-1243. EGFR inhibitors may be monoclonal antibodies such as Mab E7.6.3 (Yang, 1999, ibid.) or Mab C225 (ATCC accession number HB-8508) or antibodies or antibody fragments thereof with binding specificity.

[0219] Small molecule antagonists of EGFR include gefitinib (Iressa®), erlotinib (Tarceva®), and lapatinib (TykerB®). See, for example, Yan et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005, 39(4):565-8; and Paez et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004, 304(5676):1497-500. Further non-limiting examples of small molecule EGFR inhibitors include the EGFR inhibitors described in the following patent publications and any of all pharmaceutically acceptable salts of these EGFR inhibitors: EP 0520722, EP 0566226, WO96 / 33980, U.S. Patent No. 5,747,498, WO96 / 30347, EP 0787772, WO97 / 30034, WO97 / 30044, WO97 / 38994, WO97 / 49688, EP837063, WO98 / 02434, WO97 / 38983, WO95 / 19774, WO95 / 19970, WO97 / 13771, WO98 / 02437, WO98 / 02438, WO97 / 32881, DE 19629652, WO98 / 33798, WO97 / 32880, WO97 / 32880, EP 682027, WO97 / 02266, WO97 / 27199, WO98 / 07726, WO97 / 34895, WO96 / 31510, WO98 / 14449, WO98 / 14450, WO98 / 14451, WO95 / 09847, WO97 / 19065, WO98 / 17662, U.S. Patent No. 5,789,427, U.S. Patent No. 5,650,415, U.S. Patent No. 5,656,643, WO99 / 35146, WO99 / 35132, WO99 / 07701 and WO92 / 20642. Other non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in Traxler et al., Exp. Opin. Ther. Patents 1998, 8(12):1599-1625. In some embodiments, the EGFR inhibitor is osimertinib.

[0220] MEK inhibitors include, but are not limited to, pimatetinib, selumetinib, cobimetinib (Cotellic®), trametinib (Mekinist®), and bimetinib (Mektovi®). In some embodiments, the MEK inhibitor targets a MEK mutation that is a type I MEK1 mutation selected from D67N, P124L, P124S, and L177V. In some embodiments, the MEK mutation is a type II MEK1 mutation selected from DE51-Q58, DF53-Q58, E203K, L177M, C121S, F53L, K57E, Q56P, and K57N.

[0221] PI3K inhibitors include, but are not limited to, wortmannin; 17-hydroxywortmannin analogs as described in WO06 / 044453; 4-[2-(1H-indazol-4-yl)-6-[[4-(methanesulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as pictilisib or GDC-0941, and described in WO09 / 036082 and WO09 / 055730); 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ) 235, and described in WO06 / 122806); (S)-l-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-N-morpholinylthieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxyprop-1-one (described in WO08 / 070740); LY294002 (2-(4-morpholinyl)-8-phenyl-4H-l-benzopyran-4-one (available from Axon Medchem); PI 103 hydrochloride (3-[4-(4-morpholinylpyridino[3',2':4,5]furano[3,2-d]pyrimidin-2-yl]phenol hydrochloride (available from Axon Medchem); PIK 75 (2-Methyl-5-nitro-2-[(6-bromoimidazolo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazine-benzenesulfonic acid monohydrochloride) (available from Axon Medchem); PIK 90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[l,2-c]quinazolin-5-yl)nicotinamide) (available from Axon Medchem); AS-252424 (5-[l-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-methyl-(Z)-ylidene]-thiazolidin-2,4-dione) (available from Axon Medchem); TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrimidin-4-one) (available from Axon Medchem); Medchem obtained); XL-765; and XL-147.Other PI3K inhibitors include demethoxyviridin, perifoxetine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI 00-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136.

[0222] AKT inhibitors include, but are not limited to, Akt-1-1 (inhibiting Aktl) (Barnett et al., Biochem. J. 2005, 385(Pt.2): 399-408); Akt-1-1,2 (inhibiting Akl and 2) (Barnett et al., Biochem. J. 2005, 385(Pt.2): 399-408); API-59CJ-Ome (e.g., Jin et al., Br. J. Cancer 2004, 91:1808-12); 1-H-imidazo[4,5-c]pyridyl compounds (e.g., WO 05 / 011700); indole-3-methanol and its derivatives (e.g., U.S. Patent No. 6,656,963; Sarkar and Li J Nutr. 2004, 134(12 Supplement):3493S-3498S); perifoxine (e.g., interfering with Akt membrane localization; Dasmahapatra et al., Clin. Cancer Res. 2004, 10(15):5242-52); phosphoinositol ether lipid analogs (e.g., Gills and Dennis Expert. Opin. Investig. Drugs 2004, 13:787-97); and triciribine (TCN or API-2 or NCI identification code: NSC 154020; Yang et al., Cancer Res. 2004, 64:4394-9).

[0223] mTOR inhibitors include, but are not limited to, ATP-competitive mTORC1 / mTORC2 inhibitors, such as PI-103, PP242, PP30; Torin 1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and its derivatives, including: tesimolimus (Torisel®); everolimus (Afinitor®; WO94 / 09010); and daforolimus. (Also known as deforolimus or AP23573); rapalogs, such as those described in WO98 / 02441 and WO01 / 14387, such as AP23464 and AP23841; 40-(2-hydroxyethyl)rapamycin; 40-[3-hydroxy(hydroxymethyl)methylpropionate]-rapamycin (also known as CC1779); 40-epi-(tetrazole)-rapamycin (also known as ABT578); 32-deoxyrapamycin; 16-pentyneoxy-32(S)-dihydrorapamycin; derivatives disclosed in WO05 / 005434; U.S. Patent No. 5,258 Derivatives disclosed in Nos. 389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842 and 5,256,790, and in WO94 / 090101, WO92 / 05179, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807 and WO2018204416; and phosphorus-containing rapamycin derivatives (e.g. WO05 / 016252). In some implementations, the mTOR inhibitor is a bisteric inhibitor (see, for example, WO2018204416, WO2019212990 and WO2019212991), such as RMC-5552.

[0224] BRAF inhibitors that can be used in combination with the compounds disclosed herein include, for example, vemurafenib, dabrafenib, and encorafenib. BRAF may contain three classes of BRAF mutations. In some embodiments, the three classes of BRAF mutations are selected from one or more of the following amino acid substitutions in human BRAF: D287H, P367R, V459L, G466V, G466E, G466A, S467L, G469E, N581S, N581I, D594N, D594G, D594A, D594H, F595L, G596D, G596R, and A762E.

[0225] MCL-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845. Myeloid leukemia-1 (MCL-1) protein is a key anti-apoptotic member of the B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 is closely associated with tumor progression and resistance, not only with traditional chemotherapy but also with targeted therapies, including BCL-2 inhibitors such as ABT-263.

[0226] In some implementations, other therapeutic agents are SHP2 inhibitors. SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, which contributes to a variety of cellular functions, including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 has two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. The two SH2 domains control the subcellular localization and functional regulation of SHP2. The molecule exists in an inactive, self-inhibiting conformation stabilized by a binding network involving residues from both the N-SH2 and PTP domains. Stimulation by cytokines or growth factors, such as those acting through receptor tyrosine kinases (RTKs), leads to the exposure of the catalytic site, resulting in enzymatic activation of SHP2.

[0227] SHP2 is involved in signal transduction via the RAS-mitogen-activated protein kinase (MAPK), JAK-STAT, or phosphatidylinositol 3-kinase-AKT pathways. Mutations in the PTPN11 gene and subsequently SHP2 have been identified in several human developmental disorders (e.g., Noonan syndrome and Leopard skin syndrome) and human cancers (e.g., juvenile myeloid leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung, and colon cancers). Some of these mutations destabilize the autoinhibitory conformation of SHP2 and promote autoactivation or enhanced growth factor-driven activation of SHP2. Therefore, SHP2 represents an attractive target for developing novel therapies for a wide range of diseases, including cancer. Combinations of SHP2 inhibitors (e.g., RMC-4550 or SHP099) with RAS pathway inhibitors (e.g., MEK inhibitors) have been shown to inhibit the proliferation of various cancer cell lines (e.g., pancreatic, lung, ovarian, and breast cancer) in vitro. Therefore, combination therapies involving SHP2 inhibitors and RAS pathway inhibitors could be a general strategy for preventing tumor resistance in various malignancies and could form the basis for triple-combination inhibitors with SOS1 inhibitors.

[0228] Non-limiting examples of such SHP2 inhibitors known in the art include: Chen et al., MolPharmacol. 2006, 70, 562; Sarver et al., J. Med. Chem. 2017, 62, 1793; Xie et al., J. Med. Chem. 2017, 60, 113734; and Igbe et al., Oncotarget, 2017, 8, 113734; and PCT applications: WO2015107493, WO2015107494, WO201507495, WO2016203404, WO2016203405, WO2016203406, WO2011022440, WO2017156397, WO2017079723, WO2017211 303. WO2012041524, WO2017211303, WO2019051084, WO2017211303, US20160030594, US20110281942, WO2010011666, WO2014113584, WO2014176488, WO2017100279, WO201 9051469, US8637684, WO2007117699, WO2015003094, WO2005094314, WO2008124815, WO2009049098, WO2009135000, WO2016191328, WO2016196591, WO2017078499, WO2017 210134, WO2018013597, WO2018129402, WO2018130928, WO20181309928, WO2018136264, WO2018136265, WO2018160731, WO2018172984 and WO2010121212, each of which is incorporated herein by reference.

[0229] In some embodiments, the SHP2 inhibitor binds to the active site. In some embodiments, the SHP2 inhibitor is a mixed irreversible inhibitor. In some embodiments, the SHP2 inhibitor binds to an allosteric site, such as a non-covalent allosteric inhibitor. In some embodiments, the SHP2 inhibitor is a covalent SHP2 inhibitor, such as an inhibitor targeting a cysteine ​​residue (C333) located outside the active site of the phosphatase. In some embodiments, the SHP2 inhibitor is a reversible inhibitor. In some embodiments, the SHP2 inhibitor is an irreversible inhibitor. In some embodiments, the SHP2 inhibitor is SHP099. In some embodiments, the SHP2 inhibitor is TNO155. In some embodiments, the SHP2 inhibitor is RMC-4550. In some embodiments, the SHP2 inhibitor is RCM-4630. In some embodiments, the SHP2 inhibitor is JAB-3068.

[0230] Proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib.

[0231] Immunotherapy includes, but is not limited to, monoclonal antibodies, immunomodulatory imides (IMiD), GITR agonists, genetically engineered T cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTE), and anti-PD-1 agents, anti-PDL-1 agents, anti-CTLA4 agents, anti-LAG1 agents, and anti-OX40 agents.

[0232] Immunomodulatory agents (IMiDs) are a class of immunomodulatory drugs containing imide groups (drugs that regulate immune responses). The IMiD class includes thalidomide and its analogues (lenalidomide, pomalidomide, and apremilast).

[0233] Exemplary anti-PD-1 antibodies and their methods of use are described in Goldberg et al., Blood 2007, 110(1):186-192; Thompson et al., Clin. Cancer Res. 2007, 13(6):1757-1761; and WO06 / 121168 A1, and elsewhere in this document.

[0234] GITR agonists include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as the GITR fusion proteins described in U.S. Patent Nos. 6,111,090, 8,586,023, WO2010 / 003118, and WO2011 / 090754; or, for example, those described in U.S. Patent Nos. 7,025,962, EP 1947183, 7,812,135, 8,388,967, 8,591,886, 7,618,632, and EP 1947183. Anti-GITR antibodies described in WO2011 / 028683, WO2013 / 039954, WO05 / 007190, WO07 / 133822, WO05 / 055808, WO99 / 40196, WO01 / 03720, WO99 / 20758, WO06 / 083289, WO05 / 115451 and WO2011 / 051726.

[0235] Another example of a therapeutic agent that can be used in combination with the compounds of this disclosure is an anti-angiogenic agent. Anti-angiogenic agents include, but are not limited to, chemical compositions synthesized in vitro, antibodies, antigen-binding regions, radionuclides, and combinations thereof. Anti-angiogenic agents can be agonists, antagonists, allosteric modulators, toxins, or more generally, can be used to inhibit or stimulate their targets (e.g., receptor or enzyme activation or inhibition), thereby promoting cell death or inhibiting cell growth. In some embodiments, one or more other therapies include an anti-angiogenic agent.

[0236] Anti-angiogenic agents can be MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase 11) inhibitors. Non-limiting examples of anti-angiogenic agents include rapamycin, tesiromolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of suitable COX-II inhibitors include alecoxib, valdecoxib, and rofecoxib. Examples of suitable matrix metalloproteinase inhibitors are described in WO96 / 33172, WO96 / 27583, WO98 / 07697, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, WO90 / 05719, WO99 / 52910, WO99 / 52889, WO99 / 29667, WO99007675, EP0606046, EP0780386, EP1786785, EP1181017, EP0818442, EP1004578 and US20090012085, as well as U.S. Patent Nos. 5,863,949 and 5,861,510. In some embodiments, the MMP-2 and MMP-9 inhibitors are inhibitors that inhibit little or no activity of MMP-1. In some embodiments, the MMP-2 and MMP-9 inhibitors are inhibitors that selectively inhibit either MMP-2 or AMP-9 relative to another matrix metalloproteinase (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors are AG-3340, RO 32-3555, and RS 13-0830.

[0237] Other exemplary anti-angiogenic agents include KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen-binding domains that specifically bind to kinase domain receptors), anti-VEGF agents (e.g., antibodies or antigen-binding domains that specifically bind to VEGF or soluble VEGF receptors or their ligand-binding domains) (e.g., VEGF-TRAP™), anti-VEGF receptor agents (e.g., antibodies or antigen-binding domains that specifically bind to them), EGFR inhibitors (e.g., antibodies or antigen-binding domains that specifically bind to them) (e.g., Vectibix® (panitumumab)), erlotinib (Tarceva®), anti-Ang1 and anti-Ang2 agents (e.g., antibodies or antigen-binding domains that specifically bind to them or their receptors (e.g., Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding domains that specifically bind to them). Other anti-angiogenic agents include Camphor, IL-8, β-FGF, Tek antagonists (US2003 / 0162712; US6,413,932), anti-TWEAK agents (e.g., those that specifically bind to antibodies or antigen-binding domains, or soluble TWEAK receptor antagonists; see US6,727,225), and ADAM unintegrin domains (US...) used to antagonize the binding of integrins to their ligands. 2002 / 0042368), antibodies or antigen-binding regions that specifically bind to anti-eph receptors or anti-hepatocyte ligands (US Patent Nos. 5,981,245, 5,728,813, 5,969,110, 6,596,852, 6,232,447, 6,057,124 and their family members), as well as anti-PDGF-BB antagonists (e.g., antibodies or antigen-binding regions that specifically bind to PDGF-BB ligands) and antibodies or antigen-binding regions that specifically bind to PDGF-BB ligands, and PDGFR kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to them). Other anti-angiogenic agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 0770622); pegaptaniboctasodium (Gilead Sciences, USA); alphastatin (BioActa, UK); M-PGA (Celgene, USA, US 5712291); ilomastat (Arriva, USA, US5892112); emaxanib (Pfizer, USA, US 5792783); vatalanib (Novartis, Switzerland); and 2-methoxyestradiol (EntreMed, USA).TLC ELL-12 (Elan, Ireland); anecrolave ​​acetate (Alcon, USA); α-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); anti-Vn Mab (Crucell, Netherlands); DAC anti-angiogenic agent (ConjuChem, Canada); angiogenesis inhibitor (Angiocidin) (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP 0970070); ARGENT technology (Ariad, USA); YIGSR-Stealth (Johnson & Johnson, USA); fibrinogen E fragment (BioActa, UK); angiogenesis inhibitor (Trigen, UK); TBC-1635 (Encysive Pharmaceuticals, USA); SC-236 (Pfizer, USA); ABT-567 (Abbott, USA); Metastatin (EntreMed, USA); Mammary filament inhibitor (maspin) (Sosei, Japan); 2-Methoxyestradiol (Oncology Sciences Corporation, USA); ER-68203-00 (IV AX, USA); BeneFin (Lane Labs, USA); Tz-93 (Tsumura, Japan); TAN-1120 (Takeda, Japan); FR-111142 (Fujisawa, Japan, JP 02233610); Platelet-4 (RepliGen, USA, EP 407122); Vascular endothelial growth factor antagonist (Borean, Denmark); Bevacizumab (pINN) (Genentech, USA); Angiogenesis inhibitor (SUGEN, USA); XL 784 (Exelixis, USA); XL 647 (Exelixis, USA); second-generation α5β3 integrin MAb (Applied Molecular Evolution, USA and Medlmmune, USA); enzartolin hydrochloride (Lilly, USA);CEP 7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC 1 (Genoa Institute of Cancer Research, Italy); rBPI 21 and BPI-derived anti-angiogenic agents (XOMA, USA); PI 88 (Progen, Australia); Cilengiptide (Merck KGaA, Germany, Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA); AVE 8062 (Ajinomoto, Japan); AS 1404 (Cancer Research Laboratory, New Zealand); SG 292 (Telios, USA); Endostatin (Boston Children's Hospital, USA); ATN 161 (Attenuon, USA); 2-Methoxyestradiol (Boston Children's Hospital, USA); ZD 6474 (AstraZeneca, UK); ZD 6126 (Angiogene Pharmaceuticals, UK); PPI 2458 (Praecis, USA); AZD 9935 (AstraZeneca, UK); AZD 2171 (AstraZeneca, UK); Vataranib (pINN) (Novartis, Switzerland and Schering AG, Germany); Tissue factor pathway inhibitor (EntreMed, USA); Pinn (Gilead Sciences, USA); Xanthorrhizol (Yonsei University, South Korea); Gene-based VEGF-2 vaccine (Scripps Clinic and Research Foundation, USA); SPV5.2 (Supratek, Canada); SDX 103 (University of California, San Diego, USA); PX 478 (ProlX, USA); METASTATIN (EntreMed, USA);Troponin I (Harvard University, USA); SU 6668 (SUGEN, USA); OXI 4503 (OXiGENE, USA); o-guanidine (Dimensional Pharmaceuticals, USA); motuporamine C (British Columbia University, Canada); CDP 791 (Celltech Group, UK); Atemod (pINN) (GlaxoSmithKline, UK); E 7820 (Eisai, Japan); CYC 381 (Harvard University, USA); AE 941 (Aeterna, Canada); Angiogenesis vaccine (EntreMed, USA); urokinase plasminogen activator inhibitor (Dendreon, USA); oglufanide (pINN) (Melmotte, USA); HIF-1α inhibitor (Xenova, USA). UK); CEP5214 (Cephalon, USA); BAY RES 2622 (Bayer, Germany); Angiogenesis Inhibitor (InKine, USA); A6 (Angstrom, USA); KR 31372 (Korea Research Institute of Chemical Technology, South Korea); GW 2286 (GlaxoSmithKline, UK); EHT 0101 (ExonHit, France); CP 868596 (Pfizer, USA); CP 564959 (OSI, USA); CP 547632 (Pfizer, USA); 786034 (GlaxoSmithKline, UK); KRN 633 (Kirin Brewery, Japan); 2-methoxyestradiol tumor angiogenesis inhibitory peptide intraocular drug delivery system (anginex) (Maastricht University, Netherlands and Minnesota University, USA);ABT 510 (Abbott, USA); AAL 993 (Novartis, Switzerland); VEGI (ProteomTech, USA); Tumor necrosis factor alpha inhibitor; SU 11248 (Pfizer, USA and SUGEN USA); ABT518 (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Children's Hospital, USA and EntreMed, USA); KDR MAb (ImClone Systems, USA); α5β MAb (ProteinDesign, USA); KDR kinase inhibitor (Celltech Group, UK and Johnson & Johnson, USA); GFB116 (South Florida University, USA and Yale University, USA); CS 706 (Sankyo, Japan); comprehendingin A4 prodrug (Arizona State University, USA); chondroitinase AC (IBEX, Canada); BAY RES 2690 (Bayer, Germany); AGM 1470 (Harvard University, USA, Takeda, Japan, and TAP, USA); AG 13925 (Agouron, USA); Tetrathiomolybdate (University of Michigan, USA); GCS 100 (Wayne State University, USA); CV 247 (Ivy Medical, UK); CKD 732 (Chong Kun Dang, South Korea); Irsogladine (Nippon Shinyaku, Japan); RG 13577 (Aventis, France); WX 360 (Wilex, Germany); Squalamine (Genaera, USA); RPI 4610 (Sirna, USA); Heparanase inhibitor (InSight, Israel); KL 3106 (Kolon, South Korea); and Honokiol (Emory University, USA);ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK 229561 (Novartis, Switzerland and Schering AG, Germany); XMP 300 (XOMA, USA); VGA 1102 (Taisho, Japan); VE cadherin 2 antagonist (ImClone Systems, USA); Vasostatin (National Institutes of Health, USA); Flk-1 (ImClone Systems, USA); TZ 93 (Tsumura, Japan); TumStatin (Beth Israel Hospital, USA); truncated soluble FLT 1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA); Tie-2 ligand (Regeneron, USA); and thrombospondin 1 inhibitor (Allegheny Health, Education and Research Foundation, USA).

[0238] Other examples of therapeutic agents that can be used in combination with the compounds disclosed herein include agents (e.g., antibodies, antigen-binding domains, or soluble receptors) that specifically bind to growth factors and inhibit their activity, such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor) and antibodies or antigen-binding domains that specifically bind to their receptor c-Met.

[0239] Another example of a therapeutic agent that can be used in combination with the compounds disclosed herein is an autophagy inhibitor. Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafloxacin A1, 5-amino-4-imidazolamide riboside (AICAR), okadaic acid, autophagy-inhibiting algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vincristine. Additionally, antisense or siRNAs that inhibit protein expression, including but not limited to ATG5 (which is involved in autophagy), may also be used. In some embodiments, one or more other therapies include autophagy inhibitors.

[0240] Another example of a therapeutic agent that can be used in combination with the compounds disclosed herein is an antitumor agent. In some embodiments, one or more other therapies include an antitumor agent. Non-limiting examples of antitumor agents include acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, hexamethylmelamine, aifostine, aminolevulinic acid, amrubicin, acridine, anagrelide, anastrozole, ancer, ancestim, arglabin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, and cytarabine. ocfosfate), DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, deoxyfluorouridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, diclofenac (HIT), interferon-alpha, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, beta-epoetinbeta), etoposide phosphate, exemestane, escitaline, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, formustin, gallium nitrate, gemcitabine, gemtuzumab / ozogamicin, tegafur (gimeracil / oteracil / tegafur combination), glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronic acid Interferon (acid), Idarubicin, Imiquimod, Interferon α, Natural Interferon α, Interferon α-2, Interferon α-2a, Interferon α-2b, Interferon α-Nl, Interferon α-n3, Interferon αcon-1, Natural Interferon α, Interferon β, Interferon β-la, Interferon β-lb, Interferon γ, Natural Interferon γ-la, Interferon γ-lb, Interleukin-1β, Iobenguane, Irinotecan, Isopridine, Lanreotide, LC 9018 (Yakult), Leflunomide, Lenograstim, Lentinan sulfate, Letrozole, Leukocyte α Interferon, Leuprorelin, Levamisole +Fluorouracil, liarozole, lobaplatin, chlordamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mismatched double-stranded RNA, mitoxone, dibromoceroxyl, mitoxone, molgramostim, nafarelin, naloxone +pentazocine, nartograstim, nedaplatin, nilutet, noscapine, novel erythropoiesis-stimulating protein, NSC631570, octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronate, pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit anti-thymocyte polyclonal antibody, peginterferon alfa-2a, porfimer sodium, rranoxifene, raltitrexed, rasburiembodiment, rhenium Re 186 etidronate, RII retinamide, rituximab, romurtide, samarium 153Sm (samarium(153 Sm) lexidronam), sargramostim, sobuzoxane, sonermin, strontium chloride-89, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecoxide, thalidomide, thymalfasin, thyroid-stimulating hormone alpha, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan, retinoic acid, tralostane, trimethoprim, triptorelin, natural tumor necrosis factor alpha, ubenmexican, bladder cancer vaccine, Maruyama vaccine Vaccines, melanoma lysate vaccines, valrubicin, verteporfin, vinorelbine, virulizin, zinostatinstimalamer, or zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotides, bcl-2 (Genta), APC 8015 (Dendreon), decitabine, dexaminoglutethimide, diazinon, EL 532(Elan), EM 800 (Endorecherche), enuracil, etanidazole, fenretinide, filgrastim, SD01 (Amgen), fulvestrant, galocitabine, gastrin-17 immunogen, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastine, IM 862 (Cytran), interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), individual genotype 105AD7 MAb (CRC) Technology), individual genotype CEA MAb (Trilex), LYM-1-iodine-131 MAb (Techni clone), polymorphic epithelial mucin-yttrium-90 MAb (Antisoma), marimastat, menogaril, mitumomab, motexafingadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering)The options include the Institute, the melanoma tumor lysing agent vaccine (New York Medical College), the viral melanoma cell lysing agent vaccine (Royal Newcastle Hospital), or valspodar.

[0241] Other examples of therapeutic agents that can be used in combination with the compounds disclosed herein include ipilimumab (Yervoy®); trimemumab; galiximab; nivolumab, also known as BMS-936558 (Opdivo®); pembrolizumab (Keytruda®); avelumab (Bavencio®); AMP224; BMS-936559; MPDL3280A, also known as RG7446; MEDI-570; AMG557; MGA271; IMP321; BMS-663513; PF-05082566; CDX-1127; and anti-OX40 (Providence Health). Services); huMAbOX40L; atacicept; CP-870893; lucarumumab; dacetuzumab; muromonab-CD3; ipilumab; MEDI4736 (Imfinzi®); MSB0010718C; AMP224; adalimumab (Humira®); ado-trastuzumab (Kadcyla®); aflibercept (Eylea®); Camppath®; basiliximab (Simulect®); belimumab Benlysta®; Simulect®; Benlysta®; Adcetris®; Ilaris®; Cimzia®; Zenapax®Daratumumab (Darzalex®); denosumab (Prolia®); eculizumab (Soliris®); efalizumab (Raptiva®); gemtuzumab / omabozogamicin (Mylotarg®); golimumab (Simponi®); zevalin®; infliximab (Remicade®); motavizumab (Numax®); natalizumab (Tysabri®); obinutuzumab (Gazyva®); ofatumumab (Arzerra®); omalizumab (Xolair®); palivizumab (Synagis®); pertuzumab (Perjeta®); pertuzumab (Perjeta®); ranibizumab (Lucentis®); raxibacumab (Abthrax®); tocilizumab (Actemra®); tosimoumab; tosimoumab-i-131; tosimoumab and tosimoumab-i-131 (Bexxar®); ustekinumab (Stelara®); AMG102; AMG 386; AMG 479; AMG 655; AMG 706; AMG 745; and AMG 951.

[0242] In some embodiments, other compounds used in combination therapy with the compounds disclosed herein are selected from the group consisting of: CDK4 / 6 inhibitors (e.g., abecilibi, pebocilib, or ribociclib), KRAS:GDP G12C inhibitors (e.g., AMG 510, MRTX 1257) or other mutant Ras:GDP inhibitors, KRAS:GTP G12C inhibitors or other mutant Ras:GTP inhibitors, MEK inhibitors (e.g., refatinib, selumetinib, trametinib, or cobimetinib), SHP2 inhibitors (e.g., TNO155, RMC-4630), ERK inhibitors, and RTK inhibitors (e.g., EGFR inhibitors).

[0243] In some embodiments, other compounds used in combination therapy with the compounds of this disclosure are selected from the group consisting of: ABT-737, AT-7519, carfilzomib, cobimetinib, danusertib, dasatinib, doxorubicin, GSK-343, JQ1, MLN-7243, NVP-ADW742, paclitaxel, pebocillin, and volasertib. In some embodiments, other compounds used in combination therapy with the compounds of this disclosure are selected from the group consisting of: neratinib, acetinib, and reversine.

[0244] Depending on the condition being treated, the compounds described herein may be used in combination with the agents disclosed herein or other suitable agents. Therefore, in some embodiments, one or more of the compounds disclosed herein will be administered co-administered with other therapeutic agents described herein. When used in combination therapy, the compounds described herein may be administered simultaneously or separately with a second agent. Such combination administration may include simultaneous administration in the same dosage form, simultaneous administration in separate dosage forms, and separate administration of two agents. That is, the compounds described herein and any of the agents described herein may be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds disclosed herein and any of the therapies described herein may be administered simultaneously, wherein the two agents are present in separate formulations. In another alternative, the compounds disclosed herein may be administered first, followed by any of the therapies described herein, or vice versa. In some embodiments of the single-administration regimen, the compounds disclosed herein and any of the therapies described herein are administered at intervals of minutes, hours, or days.

[0245] In some embodiments, the combination therapy employs two therapeutic agents: one is a compound of this disclosure and the second is selected from the therapeutic agents described herein. In some embodiments, the combination therapy employs three therapeutic agents: one is a compound of this disclosure and the other two are selected from the therapeutic agents described herein. In some embodiments, the combination therapy employs four or more therapeutic agents: one is a compound of this disclosure and the other three are selected from the therapeutic agents described herein.

[0246] In some embodiments of any of the methods described herein, a first therapy (e.g., a compound of this disclosure) and one or more other therapies are administered simultaneously or sequentially. The first therapy may be administered immediately before or after one or more other therapies, for a maximum of 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or for a maximum of 1-7, 1-14, 1-21, or 1-30 days.

[0247] In this section, all pharmaceutical preparations described in the references are incorporated by way of citation, whether explicitly stated or not.

[0248] 6. Reagent test kit

[0249] Another aspect of this disclosure provides a kit comprising a compound of any of the formulas described above or a pharmaceutical composition comprising a compound of any of the formulas described above. In addition to compounds of any of the formulas described above or pharmaceutical compositions thereof, the kit may also comprise a diagnostic agent or a therapeutic agent. The kit may also include instructions for use in diagnostic or therapeutic methods. In some embodiments, the kit comprises a compound of any of the formulas described above or a pharmaceutical composition thereof and a diagnostic agent. In other embodiments, the kit comprises a compound of any of the formulas described above or a pharmaceutical composition thereof.

[0250] In yet another embodiment, this disclosure includes a kit suitable for performing the treatment methods described herein. In one embodiment, the kit contains a first dosage form containing one or more of the compounds of this disclosure in an amount sufficient to perform the methods of this disclosure. In another embodiment, the kit contains one or more of the compounds of this disclosure in an amount sufficient to perform the methods of this disclosure, as well as a container for the dosage and a container for the dosage.

[0251] 7. preparation

[0252] Compounds of any of the formulas described above can be prepared using the general and specific methods described below, employing common knowledge of those skilled in the art of synthetic organic chemistry. Such common knowledge can be found in standard reference books, such as... Comprehensive Organic Chemistry , Barton and Ollis, eds., Elsevier; Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Larock, John Wiley and Sons; and Compendium of Organic Synthetic Methods Volumes I-XII (published by Wiley-Interscience). The starting materials used in this paper are commercially available or can be prepared by conventional methods known in the art.

[0253] In the preparation of compounds of any of the formulas described above, it should be noted that some of the preparation methods described herein may require protection of distal functional groups (e.g., primary amines, secondary amines, and carboxyl groups in any of the precursors described above). The need for such protection will vary depending on the nature of the distal functional groups and the conditions of the preparation method. The need for such protection is readily determined by those skilled in the art. The use of such protection / deprotection methods is also within the capabilities of those skilled in the art. For a general description of protecting groups and their uses, see Greene, Protective Groups in Organic Synthesis , John Wiley & Sons, New York, 1991.

[0254] For example, some compounds contain primary amine or carboxylic acid functional groups that, if left unprotected, may interfere with reactions at other sites on the molecule. Therefore, such functional groups can be protected with appropriate protecting groups that can be removed in subsequent steps. Suitable protecting groups for amines and carboxylic acids include those commonly used in peptide synthesis (e.g., N-tert-butoxycarbonyl (Boc), benzooxycarbonyl (Cbz), and 9-fluorenylmethoxycarbonyl (Fmoc) for amines, and lower alkyl or benzyl esters for carboxylic acids), which generally do not react chemically under the described reaction conditions and can usually be removed without chemically altering other functional groups in compounds of any of the formulas described above.

[0255] The procedures described below are intended to provide a general description of the methods used in the preparation of the compounds disclosed herein. Some compounds of this disclosure may contain stereochemical names (…). R )or( S ( ) a single or multiple chiral centers. It will be apparent to those skilled in the art that all synthetic transformations can be carried out in a similar manner, regardless of whether the material is enantiomerically enriched or racemic. Furthermore, the resolution of the desired optically active material can be performed at any desired point in the sequence using well-known methods, such as those described herein and in the chemical literature.

[0256] Example

[0257] abbreviation

[0258] ACN Acetonitrile

[0259] BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)

[0260] BPOD (phenylphosphodichloro)

[0261] DAST diethylaminosulfur trifluoride

[0262] DCM dichloromethane

[0263] DIEA N,N-Diisopropylethylamine

[0264] DIPEA N,N-Diisopropylethylamine

[0265] DMAP 4-Dimethylaminopyridine

[0266] DMF N,N-dimethylformamide

[0267] DMSO (dimethyl sulfoxide)

[0268] Dppf 1,1'-bis(diphenylphosphino)ferrocene

[0269] EA (ethyl acetate)

[0270] EtOAc (ethyl acetate)

[0271] FA Formic acid

[0272] HATU N-[(dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin-l-yl] [Methylene]-N-methylmethylammonium hexafluorophosphate N oxide

[0273] HPLC (High-Performance Liquid Chromatography)

[0274] i-PrOH isopropanol

[0275] LC-MS (Liquid Chromatography-Mass Spectrometry)

[0276] LiHMDS Bis(trimethylsilyl)aminolithium

[0277] MeOH (methanol)

[0278] Mn(TMHD)3 Tris(Dapeptylmethane)manganese

[0279] (III)Pd2(dba)3 tris(diphenylmethylacetone)dipalladium(0)

[0280] Pd(dppf)Cl2 dichloro[l,l'-bis(diphenylphosphino)ferrocene]palladium

[0281] PE petroleum ether

[0282] Preparative HPLC and Preparative-grade High Performance Liquid Chromatography

[0283] RockPhos Pd G3 [(2-di-tert-butylphosphino-3-methoxy-6-methyl-2′,4′,6′-triisocyanate] [propyl-1,1′-biphenyl)-2-(2-aminobiphenyl)]palladium(II)methanesulfonate

[0284] RT room temperature

[0285] Ruphos 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl

[0286] t -BuXPhos-Pd-G3 [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2- [(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate

[0287] TEA Triethylamine

[0288] THF Tetrahydrofuran

[0289] Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran

[0290] Part 1. Synthetic methods for preparing intermediates

[0291] Intermediate 72

[0292] Step 1: A solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.00 g, 3.23 mmol) in HCl (5.0 mL, 4.0 M in EtOAc, 20.0 mmol) was stirred at 25 °C for 4 hours. The reaction mixture was concentrated under vacuum to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-1,2,3,6-tetrahydropyridine (500 mg, 74% yield). The crude product was used directly in the next step without further purification. LC-MS: m / z [M+H] + 210.1.

[0293] Step 2: Triethylamine (43.6 mg, 430 μmol, 60.0 μL) was added to a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-1,2,3,6-tetrahydropyridine (30.0 mg, 143 μmol) in dichloromethane (5.0 mL) at 0 °C, followed by the addition of N,N-dimethylcarbamoyl chloride (15.4 mg, 143 μmol, 13.2 μL). The mixture was stirred at 0 °C for 2.5 h, and then diluted with 5.0 mL of water. The mixture was extracted with DCM (3 × 20 mL). The organic phase was washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-3,6-dihydro-2H-pyridine-1-carboxamide (30.0 mg, 75% yield) as a yellow solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 281.1.

[0294] Intermediate 73

[0295] Step 1: Methanol (200 mg, 6.24 mmol, 253 μL) was added to a stirred solution of triphosgene (1.85 g, 6.24 mmol) in dichloromethane (25.0 mL) at 0 °C. The mixture was stirred at 0 °C for 10 min, followed by dropwise addition of dichloromethane (1.0 mL) containing pyridine (1.48 g, 18.7 mmol, 1.5 mL). The mixture was stirred at 5 °C for 1 h, then diluted with dichloromethane (25.0 mL) and washed with water (3 × 5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a crude product (300 mg, 51% yield) as a liquid oil, which was used in the next step without further purification.

[0296] Step 2: Triethylamine (64.3 mg, 635 μmol, 88.5 μL) was added to a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine (44.3 mg, 212 μmol) in dichloromethane (5.0 mL) at 0 °C, followed by the addition of methyl chloroformate (20.0 mg, 212 μmol). The mixture was stirred at 0 °C for 2.5 hours, and then diluted with water (10.0 mL). The mixture was extracted with DCM (3 × 20 mL), washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (30.0 mg, 53% yield) as a yellow solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 268.1.

[0297] Intermediate 74

[0298] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-1,2,3,6-tetrahydropyridine (100 mg, 478 μmol), 2-bromooxazole (70.8 mg, 478 μmol), and K₂CO₃ (198.3 mg, 1.43 mmol) was dissolved in DMF (3.0 mL) at 25 °C. The mixture was heated to 80 °C and stirred at that temperature for 4 hours, followed by filtration. The filtrate was concentrated under vacuum, and the residue was purified by preparative HPLC with MeCN / water to give 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-3,6-dihydro-2H-pyridin-1-yl]oxazole (20.0 mg, 15% yield) as a pale yellow solid. LC-MS: m / z [M+H] + 277.2.

[0299] Intermediate 75

[0300] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine (200 mg, 957 μmol), 2-hydroxyacetic acid (72.7 mg, 957 μmol, 57.3 μL), and DIPEA (371 mg, 2.87 mmol, 500 μL) was dissolved in THF (5.0 mL) at 0 °C, followed by the slow addition of HATU (363.7 mg, 957 μmol) at 0 °C. The reaction mixture was heated to 25 °C and stirred at that temperature for 4 hours. The solvent was removed under vacuum, and the residue was purified by rapid silica gel column chromatography and further purified by preparative HPLC with MeCN / water to give 2-hydroxy-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)-3,6-dihydro-2H-pyridin-1-yl]acetone (100 mg, 39% yield) as a white solid. LC-MS: m / z [M+H] + 268.2.

[0301] Intermediate 76

[0302] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentan-2-yl)cyclohexyl-3-en-1-amine (30.0 mg, 134 μmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (31.2 mg, 134 μmol, 19.4 μL), and potassium carbonate (55.8 mg, 403 μmol) was dissolved in dioxane (5.0 mL) at 25 °C. The reaction mixture was heated to 80 °C and stirred at that temperature for 4 hours. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC with MeCN / water to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentan-2-yl)-N-(2,2,2-trifluoroethyl)cyclohexyl-3-en-1-amine (30.0 mg, 73% yield) as a pale yellow solid. LC-MS: m / z [M+H] + 306.2.

[0303] Intermediate 77

[0304] A mixture of 2-[4-(bromomethyl)-3-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (50.0 mg, 159 μmol) and methylamine (2.0 mL, 7.0 M in MeOH, 14 mmol) in methanol was stirred at 25 °C for 2 hours. The solvent was then removed under vacuum to give 1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane-2-yl)phenyl]-N-methyl-methylamine (30.0 mg, 71% yield), a pale yellow oil, which was used in the next step without further purification. LC-MS: m / z [M+H] + 266.2.

[0305] Intermediate 78

[0306] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-1,2,3,6-tetrahydropyridine (50.0 mg, 239 μmol), 3-bromopropionitrile (32.0 mg, 239 μmol, 19.8 μL), and potassium carbonate (99.2 mg, 717 μmol) was dissolved in dioxane (5.0 mL) at 25 °C. The reaction mixture was heated to 60 °C and stirred at that temperature for 12 hours, after which it was used directly in the next step without further purification. LC-MS: m / z [M+H] + 263.1.

[0307] Intermediate 79

[0308] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-1,2,3,6-tetrahydropyridine (50.0 mg, 239 μmol), 1-bromo-2-fluoroethane (30.4 mg, 239 μmol), and potassium carbonate (99.2 mg, 717 μmol) was dissolved in dioxane (5.0 mL) at 25 °C. The reaction mixture was heated to 60 °C and stirred at that temperature for 12 h, and then used directly in the next step without further purification. LC-MS: m / z [M+H] + 256.1.

[0309] Intermediate 80

[0310] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-1,2,3,6-tetrahydropyridine (50.0 mg, 239 μmol), 2-bromo-5-methyl-1,3,4-oxadiazole (39.0 mg, 239 μmol), and potassium carbonate (99.0 mg, 717 μmol) was dissolved in dioxane (5 mL) at 25 °C. The reaction mixture was heated to 60 °C and stirred at that temperature for 3 hours. The solvent was then removed under vacuum to give 2-methyl-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-1,3,4-oxadiazole (30.0 mg, 43% yield), which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 292.1.

[0311] Intermediate 81

[0312] Step 1: A mixture of N-methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentan-2-yl)cyclohex-3-en-1-yl]carbamate tert-butyl (40.0 mg, 119 μmol) in HCl (3.0 mL, 4.0 M in EtOAc, 12 mmol) was stirred at 25 °C for 4 hours. The reaction mixture was then concentrated under vacuum to give N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentan-2-yl)cyclohex-3-en-1-amine (20.0 mg, 71% yield), which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 238.1.

[0313] Step 2: Triethylamine (25.6 mg, 253 μmol, 35.3 μL) was added to a mixture of N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)cyclohexyl-3-en-1-amine (20.0 mg, 84.3 μmol) in dichloromethane (5.0 mL) at 0 °C, followed by the addition of acetyl chloride (7.9 mg, 101 μmol, 6.1 μL). The mixture was stirred at 0 °C for 2.5 h, and then diluted with 5.0 mL of water. The mixture was extracted with DCM (3 × 20 mL). The combined organic phases were washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give N-methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentan-2-yl)cyclohex-3-en-1-yl]acetamide (20.0 mg, 85% yield) as a yellow solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 280.2.

[0314] Intermediate 82

[0315] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentan-2-yl)cyclohexyl-3-en-1-amine (30.0 mg, 134 μmol), 2-bromo-5-methyl-1,3,4-oxadiazole (21.9 mg, 134 μmol), and potassium carbonate (55.7 mg, 403 μmol) was dissolved in dioxane (5.0 mL). The reaction mixture was heated to 60 °C and stirred at that temperature for 3 hours. The solvent was then removed under vacuum to give 5-methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentan-2-yl)cyclohexyl-3-en-1-yl]-1,3,4-oxadiazole-2-amine (15.0 mg, 37% yield), which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 306.2.

[0316] Intermediate 83

[0317] Triethylamine (19.2 mg, 190 μmol, 26.5 μL) was added to a mixture of N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)cyclohexyl-3-en-1-amine (15.0 mg, 63.3 μmol) in dichloromethane (5.0 mL) at 0 °C, followed by the addition of 2-cyanoacetyl chloride (6.6 mg, 63 μmol). The mixture was stirred at the stated temperature for 2.5 h, then diluted with 5.0 mL of water and extracted with DCM (3 × 20 mL). The organic phase was washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-cyano-N-methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentan-2-yl)cyclohex-3-en-1-yl]acetamide (10.0 mg, 52% yield) as a yellow solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 305.2.

[0318] Intermediate 84

[0319] Lithium bis(trimethylsilyl)amino (0.83 mL, 1.0 M in THF, 830 μmol) was added to a stirred solution of 1,4-dioxaspiro[4.5]dec-8-one (86.2 mg, 552 μmol) and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethanesulfonyl)methanesulfonamide (237 mg, 662 μmol) in THF (10.0 mL) at -78 °C. The mixture was stirred at said temperature for 2 hours, then quenched with water and extracted with diethyl ether. The organic phase was dried over MgSO4 and the solvent was removed under vacuum to give 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonic acid (50.0 mg, 31% yield) as a yellow oil, which was used directly in the next step without further purification.

[0320] Intermediate 85

[0321] Lithium bis(trimethylsilyl)amino (0.90 mL, 1.0 M in THF, 900 μmol) was added to a stirred solution of 1-azaspiro[4.5]decane-2,8-dione (100 mg, 598 μmol) and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethanesulfonyl)methanesulfonamide (214 mg, 598 μmol) in THF (10.0 mL) at -78 °C. The mixture was stirred at said temperature for 2 hours, then quenched with water and extracted with diethyl ether. The organic phase was dried over MgSO4 and the solvent was removed under vacuum to give trifluoromethanesulfonic acid (2-oxo-1-azaspiro[4.5]dec-7-en-8-yl) ester (50.0 mg, 28% yield) as a yellow oil, which was used directly in the next step without further purification.

[0322] Intermediate 86

[0323] A mixture of 2-bromo-5-iodopyridine (100 mg, 352 μmol), 2-methylbut-3-yn-2-ol (29.6 mg, 352 μmol, 34.3 μL), bis(triphenylphosphine)palladium(II) dichloride (24.7 mg, 35.2 μmol), cuprous iodide (3.4 mg, 18 μmol), and triethylamine (107 mg, 1.06 mmol, 147 μL) was dissolved in toluene (10.0 mL) at 25 °C. The reaction mixture was heated to 110 °C and stirred at that temperature for 3 hours. The solvent was removed under vacuum, and the residue was purified by rapid silica gel column chromatography, eluting with EtOAc / petroleum ether (EtOAc increased from 0% to 30%), to give 4-(6-bromo-3-pyridyl)-2-methylbut-3-yn-2-ol (50.0 mg, 60% yield) as a yellow solid. LC-MS: m / z [M+H] + 240.2.

[0324] Intermediate 87

[0325] Step 1: A mixture of 1,4-dioxaspiro[4.5]dec-8-one (500 mg, 3.20 mmol), 4-aminobutyric acid (495 mg, 4.80 mmol), triethylamine (972 mg, 9.60 mmol, 1.34 mL), and sodium triacetoxyborohydride (1.02 g, 4.80 mmol) in 1,2-dichloroethane (10.0 mL) was stirred at 25 °C for 24 hours. The reaction mixture was quenched with water and extracted with dichloromethane (3 × 80 mL). The organic layer was dried over MgSO4, filtered, and the solvent was removed under vacuum to give 1-(1,4-dioxaspiro[4.5]dec-8-yl)pyrrolidine-2-one (500 mg, 69% yield) as a light brown oil, which was used in the next step without further purification. LC-MS: m / z [M+H] + 226.2.

[0326] Step 2: A mixture of 1-(1,4-dioxaspiro[4.5]dec-8-yl)pyrrolidine-2-one (500 mg, 2.22 mmol) in hydrochloric acid (10.0 mL, 4.0 mol / L in EtOAc, 40.0 mmol) was stirred at 25 °C for 8 hours. The solvent was then removed under vacuum to give a yellow solid of 1-(4-oxocyclohexyl)pyrrolidine-2-one (300 mg, 75% yield), which was used in the next step without further purification. LC-MS: m / z [M+H] + 182.2.

[0327] Step 3: Lithium bis(trimethylsilyl)amino (0.83 mL, 1.0 M in THF, 830 μmol) was added to a stirred solution of 1,4-dioxaspiro[4.5]dec-8-one (86.2 mg, 552 μmol) and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethanesulfonyl)methanesulfonamide (237 mg, 662 μmol) in THF (10.0 mL) at -78 °C. The mixture was stirred at said temperature for 2 hours, then quenched with water and extracted with diethyl ether. The organic phase was dried over MgSO4 and the solvent was removed under vacuum to give 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonic acid (50.0 mg, 31% yield) as a yellow oil, which was used directly in the next step without further purification.

[0328] Intermediate 88

[0329] Step 1: TEA (396 mg, 3.9 mmol, 545 μL) was added to a stirred solution of 5-bromo-2-fluoro-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]pyridine-3-carboxamide (400 mg, 978 μmol) and oxetane-3-amine (85.8 mg, 1.2 mmol) in DMSO (5.0 mL). The mixture was stirred at room temperature for 10 min, then quenched with 1.0 mL of water. The solvent was removed under vacuum, and the residue was purified by preparative HPLC to give 6-bromo-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-(hydroxymethyl)-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (300 mg, 66% yield) as a yellow oil. LC-MS: m / z [M+H] + 462.9, 464.9.

[0330] Step 2: DAST (209 mg, 1.30 mmol, 172 μL) was slowly added to a stirred solution of 6-bromo-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-(hydroxymethyl)-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (300 mg, 649 μmol) in DCM (10 mL). The mixture was stirred at 25 °C for 4 hours, followed by the addition of ice water (1.0 mL). The solvent was removed under vacuum, and the residue was purified by rapid silica gel column chromatography with elution using EA / PE (EA increased from 0% to 100%) to give 6-bromo-2-(fluoromethyl)-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (150 mg, 50% yield) as a colorless oil. LC-MS: m / z [M+H] + 464.9, 466.9.

[0331] Intermediate 90

[0332] Oxycyclobutane-3-one (69.0 mg, 957 μmol, 61.0 μL) was added to a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentane-2-yl)-1,2,3,6-tetrahydropyridine (100 mg, 478 μmol) in methanol (4.0 mL). The mixture was stirred at 25 °C for 30 min, followed by the addition of NaBH3CN (60.0 mg, 956 μmol). The mixture was stirred at 25 °C for 2 h, then treated with water and extracted with EA (2 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give 1-(oxecyclobutane-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentenyl-2-yl)-1,2,3,6-tetrahydropyridine (60.0 mg, 47% yield) as a white solid, which was used in the next step without further purification. LC-MS: m / z [M+H] + 266.1.

[0333] Intermediate 91

[0334] Step 1: TEA (46.0 mg, 458 μmol, 64.0 μL) and acetyl chloride (43.0 mg, 550 μmol, 33.0 μL) were added dropwise to a stirred solution of (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (100 mg, 458 μmol) in DCM (2.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h, followed by water treatment. The mixture was extracted with DCM (2 × 10 mL), and the combined organic layers were washed with brine, dried over Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure to give (3S,4R)-4-acetamido-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (100 mg, 83% yield) as a yellow oil, which was used unpurified in the next step. LC-MS: m / z [M+H-56] + 205.1.

[0335] Step 2: TFA (745 mg, 6.53 mmol, 0.5 mL) was added to a stirred solution of (3S,4R)-4-acetamido-3-fluoropiperidin-1-carboxylate (100 mg, 384 μmol) in DCM (2.0 mL) at 25 °C. The mixture was stirred at 25 °C for 2 hours, followed by concentration under reduced pressure to give N-((3S,4R)-3-fluoropiperidin-4-yl)acetamide (50.0 mg, 81% yield) as a yellow oil, which was used in the next step without purification. LC-MS: m / z [M+H] + 161.1.

[0336] Intermediate 92

[0337] Step 1: Dihydrofuran-2,5-dione (263 mg, 2.63 mmol) was added to a stirred solution of 1-phenylmethylpiperidin-4-amine (500 mg, 2.63 mmol, 537 μL) in AcOH (3.0 mL) at 25 °C. The reaction mixture was heated to 100 °C and stirred at that temperature for 10 h. The mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was dissolved in EtOAc (15 mL) and treated with an aqueous solution of NaHCO3. The mixture was extracted with EtOAc (3 × 15 mL), and the combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography with elution using MeOH / DCM (MeOH increased from 0% to 5% over 20 min) to give 1-(1-phenylmethylpiperidin-4-yl)pyrrolidine-2,5-dione (364 mg, 51% yield) as a white solid. LC-MS: m / z [M+H] + 273.1.

[0338] Step 2: Pd / C (30.0 mg, 10% wt., 282 μmol) was added to a stirred solution of 1-(1-phenylmethylpiperidin-4-yl)pyrrolidine-2,5-dione (160 mg, 587 μmol) in methanol (5.0 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 18 hours under a hydrogen atmosphere (balloon). The mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated under reduced pressure to give 1-(piperidin-4-yl)pyrrolidine-2,5-dione (80.0 mg, 75% yield) as a colorless oil, which was used directly in the next step without purification. LC-MS: m / z [M+H] + 183.1.

[0339] Intermediates 93 and 94

[0340] Step 1: Methylmagnesium bromide (5.2 mL, 1.0 M, THF, 5.2 mmol) was slowly added to a stirred solution of methyl 3-fluoro-4-oxopiridine-1-carboxylate (1.00 g, 3.98 mmol) in THF (5.0 mL) at -78 °C. The mixture was stirred at -78 °C for 2 h, then quenched with aqueous NH4Cl solution and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography by elution with EtOAc / petroleum ether (EtOAc increased from 0% to 50% over 20 min) to give (cis, racemic)-benzyl-3-fluoro-4-hydroxy-4-methylpiperidine-1-carboxylate (500 mg, 47% yield) as a colorless oil. LC-MS: m / z [M+H] + 268.0 mg, and (trans, racemic)-benzyl-3-fluoro-4-hydroxy-4-methylpiperidine-1-carboxylate as a colorless oil (80.0 mg, 8% yield), LC-MS: m / z [M+H] + 268.0.

[0341] Step 2: Pd(OH)₂ (60.0 mg, 427 μmol) was added to a stirred solution of (cis, racemic)-benzyl-3-fluoro-4-hydroxy-4-methylpiperidine-1-carboxylate (180 mg, 673 μmol) in ethanol (4.0 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 18 hours under a hydrogen atmosphere (balloon). The mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated under reduced pressure to give (cis, racemic)-3-fluoro-4-methylpiperidine-4-ol (80.0 mg, 89% yield) as a colorless oil, which was used unpurified in the next step. LC-MS: m / z [M+H] + 134.1.

[0342] Step 3: Pd(OH)₂ (20.0 mg, 142 μmol) was added to a stirred solution of (trans-racemic)-benzyl-3-fluoro-4-hydroxy-4-methylpiperidine-1-carboxylate (80.0 mg, 299 μmol) in ethanol (2.0 mL). The reaction mixture was stirred at 25 °C for 18 hours under a hydrogen atmosphere (balloon). The mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated under reduced pressure to give (trans-racemic)-3-fluoro-4-methylpiperidine-4-ol (30.0 mg, 75% yield) as a colorless oil, which was used unpurified in the next step. LC-MS: m / z [M+H] + 134.1.

[0343] Intermediate 95

[0344] Step 1: K₂CO₃ (1.27 g, 9.19 mmol) was added to a stirred solution of 4-bromo-1H-pyrazole (675 mg, 4.59 mmol) and 2-bromocyclobut-1-one (1.03 g, 6.89 mmol) in ACN (10.0 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 18 hours. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether (EtOAc increased from 0% to 30% in 20 minutes), to give 2-(4-bromo-1H-pyrazole-1-yl)cyclobut-1-one (575 mg, 58% yield) as a white solid. LC-MS: m / z [M+H] + 214.9.

[0345] Step 2: NaBH4 (93.0 mg, 2.45 mmol) was added to a stirred solution of 2-(4-bromo-1H-pyrazol-1-yl)cyclobut-1-one (527 mg, 2.45 mmol) in methanol (5.0 mL) at 25 °C. The mixture was stirred at 25 °C for 3 hours, followed by concentration under reduced pressure. The residue was dissolved in EtOAc (10 mL) and treated with NH4Cl aqueous solution (10 mL), followed by extraction with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography by elution with EtOAc / petroleum ether (EtOAc increased from 0% to 30% within 20 minutes) to give 2-(4-bromo-1H-pyrazol-1-yl)cyclobut-1-ol (120 mg, 23% yield) as a white oil. LC-MS: m / z [M+H] + 216.9.

[0346] Step 3: To a stirred solution of 2-(4-bromo-1H-pyrazol-1-yl)cyclobut-1-ol (120 mg, 553 μmol) in 1,4-dioxane (5.0 mL), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhecyclopentane) (281 mg, 1.11 mmol), Pd(dppf)Cl2 (20.0 mg, 27.6 μmol), and KOAc (136 mg, 1.38 mmol) were added sequentially. The mixture was heated to 100 °C and stirred at that temperature for 18 hours. The reaction mixture was cooled to 25°C and concentrated under reduced pressure to give 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)cyclobut-1-ol (146 mg, 100% yield), which was used directly in the next step without purification. LC-MS: m / z [M+H] + 265.1.

[0347] Intermediate 96

[0348] Step 1: Cs₂CO₃ (24.0 g, 73.7 mmol) was added to a solution of 3-oxabicyclo[3.1.0]hexane (3.10 g, 36.9 mmol) in NMP (50.0 mL) at 25 °C, followed by the addition of 4-bromo-1H-pyrazole (5.42 g, 36.85 mmol). The mixture was heated to 120 °C and stirred at that temperature for 18 hours. The reaction mixture was cooled to 25 °C, poured onto water (150 mL), and extracted with CH₂Cl₂ (3 × 150 mL). The combined organic layers were washed with water (3 × 150 mL) and a saturated aqueous solution of NaCl (200 mL), dried over Na₂SO₄, and concentrated under vacuum. The crude product was purified by rapid silica gel column chromatography (0-60% ethyl acetate / petroleum ether) to give (trans, racemic)-4-(4-bromopyrazol-1-yl)tetrahydrofuran-3-ol (5.20 g, 61% yield) as a colorless solid. LC-MS: m / z [M+H] + 233.0.

[0349] Step 2: To a stirred solution of (trans, racemic)-4-(4-bromopyrazol-1-yl)tetrahydrofuran-3-ol (100 mg, 429 μmol) in 1,4-dioxane (6.0 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborthopentenyl-2-yl)-1,3,2-dioxaborthopentenane (218 mg, 858 μmol), Pd(dppf)Cl2 (15.7 mg, 21.5 μmol), and KOAc (105 mg, 1.07 mmol) were added sequentially. The mixture was heated to 100 °C and stirred at that temperature for 12 hours. The reaction mixture was cooled to 25°C to give (trans, racemic)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)pyrazol-1-yl]tetrahydrofuran-3-ol (120 mg, 100% yield), which was used directly in the next step without further treatment. LC-MS: m / z [M+H] + 281.1.

[0350] Intermediate 97

[0351] Step 1: A solution of DIAD (3.25 g, 16.1 mmol, 3.17 mL) in THF (10 mL) was added to a stirred solution of (trans, racemic)-4-(4-bromopyrazol-1-yl)tetrahydrofuran-3-ol (2.50 g, 10.7 mmol), 4-nitrobenzoic acid (1.79 g, 10.7 mmol), and PPh3 (4.22 g, 16.1 mmol) in anhydrous THF (45.0 mL). The reaction mixture was heated to 25 °C and stirred at that temperature for 16 hours. The reaction mixture was cooled to 0 °C, quenched with H2O (30 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water (50 mL) and a saturated aqueous sodium chloride solution (60 mL), dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by rapid silica gel column chromatography (0-60% ethyl acetate / petroleum ether) to give 4.90 g of colorless solid 4-nitrobenzoic acid [(cis, racemic)-4-(4-bromopyrazol-1-yl)tetrahydrofuran-3-yl] ester, which was used in the next step without further purification. LC-MS: m / z [M+H] + 382.0.

[0352] Step 2: LiOH (921 mg, 38.5 mmol) was added to a stirred solution of 4-nitrobenzoic acid [(cis, racemic)-4-(4-bromopyrazole-1-yl)tetrahydrofuran-3-yl] ester (4.90 g, 12.8 mmol) in THF (30 mL), MeOH (10 mL), and water (20 mL) at 25 °C. The mixture was stirred at said temperature for 6 hours, then diluted with water (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water (50 mL) and saturated sodium chloride aqueous solution (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by rapid silica gel column chromatography (0-60% ethyl acetate / petroleum ether) to give (cis, racemic)-4-(4-bromopyrazole-1-yl)tetrahydrofuran-3-ol (1.90 g, 64% yield) as a white solid. LC-MS: m / z [M+H] + 233.0.

[0353] Step 3: KOAc (168 mg, 1.72 mmol) and Pd(dppf)Cl2 (62.3 mg, 85.8 μmol) were added sequentially to a stirred solution of (cis, racemic)-4-(4-bromopyrazol-1-yl)tetrahydrofuran-3-ol (200 mg, 858 μmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhecyclopentane) (262 mg, 1.03 mmol) in dioxane (6.0 mL) at 25 °C. The mixture was heated to 100°C and stirred at that temperature for 16 hours, then cooled and concentrated under reduced pressure to give (cis, racemic)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)-1H-pyrazol-1-yl)tetrahydrofuran-3-ol, which was used in the next step without further purification. LC-MS (ESI+): m / z [M+H] + 281.2.

[0354] Intermediate 99

[0355] TEA (155 mg, 1.53 mmol, 213 μL) was added to a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentane-2-yl)-1,2,3,6-tetrahydropyridine (80.0 mg, 383 μmol) and 3,4-dimethoxycyclobut-3-ene-1,2-dione (217 mg, 1.53 mmol) in DMF (3.0 mL). The mixture was stirred at said temperature for 16 hours, then ice water was added and the mixture was extracted with EA. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 100 mg (82% yield) of a white solid, 3-methoxy-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentane-2-yl)-3,6-dihydropyridin-1(2H)-yl)cyclobut-3-en-1,2-dione, which was used in the next step without further purification. LC-MS: m / z [M+H] + 320.2.

[0356] Intermediate 100

[0357] DIPEA (309 mg, 2.39 mmol, 416 μL) and HATU (273 mg, 717 μmol) were added to a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-1,2,3,6-tetrahydropyridine (100 mg, 478 μmol) and formic acid (44.0 mg, 956 μmol, 36.1 μL) in DCM (3.0 mL) at 25 °C. The mixture was stirred at said temperature for 2 hours, then ice water was added and the mixture was extracted with DCM. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with elution using DCM / MeOH (MeOH increased from 0% to 5% over 30 minutes) to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)-3,6-dihydropyridine-1(2H)-carboxaldehyde (111 mg, 98% yield) as a white solid. LC-MS: m / z [M+H] + 238.2.

[0358] Intermediate 101

[0359] Dimethylphosphonochloride (53.8 mg, 478 μmol) was added to a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-1,2,3,6-tetrahydropyridine (50.0 mg, 239 μmol) in DCM (3.0 mL). The mixture was heated to 25 °C and stirred at that temperature for 2 hours. The mixture was treated with ice water and extracted with DCM. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with elution using DCM / MeOH (MeOH increased from 0% to 6% over 30 minutes) to give dimethyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-3,6-dihydropyridine-1(2H)-yl)phosphine oxide (65.0 mg, 95% yield) as a white solid. LC-MS: m / z [M+H] + 286.2.

[0360] Intermediate 102

[0361] Step 1: PBr3 (19.9 g, 73.4 mmol, 6.90 mL) was added to a stirred solution of DMF (5.48 g, 74.9 mmol, 5.80 mL) in CHCl3 (25 mL) at 0 °C. The reaction mixture was stirred at this temperature for 1 hour, followed by the addition of tetrahydropyran-4-one (2.00 g, 20.0 mmol, 1.85 mL). The reaction mixture was heated to 25 °C and stirred at this temperature for 8 hours. The mixture was quenched with water (50 mL) and then extracted with DCM (50 mL × 3). The combined organic phases were dried over Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure. The residue was used in the next step without further purification.

[0362] Step 2: Hydroxylamine hydrochloride (1.38 g, 19.9 mmol, 828 μL) was added to a stirred solution of 4-bromo-3,6-dihydro-2H-pyran-5-carboxaldehyde (3.80 g, 19.9 mmol) in DMF (20 mL) at 25 °C. The reaction mixture was stirred at this temperature for 1 hour, followed by the addition of T3P (50 wt.% in DMF, 6.33 g, 19.9 mmol, 4.50 mL). The reaction mixture was stirred at this temperature for 8 hours, followed by quenching with NaHCO3 (50 mL) and extraction with EtOAc (50 mL × 3). The combined organic phases were dried over Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (20 mL), followed by the addition of SOCl2 (2.37 g, 19.9 mmol, 1.45 mL) at 0 °C. The reaction mixture was stirred at the stated temperature for 1 hour, then quenched with NaHCO3 (50 mL), followed by extraction with DCM (50 mL × 3). The combined organic phases were dried over Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure. The residue was filtered through a short silica gel pad and used in the next step without further purification.

[0363] Step 3: To a stirred solution of 4-bromo-3,6-dihydro-2H-pyran-5-carboxynitrile (188 mg, 1000 μmol) in dioxane (10.0 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxabortane-2-yl)-1,3,2-dioxabortane (381 mg, 1.50 mmol), Pd(dppf)Cl2 (73.2 mg, 100 μmol), and KOAc (245 mg, 2.50 mmol, 156 μL) were added sequentially. The mixture was heated to 100 °C and stirred at that temperature for 3 hours, then cooled and concentrated under reduced pressure. The residue was used in the next step without further purification.

[0364] Intermediate 64

[0365] Step 1: 3-Bromo-2-methylbenzonitrile (5.00 g, 25.5 mmol) was subjected to treatment at 25°C. nNaHCO3 (6.43 g, 76.5 mmol), lithium trifluoromethanesulfonate (3.98 g, 25.5 mmol), and Pd(dppf)Cl2·DCM (2.08 g, 2.55 mmol) were added to a stirred solution of -BuOH (50.0 mL). The mixture was heated to 100 °C and stirred at that temperature for 20 h. The mixture was cooled to 25 °C, and 3 M HCl / water (3.0 mL) was added to the mixture. The mixture was stirred at 25 °C for 1 h, diluted with EA, washed with brine, and dried over anhydrous sodium sulfate. After filtration and solvent evaporation, the residue was purified by silica gel chromatography by elution with EtOAc / petroleum ether (EtOAc increased from 0% to 10% in 30 min) to give 3-acetyl-2-methylbenzonitrile (3.45 g, 85% yield) as a yellow solid. LC-MS: m / z [M+H] + 160.0.

[0366] Step 2: (R)-(+)-2-methyl-2-propanesulfinamide (3.94 g, 32.5 mmol) and ethyl titanate (14.8 g, 65.0 mmol, 13.6 mL) were added to a stirred solution of 3-acetyl-2-methylbenzonitrile (3.45 g, 21.7 mmol) in THF (50.0 mL) at 25 °C. The mixture was heated to 80 °C and stirred at that temperature for 16 hours. Ice water and EA were then added, and the aqueous layer was extracted with EA. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (R, E)-N-(1-(3-cyano-2-methylphenyl)ethylene)-2-methylpropane-2-sulfinamide (5.60 g, 98% yield), which was used in the next step without further purification. LC-MS: m / z [M+H] + 262.0.

[0367] Step 3: Sodium borohydride (807 mg, 21.34 mmol) was added to a stirred solution of (R, E)-N-[1-(3-cyano-2-methyl-phenyl)ethylene]-2-methyl-propane-2-sulfinamide (5.60 g, 21.3 mmol) in THF (60.0 mL). The mixture was heated to 25 °C and stirred at that temperature for 6 hours. Ice water and EA were then added. The aqueous layer was extracted with EA, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography by elution with EtOAc / petroleum ether (EtOAc increased from 0% to 33% in 30 minutes) to give (R)-N-[1-(3-cyano-2-methyl-phenyl)ethyl]-2-methyl-propane-2-sulfinamide (4.35 g, 77% yield) as a yellow oil. LC-MS: m / z [M+H] + 264.0.

[0368] Step 4: Dioxane (40.0 mL) containing 4 N HCl was added to a stirred solution of (R)-N-[1-(3-cyano-2-methyl-phenyl)ethyl]-2-methyl-propane-2-sulfinamide (4.35 g, 16.5 mmol) in EtOH (40.0 mL). The mixture was stirred at 25 °C for 1.5 h. The solution was removed under vacuum, and the solid was collected and diluted with water. The mixture was adjusted to pH = 8 with aqueous NaHCO3 solution and extracted with EA (3 × 100 mL). The combined organic layers were concentrated to give (R)-3-(1-aminoethyl)-2-methylbenzonitrile (2.5 g, 15.60 mmol, 94.84% yield) as a pale yellow oil. LC-MS: m / z [M+H] + 161.0.

[0369] Intermediate 48

[0370] Step 1: (2S)-2-aminoprop-1-ol (96.0 mg, 1.28 mmol, 99.5 μL) and TEA (129 mg, 1.28 mmol, 178 μL) were added sequentially to a stirred solution of 5-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-2-fluoro-pyridine-3-carboxamide (100 mg, 256 μmol) in DMSO (2.0 mL) at 25 °C. The reaction mixture was heated to 90 °C and stirred at that temperature for 3 hours. The reaction mixture was cooled to 25 °C, quenched with saturated NaHCO3 aqueous solution (10 mL), and extracted with EtOAc (50 mL × 2). The combined organic phases were dried over Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether (EtOAc increased from 0% to 100% within 20 minutes) to give 5-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-2-[[(1S)-2-hydroxy-1-methyl-ethyl]amino]pyridine-3-carboxamide (90 mg, 79% yield) as a clear oil. LC-MS: m / z [M+H] + 446.5.

[0371] Step 2: TEA (204 mg, 2.02 mmol, 281 μL) and methanesulfonyl methanesulfonate (105 mg, 605 μmol) were added sequentially to a stirred solution of 5-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-2-[[(1S)-2-hydroxy-1-methyl-ethyl]amino]pyridine-3-carboxamide (90 mg, 202 μmol) in DCM (2.0 mL). The reaction mixture was stirred at this temperature for 10 min, then quenched with saturated NaHCO3 aqueous solution (5.0 mL) and extracted with DCM (30 mL × 2). The combined organic phases were dried over Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether (EtOAc increased from 0% to 100% in 20 minutes) to give (2S)-6-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (25.0 mg, 29% yield) as a yellow solid. LC-MS: m / z [M+H] + 428.5.

[0372] Intermediate 49

[0373] Step 1: To a stirred solution of 2,5-dichloro-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]pyridine-3-carboxamide (100 mg, 275 μmol) in DMSO (2.0 mL), (2S)-2-aminoprop-1-ol (103 mg, 1.38 mmol, 107 μL) and TEA (139 mg, 1.38 mmol, 192 μL) were added sequentially. The reaction mixture was heated to 90 °C and stirred at that temperature for 3 hours. The reaction mixture was cooled to 25 °C, quenched with a saturated aqueous solution of NaHCO3 (10 mL), and extracted with EtOAc (50 mL × 2). The combined organic phases were dried over Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether (EtOAc increased from 0% to 100% within 20 minutes) to give 6-chloro-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-3-[[(1S)-2-hydroxy-1-methyl-ethyl]amino]pyridazine-4-carboxamide (78.0 mg, 71% yield) as a clear oil. LC-MS: m / z [M+H] + 402.6.

[0374] Step 2: TEA (196 mg, 1.94 μmol) and methanesulfonyl methanesulfonate (101 mg, 581 μmol) were added sequentially to a stirred solution of 6-chloro-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-3-[[(1S)-2-hydroxy-1-methyl-ethyl]amino]pyridazine-4-carboxamide (78 mg, 194 μmol) in DCM (2.0 mL) at 25 °C. The reaction mixture was stirred at this temperature for 10 min, then quenched with saturated NaHCO3 aqueous solution (5.0 mL) and extracted with DCM (30 mL × 2). The combined organic phases were dried over Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography with elution using EtOAc / petroleum ether (EtOAc increased from 0% to 100% within 20 minutes) to give (2S)-6-chloro-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-2-methyl-2,3-dihydroimidazo[1,2-b]pyridazine-8-carboxamide (40.0 mg, 54% yield) as a yellow solid. LC-MS: m / z [M+H] + 385.6.

[0375] Intermediate 50

[0376] Step 1: Phosphoryl trichlorophosphate (7.29 g, 47.6 mmol, 4.43 mL) was added to a stirred solution of (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl-1-amine (3.00 g, 15.9 mmol) and 5-bromo-2-fluoronicotinic acid (4.19 g, 19.0 mmol) in DCM (30.0 mL) and pyridine (10.0 mL). The mixture was heated to 25 °C and stirred at that temperature for 2 hours. The reaction mixture was quenched with ice water and extracted with DCM. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with elution using DCM / MeOH (MeOH increased from 0% to 5% over 30 minutes) to give (R)-5-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-fluoronicotinamide (5.60 g, 90% yield) as a white solid. LC-MS: m / z [M+H] + 392.2.

[0377] Step 2: TEA (4.97 g, 49.1 mmol, 6.84 mL) was added to a stirred solution of 5-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]-2-fluoropyridine-3-carboxamide (6.40 g, 16.4 mmol) and (R)-2-aminoprop-1-ol (1.47 g, 19.6 mmol) in DMSO (70.0 mL) at 25 °C. The mixture was heated to 80 °C and stirred at that temperature for 6 hours. The mixture was then cooled, diluted with EA, and washed with brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum to give 5-bromo-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-(((R)-1-hydroxyprop-2-yl)amino)nicotinamide (7.30 g, 99% yield) as a yellow oil. LC-MS: m / z [M+H] + 447.2.

[0378] Step 3: TEA (8.28 g, 81.8 mmol, 11.4 mL) and methanesulfonic anhydride (5.70 g, 32.72 mmol) were added to a stirred solution of 5-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-2-[[(1R)-2-hydroxy-1-methyl-ethyl]amino]pyridine-3-carboxamide (7.30 g, 16.4 mmol) in DCM (100 mL) at 25 °C. The mixture was stirred at 25 °C for 30 min. The mixture was then quenched with water, diluted with DCM, and washed with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with elution using DCM / MeOH (MeOH increased from 0% to 2% over 30 minutes) to give (R)-6-bromo-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (6.40 g, 91% yield) as a yellow solid. LC-MS: m / z [M+H] + 429.0.

[0379] Intermediate 71

[0380] Step 1: Phosphoryl trichlorophosphate (6.66 g, 43.4 mmol, 4.05 mL) was added to a stirred solution of (R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl-1-amine (3.00 g, 14.5 mmol), 5-bromo-2-fluoronicotinic acid (3.82 g, 17.4 mmol) in DCM (30.0 mL) and pyridine (10.0 mL) at 0 °C. The mixture was heated to 25 °C and stirred at that temperature for 2 hours. Ice water was added to the reaction mixture and it was extracted with DCM. The organic phase was washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with elution using DCM / MeOH (MeOH increased from 0% to 5% over 30 minutes) to give 5-bromo-2-fluoro-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]pyridine-3-carboxamide (5.30 g, 89% yield) as a white solid. LC-MS: m / z [M+H] + 410.2.

[0381] Step 2: TEA (3.93 g, 38.9 mmol, 5.42 mL) was added to a stirred solution of 5-bromo-2-fluoro-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]pyridine-3-carboxamide (5.30 g, 12.9 mmol) and (R)-2-aminoprop-1-ol (1.17 g, 15.5 mmol) in DMSO (60.0 mL). The mixture was heated to 80 °C and stirred at that temperature for 6 hours. The mixture was then diluted with EA, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 5-bromo-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-(((S)-1-hydroxypropyl-2-yl)amino)nicotinamide (5.80 g, 96% yield) as a yellow oil. LC-MS: m / z [M+H] + 465.2.

[0382] Step 3: TEA (6.32 g, 62.5 mmol, 8.71 mL) and methanesulfonic anhydride (4.35 g, 25.0 mmol) were added to a stirred solution of 5-bromo-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-[[(1S)-2-hydroxy-1-methyl-ethyl]amino]pyridine-3-carboxamide (5.80 g, 12.49 mmol) in DCM (100.0 mL) at 25 °C. The mixture was stirred at 25 °C for 30 minutes. The mixture was then quenched with water, diluted with DCM, washed with brine, and dried over anhydrous sodium sulfate. After filtration and vacuum evaporation of the solvent, the residue was purified by silica gel chromatography with elution using DCM / MeOH (MeOH increased from 0% to 2% over 30 minutes) to give (R)-6-bromo-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (4.80 g, 86% yield) as a yellow solid. LC-MS: m / z [M+H] + 447.0.

[0383] Intermediate 89

[0384] Step 1: Cesium fluoride (954 mg, 6.28 mmol) was added to a stirred solution of 3,6-dichloro-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]pyridazine-4-carboxamide (2.00 g, 5.23 mmol) and 2-amino-2-methyl-prop-1-ol (467 mg, 5.23 mmol) in DMSO (5.0 mL). The mixture was heated to 80°C and stirred at that temperature for 3 hours. The solvent was removed under vacuum and the residue was purified by rapid silica gel column chromatography with elution with EtOAc / petroleum ether to give 6-chloro-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-3-[(2-hydroxy-1,1-dimethyl-ethyl)amino]pyridazine-4-carboxamide (1.00 g, 44% yield) as a yellow oil. LC-MS: m / z [M+H] + 435.1.

[0385] Step 2: Methanesulfonic anhydride (801 mg, 4.60 mmol) was slowly added to a stirred solution of 6-chloro-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-3-[(2-hydroxy-1,1-dimethyl-ethyl)amino]pyridazine-4-carboxamide (1.00 g, 2.30 mmol) and triethylamine (1.16 g, 11.50 mmol, 1.60 mL) in dichloromethane (10.0 mL). The mixture was stirred at the stated temperature for 10 minutes, after which the solvent was removed under vacuum. The residue was purified by rapid silica gel column chromatography, eluting with EtOAc / petroleum ether, to give 6-chloro-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2,2-dimethyl-3H-imidazo[1,2-b]pyridazine-8-carboxamide (700 mg, 73% yield) as a yellow solid. LC-MS: m / z [M+H] + 417.1.

[0386] Intermediate 98

[0387] Step 1: (R)-1-((tert-butyldimethylsilyl)oxy)prop-2-amine (1.59 g, 8.37 mmol) and TEA (1.59 g, 15.7 mmol, 2.20 mL) were added sequentially to a stirred solution of (R)-3,6-dichloro-N-(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)pyridazine-4-carboxamide (2.00 g, 5.23 mmol) in DMSO (6.0 mL) at 25 °C. The reaction mixture was heated to 90 °C and stirred at that temperature for 10 hours. The mixture was diluted with water and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether (EtOAc increased from 0% to 30% within 20 minutes) to give a pale yellow oil, 3-(((R)-1-((tert-butyldimethylsilyl)oxy)propyl-2-yl)amino)-6-chloro-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)pyridazine-4-carboxamide (2.10 g, 71% yield). LC-MS: m / z [M+H] + 535.2.

[0388] Step 2: TBAF (6.0 mL, 1.0 M in THF, 6.0 mmol) was added to a stirred solution of 3-(((R)-1-((tert-butyldimethylsilyl)oxy)propyl-2-yl)amino)-6-chloro-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)pyridazine-4-carboxamide (2.10 g, 3.92 mmol) in THF (6.0 mL). The mixture was stirred at 25 °C for 18 hours, then treated with water and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether (EtOAc increased from 0% to 50% within 20 minutes) to give a yellow oil, 6-chloro-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-3-(((R)-1-hydroxypropyl-2-yl)amino)pyridazine-4-carboxamide (1.60 g, 96% yield). LC-MS: m / z [M+H] + 421.1.

[0389] Step 3: TEA (1.92 g, 19.0 mmol, 2.6 mL) and methanesulfonic anhydride (1.32 g, 7.60 mmol) were added sequentially to a stirred solution of 6-chloro-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-3-(((R)-1-hydroxypropyl-2-yl)amino)pyridazine-4-carboxamide (1.60 g, 3.80 mmol) in DCM (6.0 mL). The reaction mixture was stirred at 25 °C for 1 hour. The mixture was treated with water and extracted with DCM (3 × 15 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether (EtOAc increased from 0% to 30% within 20 minutes) to give (R)-6-chloro-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methyl-2,3-dihydroimidazo[1,2-b]pyridazine-8-carboxamide (1.26 g, 82% yield) as a red solid. LC-MS: m / z [M+H] + 403.1.

[0390] Intermediate 132

[0391] Step 1: TEA (155 mg, 1.53 mmol, 214 μL) was added to a stirred solution of (R)-5-bromo-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-fluoronicotinamide (200 mg, 511 μmol) and (R)-1-aminoprop-2-ol (76.8 mg, 1.02 mmol) in DMSO (3.0 mL). The mixture was heated to 80 °C and stirred at that temperature for 6 hours, then diluted with EA and washed with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 5-bromo-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-(((R)-2-hydroxypropyl)amino)nicotinamide (228 mg, 99% yield) as a yellow oil, which was used in the next step without further purification. LC-MS: m / z [M+H] + 447.0.

[0392] Step 1: Methanesulfonic anhydride (445 mg, 2.55 mmol) was added to a stirred solution of 5-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-2-[[(2R)-2-hydroxypropyl]amino]pyridine-3-carboxamide (228 mg, 511 μmol) in TEA (2.0 mL) and DCM (2.0 mL). The mixture was stirred at 25 °C for 16 hours, then quenched with water, diluted with DCM, and diluted with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with dichloromethane / methanol (methanol increased from 0% to 2% over 30 minutes) to give (S)-6-bromo-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (80.0 mg, 36% yield) as a yellow solid. LC-MS: m / z [M+H] + 427.9.

[0393] Intermediate 133

[0394] Step 1: TEA (155 mg, 1.53 mmol, 214 μL) was added to a stirred solution of (R)-5-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-fluoronicotinamide (200 mg, 511 μmol) and (S)-1-aminoprop-2-ol (76.8 mg, 1.02 mmol, 80.0 μL) in DMSO (3.0 mL). The mixture was heated to 80 °C and stirred at that temperature for 6 hours, then diluted with EA and washed with brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum to give 5-bromo-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-(((S)-2-hydroxypropyl)amino)nicotinamide (226 mg, 99% yield) as a yellow oil, which was used in the next step without further purification. LC-MS: m / z [M+H] + 447.0.

[0395] Step 2: Methanesulfonic anhydride (534 mg, 3.07 mmol) was added to a stirred solution of 5-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-2-[[(2S)-2-hydroxypropyl]amino]pyridine-3-carboxamide (226 mg, 510 μmol) in TEA (2.0 mL) and DCM (2.0 mL). The mixture was stirred at 25 °C for 16 hours, then quenched with water, diluted with DCM, and washed with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with dichloromethane / methanol (methanol increased from 0% to 2% over 30 minutes) to give (R)-6-bromo-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (150 mg, 68% yield) as a yellow solid. LC-MS: m / z [M+H] + 427.9.

[0396] Intermediate 109

[0397] Step 1: (1R,2R)-2-aminocyclopentanol (98.9 mg, 978 μmol) and TEA (247 mg, 2.44 mmol, 341 μL) were added sequentially to a stirred solution of 5-bromo-2-fluoro-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]pyridine-3-carboxamide (200 mg, 489 μmol) in DMSO (5.0 mL) at 25 °C. The mixture was heated to 80 °C and stirred at that temperature for 2 hours, then diluted with EA and washed with brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by rapid silica gel column chromatography, eluting with EA / PE (EA increased from 0% to 100%) to give a yellow oil, 5-bromo-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-[[(1R,2R)-2-hydroxycyclopentyl]amino]pyridine-3-carboxamide (150 mg, 63% yield). LC-MS: m / z [M+H] + : 490.0 / 492.0.

[0398] Step 2: Methanesulfonic anhydride (107 mg, 612 μmol) was slowly added to a stirred solution of 5-bromo-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-[[(1R,2R)-2-hydroxycyclopentyl]amino]pyridine-3-carboxamide (150 mg, 306 μmol) and triethylamine (155 mg, 1.53 mmol, 213 μL) in dichloromethane (10.0 mL). The mixture was heated to 60 °C and stirred at that temperature for 2 hours, followed by quenching with 1.0 mL of water. The solvent was removed under vacuum. The residue was purified by rapid silica gel column chromatography with elution using EA / PE (EA increased from 0% to 100%) to give (2S,6R)-11-bromo-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-1,7-diazatricyclo[6.4.0.02,6]dodec-7,9,11-trien-9-carboxamide (100 mg, 69% yield) as a yellow solid. LC-MS: m / z [M+H] + : 472.0 / 474.0.

[0399] Intermediate 110

[0400] Step 1: Trans-4-amino-tetrahydrofuran-3-ol (50.4 mg, 489 μmol) and TEA (148 mg, 1.47 mmol, 204 μL) were added sequentially to a stirred solution of 5-bromo-2-fluoro-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]pyridine-3-carboxamide (200 mg, 489 μmol) in DMSO (5.0 mL) at 25 °C. The mixture was heated to 80 °C and stirred at that temperature for 2 hours, followed by quenching with 1.0 mL of water. The solvent was removed under vacuum. The residue was purified by rapid silica gel column chromatography, eluting with EA / PE (EA increased from 0% to 100%) to give a yellow oil, 5-bromo-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-[[(3R,4S)-4-hydroxytetrahydrofuran-3-yl]amino]pyridine-3-carboxamide (100 mg, 42% yield). LC-MS: m / z [M+H] + : 491.9 / 493.9.

[0401] Step 2: Methanesulfonic anhydride (84.9 mg, 488 μmol) was slowly added to a stirred solution of 5-bromo-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-[[(3R,4S)-4-hydroxytetrahydrofuran-3-yl]amino]pyridine-3-carboxamide (60.0 mg, 122 μmol) and triethylamine (123 mg, 1.22 mmol, 170 μL) in dichloromethane (10.0 mL). The mixture was heated to 60 °C and stirred at that temperature for 2 hours, followed by quenching with 1.0 mL of water. The solvent was removed under vacuum. The residue was purified by rapid silica gel column chromatography with EA / PE elution (EA from 0% to 100%) to give (2R,6S)-11-bromo-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-4-oxa-1,7-diazatricyclo[6.4.0.02,6]dodec-7,9,11-trien-9-carboxamide (30.0 mg, 52% yield) as a yellow solid. LC-MS: m / z [M+H] + :473.9 / 475.9.

[0402] Intermediate 111

[0403] Step 1: (1R,2R)-2-aminocyclohexanol (67.6 mg, 587 μmol) and TEA (148 mg, 1.47 mmol, 204 μL) were added sequentially to a stirred solution of 5-bromo-2-fluoro-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]pyridine-3-carboxamide (200 mg, 489 μmol) in DMSO (5.0 mL) at 25 °C. The mixture was heated to 80 °C and stirred at that temperature for 2 hours, followed by quenching with 1.0 mL of water. The solvent was removed under vacuum. The residue was purified by rapid silica gel column chromatography, eluting with EA / PE (EA from 0% to 100%) to give a yellow oil, 5-bromo-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-[[(1R,2R)-2-hydroxycyclohexyl]amino]pyridine-3-carboxamide (180 mg, 73% yield). LC-MS: m / z [M+H] + : 504.0 / 506.0.

[0404] Step 2: Triethylamine (181 mg, 1.78 mmol, 249 μL) and methanesulfonic anhydride (93.3 mg, 535 μmol) were slowly added sequentially to a stirred solution of 5-bromo-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-[[(1R,2R)-2-hydroxycyclohexyl]amino]pyridine-3-carboxamide (180 mg, 357 μmol) in dichloromethane (10.0 mL) at 25 °C. The mixture was heated to 60 °C and stirred at that temperature for 2 hours, followed by quenching with 1.0 mL of water. The solvent was removed under vacuum. The residue was purified by rapid silica gel column chromatography, eluting with EA / PE (EA from 0% to 100%) to give (5aR,9aS)-2-bromo-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-5a,6,7,8,9,9a-hexahydropyrido[1,2-a]benzimidazole-4-carboxamide (60.0 mg, 35% yield) as a yellow solid. LC-MS: m / z [M+H] + : 486.0 / 488.0.

[0405] Intermediate 112

[0406] Step 1: TEA (148 mg, 1.47 mmol, 204 μL) was slowly added to a stirred solution of 5-bromo-2-fluoro-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]pyridine-3-carboxamide (200 mg, 489 μmol) and (3R,4R)-3-aminotetrahydropyran-4-ol (68.7 mg, 587 μmol) dissolved in DMSO (5.0 mL). The mixture was heated to 80 °C and stirred at that temperature for 2 hours, followed by quenching with 1.0 mL of water. The solvent was removed under vacuum. The residue was purified by rapid silica gel column chromatography, eluting with EA / PE (EA from 0% to 100%) to give a yellow oil, 5-bromo-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-[[(3R,4R)-4-hydroxytetrahydropyran-3-yl]amino]pyridine-3-carboxamide (150 mg, 61% yield). LC-MS: m / z [M+H] + : 506.0 / 508.0.

[0407] Step 2: Triethylamine (150 mg, 296 μmol) and methanesulfonic anhydride (103 mg, 593 μmol) were slowly added sequentially to a stirred solution of 5-bromo-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-[[(3R,4R)-4-hydroxytetrahydropyran-3-yl]amino]pyridine-3-carboxamide (150 mg, 296 μmol) in dichloromethane (10.0 mL) at 25 °C. The mixture was heated to 60 °C and stirred at that temperature for 2 hours, followed by quenching with 1.0 mL of water. The solvent was removed under vacuum. The residue was purified by rapid silica gel column chromatography with EA / PE elution (EA from 0% to 100%) to give (2S,7S)-12-bromo-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-5-oxa-1,8-diazatricyclo[7.4.0.02,7]tetadeca-8,10,12-trien-10-carboxamide (100 mg, 69% yield) as a yellow solid. LC-MS: m / z [M+H] + : 487.9 / 489.9.

[0408] Similar to the representative procedure described for intermediate 48, the following intermediate was prepared.

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419] Intermediate 140

[0420] Step 1: NBS (18.32 g, 102.96 mmol) was added to a solution of 2,3-dihydropyran-6-one (5.0 g, 50.97 mmol) in carbon tetrachloride (250 mL), followed by the addition of benzoyl peroxide (658.5 mg, 2.04 mmol, 75% purity). The mixture was stirred at 95 °C for 15 hours, then cooled to room temperature and concentrated under vacuum. The crude product was purified by rapid silica gel column chromatography (0-30% ethyl acetate / petroleum ether) to give 2,3-dibromo-2,3-dihydropyran-6-one (7.5 g), which was used without further purification.

[0421] Step 2: TEA (11.86 g, 117.24 mmol, 16.3 mL) was added to a solution of 2,3-dibromo-2,3-dihydropyran-6-one (7.5 g, 29.31 mmol) in chloroform (100 mL) at 0 °C. The mixture was stirred at this temperature for 4 hours. The reaction mixture was concentrated, filtered through a diatomaceous earth pad with ethyl acetate / petroleum ether (1:1), and the solvent was removed under reduced pressure. The crude product was purified by rapid chromatography (ethyl acetate / petroleum ether = 0 / 1–10%) to give 5-bromopyran-2-one (1.6 g, 31% yield) as a white solid. LC-MS: m / z [M+H] + 174.9, 176.9.

[0422] Intermediate 148

[0423] Triethylamine (876 mg, 8.66 mmol, 1.21 mL) was added to a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (400 mg, 2.06 mmol) and (S)-2-methylethylene oxide (359 mg, 6.18 mmol) in ACN (3.0 mL) at 25 °C. The mixture was heated to 100 °C and stirred at that temperature for 12 hours. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether (EtOAc increased from 0% to 35% within 20 minutes) to give (S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)-1H-pyrazol-1-yl)prop-2-ol (410 mg, 79% yield) as a white oil. LC-MS: m / z [M+H] + 253.2.

[0424] Intermediate 149

[0425] TEA (876 mg, 8.66 mmol, 1.21 mL) was added to a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (400 mg, 2.06 mmol) and (R)-2-methylethylene oxide (359 mg, 6.18 mmol) in ACN (3.0 mL) at 25 °C. The mixture was heated to 100 °C and stirred at that temperature for 12 hours. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether (EtOAc increased from 0% to 35% within 20 minutes) to give (R)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)-1H-pyrazol-1-yl)prop-2-ol (420 mg, 81% yield) as a white oil. LC-MS: m / z [M+H] + 253.2.

[0426] Intermediate 150

[0427] Ethyl magnesium bromide (601 mg, 4.51 mmol) was added dropwise to a stirred solution of methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)acetate (400 mg, 1.50 mmol) and titanium tetraisopropionate (214 mg, 752 μmol, 224 μL) in THF (4.0 mL) for 30 minutes at 60 °C. The mixture was stirred at 60 °C for 2 hours. The reaction mixture was cooled to 25 °C, diluted with water (10 mL), and extracted with EtOAc (20 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether (EtOAc increased from 0% to 40% within 20 minutes) to give 1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)methyl)cyclopropane-1-ol (10.0 mg, 2.5% yield) as a white oil. LC-MS: m / z [M+H] + 265.2.

[0428] Intermediate 155

[0429] Step 1: A solution of lithium diisopropylamino (2.0 N, 4.4 mL) was added to a solution of 4-bromo-2-methylpyridine (1 g, 5.8 mmol, 690 μL) in THF (20.0 mL) at -78 °C. The mixture was stirred at -78 °C for 15 min, followed by dropwise addition of acetone (405.2 mg, 7.0 mmol, 512 μL). The mixture was stirred at -78 °C for 45 min, followed by quenching with a saturated aqueous ammonium chloride solution. The aqueous layer was extracted with DCM (3 × 50 mL), and the combined organic extracts were dried over MgSO4 and concentrated under vacuum. The residue was purified by rapid silica gel column chromatography, eluting with EA / PE from 0% to 50%, to give 1-(4-bromo-2-pyridyl)-2-methyl-prop-2-ol (1.0 g, 75% yield) as a yellow oil. LC-MS: m / z [M+H] + 230.0 / 232.0.

[0430] Step 2: To a stirred solution of 1-(4-bromo-2-pyridyl)-2-methyl-prop-2-ol (100 mg, 434.6 μmol) in dioxane (10.0 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxabortane-2-yl)-1,3,2-dioxabortane (220.7 mg, 869.2 μmol), Pd(dppf)Cl2 (31.8 mg, 43.5 μmol), and KOAc (106.6 mg, 1.1 mmol) were added sequentially. The mixture was stirred at 100 °C for 4 hours and then used directly in the next step without further purification. LC-MS: m / z [M+H] + 196.1.

[0431] Intermediate 156

[0432] Step 1: A solution of lithium diisopropylamino (2.0 N, 4.4 mL) was added to a solution of 4-bromo-2-methylpyridine (1.0 g, 5.8 mmol, 690 μL) in THF (20.0 mL) at -78 °C. The mixture was stirred at -78 °C for 15 min, followed by the addition of N-methoxy-N-methylacetamide (599 mg, 5.8 mmol). The mixture was stirred at -78 °C for 45 min, followed by quenching with a saturated aqueous ammonium chloride solution. The aqueous layer was extracted with DCM (3 × 50 mL), and the combined organic extracts were dried over MgSO4 and concentrated under vacuum. The residue was purified by rapid silica gel column chromatography, eluting with EA / PE from 0% to 50%, to give 1-(4-bromo-2-pyridyl)prop-2-one (1.0 g, 80% yield) as a yellow oil. LC-MS: m / z [M+H] + 214.0 / 216.0.

[0433] Step 2: Sodium borohydride (58.7 mg, 934 μmol) was added to a stirred solution of 1-(4-bromo-2-pyridyl)prop-2-one (100 mg, 467 μmol) in MeOH (120 mL) at 0 °C. The reaction mixture was stirred at this temperature for 30 min, then treated with hydrochloric acid (1.0 mL, 1.0 N) and stirred for 10 min. The reaction mixture was neutralized with 1 N NaOH and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography, eluting with EA / PE from 0% to 100%, to give 1-(4-bromo-2-pyridyl)prop-2-ol (60.0 mg, 59% yield) as a yellow oil. LC-MS: m / z [M+H] + 216.0 / 218.0.

[0434] Step 3: To a stirred solution of 1-(4-bromo-2-pyridyl)prop-2-ol (50.0 mg, 231 μmol) in dioxane (10.0 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxabortopentane-2-yl)-1,3,2-dioxabortane (117.5 mg, 462.8 μmol), Pd(dppf)Cl2 (16.9 mg, 23.1 μmol), and KOAc (56.8 mg, 579 μmol) were added sequentially. The mixture was stirred at 100 °C for 4 hours and then used directly in the next step without further purification. LC-MS: m / z [M+H] + 182.1.

[0435] Intermediate 157

[0436] Step 1: Thionyl chloride (809 mg, 6.0 mmol, 486 μL) was slowly added to a solution of tetrahydropyran-4-one (500 mg, 5.0 mmol, 461 μL) in CCl4 (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 4 hours, followed by quenching with cold water. The mixture was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was used in the next step without further purification.

[0437] Step 2: Potassium bis(trimethylsilyl)amino (711.6 mg, 3.6 mmol) was added to a stirred solution of 400 mg (3.0 mmol) of 3-chlorotetrahydropyran-4-one in 15.0 mL of THF at -78 °C. The reaction mixture was stirred at -78 °C for 30 min, followed by the addition of N-(5-chloro-2-pyridyl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (1.4 g, 3.6 mmol). The reaction mixture was then heated to room temperature and stirred for 12 h. The volatiles were then removed under reduced pressure to give a brown residue, which was used in the next step without further purification.

[0438] Intermediate 158

[0439] Step 1: Toluenesulfonyl chloride (642 mg, 3.37 mmol) was added to a stirred solution of 3-(benzyloxy)cyclobut-1-ol (500 mg, 2.81 mmol) and TEA (852 mg, 8.42 mmol, 1.17 mL) in DCM (5.0 mL) at 0 °C. The mixture was heated to 25 °C and stirred at that temperature for 16 h. The reaction mixture was treated with ice water (5.0 mL) and extracted with DCM. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with elution of methanol / dichloromethane (methane increased from 0% to 2% over 20 min) to give 3-(benzyloxy)cyclobutyl 4-methylbenzenesulfonic acid (720 mg, 77% yield) as a white oil. LC-MS: m / z [M+H] + 333.2.

[0440] Step 2: A stirred mixture of 4-methylbenzenesulfonic acid (3-benzoxycyclobutyl) ester (720 mg, 2.17 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-1H-pyrazole (420 mg, 2.17 mmol), and cesium carbonate (1.41 g, 4.33 mmol) in NMP (10.0 mL) was microwave-treated at 110 °C for 0.5 h. The solution was diluted with EA and washed with H2O and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether (EtOAc increased from 0% to 40% within 20 minutes) to give 1-(3-(benzyloxy)cyclobutyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)-1H-pyrazole (330 mg, 43% yield) as a white oil. LC-MS: m / z [M+H] + 355.2.

[0441] Step 3: Pd / C (10% wt., 100 mg) was added to a stirred solution of 1-(3-benzoxycyclobutyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentan-2-yl)pyrazole (330 mg, 932 μmol) in methanol (3.0 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h under a hydrogen atmosphere (balloon). The reaction mixture was filtered through a diatomaceous earth mat, and the filtrate was concentrated under reduced pressure to give 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentan-2-yl)-1H-pyrazole-1-yl)cyclobut-1-ol (240 mg, 98% yield) as a yellow solid. LC-MS: m / z [M+H] + 265.2.

[0442] Intermediate 159

[0443] Step 1: Toluenesulfonyl chloride (560 mg, 2.94 mmol) was added to a stirred solution of 1-(hydroxymethyl)cyclobut-1-ol (250 mg, 2.45 mmol) and TEA (743 mg, 7.34 mmol, 1.02 mL) in DCM (5.0 mL) at 0 °C. The mixture was heated to 25 °C and stirred at that temperature for 16 h. The reaction mixture was treated with 5.0 mL of ice water and extracted with DCM. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with elution of methanol / dichloromethane (methane increased from 0% to 5% over 20 min) to give methyl 4-methylbenzenesulfonic acid (1-hydroxycyclobutyl) methyl ester (340 mg, 54% yield) as a white oil. LC-MS: m / z [M+H] + 257.2.

[0444] Step 2: A mixture of methyl 4-methylbenzenesulfonic acid (1-hydroxycyclobutyl) ester (340 mg, 1.33 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentan-2-yl)-1H-pyrazole (257 mg, 1.33 mmol), and cesium carbonate (864 mg, 2.65 mmol) in NMP (5.0 mL) was microwave-treated at 110 °C for 0.5 h. The solution was diluted with EA and washed with H2O and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether (EtOAc increased from 0% to 40% within 20 minutes) to give 1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)methyl)cyclobut-1-ol (200 mg, 54% yield) as a white oil. LC-MS: m / z [M+H] + 279.2.

[0445] Intermediate 160

[0446] Step 1: Diisopropylaminolithium (2.0 N, 6.0 mL, 12.0 mmol) was added to a stirred solution of ethyl 1-phenylmethylpiperidine-4-carboxylate (2.0 g, 8.1 mmol) in THF (15.0 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 1 h, followed by the addition of bromo(methoxy)methane (1.2 g, 9.7 mmol, 792 μL). The mixture was stirred at -78 °C for 2 h, followed by quenching with water. The mixture was extracted with EtOAc (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography, eluting with EA / PE (0% to 50%), to give ethyl 1-phenylmethyl-4-(methoxymethyl)piperidine-4-carboxylate (1.2 g, 51% yield) as a colorless oil. LC-MS: m / z [M+H] + 292.2.

[0447] Step 2: Lithium aluminum hydride (210 mg, 6.2 mmol) was added to a stirred solution of ethyl 1-benzyl-4-(methoxymethyl)piperidin-4-carboxylate (1.2 g, 4.1 mmol) in THF (15.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 20 min, then quenched with cold water and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over Na₂SO₄ and evaporated under reduced pressure. The residue was purified by rapid silica gel chromatography (petroleum ether:ethyl acetate = 10:1 as eluent) to give [1-benzyl-4-(methoxymethyl)-4-piperidinyl]methanol (800 mg, 3.2 mmol, 78% yield) as a colorless oil. LC-MS: m / z [M+H] + : 250.2.

[0448] Step 3: Palladium / carbon (10% wt.%, 81.5 mg, 642 μmol) was added to a stirred solution of [1-benzyl-4-(methoxymethyl)-4-piperidinyl]methanol (800 mg, 3.2 mmol) in THF (10.0 mL). The reaction mixture was stirred at 25 °C for 16 h under a hydrogen atmosphere (balloon). The reaction mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure to give [4-(methoxymethyl)-4-piperidinyl]methanol (400 mg, 78% yield) as a colorless oil. The residue was used in the next reaction without further purification. LC-MS: m / z [M+H] + 160.1.

[0449] Intermediate 161

[0450] Step 1: Diisopropylaminolithium (2 N, 12.1 mmol, 6.0 mL) was added to a stirred solution of ethyl 1-benzylpiperidine-4-carboxylate (2.0 g, 8.1 mmol) in THF (15.0 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 1 h, followed by the addition of 2-bromoacetonitrile (1.2 g, 9.7 mmol, 676 μL). The mixture was stirred at -78 °C for 2 h, followed by quenching with water. The mixture was extracted with EtOAc (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography, eluting with EA / PE (0% to 50%), to give ethyl 1-benzyl-4-(cyanomethyl)piperidine-4-carboxylate (900 mg, 39% yield) as a colorless oil. LC-MS: m / z [M+H] + 287.1.

[0451] Step 2: Lithium aluminum hydride (160 mg, 4.7 mmol) was added to a stirred solution of ethyl 1-benzyl-4-(cyanomethyl)piperidin-4-carboxylate (900 mg, 3.1 mmol) in THF (10.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 20 min, then quenched with cold water and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over Na₂SO₄ and evaporated under reduced pressure. The residue was purified by rapid silica gel chromatography (petroleum ether:ethyl acetate = 10:1 as eluent) to give 2-[1-benzyl-4-(hydroxymethyl)-4-piperidinyl]acetonitrile (600 mg, 78% yield) as a colorless oil. LC-MS: m / z [M+H] + 245.1.

[0452] Step 3: Palladium / carbon (10% wt.%, 62.4 mg, 491 μmol) was added to a stirred solution of 2-[1-benzyl-4-(hydroxymethyl)-4-piperidinyl]acetonitrile (600 mg, 2.5 mmol) in THF (10.0 mL). The reaction mixture was stirred at 25 °C for 16 h under a hydrogen atmosphere (balloon). The reaction mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure to give 2-[4-(hydroxymethyl)-4-piperidinyl]acetonitrile (300 mg, 79% yield) as a colorless oil. The residue was used in the next step without further purification. LC-MS: m / z [M+H] + 155.1.

[0453] Part 2. Synthetic methods for preparing the claimed compounds

[0454] Examples 1 to 421 are intentionally left blank.

[0455] Example 422

[0456] Step 1: DIAD (205 mg, 1.02 mmol, 200 μL) was slowly added to a stirred solution of PPh3 (266 mg, 1.02 mmol) in THF (5.0 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min, followed by the sequential addition of 5-bromo-6-fluoropyridin-3-ol (150 mg, 781 μmol) and (S)-tetrahydrofuran-3-ol (89.0 mg, 1.02 mmol, 81.0 μL) at 0 °C. The resulting mixture was heated to room temperature and stirred for 16 h, followed by concentration under reduced pressure. The residue was purified by silica gel chromatography with elution using EtOAc / petroleum ether (EtOAc increased from 0% to 30% over 20 min) to give (R)-3-bromo-2-fluoro-5-((tetrahydrofuran-3-yl)oxy)pyridine (180 mg, 88% yield) as a colorless oil. LC-MS: m / z [M+H] + 262.0.

[0457] Step 2: In a stirred solution of (R)-3-bromo-2-fluoro-5-((tetrahydrofuran-3-yl)oxy)pyridine (200 mg, 763 μmol) in NMP (2.0 mL), potassium ethyl oxalate (238 mg, 1.53 mmol), dppp (47.2 mg, 114 μmol), and Pd(TFA)₂ (25.0 mg, 76.0 μmol) were added sequentially. The mixture was heated to 150 °C and stirred at that temperature for 20 hours. The reaction mixture was cooled to 25 °C, treated with water, and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc / petroleum ether = 3 / 1) to give ethyl (R)-2-fluoro-5-((tetrahydrofuran-3-yl)oxy)nicotinic acid as a colorless oil (20.0 mg, 10% yield). LC-MS: m / z [M+H] + 256.1.

[0458] Step 3: LiOH (9.0 mg, 392 μmol), methanol (1.0 mL), and water (1.0 mL) were added sequentially to a stirred solution of (R)-2-fluoro-5-((tetrahydrofuran-3-yl)oxy)nicotinic acid ester (20.0 mg, 78.0 μmol) in THF (2.0 mL) at 25 °C. The mixture was stirred at 25 °C for 2 hours, then acidified to pH 2.0 with HCl / EtOAc and concentrated under reduced pressure to give (R)-2-fluoro-5-((tetrahydrofuran-3-yl)oxy)nicotinic acid ester (10.0 mg, 56% yield) as a white solid, which was used in the next step without purification. LC-MS: m / z [M+H] + 228.0.

[0459] Step 4: TEA (22.0 mg, 220 μmol, 31.0 μL) and POCl3 (20.0 mg, 132 μmol, 12.0 μL) were added sequentially and slowly to a stirred solution of (R)-2-fluoro-5-((tetrahydrofuran-3-yl)oxy)nicotinic acid (10.0 mg, 44.0 μmol) and (R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl-1-amine (10.0 mg, 48.0 μmol) in DCM (2.0 mL). The resulting mixture was heated to 25 °C and stirred at 25 °C for 2 hours. The reaction mixture was quenched with ice water and extracted with DCM (2 × 25 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc / petroleum ether = 3 / 1) to give 2-fluoro-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-5-(((R)-tetrahydrofuran-3-yl)oxy)nicotinamide (13.0 mg, 71% yield) as a colorless oil. LC-MS: m / z [M+H] + 417.1.

[0460] Step 5: TEA (16.0 mg, 156 μmol, 22.0 μL) was added to a stirred solution of 2-fluoro-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-5-(((R)-tetrahydrofuran-3-yl)oxy)nicotinamide (13.0 mg, 31.0 μmol) and (R)-2-aminoprop-1-ol (7.0 mg, 94.0 μmol, 7.00 μL) in DMSO (1.0 mL). The resulting mixture was heated to 90 °C and stirred at that temperature for 20 h. The reaction mixture was cooled to 25 °C, treated with water, and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-(((R)-1-hydroxypropyl-2-yl)amino)-5-(((R)-tetrahydrofuran-3-yl)oxy)nicotinamide (12.0 mg, 81% yield), a pale yellow oil, which was used in the next step without purification. LC-MS: m / z [M+H] + 472.2.

[0461] Step 6: TEA (11.0 mg, 106 μmol, 15.0 μL) and methanesulfonic anhydride (7.0 mg, 42.0 μmol) were added sequentially to a stirred solution of N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-(((R)-1-hydroxypropyl-2-yl)amino)-5-(((R)-tetrahydrofuran-3-yl)oxy)nicotinamide (10.0 mg, 21.0 μmol) in DCM (1.0 mL). The resulting mixture was stirred at 25 °C for 10 min. The reaction mixture was quenched with aqueous NaHCO3 solution and extracted with DCM (3 × 10 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=12 / 1) to give (R)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(((R)-tetrahydrofuran-3-yl)oxy)-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (4.1 mg, 43% yield) as a pale yellow solid. LC-MS: m / z [M+H] + 454.2.

[0462] Example 441

[0463] LiHMDS (1.0 M in THF, 336 μL, 336 μmol) was added to a stirred solution of (2R)-6-bromo-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (50 mg, 112 μmol) and tetrahydropyran-4-carboxynitrile (37.4 mg, 336 μmol, 36 μL) in THF (2.0 mL). The reaction mixture was stirred at 25 °C for 16 h, then quenched with aqueous NH4Cl solution and extracted with EtOAc (10 mL × 2). The combined organic phases were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC by elution with CH3CN / water (CH3CN increased from 20% to 50% within 6 minutes) to give (2R)-6-(4-cyanotetrahydropyran-4-yl)-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (1.8 mg, 3% yield) as a yellow solid. LC-MS: m / z [M+H] + 477.1.

[0464] Example 520

[0465] Step 1: To a stirred solution of (2R)-6-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (intermediate 50, 400 mg, 934 μmol) in 1,4-dioxane (8.0 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane-2-yl)-1,3,2-dioxaborhexacyclopentane (474 ​​mg, 1.87 mmol), potassium acetate (275 mg, 2.80 mmol), and Pd(dppf)Cl2·DCM (76.3 mg, 93.4 μmol) were added sequentially. The reaction mixture was heated to 95°C and stirred at that temperature for 3 hours. The reaction mixture was cooled to 25°C and used in the next step without further purification. LC-MS: m / z [M+H-81] + 394.2.

[0466] Step 2: To a stirred solution of (2R)-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (100 mg, 210 μmol) in 1,4-dioxane (5.0 mL), 2-bromopyridine-3-carboxynitrile (77.0 mg, 420 μmol), Pd(dppf)Cl2 (15.4 mg, 21.0 μmol), Cs2CO3 (171 mg, 526 μmol), and water (1.0 mL) were added sequentially. The mixture was heated to 100 °C and stirred at that temperature for 8 hours. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by preparative HPLC by elution with CH3CN / water (CH3CN increased from 20% to 55% over 7 minutes) to give (2R)-6-(3-cyano-2-pyridyl)-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (30 mg, 32% yield) as a yellow solid. LC-MS: m / z [M+H] + 452.2.

[0467] Similar to the representative procedure described in Example 520, the following examples were prepared.

[0468]

[0469]

[0470]

[0471]

[0472] Example 675

[0473] To a stirred solution of (R)-6-chloro-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methyl-2,3-dihydroimidazo[1,2-b]pyridazin-8-carboxamide (45 mg, 112 μmol) in 1,4-dioxane (2.5 mL), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-1H-pyrazol-1-yl)prop-2-ol (59.4 mg, 223 μmol), Pd(dppf)Cl2 (4.1 mg, 5.60 μmol), K2CO3 (38.6 mg, 279 μmol), and water (0.5 mL) were added sequentially. The mixture was heated to 100 °C and stirred at that temperature for 6 hours. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc=100%) to give (R)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-6-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-2-methyl-2,3-dihydroimidazo[1,2-b]pyridazine-8-carboxamide (48.0 mg, 85% yield) as an orange solid. LC-MS: m / z [M+H] + 507.1.

[0474] Example 860

[0475] Step 1: At 25 °C, tert-butyl-dimethyl-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-methyl-2,3-dihydroimidazo[1,2-b]pyridazin-8-carboxamide (40 mg, 99 μmol) was added sequentially to a stirred solution of (2R)-6-chloro-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]methoxy]silane (52 mg, 148 μmol), Cs₂CO₃ (97.1 mg, 298 μmol), and Pd(dppf)Cl₂ (7.3 mg, 10 μmol) in dioxane (3 mL) and water (0.6 mL). The mixture was heated to 100 °C and stirred at that temperature for 16 hours. The mixture was then dissolved in water (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether (0% to 40%), to give (2R)-6-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-pyridyl]-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-methyl-2,3-dihydroimidazo[1,2-b]pyridazine-8-carboxamide (49 mg, 84% yield) as a red solid. LC-MS: m / z [M+H] + 590.3.

[0476] Step 2: TBAF (46.4 mg, 166 μmol) was added to a stirred solution of (2R)-6-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-pyridyl]-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-methyl-2,3-dihydroimidazo[1,2-b]pyridazine-8-carboxamide (49 mg, 83 μmol) in THF (3 mL). The mixture was stirred at 25 °C for 1 hour, then dissolved in water (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC by elution with CH3CN / water (CH3CN increased from 20% to 95% over 10 minutes) to give (2R)-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-6-[2-(hydroxymethyl)-4-pyridyl]-2-methyl-2,3-dihydroimidazo[1,2-b]pyridazine-8-carboxamide (3.3 mg, 8% yield) as an orange solid. LC-MS: m / z [M+H] + 476.2.

[0477] Similar to the representative procedure described in Example 675, the following example was prepared.

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510] Example 717

[0511] To (2S,6R)-11-(3,6-dihydro-2H-pyran-4-yl)-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-1,7-diazatricyclo[6.4.0.0] 2,6 Palladium / carbon (10% wt.%, 5.3 mg, 42 μmol) was added to a solution of dodecacarbon-7,9,11-trien-9-carboxamide (10 mg, 21 μmol) in THF (5 mL). The mixture was stirred at room temperature under a hydrogen atmosphere (balloon) for 30 minutes. The reaction mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give (2S,6R)-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-11-tetrahydropyran-4-yl-1,7-diazatricyclo[6.4.0.0] as a yellow solid. 2,6 Dodecano-7,9,11-triene-9-carboxamide (3.0 mg, 30% yield). LC-MS: m / z [M+H] + 478.0.

[0512] Similar to the representative procedure described in Example 717, the following example was prepared.

[0513]

[0514]

[0515] Example 584

[0516] Step 1: To a stirred solution of (R)-6-chloro-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-2,3-dihydroimidazo[1,2-b]pyridazine-8-carboxamide (80.0 mg, 208 μmol) in 1,4-dioxane (5.0 mL), tert-butyl (4-methylpiperidin-4-yl)carbamate (111 mg, 520 μmol), t-BuXPhos Pd G3 (16.5 mg, 21.0 μmol), t-BuXhos (9.0 mg, 21.0 μmol), and t-BuONa (48.0 mg, 506 μmol) were added sequentially. The mixture was heated to 85 °C and stirred at that temperature for 12 hours. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc=100%) to give tert-butyl (1-((R)-8-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)carbamoyl)-2-methyl-2,3-dihydroimidazo[1,2-b]pyridazin-6-yl)-4-methylpiperidin-4-yl)carbamate (10.0 mg, 9% yield), as a red oil. LC-MS: m / z [M+H] + 563.3.

[0517] Step 2: TFA (745 mg, 6.53 mmol, 500 µL) was added to a stirred solution of (1-((R)-8-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)carbamoyl)-2-methyl-2,3-dihydroimidazo[1,2-b]pyridazin-6-yl)-4-methylpiperidin-4-yl)carbamate (2.0 mL) in DCM (25 °C). The mixture was stirred at 25 °C for 2 hours, followed by concentration under reduced pressure. The residue was purified by preparative HPLC by elution with CH3CN / water (CH3CN increased from 35% to 50% over 8 minutes) to give (R)-6-(4-amino-4-methylpiperidin-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-2,3-dihydroimidazo[1,2-b]pyridazine-8-carboxamide (4.0 mg, 49% yield) as a yellow solid. LC-MS: m / z [M+H] + 463.2.

[0518] Similar to the representative program described in Example 584, the following examples were prepared.

[0519]

[0520]

[0521]

[0522]

[0523]

[0524] Example 530

[0525] To a stirred solution of (R)-6-chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2,2-dimethyl-2,3-dihydroimidazo[1,2-b]pyridazine-8-carboxamide (300 mg, 752 μmol) in 1,4-dioxane (10.0 mL), 4-methylpiperidin-4-ol (173 mg, 1.50 mmol), RuPhos Pd G4 (32.0 mg, 38.0 μmol), and Cs₂CO₃ (735 mg, 2.26 mmol) were added sequentially. The mixture was heated to 100 °C and stirred at that temperature for 12 hours. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether (EtOAc increased from 0% to 100% over 30 minutes) to give (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(4-hydroxy-4-methylpiperidin-1-yl)-2,2-dimethyl-2,3-dihydroimidazo[1,2-b]pyridazine-8-carboxamide (221 mg, 62% yield) as a red solid. LC-MS: m / z [M+H] + 478.3.

[0526] Example 594

[0527] To a stirred solution of (R)-6-chloro-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-2,3-dihydroimidazo[1,2-b]pyridazine-8-carboxamide (40.0 mg, 104 μmol) in 1,4-dioxane (4.0 mL), 1,8-diazaspiro[4.5]dec-2-one (40.0 mg, 260 μmol), RuPhos Pd G4 (4.4 mg, 5.0 μmol), and Cs₂CO₃ (102 mg, 312 μmol) were added sequentially. The mixture was heated to 100 °C and stirred at that temperature for 12 hours. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by preparative HPLC by elution with CH3CN / water (CH3CN increased from 30% to 50% over 8 minutes) to give (R)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(2-oxo-1,8-diazaspiro[4.5]dec-8-yl)-2,3-dihydroimidazo[1,2-b]pyridazine-8-carboxamide (0.9 mg, 2% yield) as an orange solid. LC-MS: m / z [M+H] + 503.2.

[0528] Example 627

[0529] To a stirred solution of (R)-6-chloro-N-(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2,2-dimethyl-2,3-dihydroimidazo[1,2-b]pyridazin-8-carboxamide (35.0 mg, 83.9 μmol) in 1,4-dioxane (2.5 mL), 4-methylpiperidin-4-ol (14.5 mg, 126 μmol), RuPhos Pd G4 (3.6 mg, 4.2 μmol), and Cs₂CO₃ (82.0 mg, 252 μmol) were added sequentially. The mixture was heated to 100 °C and stirred at that temperature for 12 hours. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc=100%) to give (R)-N-(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-6-(4-hydroxy-4-methylpiperidin-1-yl)-2,2-dimethyl-2,3-dihydroimidazo[1,2-b]pyridazine-8-carboxamide (34.0 mg, 82% yield) as a red solid. LC-MS: m / z [M+H] + 496.2.

[0530] Similar to the representative procedure described with respect to Example 627, the following example was prepared.

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543] Example 554

[0544] Step 1: CDI (60.0 mg, 371 μmol) and TEA (63.0 mg, 619 μmol, 86.0 μL) were added sequentially to a stirred solution of N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(4-hydroxycyclohex-1-en-1-yl)-2,2-dimethyl-2,3-dihydroimidazo[1,2-b]pyridazine-8-carboxamide (57.0 mg, 124 μmol) in DCM (3.0 mL) at 25 °C. The mixture was stirred at 25°C for 2 hours to obtain a solution of 1H-imidazol-1-carboxylic acid 4-(8-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)carbamoyl)-2,2-dimethyl-2,3-dihydroimidazo[1,2-b]pyridazin-6-yl)cyclohex-3-en-1-yl ester (68.0 mg, 99% yield) in DCM, which was used directly in the next step. LC-MS: m / z [M+H] + 555.2.

[0545] Step 2: Cyclopropylamine (6.0 mg, 108 μmol, 8.0 μL) and TEA (11.0 mg, 108 μmol, 15.0 μL) were added sequentially to a stirred solution of 1H-imidazol-1-carboxylic acid 4-(8-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)carbamoyl)-2,2-dimethyl-2,3-dihydroimidazo[1,2-b]pyridazin-6-yl)cyclohex-3-en-1-yl ester (20.0 mg, 36.0 μmol) in DCM (1.0 mL) at 25 °C. The mixture was heated to 50 °C and stirred at that temperature for 18 hours. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc / petroleum ether = 1:1) to give 4-(8-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)carbamoyl)-2,2-dimethyl-2,3-dihydroimidazo[1,2-b]pyridazin-6-yl)cyclohexyl-3-en-1-yl ester (11.0 mg, 56% yield) as an orange solid. LC-MS: m / z [M+H] + 544.3.

[0546] Example 755

[0547] Step 1: Triethylamine (54.6 mg, 539 μmol, 75.2 μL) was added to a stirred solution of (2R)-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-6-(4-hydroxycyclohexen-1-yl)-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (50.0 mg, 108 μmol) and 1,1'-carbonyldiimidazole (52.5 mg, 324 μmol) in dichloromethane (5.0 mL). The reaction mixture was stirred at 25 °C for 1 hour, followed by vacuum concentration. The residue was purified by rapid silica gel column chromatography, eluting with hexane / ethyl acetate (ethyl acetate increased from 0% to 10%), to give a yellow solid of [4-[(2R)-8-[[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]carbamoyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridin-6-yl]cyclohex-3-en-1-yl]imidazolium-1-carboxylate (20.0 mg, 33% yield). LC-MS: m / z [M+H] + 548.1.

[0548] Step 2: [4-[(2R)-8-[[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]carbamoyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridin-6-yl]cyclohex-3-en-1-yl]imidazolium-1-carboxylate (10.0 mg, 17.9 μmol) was added to a stirred solution of dimethylamine hydrochloride (4.4 mg, 54 μmol) and triethylamine (9.1 mg, 90 μmol, 13 μL) in dichloromethane (3.0 mL). The reaction mixture was stirred at 25 °C for 10 min, followed by vacuum concentration. The residue was purified by preparative HPLC with MeCN / water to give a yellow solid of [4-[(2R)-8-[[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]carbamoyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridin-6-yl]cyclohex-3-en-1-yl]N,N-dimethyl ester (3.0 mg, 31% yield). LC-MS: m / z [M+H] + 535.2.

[0549] Similar to the representative procedure described in Example 554, the following example was prepared.

[0550]

[0551] Example 454

[0552] Step 1: At 25 °C, potassium ethyl oxalate (70.0 mg, 448 μmol), palladium(II) trifluoroacetate (7.5 mg, 22.4 μmol), and 1,3-bis(diphenylphosphino)propane (13.9 mg, 33.6 μmol) were added sequentially to a stirred solution of (2R)-6-bromo-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]ethyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (100 mg, 224 μmol) in NMP (3.0 mL). The mixture was heated to 150 °C and stirred at that temperature for 16 hours. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10:1) to give (R)-8-(((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-6-carboxylic acid ethyl ester (21.0 mg, 21% yield) as a yellow solid. LC-MS: m / z [M+H] + 440.2.

[0553] Step 2: An aqueous solution of LiOH (1.4 mL, 1.0 M, 1.4 mmol) was added to a stirred solution of (R)-8-(((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-6-carboxylate (21.0 mg, 47.8 μmol) in THF (1.0 mL) and MeOH (0.5 mL). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove most of the THF. The mixture was acidified to pH = 3 with aqueous HCl (2.0 M) and extracted with EtOAc. The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give (2R)-8-[[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]carbamoyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-6-carboxylic acid (19.0 mg, 97% yield), a yellow solid, which was used in the next step without further purification. LC-MS: m / z [M+H] + 412.2.

[0554] Step 3: Phosphoryl trichlorophosphate (21.3 mg, 138 μmol, 13.0 μL) was added to a stirred solution of (2R)-8-[[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]carbamoyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-6-carboxylic acid (19.0 mg, 46.2 μmol) and morpholine (8.0 mg, 92.4 μmol, 8.0 μL) in DCM (3.0 mL) and pyridine (1.0 mL). The mixture was heated to 25 °C and stirred at that temperature for 1 hour, followed by the addition of ice water and extraction with DCM. The organic phase was washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM / MeOH = 10:1) to give (R)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(morpholino-4-carbonyl)-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (3.6 mg, 16% yield) as a yellow solid. LC-MS: m / z [M+H] + 481.2.

[0555] Example 546

[0556] NH4COONH2 (26.0 mg, 334 μmol) and PhI(OAc)2 (43.0 mg, 134 μmol) were added to a stirred solution of (R)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(3,6-dihydro-2H-thiopyran-4-yl)-2-methyl-2,3-dihydroimidazo[1,2-b]pyridazine-8-carboxamide (30.0 mg, 67.0 μmol) in ethanol (2.0 mL). The reaction mixture was stirred at 25 °C for 2 hours, followed by water treatment. The reaction mixture was extracted with EtOAc (2 × 10 mL), and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC by elution with CH3CN / water (CH3CN increased from 30% to 55% within 7 minutes) to give (2R)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(1-imino-1-oxo-1,2,3,6-tetrahydro-116-thiopyran-4-yl)-2-methyl-2,3-dihydroimidazo[1,2-b]pyridazine-8-carboxamide (3.5 mg, 11% yield) as an orange solid. LC-MS: m / z [M+H] + 480.1.

[0557] Example 572

[0558] Step 1: A solution of N-[4-[(2R)-8-[[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]carbamoyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridin-6-yl]cyclohex-3-en-1-yl]tert-butyl carbamate (80 mg, 142.20 μmol) in HCl (4.0 M in ethyl acetate) (5 mL) was stirred at room temperature for 4 hours. LCMS showed that the reaction was complete. The reaction mixture was concentrated under vacuum to give the residue as (2R)-6-(4-aminocyclohexen-1-yl)-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridin-8-carboxamide (50 mg, 108.11 μmol, 76.03% yield). The crude product is used directly in the next reaction without further purification. Chemical formula: C 24 H 26 F4N4O. LCMS(ESI) + ) [(M+H) + ]: 463.2.

[0559] Step 2: Triethylamine (6.6 mg, 65 μmol, 9.0 μL) was added to a mixture of (2R)-6-(4-aminocyclohexen-1-yl)-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (10.0 mg, 21.6 μmol) in dichloromethane (3.0 mL), followed by the addition of 2-chloroethyl chloroformate (3.1 mg, 22 μmol). The mixture was stirred at the stated temperature for 2.5 hours, then diluted with 5.0 mL of water and extracted with DCM (3 × 20 mL). The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC with MeCN / water to give N-[4-[(2R)-8-[[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]carbamoyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridin-6-yl]cyclohexyl-3-en-1-yl]carbamate 2-chloroethyl ester (6.0 mg, 49% yield) as a yellow solid. LC-MS: m / z [M+H] + 568.2.

[0560] Step 3: A mixture of N-[4-[(2R)-8-[[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]carbamoyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridin-6-yl]cyclohex-3-en-1-yl]carbamate 2-chloroethyl ester (6.0 mg, 11 μmol) and potassium carbonate (4.4 mg, 32 μmol) in DMF (2.0 mL) was heated to 80 °C and stirred at said temperature for 3 hours. The solvent was removed under vacuum, and the residue was purified by preparative HPLC with MeCN / water to give (2R)-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-methyl-6-[4-(2-oxooxazolidine-3-yl)cyclohexen-1-yl]-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (2.0 mg, 36% yield) as a yellow solid. LC-MS: m / z [M+H] + 533.2.

[0561] Example 578

[0562] A mixture of (2R)-6-(4-aminocyclohexen-1-yl)-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (5.0 mg, 11 μmol) and tetrahydrofuran-2,5-dione (10.8 mg, 108 μmol) was dissolved in triethylamine (1.0 mL) at 25 °C. The reaction mixture was heated to 110 °C and stirred at that temperature for 4 hours. The mixture was concentrated under vacuum, and the residue was purified by preparative HPLC with MeCN / water to give (2R)-6-[4-(2,5-dioxopyrrolidone-1-yl)cyclohexen-1-yl]-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (3.0 mg, 51% yield) as a yellow solid. LC-MS: m / z [M+H] + 545.2.

[0563] Example 596

[0564] Step 1: Oxaloyl chloride (165 mg, 1.30 mmol, 114 μL) was added dropwise to a stirred solution of 3-fluoropropionic acid (100 mg, 1.09 mmol) and triethylamine (330 mg, 3.26 mmol, 454 μL) in dichloromethane (3.0 mL) at 0 °C. The mixture was stirred at 25 °C for 30 minutes and then used directly in the next step without further processing.

[0565] Step 2: Triethylamine (27.5 mg, 271 μmol, 37.8 μL) was added to a mixture of (2R)-6-(4-aminocyclohexen-1-yl)-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (20.0 mg, 43.2 μmol) in dichloromethane (2.0 mL), followed by the addition of 3-fluoropropionyl chloride (10.0 mg, 90.5 μmol). The mixture was stirred at the stated temperature for 2.5 hours, after which the solvent was removed under vacuum. The residue was purified by preparative HPLC with MeCN / water to give (2R)-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-methyl-6-[4-(propenyloylamino)cyclohexen-1-yl]-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (2.0 mg, 4% yield) as a yellow solid. LC-MS: m / z [M+H] + 517.2.

[0566] Example 597

[0567] Triethylamine (5.5 mg, 54.1 μmol, 7.53 μL) was added to a mixture of (2R)-6-(4-aminocyclohexen-1-yl)-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (10.0 mg, 21.6 μmol) in dichloromethane (5.0 mL), followed by the addition of 2-methoxyacetyl chloride (2.4 mg, 22 μmol). The mixture was stirred at the stated temperature for 2.5 hours, then diluted with 5.0 mL of water and extracted with DCM (3 × 20 mL). The organic phase was washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC with MeCN / water to give (2R)-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-6-[4-[(2-methoxyacetyl)amino]cyclohexen-1-yl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (5.0 mg, 43% yield) as a yellow solid. LC-MS: m / z [M+H] + 535.2.

[0568] Example 602

[0569] Step 1: Sodium hydroxide (1.0 mL, 4.0 mol / L in water, 4.0 mmol) was added dropwise to a stirred solution of ethyl 2-fluoroacetate (100 mg, 943 μmol, 91.5 μL) in ethanol (3.0 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 12 hours, after which the solvent was removed under vacuum to give sodium 2-fluoroacetate (50.0 mg, 68% yield) as a white solid, which was used directly in the next step without further purification.

[0570] Step 2: A mixture of sodium 2-fluoroacetate (10.0 mg, 128 μmol), (2R)-6-(4-aminocyclohexen-1-yl)-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (59.3 mg, 128 μmol), HATU (58.4 mg, 154 μmol), and DIPEA (38.9 mg, 384 μmol, 53.6 μL) in DMF (2.0 mL) was stirred at 25 °C for 1 hour, and then diluted with EtOAc (20.0 mL). The mixture was washed with water (20 mL), and the organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel column chromatography with elution using MeOH / DCM (MeOH increased from 0% to 50%) to give (2R)-6-[4-[(2-fluoroacetyl)amino]cyclohexen-1-yl]-N-[(1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (2.0 mg, 3% yield) as a white solid. LC-MS: m / z [M+H] + 523.2.

[0571] Example 601

[0572] Step 1: Phosphoryl trichloroethylene (340 mg, 2.22 mmol, 207 μL) was added to a stirred solution of (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl-1-amine hydrochloride (200 mg, 739 μmol) and 5-bromo-2-fluoronicotinic acid (195 mg, 886 μmol) in pyridine (1.0 mL) and DCM (3.0 mL). The mixture was heated to 25 °C and stirred at that temperature for 2 hours, followed by the addition of ice water. The mixture was extracted with DCM, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with elution using DCM / MeOH (MeOH increased from 0% to 5% over 30 minutes) to give (R)-5-bromo-2-fluoro-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)nicotinamide (300 mg, 93% yield) as a white solid. LC-MS: m / z [M+H] + 437.2.

[0573] Step 2: TEA (209 mg, 2.06 mmol, 287 μL) was added to a stirred solution of 5-bromo-2-fluoro-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]pyridine-3-carboxamide (300 mg, 688 μmol) and (R)-(-)-2-amino-1-propanol (77.5 mg, 1.03 mmol) in DMSO (5.0 mL). The mixture was heated to 80 °C and stirred at that temperature for 6 hours. The mixture was diluted with EA, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (Z)-5-bromo-2-(((R)-1-hydroxypropyl-2-yl)imino)-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-1,2-dihydropyridine-3-carboxamide (340 mg, 100% yield), a yellow oil. LC-MS: m / z [M+H] + 492.0.

[0574] Step 3: TEA (350 mg, 3.46 mmol, 482 μL) and methanesulfonic anhydride (241 mg, 1.38 mmol) were added to a stirred solution of (Z)-5-bromo-2-(((R)-1-hydroxypropyl-2-yl)imino)-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-1,2-dihydropyridine-3-carboxamide (340 mg, 692 μmol) in DCM (5.0 mL). The mixture was stirred at 25 °C for 30 min, then quenched with water, diluted with DCM, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with elution using DCM / MeOH (MeOH increased from 0% to 2% over 30 minutes) to give (R)-6-bromo-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (270 mg, 82% yield) as a yellow solid. LC-MS: m / z [M+H] + 474.0.

[0575] Step 4: To a stirred solution of (2R)-6-bromo-2-methyl-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (50.0 mg, 106 μmol) in 1,4-dioxane (3.0 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)pyridine (43.3 mg, 211 μmol), potassium phosphate (67.3 mg, 317 μmol), Pd(dppf)Cl2 (7.7 mg, 10.6 μmol), and water (0.3 mL) were added sequentially. The mixture was heated to 100 °C and stirred at that temperature for 8 hours. The reaction mixture was cooled to 25 °C, diluted with water, and extracted with EtOAc. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM / MeOH = 10:1) to give (R)-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(pyridin-4-yl)-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (30.0 mg, 60% yield) as a yellow solid. LC-MS: m / z [M+H] + 472.2.

[0576] Step 5: Stannous chloride dihydrate (57.4 mg, 255 μmol) was added to a stirred solution of (2R)-2-methyl-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-(4-pyridyl)-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (30.0 mg, 63.6 μmol) in 2.0 N HCl aqueous solution (2.0 mL) and ethanol (2.0 mL). The mixture was stirred at 25 °C for 2 hours, then the mixture was adjusted to pH = 10 with 2.0 M NaOH aqueous solution and extracted with DCM, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM / MeOH = 10:1) to give (R)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(pyridin-4-yl)-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (17.0 mg, 60% yield) as a yellow solid. LC-MS: m / z [M+H] + 442.2.

[0577] Similar to the representative procedure described with respect to Example 601, the following example was prepared.

[0578]

[0579] Example 655

[0580] Step 1: Stannous chloride dihydrate (143 mg, 634 μmol) was added to a stirred solution of (R)-6-bromo-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (60.0 mg, 127 μmol) in HCl aqueous solution (3.0 mL, 3.0 N) and ethanol (3.0 mL). The mixture was stirred at 25 °C for 4 hours, then adjusted to pH = 10 with NaOH aqueous solution (2.0 M) and extracted with DCM. The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10:1) to give (R)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-bromo-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (50.0 mg, 89% yield) as a yellow solid. LC-MS: m / z [M+H] + 444.2.

[0581] Step 2: To a stirred solution of (2R)-N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-6-bromo-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (40.0 mg, 90.2 μmol) in 1,4-dioxane (3.0 mL), 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-1H-pyrazole (46.6 mg, 180 μmol), potassium phosphate (57.5 mg, 270 μmol), and Pd(dppf)Cl2 (6.6 mg, 9.0 μmol) and water (0.3 mL) were added sequentially. The mixture was heated to 100 °C and stirred at that temperature for 8 hours. The reaction mixture was cooled to 25°C, diluted with water (10 mL), and extracted with EtOAc (20 mL × 2). The combined organic phases were dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10:1) to give (R)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (14.0 mg, 31% yield) as a yellow solid. LC-MS: m / z [M+H] + 495.2.

[0582] Similar to the representative procedure described in Example 655, the following example was prepared.

[0583]

[0584]

[0585] Example 687

[0586] 4-ethynylpyridine (29.8 mg, 289 μmol), triphenylphosphine (9.5 mg, 36 μmol), and palladium diacetate (16.2 mg, 72.2 μmol) were added sequentially to a stirred solution of (R)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-bromo-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (80.0 mg, 180 μmol) in TEA (3.0 mL) and THF (3.0 mL) at 25 °C. The mixture was heated to 100 °C and stirred at that temperature for 48 hours. The reaction mixture was cooled to 25 °C, diluted with water (10 mL), and extracted with EtOAc (20 mL × 2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10:1) to give (R)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(pyridin-4-ylethynyl)-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (14.0 mg, 17% yield) as a yellow solid. LC-MS: m / z [M+H] + 466.2.

[0587] Similar to the representative program described in Example 687, the following example was prepared.

[0588]

[0589] Example 599

[0590] Step 1: To a stirred solution of (2R)-6-chloro-2-methyl-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-2,3-dihydroimidazo[1,2-b]pyridazin-8-carboxamide (80.0 mg, 186 μmol) in 1,4-dioxane (3.0 mL), 4-methylpiperidin-4-carboxynitrile (57.8 mg, 465 μmol), RuPhos Pd G4 (15.8 mg, 18.6 μmol), and Cs₂CO₃ (182 mg, 558 μmol) were added sequentially. The mixture was heated to 100 °C and stirred at that temperature for 20 hours. The reaction mixture was cooled to 25 °C, diluted with water, and extracted with EtOAc. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM / MeOH = 10:1) to give (R)-6-(4-cyano-4-methylpiperidin-1-yl)-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-2,3-dihydroimidazo[1,2-b]pyridazine-8-carboxamide (40.0 mg, 41% yield) as a red solid. LC-MS: m / z [M+H] + 518.2.

[0591] Step 2: Stannous chloride dihydrate (87.2 mg, 386 μmol) was added to a stirred solution of (2R)-6-(4-cyano-4-methyl-1-pyridyl)-2-methyl-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-2,3-dihydroimidazo[1,2-b]pyridazine-8-carboxamide (40.0 mg, 77.3 μmol) in 2.0 N HCl aqueous solution (2.0 mL) and ethanol (2.0 mL). The mixture was stirred at 25 °C for 4 hours. The mixture was adjusted to pH 10 with 2.0 M NaOH aqueous solution and extracted with DCM, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM / MeOH = 10:1) to give (R)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(4-cyano-4-methylpiperidin-1-yl)-2-methyl-2,3-dihydroimidazo[1,2-b]pyridazine-8-carboxamide (20.0 mg, 53% yield) as a yellow solid. LC-MS: m / z [M+H] + 488.2.

[0592] Example 621

[0593] Step 1: Stannous chloride dihydrate (143 mg, 634 μmol) was added to a stirred solution of (R)-6-bromo-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (60.0 mg, 127 μmol) in 3.0 N HCl aqueous solution (3.0 mL) and ethanol (3.0 mL). The mixture was stirred at 25 °C for 4 hours. The mixture was adjusted to pH = 10 with 2.0 M NaOH aqueous solution and extracted with DCM. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM / MeOH = 10:1) to give (R)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-bromo-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (50.0 mg, 88% yield) as a yellow solid. LC-MS: m / z [M+H] + 444.2.

[0594] Step 2: Sodium tert-butoxide (32.5 mg, 338 μmol) and tBuXPhos-Pd-G3 (9.0 mg, 11.2 μmol) were added to a stirred solution of (2R)-N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-6-bromo-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (50.0 mg, 113 μmol) and morpholine (39.0 mg, 451 μmol, 39.0 μL) in 1,4-dioxane (3.0 mL). The mixture was heated to 100 °C and stirred at that temperature for 24 hours. The mixture was cooled to 25 °C, diluted with EA, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM / MeOH = 10:1) to give (R)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-N-morpholino-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (2.0 mg, 4% yield) as a yellow solid. LC-MS: m / z [M+H] + 450.2.

[0595] Example 606

[0596] Step 1: TEA (3.78 g, 37.34 mmol, 5.20 mL), tributyl(1-ethoxyvinyl)tin (5.39 g, 14.9 mmol, 5.05 mL), and bis(triphenylphosphine)palladium(II) dichloride (873 mg, 1.24 mmol) were added sequentially to a stirred solution of 3-bromo-5-(trifluoromethyl)phenol (3.00 g, 12.5 mmol) in anhydrous 1,4-dioxane (30.0 mL) at 25 °C. The mixture was heated to 100 °C and stirred at that temperature for 16 h. The reaction mixture was cooled to room temperature and treated with 1.0 N HCl and stirred for 3 h. The aqueous layer was extracted with EtOAc, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel column chromatography, eluting with EtOAc / PE (from 10% to 20% over 60 minutes) to give a yellow oil, 1-(3-hydroxy-5-(trifluoromethyl)phenyl)ethyl-1-one (2.40 g, 94% yield). LC-MS: m / z [M+H] + 205.2.

[0597] Step 2: A mixture of 1-[3-hydroxy-5-(trifluoromethyl)phenyl]ethyl-1-one (2.40 g, 11.8 mmol) and (R)-2-methylpropane-2-sulfinamide (2.85 g, 23.5 mmol) in THF (25.0 mL) and ethyl titanate (12.0 mL) was heated to 85 °C and stirred at that temperature for 6 hours. The mixture was diluted in DCM and water and filtered. The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel column chromatography, eluting with EtOAc / PE (from 10% to 100% in 30 min) to give (R,E)-N-(1-(3-hydroxy-5-(trifluoromethyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide (3.60 g, 99% yield) as a yellow solid. LC-MS: m / z [M+H] + 308.2.

[0598] Step 3: Cerium trichloride (1.73 g, 7.03 mmol) was added to a stirred mixture of (R,E)-N-(1-(3-hydroxy-5-(trifluoromethyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide (3.60 g, 11.7 mmol) in MeOH (40.0 mL) at 25 °C, followed by fractional addition of NaBH4 (886 mg, 23.4 mmol). The mixture was stirred at 25 °C for 30 min, then ice water was added and extracted with DCM. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel column chromatography (eluting with MeOH / DCM, increasing from 0% to 4% in 30 min) to give (R)-N-((R)-1-(3-hydroxy-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (3.00 g, 83% yield) as a yellow solid. LC-MS: m / z [M+H] + 310.2.

[0599] Step 4: HCl / EtOH (6.0 mL, 4.0 M, 24 mmol) was added to a stirred solution of (R)-N-((R)-1-(3-hydroxy-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (0.65 g, 2.10 mmol) in ethanol (6.0 mL) at 25 °C. The mixture was stirred at 25 °C for 0.5 h, followed by vacuum concentration to give (R)-3-(1-aminoethyl)-5-(trifluoromethyl)phenol hydrochloride (500 mg, 98% yield) as a yellow solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 206.2.

[0600] Step 5: DIPEA (802 mg, 6.21 mmol, 1.08 mL) and HATU (1.18 g, 3.10 mmol) were added to a stirred solution of 3-[(1R)-1-aminoethyl]-5-(trifluoromethyl)phenol hydrochloride (500 mg, 2.07 mmol) and 5-bromo-2-fluoronicotinic acid (546 mg, 2.48 mmol) in DCM (5.0 mL) at 25 °C. The mixture was stirred at 25 °C for 2 hours, followed by the addition of ice water and extraction with DCM. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with elution using DCM / MeOH (MeOH eluted from 0% to 5% over 30 minutes) to give (R)-5-bromo-2-fluoro-N-(1-(3-hydroxy-5-(trifluoromethyl)phenyl)ethyl)nicotinamide (800 mg, 95% yield) as a white solid. LC-MS: m / z [M+H] + 408.2.

[0601] Step 6: TEA (596 mg, 5.89 mmol, 821 μL) was added to a stirred solution of 5-bromo-2-fluoro-N-[(1R)-1-[3-hydroxy-5-(trifluoromethyl)phenyl]ethyl]pyridine-3-carboxamide (800 mg, 1.96 mmol) and acetyl chloride (185 mg, 2.36 mmol, 143 μL) in DCM (10.0 mL). The mixture was stirred at 25 °C for 2 hours, followed by the addition of ice water and extraction with DCM. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with elution using DCM / MeOH (MeOH increased from 0% to 5% over 30 minutes) to give (R)-3-(1-(5-bromo-2-fluoronicotinamide)ethyl)-5-(trifluoromethyl)phenyl acetate (420 mg, 48% yield) as a white solid. LC-MS: m / z[M+H] + 450.2.

[0602] Step 7: TEA (284 mg, 2.81 mmol, 391 μL) was added to a stirred solution of [3-[(1R)-1-[(5-bromo-2-fluoro-pyridin-3-carbonyl)amino]ethyl]-5-(trifluoromethyl)phenyl]acetate (420 mg, 935 μmol) and (R)-2-aminoprop-1-ol (105 mg, 1.40 mmol) in DMSO (4.0 mL). The mixture was heated to 80 °C and stirred at that temperature for 6 hours. The mixture was diluted with EA, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (Z)-5-bromo-N-((R)-1-(3-hydroxy-5-(trifluoromethyl)phenyl)ethyl)-2-(((R)-1-hydroxypropyl-2-yl)imino)-1,2-dihydropyridine-3-carboxamide (430 mg, 99% yield), which was used directly in the next step without further purification. LC-MS: m / z [M+H + 462.0.

[0603] Step 8: TEA (471 mg, 4.65 mmol, 648 μL) was added to a stirred solution of (Z)-5-bromo-N-((R)-1-(3-hydroxy-5-(trifluoromethyl)phenyl)ethyl)-2-(((R)-1-hydroxypropyl-2-yl)imino)-1,2-dihydropyridine-3-carboxamide (430 mg, 930 μmol) in DCM (8.0 mL), followed by the addition of methanesulfonic anhydride (324 mg, 1.86 mmol). The mixture was stirred at 25 °C for 2 hours, then ice water was added and the mixture was extracted with DCM. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with elution using DCM / MeOH (MeOH increased from 0% to 2% over 30 minutes) to give 3-((R)-1-((R)-6-bromo-2-methyl-2,3-dihydroimidazo[1,2-a]pyridin-8-carboxamido)ethyl)-5-(trifluoromethyl)phenyl ester of methanesulfonic acid (420 mg, 86% yield) as a yellow solid. LC-MS: m / z [M+H] + 522.0.

[0604] Step 9: [3-[(1R)-1-[[(2R)-6-bromo-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carbonyl]amino]ethyl]-5-(trifluoromethyl)phenyl] ester (420 mg, 804 μmol) was added to a stirred solution of ethanol (6.0 mL, 20% wt.%) and ethanol (6.0 mL) containing sodium ethoxide. The mixture was stirred at 25 °C for 2 hours, followed by the addition of ice water and extraction with DCM. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with elution using DCM / MeOH (MeOH increased from 0% to 5% over 30 minutes) to give (R)-6-bromo-N-((R)-1-(3-hydroxy-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (260 mg, 73% yield) as a white solid. LC-MS: m / z [M+H] + 445.2.

[0605] Step 10: To a stirred solution of (2R)-6-bromo-N-[(1R)-1-[3-hydroxy-5-(trifluoromethyl)phenyl]ethyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (50.0 mg, 113 μmol) in 1,4-dioxane (3.0 mL), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-1H-pyrazole (46.8 mg, 225 μmol), potassium phosphate (71.7 mg, 337 μmol), Pd(dppf)Cl2 (8.2 mg, 11.3 μmol), and water (0.3 mL) were added sequentially. The mixture was heated to 100 °C and stirred at that temperature for 8 hours. The reaction mixture was cooled to 25 °C, diluted with water, and extracted with EtOAc. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM / MeOH = 10:1) to give (R)-N-((R)-1-(3-hydroxy-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (17.0 mg, 33% yield) as a yellow solid. LC-MS: m / z [M+H] + 446.2.

[0606] Similar to the representative procedure described with respect to Example 606, the following example was prepared.

[0607]

[0608] Example 605

[0609] Step 1: TEA (3.53 g, 34.9 mmol, 4.86 mL), tributyl(1-ethoxyvinyl)tin (5.04 g, 13.9 mmol, 4.71 mL), and bis(triphenylphosphine)palladium(II) dichloride (816 mg, 1.16 mmol) were added to a stirred solution of 3-bromo-4-fluoro-5-(trifluoromethyl)aniline (3.00 g, 11.6 mmol) in 1,4-dioxane (30.0 mL) at 25 °C. The mixture was heated to 100 °C and stirred at that temperature for 16 h. The reaction mixture was cooled to room temperature and treated with 1.0 N HCl and stirred for 3 h. The aqueous layer was extracted with EtOAc, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with elution using DCM / MeOH (MeOH increased from 0% to 2% over 30 minutes) to give a yellow oil, 1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl-1-one (2.40 g, 93% yield). LC-MS: m / z [M+H] + 222.2.

[0610] Step 2: A mixture of 1-[5-amino-2-fluoro-3-(trifluoromethyl)phenyl]ethyl ketone (2.40 g, 10.9 mmol) and (R)-2-methylpropane-2-sulfinamide (2.63 g, 21.7 mmol) in THF (25.0 mL) and ethyl titanate (10.0 mL) was heated to 85 °C and stirred at that temperature for 6 hours. The mixture was diluted in DCM and water and filtered. The filtrate was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel column chromatography, eluting with EtOAc / PE (from 10% to 100% in 30 minutes) to give (R,E)-N-(1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide (3.50 g, 99% yield) as a yellow solid. LC-MS: m / z [M+H] + 325.2.

[0611] Step 3: Cerium trichloride (1.60 g, 6.47 mmol, 402 μL) was added to a stirred mixture of (R,E)-N-(1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide (3.50 g, 10.8 mmol) in MeOH (30.0 mL) at 25 °C, followed by fractional addition of NaBH4 (817 mg, 21.6 mmol). The mixture was stirred for 30 minutes, then ice water was added and extracted with DCM. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel column chromatography, eluting with DCM / MeOH (from 0% to 4% in 30 minutes) to give (R)-N-((R)-1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (3.20 g, 90% yield) as a yellow solid. LC-MS: m / z [M+H] + 327.2.

[0612] Step 4: HCl / EtOH (30.0 mL, 4.0 M, 120 mmol) was added to a stirred solution of (R)-N-[(1R)-1-[5-amino-2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-methyl-propane-2-sulfinamide (3.20 g, 9.81 mmol) in ethanol (30.0 mL) at 25 °C. The mixture was stirred at this temperature for 0.5 h, followed by vacuum concentration to give (R)-3-(1-aminoethyl)-4-fluoro-5-(trifluoromethyl)aniline hydrochloride (2.50 g, 99% yield) as a yellow solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 259.2.

[0613] Step 5: DIPEA (600 mg, 4.64 mmol, 808 μL) and HATU (882 mg, 2.32 mmol) were added to a stirred solution of 3-[(1R)-1-aminoethyl]-4-fluoro-5-(trifluoromethyl)aniline hydrochloride (400 mg, 1.55 mmol) and 5-bromo-2-fluoronicotinic acid (408 mg, 1.86 mmol) in DCM (5.0 mL) at 25 °C. The mixture was stirred at 25 °C for 2 hours, then ice water was added and the mixture was extracted with DCM. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with elution using DCM / MeOH (MeOH increased from 0% to 5% over 30 minutes) to give (R)-N-(1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-5-bromo-2-fluoronicotinamide (600 mg, 91% yield) as a white solid. LC-MS: m / z [M+H] + 425.2.

[0614] Step 6: TEA (429 mg, 4.24 mmol, 591 μL) was added to a stirred solution of N-[(1R)-1-[5-amino-2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-5-bromo-2-fluoro-pyridine-3-carboxamide (600 mg, 1.41 mmol) and (R)-2-aminoprop-1-ol (159 mg, 2.12 mmol) in DMSO (10.0 mL). The mixture was heated to 80 °C and stirred at that temperature for 6 hours. The mixture was then diluted with EA, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (Z)-N-((R)-1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-5-bromo-2-(((R)-1-hydroxypropyl-2-yl)imino)-1,2-dihydropyridine-3-carboxamide (670 mg, 99% yield), a yellow oil. LC-MS: m / z [M+H] + 480.0.

[0615] Step 7: TEA (707 mg, 6.99 mmol, 974 μL) was added to a stirred solution of (2Z)-N-[(1R)-1-[5-amino-2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-5-bromo-2-[(1R)-2-hydroxy-1-methyl-ethyl]imino-1H-pyridine-3-carboxamide (670 mg, 1.40 mmol) in DCM (10.0 mL), followed by the addition of methanesulfonic anhydride (365 mg, 2.10 mmol). The mixture was stirred at 25 °C for 30 min, then ice water was added and the mixture was extracted with DCM. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with elution using DCM / MeOH (MeOH increased from 0% to 2% over 30 minutes) to give (R)-N-((R)-1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-6-bromo-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (160 mg, 25% yield) as a yellow solid. LC-MS: m / z [M+H] + 462.0.

[0616] Step 8: To a stirred solution of (2R)-N-[(1R)-1-[5-amino-2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-6-bromo-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (50.0 mg, 108 μmol) in 1,4-dioxane (3.0 mL), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)-1H-pyrazole (45.1 mg, 217 μmol), potassium phosphate (69.0 mg, 325 μmol), Pd(dppf)Cl2 (7.9 mg, 10.8 μmol), and water (0.3 mL) were added sequentially. The mixture was heated to 100 °C and stirred at that temperature for 8 hours. The reaction mixture was cooled to 25°C, diluted with water, extracted with EtOAc, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM / MeOH = 10:1) to give (R)-N-((R)-1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (5.6 mg, 11% yield) as a yellow solid. LC-MS: m / z [M+H] + 463.2.

[0617] Similar to the representative procedure described with respect to Example 605, the following example was prepared.

[0618]

[0619] Example 504

[0620] Hydroxylamine hydrochloride (14.8 mg, 213 μmol) was added to a stirred solution of (2R)-6-(2-acetyl-4-pyridyl)-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (10.0 mg, 21.4 μmol) in ethanol (2.0 mL) and water (0.5 mL). The mixture was heated to 80 °C and stirred at that temperature for 8 hours. The reaction mixture was diluted with water, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC by elution with CH3CN / water (CH3CN increased from 20% to 95% over 8 minutes) to give (2R)-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-6-[2-[(Z)-N-hydroxy-C-methyl-iminoyl]-4-pyridyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (6.5 mg, 63% yield) as an orange solid. LC-MS: m / z [M+H] + 484.2.

[0621] Example 492

[0622] To a stirred solution of (2R)-6-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (50 mg, 118 μmol) in dioxane (2.0 mL), 1H-pyrazole-4-carboxynitrile (16.3 mg, 175 μmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (16.6 mg, 117 μmol), Cs₂CO₃ (38.0 mg, 118 μmol), and CuI (22.2 mg, 117 μmol) were added sequentially. The mixture was heated to 110 °C and stirred at that temperature for 48 hours. The reaction mixture was cooled to 25 °C, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC by elution with CH3CN / water (CH3CN increased from 20% to 95% over 8 minutes) to give (2R)-6-(4-cyanopyrazol-1-yl)-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (11.6 mg, 23% yield) as an orange solid. LC-MS: m / z [M+H] + 441.1.

[0623] Similar to the representative procedure described with respect to Example 492, the following examples were prepared.

[0624]

[0625] Example 779

[0626] To a stirred solution of (R)-6-bromo-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (50.0 mg, 112 μmol) in 1,4-dioxane (3.0 mL), 4-(tributyltinyl)thiazole (62.9 mg, 168 μmol), bis(triphenylphosphine)palladium(II) dichloride (7.9 mg, 11 μmol), and TEA (56.7 mg, 560 μmol, 78.0 μL) were added sequentially. The mixture was heated to 100 °C and stirred at that temperature for 16 hours. The reaction mixture was cooled to 25 °C, diluted with water, and extracted with EtOAc. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM / MeOH = 10:1) to give (R)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(thiazolyl-4-yl)-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (4.8 mg, 10% yield) as a yellow solid. LC-MS: m / z [M+H] + 451.2.

[0627] Similar to the representative procedure described with respect to Example 779, the following examples were prepared.

[0628]

[0629] Example 648

[0630] Step 1: Sulfuric acid (7.07 g, 72.1 mmol) was added to a mixture of 4-fluoro-3-(trifluoromethyl)benzoic acid (3.00 g, 14.4 mmol) and nitric acid (15.0 mL) at 0 °C. The mixture was stirred at 75 °C for 5 hours, then quenched with ice water (40.0 mL) and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 4-fluoro-3-nitro-5-(trifluoromethyl)benzoic acid (2.50 g, 69% yield) as a white solid, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 253.9.

[0631] Step 2: Iron powder (1.65 g, 29.6 mmol, 211 μL) and ammonium chloride (1.59 g, 29.6 mmol) were added sequentially to a solution of 4-fluoro-3-nitro-5-(trifluoromethyl)benzoic acid (2.50 g, 9.88 mmol) in ethanol / water (10.0 mL) at 25 °C. The mixture was stirred at 25 °C for 5 hours, then quenched with ice water (40.0 mL) and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 3-amino-4-fluoro-5-(trifluoromethyl)benzoic acid (2.00 g, 91% yield), which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 223.9.

[0632] Step 3: TEA (907 mg, 8.96 mmol, 1.25 mL) and acetyl acetate (2.75 g, 26.9 mmol, 2.54 mL) were added sequentially to a solution of 3-amino-4-fluoro-5-(trifluoromethyl)benzoic acid (2.00 g, 8.96 mmol) in DCM (10.0 mL) at 25 °C. The mixture was stirred at this temperature for 3 hours, then quenched with an aqueous solution of NaHCO3 (5.0 mL) and filtered. The filtrate was extracted with DCM. The combined organic layers were dried over Na2SO4 and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with EtOAc / petroleum ether elution to give 3-acetamido-4-fluoro-5-(trifluoromethyl)benzoic acid (1.50 g, 63% yield) as a colorless oil. LC-MS: m / z [M+H] + 265.9.

[0633] Step 4: HOBt (1.73 g, 11.31 mmol), EDCI (2.17 g, 11.3 mmol), N-methoxymethylamine (346 mg, 5.66 mmol), and 4-methylmorpholine (1.72 g, 17.0 mmol, 1.87 mL) were added sequentially to a solution of 3-acetamido-4-fluoro-5-(trifluoromethyl)benzoic acid (1.50 g, 5.66 mmol) in DCM (20.0 mL) at 25 °C. The mixture was stirred at said temperature for 3 hours, followed by concentration under reduced pressure. The residue was diluted with water (20.0 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography, eluting with EtOAc / petroleum ether, to give 3-acetamido-4-fluoro-N-methoxy-N-methyl-5-(trifluoromethyl)benzamide (1.00 g, 57% yield) as a colorless oil. LC-MS: m / z [M+H] + 309.0.

[0634] Step 5: A solution of bis(trimethylsilyl)aminolithium (3.24 mL, 1.0 M, 3.24 mmol) in THF (10.0 mL) was added at 0 °C. The mixture was stirred at 0 °C for 30 min, followed by the addition of methylmagnesium bromide (3.64 mL, 1.0 M, 3.64 mmol). The mixture was stirred at 0 °C for 3 h, followed by quenching with ice water (2.0 mL). The mixture was adjusted to pH 4 with HCl and then extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC to give N-[5-acetyl-2-fluoro-3-(trifluoromethyl)phenyl]acetamide (600 mg, 70% yield) as a colorless oil. LC-MS: m / z [M+H] + 263.9.

[0635] Step 6: Ethyl titanate (1.56 g, 6.84 mmol, 1.43 mL) and (R)-2-methylpropane-2-sulfinamide (553 mg, 4.56 mmol) were added sequentially to a solution of N-[5-acetyl-2-fluoro-3-(trifluoromethyl)phenyl]acetamide (600 mg, 2.28 mmol) in THF (30 mL) at 25 °C. The mixture was heated to 80 °C and stirred at that temperature for 2 hours, then cooled to 0 °C and used directly in the next step without any further treatment.

[0636] Step 7: Sodium borohydride (185.86 mg, 4.91 mmol) was added to a stirred solution of N-[5-[(E)-N-[(R)-tert-butylsulfinyl]-C-methyl-iminoyl]-2-fluoro-3-(trifluoromethyl)phenyl]acetamide (600 mg, 1.64 mmol) in methanol (5.0 mL) at 0 °C. The mixture was heated to 25 °C and stirred at that temperature for 2 hours, then filtered and washed with THF (50 mL × 2). The filtrate was concentrated under vacuum and the residue was purified by rapid silica gel column chromatography, eluting with EtOAc / petroleum ether, to give N-[5-[1-[[(R)-tert-butylsulfinyl]amino]ethyl]-2-fluoro-3-(trifluoromethyl)phenyl]acetamide (500 mg, 83% yield) as a yellow oil. LC-MS: m / z [M+H] + 369.0.

[0637] Step 8: HCl (5.0 mL, 4.0 M in EtOAc, 20 mmol) was added to a solution of N-[5-[1-[[(R)-tert-butylsulfinyl]amino]ethyl]-2-fluoro-3-(trifluoromethyl)phenyl]acetamide (500 mg, 1.36 mmol) in MeOH (2.0 mL) at 25 °C. The mixture was stirred at this temperature for 10 min, then concentrated under reduced pressure to give N-[5-[(1R)-1-aminoethyl]-2-fluoro-3-(trifluoromethyl)phenyl]acetamide (300 mg, 84% yield) as a yellow oil, which was used directly in the next step without further purification. LC-MS: m / z [M+H] + 265.0.

[0638] Step 9: A mixture of N-[5-[(1R)-1-aminoethyl]-2-fluoro-3-(trifluoromethyl)phenyl]acetamide (300 mg, 1.14 mmol), 5-bromo-2-fluoro-pyridine-3-carboxylic acid (250 mg, 1.14 mmol), HATU (475 mg, 1.25 mmol), and DIPEA (440 mg, 3.41 mmol, 593 μL) in DMF (5.0 mL) was stirred at 25 °C for 30 min. The mixture was then diluted with MeOH and purified by preparative HPLC using MeCN / water to give N-[(1R)-1-[3-acetamido-4-fluoro-5-(trifluoromethyl)phenyl]ethyl]-5-bromo-2-fluoro-pyridine-3-carboxamide (300 mg, 57% yield) as a yellow solid. LC-MS: m / z [M+H] + 465.9.

[0639] Step 10: A mixture of N-[(1R)-1-[3-acetamido-4-fluoro-5-(trifluoromethyl)phenyl]ethyl]-5-bromo-2-fluoro-pyridine-3-carboxamide (300 mg, 644 μmol), (2R)-2-aminoprop-1-ol (72.5 mg, 965 μmol), and TEA (195 mg, 1.93 mmol, 269 μL) in DMSO (10.0 mL) was heated to 80 °C and stirred at that temperature for 2 hours. The mixture was cooled and purified by preparative HPLC with MeCN / water to give N-[(1R)-1-[3-acetamido-4-fluoro-5-(trifluoromethyl)phenyl]ethyl]-5-bromo-2-[[(1R)-2-hydroxy-1-methyl-ethyl]amino]pyridine-3-carboxamide (300 mg, 89% yield) as a yellow oil. LC-MS: m / z [M+H] + 520.9.

[0640] Step 11: Methanesulfonic anhydride (201 mg, 1.15 mmol) was slowly added to a stirred solution of N-[(1R)-1-[3-acetamido-4-fluoro-5-(trifluoromethyl)phenyl]ethyl]-5-bromo-2-[[(1R)-2-hydroxy-1-methyl-ethyl]amino]pyridine-3-carboxamide (300 mg, 575 μmol) and triethylamine (291 mg, 2.88 mmol, 401 μL) in dichloromethane (10.0 mL). The mixture was stirred at said temperature for 10 minutes, and then quenched with 1.0 mL of water. The solvent was removed under vacuum, and the residue was purified by preparative HPLC with MeCN / water to give (2R)-N-[(1R)-1-[3-acetamido-4-fluoro-5-(trifluoromethyl)phenyl]ethyl]-6-bromo-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (200 mg, 69% yield) as a yellow solid. LC-MS: m / z [M+H] + 503.0.

[0641] Step 12: To a stirred solution of (2R)-N-[(1R)-1-[3-acetamido-4-fluoro-5-(trifluoromethyl)phenyl]ethyl]-6-bromo-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (50.0 mg, 99.4 μmol) in dioxane / water (10.0 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)pyridine (24.0 mg, 119 μmol), Pd(PPh3)4 (11.0 mg, 9.9 μmol), and K2CO3 (34.0 mg, 248 μmol) were added sequentially. The mixture was heated to 90 °C and stirred at that temperature for 4 hours, then cooled, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel column chromatography using DCM / MeOH = 10:1 to 1:1 and further purified by preparative HPLC with MeCN / water to give (2R)-N-[(1R)-1-[3-acetamido-4-fluoro-5-(trifluoromethyl)phenyl]ethyl]-2-methyl-6-(4-pyridyl)-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (20.0 mg, 40% yield) as a yellow solid. LC-MS: m / z [M+H] + 502.0.

[0642] Step 13: A solution of (2R)-N-[(1R)-1-[3-acetamido-4-fluoro-5-(trifluoromethyl)phenyl]ethyl]-2-methyl-6-(4-pyridyl)-2,3-dihydroimidazole[1,2-a]pyridine-8-carboxamide (20.0 mg, 39.9 μmol) in hydrochloric acid (10.0 mL, 6.0 M in water, 60.0 mmol) was heated to 80 °C and stirred at that temperature for 30 minutes, then cooled and adjusted to pH = 7. The solvent was removed under vacuum, and the residue was purified by preparative HPLC with MeCN / water to give (2R)-N-[(1R)-1-[3-amino-4-fluoro-5-(trifluoromethyl)phenyl]ethyl]-2-methyl-6-(4-pyridyl)-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxamide (5.0 mg, 27% yield) as a yellow solid. LC-MS: m / z [M+H] + 460.1.

[0643] Similar to the representative procedure described in Example 648, the following example was prepared.

[0644]

[0645] Example 802

[0646] HCl / EtOAc (0.2 mL, 0.8 mmol, 4.0 M) was added to a stirred solution of (R)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2,3-dihydroimidazo[1,2-b]pyridazine-8-carboxamide (15.0 mg, 30.5 μmol) in EtOAc (2.0 mL). The mixture was stirred at 25 °C for 18 hours. The reaction mixture was treated with aqueous NaHCO3 solution and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC by elution with CH3CN / water (CH3CN increased from 20% to 50% over 8 minutes) to give (R)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(4-oxopiperidin-1-yl)-2,3-dihydroimidazo[1,2-b]pyridazine-8-carboxamide (6.0 mg, 42% yield) as a red solid. LC-MS: m / z [M+H] + 447.9.

[0647] Bioassay

[0648] a. KRAS::SOS1 AlphaScreen binding assay

[0649] The assay was used to determine the efficacy of the compound in inhibiting the protein-protein interaction between SOS1 and KRAS G12D under defined biochemical conditions. The IC50 of a given compound... 50 The lower the value, the higher the potency of the SOS1 inhibitor compound under the test conditions.

[0650] Reagents: GST-TEV-SOS1 (564-1049) and His-TEV-Avi-KRAS G12D (1-169) were purchased from VivaBiotech (Shanghai) Ltd.

[0651] GDP (Sigma, catalog number G7127) AlphaLISA glutathione receptor microbeads (PerkinElmer, catalog number AL109C) AlphaScreen streptavidin donor microbeads (PerkinElmer, catalog number 6760002S) Test plate: ProxiPlate-384 Plus white 384 shallow-well microplate (PerkinElmer, catalog number 6008280)

[0652] Assay buffer: PBS, pH 7.4 (Gibco, catalog number 10010023) 0.05% Tween 20 (Sigma, catalog number P7949-100ML) 0.1% Bovine Serum Albumin (BSA) (Sigma, Catalog No. A1933-5G)

[0653] Measurement protocol: The SOS1 inhibitor compound was diluted to a final starting concentration of 1 μM. Serial dilutions of the compound were performed using a Tecan D300e digital dispenser, resulting in nine concentrations at a 1:3 ratio. 100 nL of the compound solution was transferred to each well of a 384-well assay plate, covering the range from 1 μM to a minimum of 0.15 nM, in duplicate. 10 nM (final assay concentration) KRAS G12D, 5 nM (final assay concentration) SOS1, and 10 μM (final assay concentration) GDP were mixed in assay buffer, and 5 μL of the KRAS::SOS1 GDP mixture was added to the 100 nL of compound solution in the assay plate (final dilution for assay: 1:100, final DMSO concentration: 1%). After incubation for 30 minutes, AlphaLISA glutathione receptor beads and AlphaScreen streptavidin donor beads were mixed in assay buffer to a concentration of 5 μg / mL (final assay concentration), and 5 μL of the bead mixture was added to the assay plate. The assay plate was incubated at room temperature in a dark incubator for 3 hours. After 3 hours of incubation, the signal was measured using an Envision (PerkinElmer) transilluminator. The excitation wavelength was 680 nm and the emission wavelength was 615 nm. The IC50 was calculated and analyzed using GraphPad Prism. 50 value.

[0654] KRAS::SOS1 AlphaScreen binding assay of compound IC 50 value

[0655]

[0656]

[0657]

[0658]

[0659] The purpose of cell proliferation assays is to detect the efficacy of compounds in inhibiting SOS1-mediated cancer cell proliferation in a confined cellular environment in vitro. 50 The lower the value, the higher the potency of the compound under the stated assay conditions. SOS1 inhibitor compounds were observed to exhibit potent inhibitory effects on the proliferation of KRAS mutant human cancer cell lines.

[0660] Cell proliferation assays were performed using the human non-small cell lung cancer (NSCLC) cell line NCI-H358 with the KRAS G12C mutation under three-dimensional (3D) ultra-low conditions.

[0661] Materials used: 96-well transparent round-bottom ultra-low adhesion microplate (Corning, catalog number 7007) 96-well transparent flat-bottomed white polystyrene TC-treated microplate (Corning, catalog number 3610) RPMI-1640 medium (Gibco, catalog number 22400105) Fetal bovine serum (FBS) (Gibco, catalog number 10099141C) 0.25% Trypsin-EDTA (Gibco, catalog number 25200056) Penicillin-Streptomycin (Gibco, catalog number 15140122) CellTiter-Glo 3D Cell Viability Assay Product (Promega, Catalog No. G9683)

[0662] Measurement protocol: NCI-H358 cells (ATCC, catalog number CRL-5807) were grown in cell culture flasks using RPMI medium supplemented with 10% FBS. Cells were cultured in a humid atmosphere at 37°C and 5% CO2, and passaged twice weekly. Cells were treated with trypsin, counted, and plated in 96-well ultra-low adhesion plates for 3D cell viability assays. On day 2 after platening, serial dilutions of the SOS1 inhibitor compound were performed using a Tecan D300e digital dispenser to assess its concentration-dependent effect on cell viability. The test compound concentrations covered the range from 5 μM to 0.76 nM, with 1:3 serial dilutions for a total of 9 concentrations. 0.5 μL of each serial dilution was added in duplicate. Three days later, the effect of the SOS1 inhibitor compound on cell viability in 3D mode was measured using a CellTiter-Glo 3D cell viability assay. Luminescence intensity was measured using Envision (PerkinElmer). Data were analyzed and IC50 was calculated using GraphPad Prism. 50 value.

[0663] Compound IC in H358 cell proliferation assay 50 value

[0664]

[0665]

[0666]

[0667]

[0668]

Claims

1. A compound of formula (I'): (I')， Its pharmaceutically acceptable salts, tautomers, or stereoisomers, among which: Expressed by formula (A') or (B'): (A') or (B'), R 9 R 9' and R 9'' Each of the elements is independently H, halogen, or C. 1-6 alkyl; R 10 R 10' and R 10'' The elements in the formula are independently H, halogen, and C. 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 Alkylene C 1-4 Alkoxy, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne, 3- to 6-membered carbocyclic, 4- to 6-membered heterocyclic, phenyl, or 5- to 6-membered heteroaryl; or R 9 R 9' R 9'' R 10 R 10' and R 10'' Any two of them together with the carbon atom they are attached to form a 3- to 6-membered carbon cyclic group or a 4- to 6-membered heterocyclic group; in R represents 1 The connection point; Indicates the connection point of the C=O group; Y is CR y Or N; where R y H, halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 alkoxy, 3 to 6-membered carbocyclic, 3 to 12-membered heterocyclic, 6 to 10-membered aryl, or 5 to 10-membered heteroaryl, wherein R y The carbocyclic, heterocyclic, aryl, or heteroaryl groups represented are optionally surrounded by one to three groups selected from -OH, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Alkoxy and C 1-6 Substitution of haloalkoxy groups; Ring A is phenyl; R 7 Each occurrence is independently of halogen, -CN, or C. 1-4 Alkyl, C 1-4 Halogenated groups (optionally substituted with -OH), OH, or NR 7a R 7b ; R 7a and R 7b Each of them is independently H or C 1-4 alkyl, or Two adjacent R 7 The group, together with the atoms it is attached to, forms a 4- to 6-membered carbon ring or a 4- to 6-membered heterocycle; wherein the 4- to 6-membered carbon ring or 4- to 6-membered heterocycle is optionally bonded by one or more halogens or C. 1-4 Alkyl substitution; n is 0, 1, 2, 3 or 4; R 1 Halogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3 to 12-membered carbocyclic, -O-3 to 12-membered carbocyclic, -NH-3 to 12-membered carbocyclic, 3 to 12-membered heterocyclic, -C(=O)-3 to 12-membered heterocyclic, -O-3 to 12-membered heterocyclic, -NH-3 to 12-membered heterocyclic, 6 to 10-membered aryl, -O-6 to 10-membered aryl, -NH-6 to 10-membered aryl, 5 to 10-membered heteroaryl, -O-5 to 10-membered heteroaryl or -NH-5 to 10-membered heteroaryl, wherein R 1 Represented or by R 1 The alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, aryl, or heteroaryl groups represented are optionally surrounded by one or more R groups. 11 Replace; among them R 11 Each time it appears, it is independently selected from halogen, -CN, oxo (where appropriate), =NH (where appropriate), C. 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group (optionally C 1-4 hydroxyalkyl substitution), C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylene C 1-4 Alkoxy, OR 1a -CHO, -COOH, -C(O)R 1a -C(O)OR 1a -(CH2) 0或1 C(O)NR 1a R 1b -C(O)CH2NR 1a R 1b -OC(O)NR 1a R 1b -NO2, -(CH2) 0或1 NR 1a R 1b -NR 1a C(O)R 1a -P(O)R 1a R 1b -(CH2) 0或 1SO2R 1a -(CH2) 0或1 SO2NR 1a R 1b -(CH2) 0或1 -3 to 6-membered carbocyclic groups, 3 to 12-membered heterocyclic groups, and 5 to 10-membered heteroaryl groups. Among them, R 11 Represented or by R 11 The C in the group represented 1-6 Alkyl groups are optionally surrounded by one or more deuterium, CN, OH, =NOH, C 1-6 Alkyl or C 1-6 Alkoxy substitution, By R 11 Represented or by R 11 The C in the group represented 1-6 The alkoxy group may optionally be replaced by one or more deuterium or halogens; By R 11 Represented or by R 11 The 3- to 6-membered carbocyclic group, 3- to 12-membered heterocyclic group, or 5- to 10-membered heteroaryl group in the indicated group is optionally surrounded by one or more CN, -OH, oxo (where appropriate), C 1-6 Alkyl or C 1-6 Alkyl substitution; R 1a and R 1b Independently select H and C 1-6 Alkyl, C 2-6 The group consisting of alkenyl, 3- to 6-membered carbocyclic, 4- to 6-membered heterocyclic and 5- to 6-membered heteroaryl groups, wherein R 1a Or R 1b The alkyl, carbocyclic, heterocyclic, or heteroaryl groups represented are optionally surrounded by one or more halogens, CN, OH, C 1-6 Alkyl or C 1-6 Alkoxy substitution; or R 1a and R 1b Together with the N or P atoms to which they are attached, they form a group optionally bonded by C. 1-6 Alkyl-substituted 4- to 6-membered heterocyclic groups; The heterocyclic group comprises 1 to 3 heteroatoms selected from oxygen, nitrogen, phosphorus and sulfur; and the heteroaryl group comprises 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur.

2. The compound of claim 1, its pharmaceutically acceptable salt or stereoisomer, wherein the compound is represented by formula (IIA') or (IIB'): (IIA') or (IIB'); Where Y is CR y Or N; R y H, halogen, -CN, C 1-4 Alkyl or C 1-4 Alkyl group.

3. The compound of claim 2, its pharmaceutically acceptable salt or stereoisomer, wherein the compound is represented by formula (IIIA'-1), (IIIA'-2), (IIIB'-1) or (IIIB'-2): (IIIA'-1)、 (IIIA'-2)、 (IIIB'-1) or (IIIB'-2).

4. The compound according to claim 3, its pharmaceutically acceptable salt or stereoisomer, wherein the compound is represented by formula (VA') or (VB'): (VA')、 (VB').

5. The compound of claim 3, its pharmaceutically acceptable salt or stereoisomer, wherein the compound is represented by formula (VC') or (VD'): (VC') or (VD').

6. The compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt or stereoisomer, wherein... R 9 R 9' and R 9'' Each of them is independently H or C 1-2 alkyl; R 10 R 10' and R 10'' Each of them is independently H and C. 1-4 Alkyl, C 1-4 Halogenated, C 1-4 Hydroxyalkyl, C 1-4 Alkylene C 1-4 Alkoxy, C 1-4 alkoxy, 3- to 6-membered cycloalkyl or phenyl; or R 9 and R 10 R 9' and R 10' R 9'' and R 10'' R 10 and R 10' and R 10' and R 10'' Any one of the groups, together with the carbon atoms to which it is attached, forms a 3- to 6-membered cycloalkyl group or a 4- to 6-membered heterocyclic group.

7. The compound according to claim 6, its pharmaceutically acceptable salt or stereoisomer, wherein... R 9 R 9' and R 9'' Each of them is independently H or -CH3; R 10 R 10' and R 10'' Each of the following can be independently H, -CH3, ethyl, isopropyl, tert-butyl, isobutyl, -CH2F, -CH2OH, -CH2OCH3, cyclohexyl, tetrahydro-2H-pyranyl, or phenyl; or R 9 and R 10 R 9' and R 10' R 9'' and R 10'' R 10 and R 10' and R 10' and R 10'' Any group of atoms in the group, together with the carbon atoms they are attached to, forms cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, or tetrahydro-2H-pyranyl.

8. The compound according to claim 6, its pharmaceutically acceptable salt or stereoisomer, wherein... (i) R 9 and R 10 Independently H or -CH3; R 9' and R 10' Each of them is independently H; or (ii) R 9' and R 10' Each of them is independently H or -CH3; R 9 and R 10 Each of them is independently H; or (iii) R 9'' and R 10'' Each of them is independently H or -CH3; R 9 R 10 R 9' and R 10' Each of them is independently represented by H.

9. The compound according to any one of claims 1 to 8, its pharmaceutically acceptable salt or stereoisomer, wherein... R 7 Each time it appears, it is independently a halogen, -CN, -OH, -NH2, or C. 1-2 Alkyl or C 1-2 Halogenated groups (optionally substituted with -OH); or Two adjacent R 7 The group, together with the atoms it is attached to, forms a 4- to 6-membered heterocycle optionally substituted with one or two halogens; and n can be 0, 1, 2, or 3.

10. The compound of claim 9, its pharmaceutically acceptable salt or stereoisomer, wherein R 7 Each time it appears, it is independently a halogen, -CN, -OH, -NH2, or C. 1-2 Alkyl groups or C groups optionally substituted with -OH 1-2 Alkyl halide; and n is 0, 1 or 2.

11. The compound according to claim 9, its pharmaceutically acceptable salt or stereoisomer, wherein... for , , , , 、 、 、 、 、 、 、 、 、 、 , or .

12. The compound according to any one of claims 1 to 11, its pharmaceutically acceptable salt or stereoisomer, wherein: R 1 Halogen, -CN, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, 3- to 6-membered carbocyclic, 4- to 10-membered heterocyclic, -O-4- to 10-membered heterocyclic, -NH-4- to 10-membered heterocyclic, phenyl, -C(=O)-4- to 10-membered heterocyclic or 5- to 10-membered heteroaryl, wherein R 1 Represented or by R 1 The alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, phenyl, or heteroaryl groups represented are optionally surrounded by one to four R groups. 11 Replace; among them R 11 Each time it appears, it is independently selected from halogen, -CN, oxo (where appropriate), =NH (where appropriate), C. 1-4 Alkyl, C 1-4 Halogenated, C 1-4 Hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl group (optionally C 1-4 hydroxyalkyl substitution), C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Alkylene C 1-4 Alkoxy, -OR 1a -(CH2) 0或1 NR 1a R 1b -CHO, -COOH, -C(O)R 1a -C(O)OR 1a -(CH2) 0或1 C(O)NR 1a R 1b -C(O)CH2NR 1a R 1b -OC(O)NR 1a R 1b -NO2, NR 1a C(O)R 1a -(CH2) 0或1 SO2R 1a -(CH2) 0或 1SO2NR 1a R 1b -P(O)R 1a R 1b -(CH2) 0或1 -3 to 6-membered carbon cyclic groups, 4 to 6-membered heterocyclic groups, and 5 to 6-membered heteroaryl groups. Among them, R 11 Represented or by R 11 The C in the group represented 1-4 Alkyl groups are optionally surrounded by a CN, OH, =NOH, or C atom. 1-4 Alkyl or one to three deuterium substitutions; By R 11 Represented or by R 11 The C in the group represented 1-4 The alkoxy group is optionally substituted by one to three groups selected from deuterium and halogens; By R 11 Represented or by R 11 The 3- to 6-membered carbocyclic group, 4- to 6-membered heterocyclic group, or 5- to 6-membered heteroaryl group in the indicated group is optionally surrounded by one to three CN, -OH, oxo (where appropriate), C 1-6 Alkyl or C 1-6 Alkyl substitution; R 1a and R 1b Independently select H and C 1-4 Alkyl, C 2-4 The group consisting of alkenyl, 3- to 6-membered carbocyclic, 4- to 6-membered heterocyclic and 5- to 6-membered heteroaryl groups, wherein R 1a Or R 1b The alkyl, carbocyclic, heterocyclic, or heteroaryl groups indicated are optionally surrounded by one to three halogens, CN, OH, C 1-4 Alkyl or C 1-4 Alkoxy substitution; or R 1a and R 1b Together with the N or P atoms to which they are attached, they form a group optionally bonded by C. 1-4 Alkyl-substituted 4- to 6-membered heterocyclic groups.

13. The compound according to any one of claims 1 to 11, its pharmaceutically acceptable salt or stereoisomer, wherein... R 1 It is a 4- to 6-membered monocyclic carbocyclic group, a 4- to 6-membered monocyclic heterocyclic group, a phenyl group, or a 5- to 6-membered heteroaryl group, wherein R 1 The 4- to 6-membered monocyclic carbocyclic group, 4- to 6-membered monocyclic heterocyclic group, phenyl group, or 5- to 6-membered heteroaryl group is optionally surrounded by one to four R groups. 11 replace; R 11 Each time it appears, it is independently of halogen, -CN, -OH, oxo (where appropriate), C. 1-4 Alkyl, C 1-4 Halogenated, C 1-4 Alkoxy groups, -COOH, -C(O)C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, -C(O)NR 1a R 1b -OC(O)NR 1a R 1b -NO2, -(CH2) 0或 1NR 1a R 1b -NR 1a C(O)C 1-4 Alkyl, -SO2C 1-4 Alkyl group, -(CH2) 0或1 -3 to 6-membered carbocyclic groups, 4 to 6-membered monocyclic heterocyclic groups, or 5 to 6-membered heteroaryl groups; among which By R 11 Represented or by R 11 The C in the group represented 1-4 The alkyl group is optionally separated by a group selected from -CN, -OH and C. 1-4 The alkoxy group or one to three groups selected from deuterium are substituted; By R 11 Represented or by R 11 The C in the group represented 1-4 The alkoxy group is optionally substituted by one to three groups selected from deuterium and halogens; By R 11 Represented or by R 11 The 3- to 6-membered carbocyclic group, 4- to 6-membered heterocyclic group, or 5- to 6-membered heteroaryl group in the indicated group is optionally surrounded by one or two groups selected from -CN, -OH, oxo (where appropriate), and C. 1-4 Alkyl group substitution; R 1a and R 1b Independently select H and C 1-4 The group consisting of alkyl groups and 3 to 6-membered carbon cycloyl groups, wherein R 1a Or R 1b The alkyl or carbocyclic group represented is optionally surrounded by one to three halogens, -CN, -OH, C 1-4 Alkyl or C 1-4 Alkyl-substituted.

14. The compound according to any one of claims 1 to 11, its pharmaceutically acceptable salt or stereoisomer, wherein... R 1 It is cyclohexyl, cyclohexenyl, a 6-membered monocyclic heterocyclic group, phenyl, or a 5- to 6-membered heteroaryl group, wherein R 1 The cyclohexyl, cyclohexenyl, 6-membered monocyclic heterocyclic, phenyl, or 5- to 6-membered heteroaryl groups are optionally represented by one or two R groups. 11 replace; R 11 Each time it appears, it is independently of halogen, -CN, -OH, oxo (where appropriate), C. 1-4 Alkyl, C 1-4 Halogenated, C 1-4 Hydroxyalkyl, -C(O)C 1-4 Alkyl, -C(O)NR 1a R 1b -NR 1a C(O)C 1-4 Alkyl, -SO2C 1-4 Alkyl or 4- to 6-membered monocyclic heterocyclic groups; By R 11 Represented or by R 11 The C in the group represented 1-4 The alkyl group may optionally be substituted with -OH or -CN; By R 11 The 4- to 6-membered heterocyclic groups indicated are optionally surrounded by one or two groups selected from -OH, oxo (where appropriate), and C. 1-6 Alkyl group substitution; R 1a and R 1b Each of them is independently H or C 1-4 alkyl.

15. The compound according to any one of claims 1 to 11, its pharmaceutically acceptable salt or stereoisomer, wherein... R 1 CN, vinyl, ethynyl, ethoxy, isopropyl, cyclopropyl, cyclohexyl, cyclohexenyl, aziridine, -NH-tetrahydrofuranyl, furanyl, thiophene, pyrroleyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, morpholinyl, thiomorpholinyl, -NH-morpholinyl, -C(O)-morpholinyl, piperazinyl, piperidinyl, dihydropyridinyl, tetrahydropyridinyl, Dihydropyranyl, tetrahydropyranyl, -NH-tetrahydropyranyl, -O-tetrahydrofuran, dihydrothiaranyl, isoyindolone, hexahydro-1H-furano[3,4-c]pyrrole, 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazolyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 3-oxa-6-azabicyclo[ 3.1.1] Heptyl, 3-oxabicyclo[4.1.0] Heptyl, 6-oxa-3-azabicyclo[3.1.1] Heptyl, 6-oxa-2-azaspiro[3.4] Octyl, 2-oxa-5-azabicyclo[2.2.1] Heptyl, 3-azabicyclo[3.2.1] Octyl, 8-azabicyclo[3.2.1] Oct-2-enyl, bicyclo[1.1.1] Pentyl, 2,5-dihydrofuranyl, 2-oxaspiro[3.5] Non-6-enyl, 2-oxa-6-azaspiro[3.3] Heptyl, 3-oxa-8-azabicyclo[3.2.1] Octyl, 8-oxa-3-azabicyclo[3.2.1] Heterobicyclo[3.2.1]octyl, 3-oxa-9-azabicyclo[3.3.1]nonyl, 7-azaspiro[3.5]nonyl, 1-oxa-7-azaspiro[3.5]nonyl, 2-oxa-7-azaspiro[3.5]nonyl, 1,8-diazaspiro[4.5]decyl, 1-azaspiro[4.5]dec-7-enyl, 1,4-dioxaspiro[4.5]dec-7-enyl, 1,4-dioxa-8-azaspiro[4.5]decyl, pyrrolo[2,3-b]pyridyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-b]pyridyl, indazole or quinolinyl; Among them, R 1 The terms ethynyl, ethoxy, isopropyl, cyclopropyl, cyclohexyl, cyclohexenyl, aziroxybutyl, -NH-tetrahydrofuranyl, furanyl, thiophene, pyrroleyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, morpholinyl, thiomorpholinyl, -NH-morpholinyl, -C(O)-morpholinyl, piperazinyl, piperidinyl, dihydropyridinyl, tetrahydropyridinyl, dihydro Pyranyl, tetrahydropyranyl, -NH-tetrahydropyranyl, -O-tetrahydrofuran, dihydrothiaranyl, isoindolone, hexahydro-1H-furano[3,4-c]pyrrole, 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazolyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 3-oxa-6-azabicyclo[ 3.1.1] Heptyl, 3-oxabicyclo[4.1.0] Heptyl, 6-oxa-3-azabicyclo[3.1.1] Heptyl, 6-oxa-2-azaspiro[3.4] Octyl, 2-oxa-5-azabicyclo[2.2.1] Heptyl, 3-azabicyclo[3.2.1] Octyl, 8-azabicyclo[3.2.1] Oct-2-enyl, bicyclo[1.1.1] Pentyl, 2,5-dihydrofuranyl, 2-oxaspiro[3.5] Non-6-enyl, 2-oxa-6-azaspiro[3.3] Heptyl, 3-oxa-8-azabicyclo[3.2.1] Octyl, 8-oxa-3-azabicyclo[ 3.2.1] Octyl, 3-oxa-9-azabicyclo[3.3.1] Nonyl, 7-azaspiro[3.5] Nonyl, 1-oxa-7-azaspiro[3.5] Nonyl, 2-oxa-7-azaspiro[3.5] Nonyl, 1,8-diazaspiro[4.5] Decyl, 1-azaspiro[4.5] Dec-7-enyl, 1,4-dioxaspiro[4.5] Dec-7-enyl, 1,4-dioxa-8-azaspiro[4.5] Decyl, pyrrolo[2,3-b]pyridyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-b]pyridyl, indazole or quinolinyl optionally surrounded by one to four R 11 replace; R 11 Each time it appears, it is independently selected from F, Cl, -CN, -OH, -NO2, -CH3, CH2F, -CHF2, -CF3, oxo (where appropriate), =NH (where appropriate), -CH2CH3, -CH2CN, -CH2CH2CN, -CH2OH, CH2CH2OH, CH2CH2OCH3, -CH2NHCH3, -CH2CH2F, -CH2CHF2, -CH(CH3)2, -C(CH3)3, -CH2CF3, -C(CN)(CH3)2, -CH2CH(OH)CH3, -C(OH)(CH3)2, -C(CH3)2CH2OH, -CH2C(CH 3) 2OH, -CH2OCH3, -OCH3, -OCD3, -OCH2CH3, -OCHF2, -OCF3, -OCH(CH3)2, -OCH2CF3, -O-cyclopropyl, -OC(O)NHCH3, -OC(O)N(CH3)2, -OC(O)NH-cyclopropyl, cyclopropyl, aziridine, oxacyclobutyl, -CHO, -COOH, -C(O)OCH3, -C(O)CH3, -C(O)C(CH3)3, -C (O)CH2F, -C(O)CH2CH3, -C(O)CH2OH, -C(O)CH2CF3, -C(O)cyclopropyl, -C(O)cyclopentyl, -C(O)-oxacyclobutyl, -C(O)-morpholinyl, -C(O)CH2OCH3, -COCH2N(CH3)2, -C(O)NHCH3, -C(O)NHC(CH3)3, -C(O)N(CH3)2, -C(O)N(CH3)CH2CH2OCH3, -CH2 CON(CH3)2, -NH2, -NHCH3, -NHCH2CF3, -N(CH3)2, NHC(O)CH3, -NHC(O)CH2F, -NHC(O)CH2CN, -NHC(O)CH2OCH3, -N(CH3)C(O)CH3, N(CH3)C(O)CH2CN, -NH cyclopropyl, -P(O)(CH3)2, -CH2SO2CH3, -SO2CH3, -SO2NH2, morpholinyl, pyridyl, , , , , , , , , , , , , , , , , , , , , , , and .

16. The compound of claim 1, its pharmaceutically acceptable salt or stereoisomer, wherein the compound is represented by formula (VII'): (VII'), in Y is either CH or N; R 9 It is H or -CH3; R 10 For H or C 1-4 alkyl; R 1 It is a 4- to 6-membered monocyclic carbocyclic group, a 5- to 6-membered monocyclic heterocyclic group, a phenyl group, or a 5- to 6-membered heteroaryl group, wherein R 1 The 4- to 6-membered monocyclic carbocyclic group, 5- to 6-membered monocyclic heterocyclic group, phenyl group, or 5- to 6-membered heteroaryl group represented by the symbol is optionally surrounded by one to three R groups. 11 replace; R 11 Each time it appears, it is independently of halogen, -CN, -OH, oxo (where appropriate), C. 1-4 Alkyl, C 1-4 Halogenated, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -C(O)R 1a -C(O)OR 1a -C(O)NR 1a R 1b -OC(O)NR 1a R 1b -(CH2) 0或1 NR 1a R 1b -NR 1a C(O)R 1a -SO2R 1a 4 to 6-membered monocyclic heterocyclic groups or 5 to 6-membered heteroaryl groups; By R 11 Represented or in R 11 The C in the group 1-4 Alkyl groups are optionally prefixed with -CN, -OH, or -C. 1-4 Alkyl substitution; By R 11 The 4- to 6-membered heterocyclic group or 5- to 6-membered heteroaryl group represented is optionally surrounded by one or two groups selected from -CN, -OH, oxo (where appropriate), and C. 1-4 Alkyl group substitution; R 1a and R 1b Independently select H and C 1-4 The group consisting of alkyl groups and 3 to 6-membered carbon cycloyl groups, wherein R 1a Or R 1b The alkyl or carbocyclic group represented is optionally surrounded by one to three halogens, CN, OH, C 1-4 Alkyl or C 1-4 Alkyl substitution; R 7 Each time it appears, it is independently a halogen, -CN, -NH2, or C. 1-2 Alkyl groups or C groups optionally substituted with -OH 1-2 Halogenated alkyl groups; and n can be 0, 1, 2, or 3.

17. The compound of claim 16, its pharmaceutically acceptable salt or stereoisomer, wherein... R 1 It is a 5- to 6-membered monocyclic carbocyclic group, a 5- to 6-membered monocyclic heterocyclic group, a phenyl group, or a 5- to 6-membered heteroaryl group, wherein R 1 The 5- to 6-membered monocyclic carbocyclic group, 5- to 6-membered monocyclic heterocyclic group, phenyl group, or 5- to 6-membered heteroaryl group is optionally surrounded by one or two R groups. 11 replace; R 11 Each time it appears, it is independently of halogen, -CN, -OH, oxo (where appropriate), C. 1-4 Alkyl, C 1-4 Halogenated, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -C(O)C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, -C(O)NR 1a R 1b -OC(O)NR 1a R 1b -(CH2) 0或 1NR 1a R 1b -NR 1a C(O)C 1-4 Alkyl, -SO2C 1-4 Alkyl, 4- to 6-membered monocyclic heterocyclic or 5- to 6-membered heteroaryl; By R 11 Represented or in R 11 The C in the group 1-4 Alkyl groups may optionally be substituted with -CN or -OH; By R 11 The 4- to 6-membered heterocyclic group or 5- to 6-membered heteroaryl group represented is optionally surrounded by one or two groups selected from -CN, -OH, oxo (where appropriate), and C. 1-4 Alkyl group substitution; R 1a and R 1b Independently choose H or C 1-4 The group consisting of alkyl groups, wherein R 1a Or R 1b The alkyl group indicated is optionally surrounded by one to three halogens, CN, C 1-4 Alkyl or C 1-4 Alkyl-substituted.

18. The compound of claim 17, its pharmaceutically acceptable salt or stereoisomer, wherein... R 1 The derivatives are cyclohexenyl, dihydropyranyl, dihydropyridyl, dihydrothiaranyl, morpholinyl, oxazolyl, phenyl, piperidinyl, pyrazolyl, pyridyl, pyrrolidinyl, tetrahydropyranyl, tetrahydropyridyl, or thiazolyl; each optionally marked with one or two R... 11 replace; R 11 Each time it appears, it is independently selected from F, oxo (where appropriate), -OH, CN, -CH3, -CH2F, -CH2OH, -CH2CHF2, -CH2CH2CN, -CH2C(CH3)2OH, -C(O)CH3, -C(O)CH2OH, -CONHCH3, -NHCOCH3, -NHCOCH2CN, -SO2CH3, oxocyclic butyl or morpholino.

19. The compound according to any one of claims 16 to 18, its pharmaceutically acceptable salt or stereoisomer, wherein R 7 Each time it appears, it is independently -F, -Cl, -CN, -NH2, -CH3, -CHF2, -CF3, -CF2CH3, or -CF2CH2OH; R 9 It is H or -CH3; and R 10 It is -CH3; and n is 0, 1 or 2.

20. A compound listed in Table 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.

22. A method for treating an individual suffering from a disease and / or condition in which inhibiting the interaction of SOS1 with RAS family proteins or RAC1 has a therapeutic benefit, the method comprising administering to the individual a therapeutically effective amount of a compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, according to any one of claims 1 to 20.

23. A method of treating an individual suffering from cancer, comprising administering to the individual a therapeutically effective amount of the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt or stereoisomer thereof.

24. The method according to claim 22 or 23, wherein the compound or a pharmaceutically acceptable salt or stereoisomer thereof is administered in combination with a therapeutically effective amount of at least one other pharmacologically active substance.

25. The method of claim 24, wherein the at least one other pharmacologically active substance is an inhibitor of MEK and / or its mutants.

26. The method of claim 23, wherein the cancer is selected from the group consisting of: pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, squamous cell carcinoma of the head and neck, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma.

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