The use of son of sevenless (SOS) inhibitor compounds such as 7-substituted benzofurans to treat cancer

Abstract

Compounds having the following formula I, or a stereoisomer or pharmaceutically-acceptable salt thereof, where all substituents are as defined herein, are inhibitors of SOS useful for treating diseases including, among others, treating proliferative, metabolic, allergic, autoimmune and inflammatory diseases.

Description

[0001] SON OF SEVENLESS (SOS) COMPOUNDS

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No.

[0004] 63 / 711,272, filed October 24, 2024, the entire content of which is hereby incorporated herein by reference.

[0005] FIELD

[0006] This invention relates to compounds which are inhibitors of Son of Sevenless (SOS) useful for treating diseases including, among others, cancer. The invention further pertains to pharmaceutical compositions containing at least one compound according to the invention that are useful for the treatment of conditions related to the inhibition of SOS in a mammal.

[0007] REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY VIA PATENT CENTER

[0008] Incorporated herein by reference in its entirety is a Sequence Listing entitled, “20251014 SEQ 14892WOPCT” comprising SEQ ID NO: 1 through SEQ ID NO: 2, which include amino acid sequences disclosed herein. The Sequence Listing has been submitted herein in XML format via Patent Center, and thus constitutes both the paper and computer readable form thereof. The Sequence Listing was first created using WIPO Sequence on October 14, 2025, and is 8,192 bytes.

[0009] BACKGROUND OF THE INVENTION

[0010] Genetic alterations in the RAS–RAF–MEK–ERK MAP kinase (RAS / MAPK) pathway are one of the most frequent causes of cancer. The rat sarcoma viral oncogene (RAS) superfamily of small guanosine triphosphatase (GTPase) proteins is mutated in nearly 19% of all human malignancies, with KRAS being the most frequently mutated oncogene amongst RAS members and comprising approximately 30% of lung adenocarcinomas (LUAD), 50% of colorectal carcinomas (CRC), and 90% of pancreatic ductal adenocarcinomas (PDAC) [1. Simanshu, D. K., D. V. Nissley, and F. McCormick, RAS Proteins and Their Regulators in Human Disease. Cell, 2017. 170(1): p. 17-33: 2. Lee, J. K., et al., Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors. NPJ Precis Oncol, 2022. 6(1): p. 91: 3. Moore, A. R., et al., RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discov, 2020. 19(8): p. 533-552], RAS proteins cycle between an inactive guanosine diphosphate (GDP)-bound and active guanosine triphosphate (GTP)-bound state to regulate cell proliferation and survival. The Son of Sevenless (SOS) guanine nucleotide exchange factors (GEFs) promote exchange of GDP for GTP, thereby functioning as RAS activators. [4. Baltanas, F. C., et al., SOS GEFs in health and disease. Biochim Biophys Acta Rev Cancer, 2020. 1874(2): p. 188445: 5. Jeng, H. H., L. J. Taylor, and D. Bar-Sagi, Sos-mediated cross-activation of wild-type Ras by oncogenic Ras is essential for tumorigenesis. Nat Commun, 2012. 3: p. 1168: 6. Murillo, M. M., et al., Disruption of the Interaction of RAS with PI 3 -Kinase Induces Regression of EGFR-Mutant-Driven Lung Cancer. Cell Rep, 2018. 25(13): p. 3545-3553 e2: 7. Nimnual, A. andD. Bar-Sagi, The two hats of SOS. Sci STKE, 2002. 2002(145): p. pe36]. The two paralogs, S0S1 and S0S2, are ubiquitously expressed and have a high degree of structural similarity (-75%), with differences in amino acid sequence present in the C-terminal region mediating interaction with the SH3 domains of the adaptor growth factor receptor-bound protein 2 (GRB2). [8. Chardin, P., et al., Human Sosl: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science, 1993. 260(5112): p. 1338-43: 9. Esteban, L. M., et al., Ras-guanine nucleotide exchange factor sos2 is dispensable for mouse growth and development. Mol Cell Biol, 2000. 20(17): p. 6410-3: 10. Guerrero, C., et al., Expression of alternative forms of Ras exchange factors GRF and SO SI in different human tissues and cell lines. Oncogene, 1996. 12(5): p. 1097-107: 11. Pierre, S., A. S. Bats, and X. Coumoul, Understanding SOS (Son of Sevenless). Biochem Pharmacol, 2011. 82(9): p. 1049-56: 12. Vigil, D., et al., Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer, 2010. 10(12): p. 842-57.] Consequently, SOS proteins transmit activating signals from upstream receptor tyrosine kinases (RTKs) to downstream effector pathways implicated in cell growth and proliferation. While SOS1 gain-of-function mutations span all regions of the protein and are present in 1-5% of LUAD and uterine cancers [1, 13, 14], germline mutations are present at a 10% incidence in RASopathies including Noonan’s syndrome and hereditary gingival fibromatosis [5], [13. Cai, D., et al., Identification and Characterization of Oncogenic S0S1 Mutations in Lung Adenocarcinoma. Mol Cancer Res, 2019. 17(4): p.

[0011] 1002-1012: 14. Sanchez-Vega, F., et al., Oncogenic Signaling Pathways in The Cancer Genome Atlas. Cell, 2018. 173(2): p. 321-337 elO: 15. Cordeddu, V., et al., Activating Mutations Affecting the Dbl Homology Domain of S0S2 Cause Noonan Syndrome. Hum Mutat, 2015. 36(11): p. 1080-7: 16. Hart, T. C., et al., A mutation in the SOS 1 gene causes hereditary gingival fibromatosis type 1. Am J Hum Genet, 2002. 70(4): p. 943-54: 17. Roberts, A. E., et al., Germline gain-of-function mutations in S0S1 cause Noonan syndrome. Nat Genet, 2007. 39(1): p. 70-4: 18. Swanson, K. D., et al., S0S1 mutations are rare in human malignancies: implications for Noonan Syndrome patients. Genes Chromosomes Cancer, 2008. 47(3): p. 253-9: 19. Tartaglia, M., et al., Gain-of-function S0S1 mutations cause a distinctive form of Noonan syndrome. Nat Genet, 2007. 39(1): p.

[0012] 75-9], In contrast, a low percentage (<2%) of Noonan’s syndrome cases are characterized by activating mutations in SOS2 restricted to the DH domain of the protein

[0015] , [20. Lissewski, C., et al., Variants of S0S2 are a rare cause of Noonan syndrome with particular predisposition for lymphatic complications. Eur J Hum Genet, 2021. 29(1): p.

[0013] 51-60: 21. Yamamoto, G. L., et al., Rare variants in S0S2 and LZTR1 are associated with Noonan syndrome. J Med Genet, 2015. 52(6): p. 413-21], As SOS proteins activate RAS, the GTPase-activating protein neurofibromin, encoded by the NF1 tumor suppressor gene, negatively regulates RAS activation by promoting conversion of GTP-RAS to GDP -RAS and oppose RAS-GEF function. [22. Ratner, N. and S. J. Miller, A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat Rev Cancer, 2015. 15(5): p. 290-301: 23. Xu, GE., et al., The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell, 1990. 62(3): p. 599-608], Mutations in NF1 are present in approximately 7% of all cancers, with the highest incidence observed in lung and colon adenocarcinoma (10%), and at a lower frequency in RASopathies such as neurofibromatosis type 1 disorder

[0022] , [24. The Cancer Genome Atlas [TCGA] Research Network 2014], In the KRAS / MAPK pathway, S0S1 primarily mediates negative feedback inhibition upon RAF-MEK-ERK activation whereas S0S2 plays a minimal role in regulating pathway activation [1], [25. Corbalan-Garcia, S., et al., Identification of the mitogen-activated protein kinase phosphorylation sites on human Sosl that regulate interaction with Grb2. Mol Cell Biol, 1996. 16(10): p.

[0014] 5674-82: 26. Sheffels, E., et al., Anchorage-independent growth conditions reveal a differential S0S2 dependence for transformation and survival in RAS-mutant cancer cells. Small GTPases, 2021. 12(1): p. 67-78: 27. Sheffels, E., et al., Oncogenic RAS isoforms show a hierarchical requirement for the guanine nucleotide exchange factor SOS2 to mediate cell transformation. Sci Signal, 2018. 11(546)]. Functional genomic studies have demonstrated that KRAS signaling-dependent cancer cells have a reduced survival following either genetic depletion or pharmacological inhibition of S0S1 [5], [28. Hillig, R. C., et al., Discovery of potent S0S1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction. Proc Natl Acad Sci U S A, 2019. 116(7): p.

[0015] 2551-2560], Similar effects were observed in preclinical human xenograft models harboring mutations in KRAS, as S0S1 inhibitor treatment led to significant tumor growth inhibition and suppressed KRAS-MAPK pathway signaling. [29. Hofmann, M. H., et al., BI-3406, a Potent and Selective SOS 1 -KRAS Interaction Inhibitor, Is Effective in KRAS-Driven Cancers through Combined MEK Inhibition. Cancer Discov, 2021. 11(1): p. 142-157: 30. Ketcham, J. M., et al., Design and Discovery of MRTX0902, a Potent, Selective, Brain-Penetrant, and Orally Bioavailable Inhibitor of the SOSEKRAS Protein-Protein Interaction. J Med Chem, 2022. 65(14): p. 9678-9690: 31. Sudhakar, N., et al., The S0S1 Inhibitor MRTX0902 Blocks KRAS Activation and Demonstrates Antitumor Activity in Cancers Dependent on KRAS Nucleotide Loading. Mol Cancer Ther, 2024], As S0S1 inhibition shifts the tumor cell equilibrium of KRAS towards the inactive (GDP -bound) form, there is rationale to combine with KRAS G12C inhibitors that bind GDP -KRAS G12C for the treatment of KRAS G12C-mutant cancers. MRTX0902, a potent and selective inhibitor of the SOSEKRAS protein-protein interaction, which demonstrates pronounced antitumor activity as a monotherapy and combination partner of the KRAS G12C inhibitor adagrasib (KRAZATI®) in preclinical KRAS-MAPK pathway -mutant cancer models, is currently being evaluated in Phase 1 clinical trials (ClinicalTrials.gov Identifier: NCT05578092). [30. Ketcham, J. M., et al., Design and Discovery of MRTX0902, a Potent, Selective, Brain-Penetrant, and Orally Bioavailable Inhibitor of the SOSEKRAS Protein-Protein Interaction. J Med Chem, 2022. 65(14): p.

[0016] 9678-9690: 31. Sudhakar, N., et al., The S0S1 Inhibitor MRTX0902 Blocks KRAS Activation and Demonstrates Antitumor Activity in Cancers Dependent on KRAS Nucleotide Loading. Mol Cancer Ther, 2024: 32. A phase 1 / 2 study of MRTX0902 in solid tumors with mutations in the KRAS MAPK pathway. Available from:

[0017] https: / / clinicaltrials.gov / ct2 / show / NCT05578092]. As both SOS proteins function as RAS-GEFs, SOS2 can play a compensatory role following inhibition of SOS1 activity. Despite the high degree of similarity between the two SOS proteins, S0S1 plays a more dominant role in regulating cellular proliferation and migration, inflammation, redox homeostasis, and overall survival. [33. Baltanas, F. C., et al., Functional redundancy of Sosl and Sos2 for lymphopoiesis and organismal homeostasis and survival. Mol Cell Biol, 2013. 33(22): p. 4562-78: 34. Garcia-Navas, R., et al., Critical requirement of S0S1 RAS-GEF function for mitochondrial dynamics, metabolism, and redox homeostasis. Oncogene, 2021. 40(27): p. 4538-4551: 35.

[0018] Liceras-Boillos, P., et al., Sosl disruption impairs cellular proliferation and viability through an increase in mitochondrial oxidative stress in primary MEFs. Oncogene, 2016.

[0019] 35(50): p. 6389-6402: 36. Liceras-Boillos, P., et al., Differential Role of the RasGEFs Sosl and Sos2 in Mouse Skin Homeostasis and Carcinogenesis. Mol Cell Biol, 2018. 38(16): 37. Suire, S., et al., Frontline Science: TNF-alpha and GM-CSF1 priming augments the role of SOS 1 / 2 in driving activation of Ras, PI3K-gamma, and neutrophil proinflammatory responses. J Leukoc Biol, 2019. 106(4): p. 815-822], Previous studies utilizing constitutive genetic SOS1 and SOS2 knockout (KO) animal models have shown that only SOS1 is essential for embryonic development and adult fertility, as no defects were observed in the absence of SOS2 [9], [38. Qian, X., et al., The Sosl and Sos2 Ras-specific exchange factors: differences in placental expression and signaling properties. EMBO J, 2000. 19(4): p. 642-54], Markedly, in a tamoxifen-inducible null mutant mouse model, dual inactivation of SOS1 and SOS2 resulted in death within two weeks of treatment

[0033] , Two previous published studies have shown that S0S1 inhibition coupled with genetic knockout of SOS2 resulted in greater decreases in GTP -bound (active) RAS and pERK levels and enhanced cell death in KRAS G12C-mutant cells compared to KRAS G12C-mutant cells with wild-type SOS2 [29, 31], Furthermore, S0S2 is the dominant RAS-GEF implicated in KRAS-phosphoinositide 3 -kinase (KRAS-PI3K) pathway signaling for human KRAS mutant colorectal, pancreatic, and lung tumor cell survival [26, 27], As both SOS proteins are common and proximal intermediates in RTK / MAPK pathway signaling, inhibition of both SOSEKRAS and SOS2: KRAS protein-protein interactions is of interest for greater antiproliferative activity in KRAS-dependent cancers and RASopathies. SUMMARY

[0020] The present disclosure provides compounds that modulate the expression or activity of SOS. The disclosure also provides compositions, including pharmaceutical compositions, kits that include the compounds, and methods of using (or administering) and making the compounds. The compounds provided herein are useful in treating diseases, disorders, or conditions that are mediated by SOS. The disclosure also provides compounds for use in therapy. The disclosure further provides compounds for use in a method of treating a disease, disorder, or condition that is mediated by SOS. Moreover, the disclosure provides uses of the compounds in the manufacture of a medicament for the treatment of a disease, disorder or condition that is mediated by (or mediated, at least in part, by) SOS.

[0021] In one aspect, provided are compounds of Formula (I):

[0022]

[0023] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers thereof; Wherein, n is 0, 1 or 2;

[0024] Cyl is selected from Ce-io aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R100; Cy2 is selected from C3-7 monocyclic cycloalkyl, C7-10 fused bicyclic cycloalkyl, C7-10 spirocyclic cycloalkyl, C5-10 bridged bicyclic cycloalkyl, 4-7 membered monocyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, 8-10 membered fused bicyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, 7-10 membered spriocyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, and 6-10 membered bridged bicyclic heterocyclyl, containing 1 to 4 heteroatoms selected from N, O, and S, each independently optionally substituted with one to four R100;

[0025] R1is selected from hydrogen, halo, oxo, hydroxy, amino, -C(O)Ra, -C(O)ORb, -C(O)NRaRb, -N(Ra)C(O)Rb, -S(O)NRaRb, -S(O)2NRaRb, -S(O)Rg, -S(O)2Rg, -NRaRb, -ORa, -SRb, -C1-6 alkyl, 4-6 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, 5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-ealkynyl, Ce-ioaryl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl is optionally substituted with one to four R100; R2is selected from hydrogen, halo, oxo, hydroxy, amino, -C(O)Ra, -C(O)ORb, -C(O)NRaRb, -N(Ra)C(O)Rb, -S(O)NRaRb, -S(O)2NRaRb, -S(O)Rg, -S(O)2Rg, -NRaRb, -ORa, -SRb, -C1-6 alkyl, C2-6 alkenyl, C2-ealkynyl, C3-6 cycloalkyl, 4-7 membered monocyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, 5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-ealkynyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered fused bicyclic heterocyclyl and 8-10 membered fused bicyclic heteroaryl is optionally substituted with one to four R100;

[0026] R3is selected from hydrogen, halo and -C1-6 alkyl;

[0027] R4is selected from hydrogen, halo, hydroxy, amino and -C1-6 alkyl;

[0028] Each R5and R6is independently selected from hydrogen, halo, hydroxy, amino, -CN, -C(O)Ra, -C(O)ORb, -C(O)NRaRb, -N(Ra)C(O)Rb, -N(Ra)C(O)NRaRb, -N(Ra)SO2NRaRb, -S(O)NRaRb, -S(O)2NRaRb, -N(Ra)S(O)2Rb, -S(O)Rg, -S(O)2Rg, -NRaRb, -ORa, -SRb, -OC(O)Ra, -OC(O)NRaRb, C1-6 alkyl; C2-6 alkenyl, C2-ealkynyl and C3-8 cycloalkyl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-ealkynyl and C3-8 cycloalkyl is optionally substituted with one to four R100;

[0029] each Raand Rbis independently selected from absent, hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-7 membered monocyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S,, 5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, 8-10 membered fused bicyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; 8-10 membered fused bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered fused bicyclic heterocyclyl and 8-10 membered fused bicyclic heteroaryl is optionally substituted with one to four R200; alternatively, Raand Rbtogether with the atom(s) to which they are attached may form a spiro, fused or bridged ring, optionally substituted with one to four R200;

[0030] each R100is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -N(Rc)C(O)Rd, -S(O)NRcRd, -S(O)2NRcRd, -S(O)Rh, -S(O)2Rh, -NRcRd, -ORC, -SRC, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R201; alternatively two R100groups together with the atoms to which they are attached may form a C3-8 cycloalkyl or 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, each optionally substituted with one to four R201.

[0031] each Rcand Rdis independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; alternatively, Rcand Rdtogether with the atom(s) to which they are attached may form a spiro, fused or bridged ring, optionally substituted with one to four R300;

[0032] each R200and R201is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)Re, -C(O)ORe, -C(O)NReRf, -N(Re)C(O)Rf, -S(O)NReRf, -S(O)2NReRf, -S(O)R‘, -S(O)2Ri, -NReRf, -ORe, -SRe, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R300;

[0033] each Rg, Rhand R1is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, is optionally substituted with one to four R300;

[0034] wherein each R300is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)Re, -C(O)ORe, -C(O)NReRf, -N(Re)C(O)Rf, -S(O)NReRf, -S(O)2NReRf, -NReRf, S(O)Re, -S(O)2Re, -NReRf, -ORe, -SRe, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;

[0035] each Reand Rfis independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl; C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R400;

[0036] each R400is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)Rk, -C(O)ORk, -C(O)NRkR1, -N(Rk)C(O)Rl, -S(O)NRkR1, -S(O)2NRkR1, -NRkR‘, S(O)Rk, -S(O)2Rk, -NRkR‘, -ORk, -SRk, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;

[0037] each Rkand R1is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl; C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S.

[0038] In one aspect, provided are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds disclosed herein.

[0039] The present application also provides methods for the inhibition of SOS comprising administering a therapeutically effective amount of at least one of Formula I.

[0040] The present application also provides a method for treating proliferative, metabolic, allergic, autoimmune and inflammatory diseases, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds disclosed herein. The compounds of Formula I, or a pharmaceutically acceptable salt thereof, may be used to treat cancers that are mediated by, dependent on or associated with SOS activity. In certain embodiments, the disease is a solid tumor.

[0041] DETAILED DESCRIPTION

[0042] In a first aspect, provided are compounds of formula (I) that function as inhibitors of SOS:

[0043]

[0044] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers thereof; Wherein, n is 0, 1 or 2;

[0045] Cyl is selected from Ce-io aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R100;

[0046] Cy2 is selected from C3-7 monocyclic cycloalkyl, C7-10 fused bicyclic cycloalkyl, C7-10 spirocyclic cycloalkyl, C5-10 bridged bicyclic cycloalkyl, 4-7 membered monocyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, 8-10 membered fused bicyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, 7-10 membered spriocyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, and 6-10 membered bridged bicyclic heterocyclyl, containing 1 to 4 heteroatoms selected from N, O, and S, each independently optionally substituted with one to four R100;

[0047] R1is selected from hydrogen, halo, oxo, hydroxy, amino, -C(O)Ra, -C(O)ORb, -C(O)NRaRb, -N(Ra)C(O)Rb, -S(O)NRaRb, -S(O)2NRaRb, -S(O)Rg, -S(O)2Rg, -NRaRb, -ORa, -SRb, -Ci-6 alkyl, 4-6 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, 5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-ioaryl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl is optionally substituted with one to four R100; R2is selected from hydrogen, halo, oxo, hydroxy, amino, -C(O)Ra, -C(O)ORb, -C(O)NRaRb, -N(Ra)C(O)Rb, -S(O)NRaRb, -S(O)2NRaRb, -S(O)Rg, -S(O)2Rg, -NRaRb, -ORa, -SRb, -C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-7 membered monocyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, 5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered fused bicyclic heterocyclyl and 8-10 membered fused bicyclic heteroaryl is optionally substituted with one to four R100;

[0048] R3is selected from hydrogen, halo and -C1-6 alkyl;

[0049] R4is selected from hydrogen, halo, hydroxy, amino and -C1-6 alkyl;

[0050] Each R5and R6is independently selected from hydrogen, halo, hydroxy, amino, -CN, -C(O)Ra, -C(O)ORb, -C(O)NRaRb, -N(Ra)C(O)Rb, -N(Ra)C(O)NRaRb, -N(Ra)SO2NRaRb, -S(O)NRaRb, -S(O)2NRaRb, -N(Ra)S(O)2Rb, -S(O)Rg, -S(O)2Rg, -NRaRb, -ORa, -SRb, -OC(O)Ra, -OC(O)NRaRb, C1-6 alkyl; C2-6 alkenyl, C2-6 alkynyl and C3-8 cycloalkyl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C3-8 cycloalkyl is optionally substituted with one to four R100;

[0051] each Raand Rbis independently selected from absent, hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-7 membered monocyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S,, 5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, 8-10 membered fused bicyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; 8-10 membered fused bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered fused bicyclic heterocyclyl and 8-10 membered fused bicyclic heteroaryl is optionally substituted with one to four R200; alternatively, Raand Rbtogether with the atom(s) to which they are attached may form a spiro, fused or bridged ring, optionally substituted with one to four R200;

[0052] each R100is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -N(Rc)C(O)Rd, -S(O)NRcRd, -S(O)2NRcRd, -S(O)Rh, -S(O)2Rh, -NRcRd, -ORC, -SRC, Ci-6 alkyl, C2-6alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R201; alternatively two R100groups together with the atoms to which they are attached may form a C3-8 cycloalkyl or 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, each optionally substituted with one to four R201.

[0053] each Rcand Rdis independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; alternatively, Rcand Rdtogether with the atom(s) to which they are attached may form a spiro, fused or bridged ring, optionally substituted with one to four R300;

[0054] each R200and R201is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)Re, -C(O)ORe, -C(O)NReRf, -N(Re)C(O)Rf, -S(O)NReRf, -S(O)2NReRf, -S(O)R‘, -S(O)2Ri, -NReRf, -ORe, -SRe, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R300;

[0055] each Rg, Rhand Riis independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, is optionally substituted with one to four R300; wherein each R300is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)Re, -C(O)ORe, -C(0)NReRf, -N(Re)C(0)Rf, -S(0)NReRf, -S(0)2NReRf, -NReRf, S(O)Re, -S(O)2Re, -NReRf, -0Re, -SRe, Ci-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;

[0056] each Reand Rfis independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl; C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R400;

[0057] each R400is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, S(O)NRkR1, -S(O)2NRkR‘, -

[0058]

[0059] 6 alkyl, C2-6 alkenyl and C2-6 alkynyl;

[0060] each Rkand Rlis independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl; C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S.

[0061] In one embodiment, provided are compounds of formula (II):

[0062]

[0063] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers thereof.

[0064] In one embodiment, provided are compounds of formula (III):

[0065]

[0066] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers thereof. In one embodiment, provided are compounds of formula (IVa):

[0067]

[0068] Formula (IVa)

[0069] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers thereof.

[0070] In one embodiment, provided are compounds of formula (IVb):

[0071]

[0072] Formula (IVb)

[0073] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers thereof.

[0074] In one embodiment, provided are compounds of formula (V):

[0075]

[0076] Formula (V)

[0077] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers thereof; Wherein, n is 0, 1 or 2;

[0078] L1is selected from -N(Ra)-[(CH2)2-O]x-(CH2)2N(Ra)C(O)-(CH2)y-; wherein each x and y is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

[0079] Cy2 is selected from C3-7 monocyclic cycloalkyl, C7-10 fused bicyclic cycloalkyl, C7-10 spirocyclic cycloalkyl, C5-10 bridged bicyclic cycloalkyl, 4-7 membered monocyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, 8-10 membered fused bicyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, 7-10 membered spriocyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, and 6-10 membered bridged bicyclic heterocyclyl, containing 1 to 4 heteroatoms selected from N, O, and S, each independently optionally substituted with one to four R100;

[0080] R2is selected from hydrogen, halo, oxo, hydroxy, amino, -C(O)Ra, -C(O)ORb, -C(O)NRaRb, -N(Ra)C(O)Rb, -S(O)NRaRb, -S(O)2NRaRb, -S(O)Rg, -S(O)2Rg, -NRaRb, -ORa, -SRb, -C1-6 alkyl, C2-6 alkenyl, C2-ealkynyl, C3-6 cycloalkyl, 4-7 membered monocyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, 5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered fused bicyclic heterocyclyl and 8-10 membered fused bicyclic heteroaryl is optionally substituted with one to four R100;

[0081] R3is selected from hydrogen, halo and -C1-6 alkyl;

[0082] R4is selected from hydrogen, halo, hydroxy, amino and -C1-6 alkyl;

[0083] Each R5and R6is independently selected from hydrogen, halo, hydroxy, amino, -CN, -C(O)Ra, -C(O)ORb, -C(O)NRaRb, -N(Ra)C(O)Rb, -N(Ra)C(O)NRaRb, -N(Ra)SO2NRaRb, -S(O)NRaRb, -S(O)2NRaRb, -N(Ra)S(O)2Rb, -S(O)Rg, -S(O)2Rg, -NRaRb, -ORa, -SRb, -OC(O)Ra, -OC(O)NRaRb, C1-6 alkyl; C2-6 alkenyl, C2-6 alkynyl and C3-8 cycloalkyl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C3-8 cycloalkyl is optionally substituted with one to four R100;

[0084] each Raand Rbis independently selected from absent, hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-7 membered monocyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S,, 5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, 8-10 membered fused bicyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; 8-10 membered fused bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered fused bicyclic heterocyclyl and 8-10 membered fused bicyclic heteroaryl is optionally substituted with one to four R200; alternatively, Raand Rbtogether with the atom(s) to which they are attached may form a spiro, fused or bridged ring, optionally substituted with one to four R200;

[0085] each R100is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -N(Rc)C(O)Rd, -S(O)NRcRd, -S(O)2NRcRd, -S(O)Rh, -S(O)2Rh, -NRcRd, -ORC, -SRC, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R201; alternatively two R100groups together with the atoms to which they are attached may form a C3-8 cycloalkyl or 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, each optionally substituted with one to four R201.

[0086] each Rcand Rdis independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; alternatively, Rcand Rdtogether with the atom(s) to which they are attached may form a spiro, fused or bridged ring, optionally substituted with one to four R300;

[0087] each R200and R201is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)Re, -C(O)ORe, -C(O)NReRf, -N(Re)C(O)Rf, -S(O)NReRf, -S(O)2NReRf, -S(O)R‘, -S(O)2Ri, -NReRf, -ORe, -SRe, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R300;

[0088] each Rg, Rhand Riis independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, is optionally substituted with one to four R300;

[0089] wherein each R300is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)Re, -C(O)ORe, -C(O)NReRf, -N(Re)C(O)Rf, -S(O)NReRf, -S(O)2NReRf, -NReRf, S(O)Re, -S(O)2Re, -NReRf, -ORe, -SRe, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;

[0090] each Reand Rfis independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl; C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R400;

[0091] each R400is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)Rk, -C(O)ORk, -C(O)NRkR1, -N(Rk)C(O)Rl, -S(O)NRkR1, - S(O)2NRkR1, -NRkR\ S(O)Rk, -S(O)2Rk, -NRkR‘, -ORk, -SRk, Ci-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;

[0092] each Rkand R1is independently selected from hydrogen, Ci-6 alkyl, C2-6 alkenyl and C2-6 alkynyl; C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S.

[0093] In one embodiment, provided are compounds of formula I-V, wherein R1is selected from: -(CH2)mOH, -N(CH3)CH2C(O)NH2, -N(CH3)CH2C(OH)CH3, -N(CH3)CH2C(O)N(H)CH2CH3, -N(Ra)(C(Ra)(Rb))mOH, -N(Ra)(C(Ra)(Rb))mC(O)NH2, -N(Ra)(C(Ra)(Rb))mH, -N(Ra)(C(Ra)(Rb))mC(O)NH2,

[0094]

[0095] Wherein m is 0, 1, 2, 3 or 4; and,

[0096] R7is selected from -H, halo, oxo, -OH, -CN, -NH2, -C(O)NH2, -(CH2)OH, -C(O)OH, C1-6alkyl optionally substituted with one to four R100.

[0097] In one embodiment, provided are compounds of formula I-V, wherein R3is -Cl. In one embodiment, provided are compounds of formula I-V, wherein R4is -H. In one embodiment, provided are compounds of formula I-V, wherein R5is -H. In one embodiment, provided are compounds selected from the Table I or a pharmaceutically acceptable salt thereof;

[0098] TABLE I

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203] In another embodiment, there is provided a pharmaceutical composition comprising one or more compounds of Formula I, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, and a pharmaceutically acceptable carrier or diluent.

[0204] The compounds herein, or a pharmaceutically acceptable salt thereof, may be used to treat cancers that are mediated by, dependent on or associated with SOS activity. In certain embodiments, the disease is a solid tumor. In particular embodiments, the solid tumor is selected from prostate cancer, pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancers, CNS cancers, brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, or soft tissue sarcoma. In some embodiments, the solid tumor is from nonsmall cell lung cancer or small-cell lung cancer.

[0205] The following are definitions of terms used in this specification and appended claims. The initial definition provided for a group or term herein applies to that group or term throughout the specification and claims, individually or as part of another group, unless otherwise indicated.

[0206] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0207] Compounds of this invention may have one or more asymmetric centers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms of compounds of the present invention are included in the present invention. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. Cis- and / ra / 7.s-geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. The present compounds can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated. When any variable (e.g., R3) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R3, then said group may optionally be substituted with up to two R3groups and R3at each occurrence is selected independently from the definition of R3. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0208] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0209] In cases wherein there are nitrogen atoms (e.g., amines) on compounds of the present invention, these can be converted to N-oxides by treatment with an oxidizing agent (e.g., MCPBA and / or hydrogen peroxides) to afford other compounds of this invention. Thus, all shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (N— >0) derivative.

[0210] In accordance with a convention used in the art,

[0211]

[0212] is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.

[0213] A dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named.

[0214] The term "optionally substituted" in reference to a particular moiety of the compound of Formula I (e.g., an optionally substituted heteroaryl group) refers to a moiety having 0, 1, 2, or more substituents. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined below. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible and / or inherently unstable.

[0215] As used herein, the term "at least one chemical entity" is interchangeable with the term "a compound".

[0216] The prefix "Cu-v" indicates that the following group has from u to v carbon atoms. For example, "Ci-6 alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0217] As used herein, the term "alkyl" or "alkylene" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "Ci-io alkyl" (or alkylene), is intended to include Ci, C2, C3, C4, Cs, Ce, C7, Cs, C9, and C10 alkyl groups. Additionally, for example, "Ci-Ce alkyl" denotes alkyl having 1 to 6 carbon atoms. Alkyl groups can be unsubstituted or substituted so that one or more of its hydrogens are replaced by another chemical group. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, / -butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.

[0218] "Alkenyl" or "alkenylene" is intended to include hydrocarbon chains of either straight or branched configuration and having one or more double carbon-carbon bonds that may occur in any stable point along the chain. For example, "C2-6 alkenyl" (or alkenylene), is intended to include C2, C3, C4, Cs, and Ce alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl, 1 -propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3 -pentenyl, and the like.

[0219] "Alkynyl" or "alkynylene" is intended to include hydrocarbon chains of either straight or branched configuration and having one or more triple carbon-carbon bonds that may occur in any stable point along the chain. For example, "C2-6 alkynyl" (or alkynylene), is intended to include C2, C3, C4, Cs, and Ce alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like. One skilled in the field will understand that, when the designation "CO2" is used o

[0220] herein, this is intended to refer to the group c— o —.

[0221] When the term "alkyl" is used together with another group, such as in "arylalkyl", this conjunction defines with more specificity at least one of the substituents that the substituted alkyl will contain. For example, "arylalkyl" refers to a substituted alkyl group as defined above where at least one of the substituents is an aryl, such as benzyl. Thus, the term aryl(Co-4)alkyl includes a substituted lower alkyl having at least one aryl substituent and also includes an aryl directly bonded to another group, / .<?., aryl(Co)alkyl. The term "heteroarylalkyl" refers to a substituted alkyl group as defined above where at least one of the substituents is a heteroaryl.

[0222] When reference is made to a substituted alkenyl, alkynyl, alkylene, alkenylene, or alkynylene group, these groups are substituted with one to three substituents as defined above for substituted alkyl groups.

[0223] The term "alkoxy" refers to an oxygen atom substituted by alkyl or substituted alkyl, as defined herein. For example, the term "alkoxy" includes the group -O-C1-6alkyl such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, te / 7-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, and the like. "Lower alkoxy" refers to alkoxy groups having one to four carbons.

[0224] The term "cycloalkyl" refers to cyclized alkyl groups, including mono-, bi- or polycyclic ring systems. C3-7 cycloalkyl is intended to include C3, C4, Cs, Ce, and C7 cycloalkyl groups. Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, unsaturated or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,

[0225] [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shown above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. When the term "carbocycle" is used, it is intended to include "aryl". A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a bicyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.

[0226] The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, and naphthyl groups, each of which may be substituted.

[0227] Accordingly, in compounds of formula I, the term "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclooctyl, etc., as well as the following ring systems:

[0228]

[0229] and the like, which optionally may be substituted at any available atoms of the ring(s).

[0230] The term "halo" or "halogen" refers to chloro, bromo, fluoro and iodo.

[0231] The term "haloalkyl" means a substituted alkyl having one or more halo substituents. For example, "haloalkyl" includes mono, bi, and trifluoromethyl.

[0232] The term "haloalkoxy" means an alkoxy group having one or more halo substituents. For example, "haloalkoxy" includes OCF3.

[0233] The terms "heterocycle", "heterocycloalkyl", "heterocyclo", "heterocyclic", or "heterocyclyl" may be used interchangeably and refer to substituted and unsubstituted 3-to 7-membered monocyclic groups, 7- to 11 -membered bicyclic groups, and 10- to 15-membered tricyclic groups, in which at least one of the rings has at least one heteroatom (O, S or N), said heteroatom containing ring preferably having 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of such a group containing a heteroatom can contain one or two oxygen or sulfur atoms and / or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or fully unsaturated. The heterocyclo group may be attached at any available nitrogen or carbon atom. As used herein the terms "heterocycle", "heterocycloalkyl", "heterocyclo", "heterocyclic", and "heterocyclyl" include "heteroaryl" groups, as defined below.

[0234] In addition to the heteroaryl groups described below, exemplary monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 1-pyridonyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro- 1,1 -di oxothienyl and the like. Exemplary bicyclic heterocyclo groups include quinuclidinyl.

[0235] The term "heteroaryl" refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups, and 11- to 14-membered tricyclic groups which have at least one heteroatom (O, S or N) in at least one of the rings, said heteroatom-containing ring preferably having 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and / or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or nonaromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. As valence allows, if said further ring is cycloalkyl or heterocyclo it is additionally optionally substituted with =0 (oxo). Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.

[0236] Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodi oxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrol opyridyl, furopyridyl, dihydroisoindolyl, tetrahydroquinolinyl and the like.

[0237] Exemplary tricyclic heteroaryl groups include carbazolyl, benzindolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

[0238] In compounds of formula I, preferred heteroaryl groups include:

[0239]

[0240] be substituted at any available carbon or nitrogen atom.

[0241] Unless otherwise indicated, when reference is made to a specifically-named aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), heterocyclo (e.g, pyrrolidinyl, piperidinyl, and morpholinyl) or heteroaryl (e.g, tetrazolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, and furyl) the reference is intended to include rings having 0 to 3, preferably 0 to 2, substituents selected from those recited above for the aryl, cycloalkyl, heterocyclo and / or heteroaryl groups, as appropriate.

[0242] The term "carbocyclyl" or "carbocyclic" refers to a saturated or unsaturated monocyclic or bicyclic ring in which all atoms of all rings are carbon. Thus, the term includes cycloalkyl and aryl rings. Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system. Examples of mono- and bicyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1 -cyclopent- 1-enyl, l-cyclopent-2-enyl, 1-cy cl opent-3 -enyl, cyclohexyl, 1 -cyclohex- 1-enyl, l-cyclohex-2-enyl, 1 -cyclohex-3 -enyl, phenyl and naphthyl. The carbocyclic ring may be substituted in which case the substituents are selected from those recited above for cycloalkyl and aryl groups.

[0243] The term "alkylthio" refers to the group "alkyl-S-".

[0244] The term "acyl" refers to a group -C(O)R, wherein R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0245] The term "amido" refers to both a "C-amido" group which refers to the group — C(O)NRgRhand an "N-amido" group which refers to the group -NRgC(O)Rh, wherein Rgand Rhare independently selected from hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.

[0246] The term "amino" refers to the group -NRgRhwherein Rgand Rhare independently selected from hydrogen, alkyl, haloalkyl, aryl, or heteroaryl; each of which may be optionally substituted.

[0247] The term "azido" refers to -N3.

[0248] The term "carbamoyl" refers to both an "O-carbamoyl" group which refers to the group -O-C(O)NR.'RIand an "N-carbamoyl" group which refers to the group -NR1C(O)ORi, wherein R1and R> are independently selected from hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.

[0249] The term "carboxyl" refers to -C(O)OH.

[0250] The term "carboxyl ester" refers to both -OC(O)R and -C(O)ORg, wherein Rgis hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0251] The term "cyano" or "carbonitrile" refers to the group -CN.

[0252] The term "cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e. the cyclic group having at least one double bond). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C. sub.3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C. sub.3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C. sub.3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C.sub.3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C. sub.3-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0253] The term "heteroatoms" shall include oxygen, sulfur and nitrogen.

[0254] When the term "unsaturated" is used herein to refer to a ring or group, the ring or group may be fully unsaturated or partially unsaturated.

[0255] Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds and compounds useful as pharmaceutically-acceptable compounds and / or intermediate compounds useful in making pharmaceutically-acceptable compounds.

[0256] It should be understood that the selections for all groups, including for example, alkoxy, thioalkyl, and aminoalkyl, will be made by one skilled in the field to provide stable compounds.

[0257] The term "substituted", as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded. When a substituent is oxo, or keto, i.e., =0) then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. Unless otherwise specified, substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0258] Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture to a useful degree of purity, and subsequent formulation into an efficacious therapeutic agent. It is preferred that the presently recited compounds do not contain aN-halo, S(O)2H, or S(O)H group. The compounds herein may exist in a free form (with no ionization) or can form salts which are also within the scope of this invention. Unless otherwise indicated, reference to an inventive compound is understood to include reference to the free form and to salts thereof. The term "salt(s)" denotes acidic and / or basic salts formed with inorganic and / or organic acids and bases. In addition, the term "salt(s)" may include zwitterions (inner salts), e.g., when a compound of formula I, contains both a basic moiety, such as an amine or a pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. Pharmaceutically acceptable ( / .<., non-toxic, physiologically acceptable) salts are preferred, such as, for example, acceptable metal and amine salts in which the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may be useful, e.g., in isolation or purification steps which may be employed during preparation, and thus, are contemplated within the scope of the invention. Salts of the compounds of herein may be formed, for example, by reacting a compound herein with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0259] Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2-hydroxy ethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3 -phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.

[0260] Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; barium, zinc, and aluminum salts; salts with organic bases (for example, organic amines) such as trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1 -ephenamine, N,N'-dibenzylethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine or similar pharmaceutically acceptable amines and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. Preferred salts include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or nitrate salts.

[0261] The compounds can be provided as amorphous solids or crystalline solids.

[0262] Lyophilization can be employed to provide the compounds as a solid.

[0263] It should further be understood that solvates (e.g., hydrates) of the compound herein are also within the scope of the present invention. The term “solvate” means a physical association of a compound with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.

[0264] In addition, compounds herein, subsequent to their preparation, can be isolated and purified to obtain a composition containing an amount by weight equal to or greater than 99% of a compound (“substantially pure”), which is then used or formulated as described herein. Such “substantially pure” compounds of Formula I, II, III and IV, are also contemplated herein as part of the present invention.

[0265] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically-acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. The pharmaceutically-acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like.

[0266] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA (1990), the disclosure of which is hereby incorporated by reference.

[0267] “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The present invention is intended to embody stable compounds.

[0268] “Therapeutically effective amount” is intended to include an amount of a compound of the present invention alone or an amount of the combination of compounds claimed or an amount of a compound of the present invention in combination with other active ingredients effective to act as an inhibitor of SOS, or effective to treat or prevent proliferative disorders, such as cancer. As used herein, “treating” or “treatment” cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the diseasestate but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting its development; and / or (c) relieving the disease-state, i.e., causing regression of the disease state.

[0269] All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. Stereoisomers may include compounds which are optical isomers through possession of one or more chiral atoms, as well as compounds which are optical isomers by virtue of limited rotation about one or more bonds (atropisomers). The definition of compounds according to the invention embraces all the possible stereoisomers and their mixtures. It very particularly embraces the racemic forms and the isolated optical isomers having the specified activity. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates from the conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.

[0270] The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include13C and14C.

[0271] Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

[0272] Prodrugs and solvates of the inventive compounds are also contemplated. The term "prodrug" denotes a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the formula I, and / or a salt and / or solvate thereof. Any compound that will be converted in vivo to provide the bioactive agent (i.e., the compound for formula I) is a prodrug within the scope and spirit of the invention. For example, compounds containing a carboxy group can form physiologically hydrolyzable esters which serve as prodrugs by being hydrolyzed in the body to yield formula I compounds per se. Such prodrugs are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes. Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of compounds of formula I include C1-6alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl,

[0273] Ci-ealkanoyloxy-C1-6alkyl, e.g., acetoxymethyl, pivaloyloxymethyl or

[0274] propionyl oxy methyl, Ci-ealkoxycarbonyloxy-C1-6alkyl, e.g., methoxy carbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-l,3-dioxolen-4-yl)-methyl and other well known physiologically hydrolyzable esters used, for example, in the penicillin and cephalosporin arts. Such esters may be prepared by conventional techniques known in the art.

[0275] Various forms of prodrugs are well known in the art and are described in Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587 (2018).

[0276] Compounds described in the application and their salts may exist in their tautomeric form, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that the all tautomeric forms, insofar as they may exist, are included within the invention. Additionally, inventive compounds may have trans- and cis-\ somers.

[0277] The disclosure herein further relates to compounds hrein, the tautomers and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, for use as a medicament. Furthermore, the disclosure herein relates to the use of a compound herein, a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt, or a solvate thereof, or a pharmaceutical composition according to the invention, for the manufacture of a medicament.

[0278] The inventive compositions may contain other therapeutic agents as described above and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (e.g., excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.

[0279] Accordingly, the present invention further includes compositions comprising one or more compounds herein and a pharmaceutically acceptable carrier.

[0280] A "pharmaceutically acceptable carrier" refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals.

[0281] Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include without limitation the type and nature of the active agent being formulated; the subject to which the agentcontaining composition is to be administered; the intended route of administration of the composition; and, the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Remington's Pharmaceutical Sciences, 17th Edition (1985), which is incorporated herein by reference in its entirety.

[0282] The compounds hrein may be administered by any means suitable for the condition to be treated, which may depend on the need for site-specific treatment or quantity of drug to be delivered. Topical administration is generally preferred for skin-related diseases, and systematic treatment preferred for cancerous or pre-cancerous conditions, although other modes of delivery are contemplated. For example, the compounds may be delivered orally, such as in the form of tablets, capsules, granules, powders, or liquid formulations including syrups; topically, such as in the form of solutions, suspensions, gels or ointments; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (e.g., as sterile injectable aq. or non-aq. solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; rectally such as in the form of suppositories; or liposomally. Dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents may be administered. The compounds may be administered in a form suitable for immediate release or extended release.

[0283] Immediate release or extended release may be achieved with suitable pharmaceutical compositions or, particularly in the case of extended release, with devices such as subcutaneous implants or osmotic pumps.

[0284] Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and / or lactose and / or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The inventive compounds may also be orally delivered by sublingual and / or buccal administration, e.g., with molded, compressed, or freeze-dried tablets. Exemplary compositions may include fast-dissolving diluents such as mannitol, lactose, sucrose, and / or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (AVICEL®) or polyethylene glycols (PEG); an excipient to aid mucosal adhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and / or maleic anhydride copolymer (e.g., GANTREZ®); and agents to control release such as polyacrylic copolymer (e.g., CARBOPOL 934®). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.

[0285] Formulations for parenteral administration may be in the form of aqueous or nonaqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in the formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, com oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and / or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. The active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water, or with cyclodextrin (i.e. Captisol), cosolvent solubilization (i.e. propylene glycol) or micellar solubilization (i.e. Tween 80).

[0286] Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3 -butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

[0287] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0288] A sterile injectable oil-in-water microemulsion can, for example, be prepared by 1) dissolving at least one compounds in an oily phase, such as, for example, a mixture of soybean oil and lecithin; 2) combining the compound-containing oil phase with a water and glycerol mixture; and 3) processing the combination to form a microemulsion.

[0289] A sterile aqueous or oleaginous suspension can be prepared in accordance with methods already known in the art. For example, a sterile aqueous solution or suspension can be prepared with a non-toxic parenterally-acceptable diluent or solvent, such as, for example, 1,3-butane diol; and a sterile oleaginous suspension can be prepared with a sterile non-toxic acceptable solvent or suspending medium, such as, for example, sterile fixed oils, e.g., synthetic mono- or diglycerides; and fatty acids, such as, for example, oleic acid.

[0290] Exemplary compositions for nasal aerosol or inhalation administration include solutions which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and / or bioavailability, and / or other solubilizing or dispersing agents such as those known in the art. Dispersible powders and granules can, for example, be prepared by admixing at least one compounds herein, or a pharmaceutically acceptable salt thereof, with at least one dispersing and / or wetting agent; at least one suspending agent; and / or at least one preservative. Exemplary preservatives include, but are not limited to, for example, antioxidants, e.g., ascorbic acid. In addition, dispersible powders and granules can also contain at least one excipient, including, but not limited to, for example, sweetening agents; flavoring agents; and coloring agents.

[0291] Exemplary compositions for rectal administration include suppositories which may contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures but liquefy and / or dissolve in the rectal cavity to release the drug.

[0292] The therapeutically-effective amount of a compound of the present invention may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for a mammal of from about 0.05 to 1000 mg / kg; 1-1000 mg / kg; 1-50 mg / kg; 5-250 mg / kg; 250-1000 mg / kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition. Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats, horses, and the like. Thus, when the term "patient" is used herein, this term is intended to include all subjects, most preferably mammalian species that are affected by modulation of SOS-mediated functions.

[0293] The compounds herein are useful for the treatment of cancer. In one embodiment, the present application provides a combined preparation of a compounds herein and / or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, and additional therapeutic agent(s) for simultaneous, separate or sequential use in the treatment and / or prophylaxis of multiple diseases or disorders associated with SOS. In another aspect, the application provides a method of treating a patient suffering from or susceptible to a medical condition that is associated with SOS. A number of medical conditions can be treated. The method comprises administering to the patient a therapeutically effective amount of a composition comprising a compounds herein and / or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof. For example, the compounds described herein may be used to treat or proliferative diseases such as cancer, immunological disorders or inflammatory disorders.

[0294] In other embodiments, the compounds described herein may be used to treat cancers that are mediated by, dependent on or associated with SOS activity. In certain embodiments, the disease is a solid tumor. In particular embodiments, the solid tumor is selected from prostate cancer, pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancers, CNS cancers, brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, or soft tissue sarcoma. In some embodiments, the solid tumor is from non-small cell lung cancer or small-cell lung cancer.

[0295] In one embodiment, the compounds herein can be useful in the treatment of haematological malignancies. In one embodiment, hematological malignancy is selected from multiple myeloma, non-Hodgkin's lymphoma, Hodgkin lymphoma, T-cell leukaemia, mucosa-associated lymphoid tissue lymphoma, diffuse large B-cell lymphoma and mantle cell lymphoma. In one embodiment solid tumor is selected from pancreatic cancer, breast cancer, melanoma and non-small cell lung cancer.

[0296] In one embodiment, cancer is selected from a carcinoma, preferably a carcinoma of the bladder, breast, colon (including colorectal carcinomas, such as colon adenocarcinoma and colon adenoma), kidney, urothelial, uterus, epidermis, liver, lung (including adenocarcinoma, small cell lung cancer, non-small cell lung carcinomas and squamous lung cancer), oesophagus, head and neck, gall bladder, ovary, pancreas (including exocrine pancreatic carcinoma), stomach, gastrointestinal cancer (including gastrointestinal stromal tumors), cervix, endometrium, thyroid, prostate and skin. In one embodiment, the cancer is selected from pituitary cancer, a hematopoietic tumor of lymphoid lineage, for example leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma (e.g. diffuse large B-cell lymphoma, mantle cell lymphoma), T-cell leukaemia / lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; a hematopoietic tumor of myeloid lineage, for example leukemias, acute and chronic myelogenous leukemias, chronic myelomonocytic leukemia (CMML), myeloproliferative disorder, myeloproliferative syndrome, myelodysplastic syndrome, or promyelocytic leukemia; multiple myeloma; thyroid follicular cancer; hepatocellular cancer, a tumor of mesenchymal origin (e.g. Ewing's sarcoma), for example fibrosarcoma or rhabdomyosarcoma; a tumor of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma (such as glioblastoma multiforme) or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma.

[0297] In other embodiments, the compounds described herein may be used to treat cancers that are mediated by, dependent on or associated with SOS activity. In certain embodiments, the disease is a solid tumor. In particular embodiments, the solid tumor is from prostate cancer, pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancers, CNS cancers, brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, or soft tissue sarcoma. In some embodiments, the solid tumor is from non-small cell lung cancer or small-cell lung cancer.

[0298] In other embodiments, the disease is a hematologic malignancy. In certain embodiments, the disease is lymphoma, multiple myeloma, or leukemia. In certain embodiments, the hematologic malignancy is leukemia or lymphoma. In specific embodiments, the disease is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), juvenile myelomonocytic leukemia (JMML), multiple myeloma (MM), Hodgkin lymphoma, indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL, non- Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldenstrom’s macroglobulinemia (WM), minimal residual disease (MRD), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), lymphoplasmacytic lymphoma, marginal zone lymphoma, or Burkitt lymphoma. In one embodiment, the disease is T-cell acute lymphoblastic leukemia (T-ALL), or B-cell acute lymphoblastic leukemia (B-ALL). In some embodiments, non-Hodgkin lymphoma can be indolent B-cell diseases including follicular lymphoma, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma, as well as the aggressive lymphomas that include, for example, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL).

[0299] In some embodiments, the cancer is selected from hematological cancer, a lymphatic cancer. In some embodiments, the cancer comprises cancer cells with DNA damage repair pathway deficiency. In some embodiments, the cancer is a homologous recombination deficient cancer. In some embodiments, the cancer comprises cancer cells with a mutation in a gene encoding p53. In some embodiments, the mutation in a gene encoding p53 is a germline or somatic mutation. In some embodiments, the cancer comprises with cancer cells with loss of function mutation in a gene encoding p53. In some embodiments, the cancer is a BRCA1 and / or BRCA2 deficient cancer. In some embodiments, the cancer is a somatic or germline BRCA1 and / or BRCA2 mutant cancer. In some embodiments, the cancer is a Poly (ADP -ribose) polymerase (“PARP”) inhibitor refractory or resistant cancer. In some embodiments, the cancer is a PARP inhibitor resistant or refractory BRCA1 and / or BRCA2 deficient cancer. In some embodiments, the cancer cell has a germline or somatic mutation in a gene encoding ataxia telangiectasia mutated (ATM) protein kinase or ATM deficiency. In some embodiments, the cancer has a mutation in the gene encoding more than two of p53, BRCA1, BRCA2, ATM.

[0300] In a preferred embodiment, the disease or disorder is selected from cancer is selected from the group consisting of Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);

[0301] Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.

[0302] Combination Therapies

[0303] In some embodiments, the compounds described herein may be administered in conjunction with standard of care, e.g., surgery, radiation, and / or chemotherapy. In some embodiments, the compounds may be administered in conjunction with a chemotherapeutic agent. In some embodiments, the compounds may be administered in conjunction with one or more of carboplatin, cisplatin, paclitaxel, nab-paclitaxel, gemcitabine or FOLFOX. In some embodiment, the compounds may be administered in conjunction with carboplatin or nab-paclitaxel. In some embodiments, the compounds may be administered in conjunction with carboplatin and paclitaxel. In some embodiments, the compounds may be administered in conjunction with cisplatin and pemetrexed. In some embodiments, the compounds may be administered in conjunction with cisplatin and gemcitabine. In some embodiments, the compounds may be administered in conjunction with FOLFOX. In some embodiments, the compounds may be administered in conjunction with FOLFIRI. In one embodiment, the compounds may be administered in combination with decarbazine for the treatment of melanoma. In some embodiments, cisplatin is intravenously administered as a 100 mg / ml dose once every four weeks. In some embodiments, the compounds may be administered in conjunction with doxorubicin (adriamycin), cisplatin bleomycin sulfate, carmustine, chlorambucil, dacarbazine and / or cyclophosphamide hydroxyurea. In some embodiments, adriamycin is intravenously administered as a 60 mg / ml to 75 mg / ml dose once every 21 days.

[0304] In one embodiment, the compounds of the present application (e.g., a compound of Formula I, II or III, or a pharmaceutically acceptable salt, prodrug, or solvate thereof) may be used in combination with one or more additional therapeutic agent that are being used and / or developed to treat cancers or inflammatory disorders. The one or more additional therapeutic agent may be an inhibitor to Janus kinase (JAK) such as JAK1, JAK2 and / or JAK3, Tyroansine kinase (TYK), K-Ras, Mitogen activated protein kinases (MAPK), Bruton's tyrosine kinase (BTK), bromodomain containing protein inhibitor (BRD) such as BRD4, a lysyl oxidase protein (LOX), lysyl oxidase-like protein (LOXL) such as LOXL 1-5, matrix metalloprotease (MMP) such as MMP 1-10, adenosine A2B receptor (A2B), isocitrate dehydrogenase (IDH) such as IDH1, apoptosis signal - regulating kinase (ASK) such as ASK1, serine / threonine kinase TPL2, discoidin domain receptor (DDR) such as DDR1 and DDR2, histone deacetylase (HD AC), protein kinase C (PKC), or any combination thereof.

[0305] In one embodiment, the compounds of the present application may be used in combination with additional chemotherapeutic agent, an immunotherapeutic agent, a radiotherapeutic agent, an anti -neoplastic agent, an anti-cancer agent, an anti-fibrotic agent, an anti-angiogenic agent, a therapeutic antibody, or any combination thereof.

[0306] Chemotherapeutic agents may be categorized by their mechanism of action into, for example, the following groups: anti-metabolites / anti-cancer agents, such as pyrimidine analogs (floxuridine, capecitabine, and cytarabine); purine analogs, folate antagonists and related inhibitors antiproliferative / antimitotic agents including natural products such as vinca alkaloid (vinblastine, vincristine) and microtubule such as taxane (paclitaxel, docetaxel), vinblastin, nocodazole, epothilones and navelbine, epidipodophyllotoxins (etoposide, teniposide); DNA damaging agents (actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, Cytoxan, dactinomycin, daunorubicin, doxorubicin, epirubicin, iphosphamide, melphalan, merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, procarbazine, taxol, taxotere, teniposide, etoposide, triethylenethiophosphoramide); antibiotics such as dactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin), idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin; enzymes (L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine); antiplatelet agents; antiproliferative / antimitotic alkylating agents such as nitrogen mustards cyclophosphamide and analogs, melphalan, chlorambucil), and (hexamethylmelamine and thiotepa), alkyl nitrosoureas (BCNU) and analogs, streptozocin), trazenes-dacarbazinine (DTIC); antiproliferative / antimitotic antimetabolites such as folic acid analogs (methotrexate); platinum coordination complexes (cisplatin, oxiloplatinim, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones, hormone analogs (estrogen, tamoxifen, goserelin, bicalutamide, nilutamide) and aromatase inhibitors (letrozole, anastrozole); anticoagulants (heparin, synthetic heparin salts and other inhibitors of thrombin); fibrinolytic agents (such as tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel; antimigratory agents; antisecretory agents (breveldin); immunosuppressives tacrolimus sirolimus azathioprine, mycophenolate; compounds (TNP-470, genistein) and growth factor inhibitors (vascular endothelial growth factor inhibitors, fibroblast growth factor inhibitors); angiotensin receptor blocker, nitric oxide donors; anti-sense oligonucleotides; antibodies (trastuzumab, rituximab); cell cycle inhibitors and differentiation inducers (tretinoin); inhibitors, topoisomerase inhibitors (doxorubicin (adriamycin), daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan and mitoxantrone, topotecan, irinotecan, camptothesin), corticosteroids (cortisone, dexamethasone, hydrocortisone, methylpednisolone, prednisone, and prenisolone); growth factor signal transduction kinase inhibitors; dysfunction inducers, toxins such as Cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, or diphtheria toxin, and caspase activators; and chromatin.

[0307] Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; emylerumines and memylamelamines including alfretamine, triemylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimemylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (articularly cryptophycin 1 and cryptophy cin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CBI-TMI); eleutherobin; pancrati statin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, foremustine, lomustine, nimustine, ranimustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, calicheamicin gammall, dynemicin, dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carrninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as demopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replinisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; hestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformthine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; fluoropyrimidine; folinic acid; podophyllinic acid; 2-ethylhydrazide; procarbazine; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-tricUorotriemylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiopeta; taxoids, e.g., paclitaxel and docetaxel, chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide; ifosfamide; mitroxantrone; vancristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeoloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; FOLFIRI (fluorouracil, leucovorin, and irinotecan) and pharmaceutically acceptable salts, acids or derivatives of any of the above. One or more chemotherapeutic agent is used or included in the present application.

[0308] Chemotherapeutic agents may also include, for example, anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, onapristone, and toremifene; inhibitors of the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate, exemestane, formestane, fadrozole, vorozole letrozole and anastrozole; and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprohde, and goserelin; and pharmaceutically acceptable salts thereof.

[0309] The anti-angiogenic agents include, but are not limited to, retinoid acid and derivatives thereof, 2-methoxyestradiol, suramin, squalamine, tissue inhibitor of metalloproteinase- 1, tissue inhibitor of metalloproternase-2, plasminogen activator inhibitor- 1, plasminogen activator inbibitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulphate (clupeine), sulphated chitin derivatives (prepared from queen crab shells), sulphated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism, including for example, proline analogs ((l-azetidine-2-carboxylic acid (LACA), cishydroxyproline, d, 1-3,4-dehydroproline, thiaproline,.alpha. -di pyridyl, beta-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone; methotrexate, mitoxantrone, heparin, interferons, 2 macroglobulin-serum, chimp-3, chymostatin, beta-cyclodextrin tetradecasulfate, eponemycin; fumagillin, gold sodium thiomalate, d-penicillamine (CDPT), beta-1-anticollagenase-serum, alpba-2-antiplasmin, bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthronilic acid disodium or "CCA", thalidomide; angiostatic steroid, cargboxynaminolmidazole; metalloproteinase inhibitors such as BB94. Other anti-angiogenesis agents include antibodies, preferably monoclonal antibodies against these angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF / SF and Ang-l / Ang-2.

[0310] The application also provides a method for treating a subject who is undergoing one or more standard therapies, such as chemotherapy, radiotherapy, immunotherapy, surgery, or combination thereof. Accordingly, one or more therapeutic agent or inhibitors may be administered before, during, or after administration of chemotherapy, radiotherapy, immunotherapy, surgery or combination thereof.

[0311] In certain embodiments, the subject may be a human who is (i) substantially refractory to at least one chemotherapy treatment, or (ii) in relapse after treatment with chemotherapy, or both (i) and (ii). In some of embodiments, the subject is refractory to at least two, at least three, or at least four chemotherapy treatments (including standard or experimental chemotherapies).

[0312] In certain embodiments, the subject is refractory to at least one, at least two, at least three, or at least four chemotherapy treatment (including standard or experimental chemotherapy) selected from fludarabine, rituximab, obinutuzumab, alkylating agents, alemtuzumab and other chemotherapy treatments such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone); R-CHOP (rituximab-CHOP); hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine); R-hyperCVAD (rituximab-hyperCVAD); FCM (fludarabine, cyclophosphamide, mitoxantrone); R-FCM (rituximab, fludarabine, cyclophosphamide, mitoxantrone); bortezomib and rituximab; temsirolimus and rituximab; temsirolimus and Velcade. RTM.; Iodine-131 tositumomab (Bexxar. RTM.) and CHOP; CVP (cyclophosphamide, vincristine, prednisone); R-CVP (rituximab-CVP); ICE (iphosphamide, carboplatin, etoposide); R-ICE (rituximab-ICE); FCR (fludarabine, cyclophosphamide, rituximab); FR (fludarabine, rituximab); and D. T. PACE (dexamethasone, thalidomide, cisplatin, Adriamycin. RTM., cyclophosphamide, etoposide).

[0313] Examples of immunotherapeutic agents treating lymphoma or leukemia include, but are not limited to, rituximab (such as Rituxan), alemtuzumab (such as Campath, MabCampath), anti-CD19 antibodies, anti-CD20 antibodies, anti-MN-14 antibodies, anti-TRAIL, Anti-TRAIL DR4 and DR5 antibodies, anti-CD74 antibodies, apolizumab, bevacizumab, CHIR-12.12, epratuzumab (hLL2-anti-CD22 humanized antibody), galiximab, ha20, ibritumomab tiuxetan, lumiliximab, milatuzumab, ofatumumab, PRO131921, SGN-40, WT-1 analog peptide vaccine, WT1 126-134 peptide vaccine, tositumomab, autologous human tumor-derived HSPPC-96, and veltuzumab. Additional immunotherapy agents includes using cancer vaccines based upon the genetic makeup of an individual patient's tumor, such as lymphoma vaccine GTOP-99.

[0314] The therapeutic treatments can be supplemented or combined with any of the abovementioned therapies with stem cell transplantation or treatment. One example of modified approach is radioimmunotherapy, wherein a monoclonal antibody is combined with a radioisotope particle, such as indium In-111, yttrium Y-90, iodine 1-131. Examples of combination therapies include, but are not limited to, Iodine-131 tositumomab, Yttrium-90 ibritumomab tiuxetan with CHOP.

[0315] The compounds of the application can be used in combination with additional therapeutic procedures. Other therapeutic procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, infusion of stem cells, bone marrow ablation with stem cell support, in vitro-treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technique, pharmacological study, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and nonmyeloablative allogeneic hematopoietic stem cell transplantation.

[0316] The compounds of the application can be used in combination with anti-fibrotic agents. The anti-fibrotic agents include, but are not limited to, emylenemamine, hydrazine, phenylhydrazine, and their derivatives, semicarbazide, and urea derivatives, aminonitriles, such as beta-aminopropionitrile (BAPN), or 2-nitroethylamine, unsaturated or saturated haloamines, such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3 -bromopropylamine, p-halobenzylamines, selenohomocysteine lactone. Also, the anti-fibrotic agents are copper chelating agents, penetrating or not penetrating the cells. Exemplary compounds include indirect inhibitors such compounds blocking the aldehyde derivatives originating from the oxidative deamination of the lysyl and hydroxylysyl residues by the lysyl oxidases, such as the thiolamines, in particular D-penicillamine, or its analogues such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium -4-((p- 1 -dimethyl-2-amino-2-carboxyethyl)dithio)butane sulphurate, 2-acetamidoethyl-2-acetamidoethanethiol sulphanate, sodium-4-mercaptobutanesulphinate trihydrate.

[0317] The compounds of the application can be used in combination with immunotherapeutic and anti-inflammatory treatments. The immunotherapeutic agents include and are not limited to therapeutic antibodies suitable for treating patients; such as abagovomab, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, daratumumab, drozitumab, duligotumab, dusigitumab, detumomab, dacetuzumab, dalotuzumab, ecromeximab, elotuzumab, ensituximab, ertumaxomab, etaracizumab, farietuzumab, ficlatuzumab, figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotuzumab, intetumumab, ipilimumab, iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab, moxetumomab, narnatumab, naptumomab, necitumumab, nimotuzumab, nofetumomabn, ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab, radretumab, rilotumumab, rituximab, robatumumab, satumomab, sibrotuzumab, siltuximab, simtuzumab, solitomab, tacatuzumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ublituximab, veltuzumab, vorsetuzumab, votumumab, zalutumumab, CC49 and 3F8. The exemplified therapeutic antibodies may be further labeled or combined with a radioisotope particle, such as indium In-111, yttrium Y-90, iodine 1-131.

[0318] In one aspect, the immuno-oncology agent is (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co-inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses (often referred to as immune checkpoint regulators).

[0319] Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, Lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, Lymphotoxin α 1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0320] In one aspect, T cell responses can be stimulated by a combination of a compound of Formula (I) and one or more of (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, 0X40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.

[0321] Other agents that can be combined with compounds described herein for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, compounds of Formula I, II and III, can be combined with antagonists of KIR, such as lirilumab.

[0322] Yet other agents for combination therapies include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008

[0323] (WO11 / 140249; WO13169264; WO14 / 036357).

[0324] In another aspect, compounds of the present application can be used with one or more of agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-L1 / PD-1 interactions), deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse / prevent T cell anergy or exhaustion) and agents that trigger innate immune activation and / or inflammation at tumor sites. In one aspect, the immuno-oncology agent is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab.

[0325] In another aspect, the immuno-oncology agent is a PD-1 antagonist, such as an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514;

[0326] WO2012 / 145493). The immuno-oncology agent may also include pidilizumab (CT-011), though its specificity for PD-1 binding has been questioned. Another approach to target the PD-1 receptor is the recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgGl, called AMP-224

[0327] In another aspect, the immuno-oncology agent is a PD-L1 antagonist, such as an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include, for example, MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (W02007 / 005874), and MSB0010718C (WO2013 / 79174).

[0328] In another aspect, the immuno-oncology agent is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody. Suitable LAG3 antibodies include, for example, BMS-986016 (W010 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (W008 / 132601, WO09 / 44273).

[0329] In another aspect, the immuno-oncology agent is a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12 / 32433).

[0330] In another aspect, the immuno-oncology agent is a GITR agonist, such as an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, W009 / 009116) and MK-4166 (WO11 / 028683).

[0331] In another aspect, the immuno-oncology agent is an IDO antagonist. Suitable IDO antagonists include, for example, INCB-024360 (W02006 / 122150, WO07 / 75598, WO08 / 36653, WO08 / 36642), indoximod, BMS-986205, or NLG-919 (WO09 / 73620, WO09 / 1156652, WO11 / 56652, WO12 / 142237). In another aspect, the immuno-oncology agent is an 0X40 agonist, such as an agonistic 0X40 antibody. Suitable 0X40 antibodies include, for example, MEDI-6383 or MEDI-6469.

[0332] In another aspect, the immuno-oncology agent is an OX40L antagonist, such as an antagonistic 0X40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879).

[0333] In another aspect, the immuno-oncology agent is a CD40 agonist, such as an agonistic CD40 antibody. In yet another embodiment, the immuno-oncology agent is a CD40 antagonist, such as an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

[0334] In another aspect, the immuno-oncology agent is a CD47 antagonist, such as a CD47 antagonist selected from the group MIAP301, MIAP410, TTI-621, CV1, Hu5F9-G4, CC-90002, B6H12 and 2D3.

[0335] In another aspect, the immuno-oncology agent is a CD27 agonist, such as an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0336] In another aspect, the immuno-oncology agent is MGA271 (to B7H3)

[0337] (WO 11 / 109400).

[0338] The combination therapy is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.

[0339] Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single dosage form having a fixed ratio of each therapeutic agent or in multiple, single dosage forms for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment.) Where thwe combination therapy further comprises a non drug treatment, the non drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.

[0340] The present invention also provides the compounds of the present invention for use in therapy.

[0341] In another embodiment, compounds of formula I are selected from exemplified compounds or combinations of exemplified compounds or other embodiments herein.

[0342] In another embodiment are compounds having an IC50 < 1000 nM in at least one of the assays described below.

[0343] The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects and / or embodiments of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional more preferred embodiments. It is also to be understood that each individual element of the preferred embodiments is its own independent preferred embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.

[0344] METHODS OF PREPARATION

[0345] The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety by reference.

[0346] The compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work up procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Third Edition, Wiley and Sons, 1999).

[0347] EXAMPLES

[0348] Preparation of compounds, and intermediates used herein, can be prepared using procedures shown in the following Examples and related procedures. The methods and conditions used in these examples, and the actual compounds prepared in these Examples, are not meant to be limiting, but are meant to demonstrate how the compounds of can be prepared. Starting materials and reagents used in these examples, when not prepared by a procedure described herein, are generally either commercially available, or are reported in the chemical literature, or may be prepared by using procedures described in the chemical literature. The following examples illustrate the particular and preferred embodiments of the present invention and do not limit the scope of the present invention. Chemical abbreviations and symbols as well as scientific abbreviations and symbols have their usual and customary meanings unless otherwise specified. Common intermediates are generally useful for the preparation of more than one Example as shown in the Tables.

[0349] Chemical names were determined using ChemBioDraw Ultra, version 14.0.0.126 (CambridgeSoft).

[0350] The following abbreviations are used:

[0351]

[0352]

[0353] General Scheme 1-1:

[0354]

[0355] General Procedures for Intermediates and Examples for Table 1

[0356] Intermediate AA:

[0357] 3-(benzofuran-7-ylamino)-2-chlorophenol

[0358]

[0359] Stepl: To a mixture of 2-chloro-3 -methoxy aniline (100 g, 635 mmol, 1.00 eq) and 4A MS (10.0 g, 1.00 eq) in DCM (1.00 L) was added BBr3 (795 g, 3.17 mol, 5.00 eq) drop wise at -70 °C. The mixture was stirred at 20 °C for 2 hrs. The residue was poured into ice-water (2.00 L) and stirred for 5 min. The aqueous phase was extracted with dichloromethane (1.00 L x 2). The combined organic phase was washed with brine (500 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum give compound 3-amino-2-chlorophenol (80.0 g, 418 mmol, 87.8% yield) as gray solid. LCMS [M+H]+= 144.1.

[0360] Step 2: To a mixture of 3-amino-2-chlorophenol (80.0 g, 557 mmol, 1.00 eq) and 7-bromobenzofuran (121 g, 613 mmol, 1.10 eq) CS2CO3 (545 g, 1.67 mol, 3.00 eq) in dioxane (800 mL) was added BrettPhos Pd G3 (25.3 g, 27.9 mmol, 0.05 eq) in one portion at 20 °C under N2 atmosphere, then heated to 100 °C and stirred for 16 hrs. The residue filtered, concentrated in vacuo, and the residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate = 100 / 1 to 10 / 1) to give Intermediate AA (22.0 g, 84.7 mmol, 55.6% yield) as brown oil.1H NMR: 400 MHz CDCl3 δ 7.53 (d, J = 2.00 Hz, 1H), 7.21 - 7.19 (dd, J = 8.00 Hz, 1H), 7.16 - 7.07 (m, 2H), 6.96 (t, J= 8.0 Hz, 1H), 6.78 - 6.75 (dd, J= 4.00 Hz, 1H), 6.17 (d, J= 2.00 Hz, 1H), 6.53 - 6.51 (dd, J= 4.00 Hz, 1H), 6.24 (s, 1H), 5.63 (s, 1H).

[0361] Intermediate AB:

[0362] 1 -(4-chloropyrimidin-2-yl)ethan- 1 -ol

[0363]

[0364] Step 3: A mixture of 4-chloropyrimidin-2-amine (70.0 g, 540 mmol, 1.00 eq.), CH₂I₂ (434 g, 1.62 mol, 130 mL, 3.00 eq) and isopentyl nitrite (189 g, 1.62 mol, 218 mL, 3.00 eq) in THF (700 mL) was added copper (I) iodide (102 g, 540 mmol, 1.00 eq) at 20 °C, and then the mixture was stirred at 80 °C for 3 hours under a N₂ atmosphere. The mixture was filtered over diatomite, and then the organic layers were washed with aqueous Na2SO3 (400 mL × 2). The organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate = 100 / 0 to 20 / 1, Rf = 0.20, Petroleum ether / Ethyl acetate = 10 / 1) to give 4-chloro-2-iodopyrimidine (72.0 g, 299 mmol, 55.4% yield, 99.0% purity) as a yellow solid. 1H NMR: (400 MHz, DMSO-d6) δ 8.54 (d, J = 5.2 Hz, 1H), 7.79 (d, J = 5.2 Hz, 1H).

[0365] Step 4: To a solution of 4-chloro-2-iodopyrimidine (70.0 g, 291 mmol, 1.00 eq in THF (1.40 L) was added dropwise methylmagnesium bromide (3 M, 194 mL, 2.00 eq) at -65 °C. After addition, the mixture was stirred at this temperature for 1.5 hours, and then acetaldehyde (38.4 g, 873 mmol, 49.0 mL, 3.00 eq was added dropwise at - 65 °C. After 1 hour, the reaction mixture was quenched by addition NH4CI 400 mL at 0 °C, and then extracted with ethyl acetate (300 mL x 2). The combined organic layers were washed with brine (300 mL x 2), dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate = 100 / 0 to 20 / 1, Rf = 0.35, Petroleum ether / Ethyl acetate = 2 / 1). The crude product was purified by reversed-phase HPLC (column: Kromasil Eternity XT 250*80mm*10um; mobile phase: [water (NH3-H2O)-ACN]; gradient: 5%-35% B over 20 min) to give Intermediate AB (17.0 g, 113 mmol, 35.7% yield, 98.7% purity) as a yellow oil. 1H NMR: (400 MHz, DMSO-d6) δ 8.76 (d, J = 5.6 Hz, 1H), 7.59 (d, J = 5.2 Hz, 1H), 5.41 (d, 5.6 Hz, 1H), 4.77 - 4.71 (m, 1H), 1.39 (d, J = 6.8 Hz, 3H); LCMS: m / z = 159.1 (M+H)+

[0366] Intermediate AC:

[0367] N-(2-chloro-3-(l-(4-chloropyrimidin-2-yl)ethoxy)phenyl)benzofuran-7-amine

[0368]

[0369] Step 5: A stirring solution of Intermediate AA (2.07 g, 1 Eq, 7.97 mmol), l-(4-chloropyrimidin-2-yl)ethan-l-ol (1.58 g, 1.25 eq, 9.96 mmol), triphenylphosphine (3.14 g, 1.5 eq, 12.0 mmol) and THF (50 mL) was cooled to ~0 °C in an ice water bath and diisopropyl azodicarboxylate (2.42 g, 2.32 mL, 1.5 eq, 12.0 mmol) was added dropwise. The reaction mixture was heated to 45 °C. After 2 hours, the mixture was cooled to room temperature and partitioned between water (75 mL) and IP Ac (75 mL). The phases separated holding the organics in reserve. The aqueous phase was extracted IP Ac (3 x 75 mL), then all organics were combined and washed with saturated aqueous sodium chloride (75 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (Column: 120 g, mobile phase: 0% IPAc / 100% Heptane gradient to 40% IPAc / 60% Heptane). The residue was purified by column chromatography (SiCh, Heptane / isopropyl acetate = 100 / 0 to 60 / 40) to afford N-(2-chl oro-3 -(l-(4-chl oropyrimidin-2-yl)ethoxy)phenyl)benzofuran-7-amine as a light yellow solid (2.40 g, 75.2% yield, 97.9% pure). ‘HNMR: 'HNMR (400 MHz, DMSO-A) 6 (ppm) = 8.83 (d, J= 5.3 Hz, 1H), 7.93 (d, J= 1.8 Hz, 1H), 7.68 (d, J= 5.4 Hz, 1H), 7.63 (s, 1H), 7.35 (d, J= 7.6 Hz, 1H), 7.18 (t, J= 7.8 Hz, 1H), 7.05 (d, J= 7.8 Hz, 1H), 6.98 - 6.88 (m, 2H), 6.40 (d, J= 8.3 Hz, 1H), 6.31 (d, J= 8.3 Hz, 1H), 5.55 (q, J= 6.6 Hz, 1H), 1.70 (d, J= 6.5 Hz, 3H); LCMS: m / z = 400.1 (M+H)+

[0370] General Routes for Nucleophilic Aromatic Substitution Methods (NAS) for the Preparation of Examples 1-1 to 1-11

[0371] NAS-1

[0372] Example 1-1

[0373] (25)-2-((2-(l-(3-(benzofuran-7-ylamino)-2-chlorophenoxy)ethyl)pyrimidin-4- yl)amino)propan- 1 -ol

[0374]

[0375] To a stirring solution of Intermediate AC (42 mg, 1 eq, 0.10 mmol) and S-2-aminopropan-1-ol (16 mg, 2.0 eq, 0.21 mmol) in DMSO (0.8 mL) was added N-ethyl-N- isopropylpropan-2-amine (41 mg, 55 μL, 3.0 eq, 0.31 mmol). The reaction mixture was stirred at 100 °C until complete by LCMS. The reaction was added to water (10 mL) and the resulting solid was isolated by vacuum filtration. The crude material was purified by prep-HPLC (Column: Phenomenex Gemini® 5uM NX-C18 110 A; 150 x 30 mm; gradient: 5% acetonitrile (0.035% TFA) / 95% water (0.05% TFA) to 95% acetonitrile (0.035% TFA) / 5% water (0.05% TFA) over 20 min) to afford (2S)-2-((2-(1-(3-(benzofuran-7-ylamino)-2-chlorophenoxy)ethyl)pyrimidin-4-yl)amino)propan-1-ol.JH NMR:1H NMR (400 MHz, DMSO-tL) 6 (ppm) = 9.31 - 8.97 (m, 1H), 8.07 (br d, J= 6.6 Hz, 1H), 7.93 (s, 1H), 7.71 (s, 1H), 7.37 (d, J= 7.6 Hz, 1H), 7.19 (t, J= 7.7 Hz, 1H), 7.10 - 6.95 (m, 3H), 6.69 (br d, J= 6.1 Hz, 1H), 6.61 - 6.51 (m, 1H), 6.42 - 6.34 (m, 1H), 5.52 - 5.36 (m, 1H), 4.29 - 4.17 (m, 1H), 3.46 (br d, J= 15.1 Hz, 2H), 1.70 (br d, J= 6.4 Hz, 3H), 1.22 - 1.05 (m, 3H); LCMS: m / z = 439.3 (M+H)+

[0376] NAS-2

[0377] Example 1-2:

[0378] 2-((2-(l-(3-(benzofuran-7-ylamino)-2-chlorophenoxy)ethyl)pyrimidin-4-yl)amino)ethan- l-ol

[0379]

[0380] To a solution of Example AC (30.0 mg, 74.9 pmol, 1 eq.) and N,N-dimethylformamide (1.00 mL) was added 2-aminoethan-l-ol (9.16 mg, 149 pmol, 9.05 pL, 2.00 eq.). The mixture was stirred at 80 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by / c -HPLC (column: Waters Xbridge 150 * 25 mm x 5Um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 29%-59% B over 10 min) to give 2-((2-(l-(3-(benzofuran-7-ylamino)-2-chlorophenoxy)ethyl)pyrimidin-4-yl)amino)ethan-l-ol (10.5 mg, 24.7 pmol, 33% yield, 99.9% purity) as a white solid. LCMS: [M+l]+= 425.1; 'H NMR: 'H NMR (400 MHz, CDC13) 5 = 8.18 (d, J= 6.0 Hz, 1H), 7.63 (d, J= 2.4 Hz, 1H), 7.26 (br s, 1H), 7.25 - 7.21 (m, 1H), 7.19 - 7.14 (m, 1H), 6.98 - 6.92 (m, 1H), 6.91 - 6.86 (m, 1H), 6.80 (d, J= 2.4 Hz, 1H), 6.55 (s, 1H), 6.44 (d, J= 7.2 Hz, 1H), 6.25 (d, J= 6.0 Hz, 1H), 5.30 (q, J= 6.4 Hz, 1H), 3.85 - 3.73 (m, 2H), 3.65 - 3.45 (m, 2H), 1.77 (d, J= 6.4 Hz, 3H).

[0381] Table 1

[0382]

[0383]

[0384]

[0385]

[0386]

[0387] General Procedures for Intermediates and Examples for Table 2:

[0388] Intermediate BA:

[0389] tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l -methyl- lH-pyrazol-3- yl)methyl)piperidine- 1 -carboxylate

[0390]

[0391] Step 1: A mixture of tert-butyl 4-formylpiperidine-l -carboxylate (500 mg, 2.34 mmol, 1.00 eq.) and 3-bromo-1-methyl-1H-pyrazole (453 mg, 2.81 mmol, 1.20 eq) in tetrahydrofuran (5.00 mL) was degassed and purged with nitrogen for 3 times. The mixture was stirred at -65 °C for 10 minutes, and then n-BuLi (2.5 M, 1.88 mL, 2.00 eq) was added dropwise at -65 °C. The resulting mixture was stirred at -65 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was quenched by the addition of aqueous ammonium chloride (2.00 mL) at -65 °C, and then diluted with water (30.0 mL) and extracted with the mixed solvent (chloroform: isopropyl alcohol = 4:1) (30 mL x 3). The combined organic layers were washed with brine (30.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase prep-HPLC (0.1% formic acid) to give tert-butyl 4-(hydroxy(1-methyl-1H-pyrazol-3-yl)methyl)piperidine-1-carboxylate (200 mg, 677 μmol, 29% yield) as a yellow oil.1H NMR (400 MHz, CDCl3-d) 8 = 7.31 (d, J= 2.0 Hz, 1H), 6.14 (d, J= 2.0 Hz, 1H), 4.50 (br d, J= 6.4 Hz, 1H), 4.19 - 4.04 (m, 2H), 3.87 (s, 3H), 2.66 (br d, J= 11.6 Hz, 2H), 2.35 (br s, 1H), 1.92 - 1.75 (m, 2H), 1.45 (s, 9H), 1.34 - 1.20 (m, 3H); LCMS [M+l]+= 240.3.

[0392] Step 2: A mixture of tert-butyl 4-(hydroxy(1-methyl-1H-pyrazol-3-yl)methyl)piperidine-1-carboxylate (200 mg, 677.10 μmol, 1.5 eq.), triphenylphosphine (236.80 mg, 902.80 μmol, 2 eq.) and Intermediate AA (117.22 mg, 451.40 μmol, 1 eq.) in tetrahydrofuran (5.00 mL) was degassed and purged with nitrogen for 3 times. After addition, the mixture was stirred at 0 °C for 10 minutes, and then diisopropyl azodicarboxylate (183 mg, 903 μmol, 175 μL, 2 eq.) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour under a nitrogen atmosphere. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate=2 / l) and further purified by prep-HPLC (column: Waters Xbridge 150 × 25mm × 5um; mobile phase: [water (ammonia hydroxide v / v)-ACN]; gradient: 66%-96% B over 10 min) to give Intermediate BA (40.0 mg, 74.5 μmol, 17% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ = 7.68 (d, J = 2.0 Hz, 1H), 7.64 (s, 1H), 7.23 (d, J = 2.0 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 7.02 (br d, J = 7.6 Hz, 2H), 6.92 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 2.0 Hz, 1H), 6.80 - 6.74 (m, 1H), 6.25 (d, J = 7.2 Hz, 1H), 5.97 (d, J = 2.0 Hz, 1H), 3.94 (s, 2H); LCMS [M+1]+ = 481.2

[0393] Example 2-1:

[0394] (N-(2-chloro-3-((l -methyl- lH-pyrazol-3-yl)(piperidin-4-yl)methoxy)phenyl)benzofuran- 7-amine)

[0395]

[0396] Step 3: To a solution of Intermediate BA (30.0 mg, 55.9 μmol, 1.00 eq) in methanol (1.00 mL) was added oxalyl chloride (21.3 mg, 168 μmol, 14.7 μL, 3.00 eq). The mixture was stirred at 25 °C for 6 hours. The mixture was filtered. The filtrate was purified with prep-HPLC (column: Phenomenex luna C18 150 × 25mm × 10um; mobile phase: [water (formic acid)-ACN]; gradient: 19%-49% B over 10 min) to give the N-(2-chloro-3-((1-methyl-1H-pyrazol-3-yl)(piperidin-4-yl)methoxy)phenyl)benzofuran-7-amine (10.2 mg, 0.0231 mmol, 41% yield, 99% purity) as a white solid.1H NMR (400 MHz, CD3OD) 6 = 8.55 (s, 1H), 7.72 (d, = 2.0 Hz, 1H), 7.55 (d, J= 2.0 Hz, 1H), 7.31 (dd, J= 1.2, 7.6 Hz, 1H), 7.19 - 7.14 (m, 1H), 7.13 - 7.09 (m, 1H), 6.91 (t, J= 8.4 Hz, 1H), 6.85 (d, J= 2.0 Hz, 1H), 6.60 (dd, J= 1.2, 8.3 Hz, 1H), 6.51 - 6.45 (m, 1H), 6.28 (d, J= 2.0 Hz, 1H), 5.17 (d, = 6.4 Hz, 1H), 3.88 (s, 3H), 3.47 - 3.36 (m, 2H), 3.03 - 2.91 (m, 2H), 2.31 (br d, J = 11.2 Hz, 2H), 1.85 - 1.78 (m, 1H), 1.76 - 1.61 (m, 2H); LCMS [M+l]+= 437.2 Example 2-2:

[0397] (5)-A-(2-chloro-3-((l-methyl-lH-pyrazol-3-yl)(piperidin-4- yl)methoxy)phenyl)benzofuran-7-amine

[0398]

[0399] Step 1: Intermediate BA (260 mg, 484 μmol, 1.00 eq.) was purified by prep-SFC (column: DAICEL CHIRALCEL OD-H(250mm x 30mm,5um);mobile phase: [CO₂-ACN / EtOH(0.1% NH₃H₂O)]; B%:35%, isocratic elution mode) to give tert-butyl (S)-4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(1-methyl-1H-pyrazol-3-yl)methyl)piperidine-1-carboxylate (120 mg, 221 μmol, 46% yield, 99% purity) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ = 8.55 (s, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.31 (dd, J= 1.2, 7.6 Hz, 1H), 7.19 - 7.14 (m, 1H), 7.13 - 7.09 (m, 1H), 6.91 (t, J = 8.4 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 6.60 (dd, J = 1.2, 8.3 Hz, 1H), 6.51 - 6.45 (m, 1H), 6.28 (d, J = 2.0 Hz, 1H), 5.17 (d, J = 6.4 Hz, 1H), 3.88 (s, 3H), 3.47 - 3.36 (m, 2H), 3.03 - 2.91 (m, 2H), 2.31 (br d, J = 11.2 Hz, 2H), 1.85 - 1.78 (m, 1H), 1.76 - 1.61 (m, 2H); LCMS [M+1]+= 481.2

[0400] Step 2: To a solution of tert-butyl (S)-4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(1-methyl-1H-pyrazol-3-yl)methyl)piperidine-1-carboxylate (120 mg, 221 μmol, 1.00 eq) in methanol (2.00 mL) was added oxalyl chloride (140 mg, 1.11 mmol, 96.8 μL, 5.00 eq). The mixture was stirred at 25 °C for 3 hours. The mixture was filtered. The filtrate was purified with prep-HPLC (column: Phenomenex luna C18 150 × 25mm × 10um;mobile phase: [water (Formic acid)-ACN];gradient:18%-48% B over 10 min) to give the (S)-N-(2-chloro-3-((1-methyl-1H-pyrazol-3-yl)(piperidin-4-yl)methoxy)phenyl)benzofuran-7-amine (48.0 mg, 109 μmol, 49% yield, 99% purity) as a white solid. 'H NMR (400 MHz, CD3OD) 6 = 8.55 (s, 1H), 7.72 (d, = 2.0 Hz, 1H), 7.55 (d, J= 2.0 Hz, 1H), 7.31 (dd, J = 1.2, 7.6 Hz, 1H), 7.20 - 7.14 (m, 1H), 7.13 - 7.09 (m, 1H), 6.91 (t, J= 8.4 Hz, 1H), 6.86 (d, = 2.0 Hz, 1H), 6.61 (dd, J= 1.2, 8.3 Hz, 1H), 6.48 (d, J= 7.6 Hz, 1H), 6.28 (d, J = 2.0 Hz, 1H), 5.18 (d, J= 6.4 Hz, 1H), 3.88 (s, 3H), 3.52 - 3.36 (m, 2H), 3.00 (dq, J= 2.8, 12.8 Hz, 2H), 2.40 - 2.25 (m, 2H), 1.92 - 1.60 (m, 3H); LCMS [M+l]+= 437.2 Example 2-3:

[0401] (R)-A-(2-chl oro-3 -(( 1 -methyl- 1 H-pyrazol-3 -yl)(piperidin-4- yl)methoxy)phenyl)benzofuran-7-amine

[0402]

[0403] Step 1: Intermediate BA (260 mg, 484 μmol, 1.00 eq.) was purified by prep-SFC (column: DAICEL CHIRALCEL OD-H(250mm x 30mm,5um);mobile phase: [CO₂-ACN / EtOH(0.1% NH₃H₂O)]; B%:35%, isocratic elution mode) to give tert-butyl (R)-4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l -methyl- lrt-pyrazol-3-yl)methyl)piperidine-l -carboxylate (120 mg, 221 μmol, 46% yield, 99% purity) as a white solid. LCMS [M+1]+= 481.2

[0404] Step 2: To a solution of tert-butyl (R)-4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-m ethyl- U / -pyrazol-3 -yl)m ethyl)piperi dine- 1 -carboxylate (120 mg, 221 μmol, 1.00 eq.) in methanol (2.00 mL) was added oxalyl dichloride (140 mg, 1.00 mmol, 96.8 μL, 5.00 eq.). The mixture was stirred at 25 °C for 6 hours. The mixture was filtered. The filtrate was purified with prep-HPLC (column: Phenomenex luna C18 150 x 25 mm x 10 pm; mobile phase: [water (0.1 % formic acid)-ACN];gradient:17%-47% B over 10 min) to give the (A)-A-(2-chloro-3-((l -methyl- lH-pyrazol-3-yl)(piperi din-4-yl)methoxy)phenyl)benzofuran-7-amine (47.0 mg, 106 μmol, 48% yield, 99% purity) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ = 8.55 (s, 1H), 7.72 (d, J= 2.0 Hz, 1H), 7.55 (d, = 2.0 Hz, 1H), 7.31 (dd, J= 1.2, 7.6 Hz, 1H), 7.19 - 7.14 (m, 1H), 7.13 - 7.09 (m, 1H), 6.91 (t, J= 8.4 Hz, 1H), 6.86 (d, J= 2.0 Hz, 1H), 6.61 (dd, J= 1.2, 8.4 Hz, 1H), 6.52 - 6.43 (m, 1H), 6.28 (d, J= 2.4 Hz, 1H), 5.18 (d, J= 6.4 Hz, 1H), 3.88 (s, 3H), 3.52 - 3.37 (m, 2H), 3.00 (dq, J= 3.2, 13.2 Hz, 2H), 2.32 (br d, J= 11.6 Hz, 2H), 1.88 - 1.58 (m, 3H); LCMS [M+1]+= 437.2. General Reductive Amination Methods (RA) and Purification Methods (PM) for the Preparation of Examples 2-2 to 2-37

[0405] Reductive Amination (RA-1)

[0406] Example 2-4:

[0407] 4-(4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-methyl-U7-pyrazol-3- yl)methyl)piperidin- 1 -yl)cyclohexan- 1 -ol

[0408]

[0409] To a solution of Example 2-1 (30.0 mg, 0.069 mmol) in MeOH (3 mL) was added 4-hydroxycyclohexan-l-one to (24 mg, 0.2 mmol) and NaBH₃CN (17.3 mg, 0.276 mmol). Then mixture was stirred at room temperature for 4 hours, the reaction was purified by prep-HPLC (ACN and H₂O with 0.05% NH₄HCO₃ as the mobile phases) to give 4-(4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-methyl-l / / -pyrazol-3-yl)methyl)piperidin-l-yl)cyclohexan-l-ol (7.6 mg, 20.6% yield) as off-white solid. ¹H NMR (400 MHz, CD₃OD) δ (ppm) = 7.72 (d, J= 2.1 Hz, 1H), 7.51 (s, 1H), 7.29 (dd, J= 1.2, 7.3 Hz, 1H), 7.18 - 7.07 (m, 2H), 6.90 (t, J= 8.3 Hz, 1H), 6.85 (d, J= 2.1 Hz, 1H), 6.61 (d, J= 8.3 Hz, 1H), 6.49 (br d, J= 8.4 Hz, 1H), 6.30 - 6.20 (m, 1H), 5.10 (d, J= 7.1 Hz, 1H), 3.86 (s, 3H), 3.11 - 2.94 (m, 2H), 2.49 - 2.24 (m, 3H), 2.22 - 1.91 (m, 4H), 1.90 - 1.46 (m, 8H), 1.43 - 1.20 (m, 2H); LCMS [M+H]+= 535.2.

[0410] Reductive Amination (RA-2)

[0411] Example 2-5:

[0412] N-(2-chloro-3-((l-methyl-lH-pyrazol-3-yl)(l-(spiro[2.5]octan-6-yl)piperidin-4-yl)methoxy)phenyl)benzofuran-7-amine

[0413]

[0414] To a solution of Example 2-1 (15.0 mg, 0.034 mmol) in DCM (1.0 mL) was added spiro[2.5]octan-6-one (6.4 mg, 0.051 mmol) and acetic acid (2.1 mg, 2.0 μL, 0.034 mmol). The reaction mixture was stirred at room temperature for 30 minutes at which time sodium triacetoxyborohydride (18.0 mg, 0.086 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture quenched by the addition of acetone (2 drops) and concentrated in vacuo. The crude material was purified by prep-HPLC (Column: Phenomenex Gemini® 5uM NX-C18 110 A; 150 x 30 mm; gradient: 5% acetonitrile (0.035% TFA) / 95% water (0.05% TFA) to 95% acetonitrile (0.035% TFA) / 5% water (0.05% TFA) to give A-(2-chl oro-3 -((1 -methyl- lJT-pyrazol-3 -yl)( 1 -(spiro[2.5]octan-6-yl)piperidin-4-yl)methoxy)phenyl)benzofuran-7-amine (5.55 mg, 30% yield) as a white solid. ¹H NMR (CD₃OD) δ: 7.60-7.64 (m, 1H), 7.44-7.48 (m, 1H), 7.19-7.24 (m, 1H), 6.99-7.10 (m, 2H), 6.78-6.85 (m, 1H), 6.73-6.77 (m, 1H), 6.48-6.54 (m, 1H), 6.35-6.40 (m, 1H), 6.16-6.19 (m, 1H), 5.07-5.12 (m, 1H), 3.75-3.81 (m, 3H), 3.42-3.56 (m, 2H), 2.98-3.17 (m, 3H), 2.30-2.38 (m, 1H), 2.19-2.29 (m, 1H), 1.93-2.01 (m, 2H), 1.52-1.89 (m, 7H), 0.93-1.02 (m, 2H), 0.16-0.34 (m, 4H); LCMS [M+H]+= 545.3. Reductive Amination (RA-3)

[0415] Example 2-6:

[0416] A-(2-chl oro-3 -((l-(l-cy cl obutylethyl)piperidin-4-yl)(l -methyl- lJT-pyrazol-3- yl)methoxy)phenyl)benzofuran-7-amine

[0417]

[0418] A mixture of Example 2-1 (52 mg, 0.12 mmol), 1-cyclobutylethan-l-one (14 mg, 0.14 mmol) and titanium (IV) isopropoxide (68 mg, 72 uL, 0.24 mmol) was heated to 65 °C for 3.5 hours, then cooled to room temperature. To the stirring mixture was added sodium borohydride (14 mg, 0.36 mmol) and MeOH (2 mL). After 2 hours, the reaction mixture was partitioned between iPrOAc (10 mL) and 5% aqueous NaOH (10 mL). After aggitation, the resulting solids were filtered through celite and the filter pad rinsed with iPrOAc (15 mL). The organics were separated and washed with saturated NaCl (20 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by prep-HPLC (Column: Phenomenex Gemini® 5uM NX-C18 110 A; 150 x 30 mm; gradient: 5% acetonitrile (0.035% TFA) / 95% water (0.05% TFA) to 95% acetonitrile (0.035% TFA) / 5% water (0.05% TFA) to give 7V-(2-chl oro-3 -((1 -( 1 -cy cl obutylethyl)piperidin-4-yl)(l -methyl- 17 / -pyrazol -3 -yl)methoxy)phenyl)benzofuran-7-amine (18 mg, 24% yield) as a white solid. ¹H NMR (400 MHz, CD₃OD, 298 K) δ (ppm) = 7.72 (d, J= 2.1 Hz, 1H), 7.56 (d, J= 2.1 Hz, 1H), 7.31 (d, J= 7.5 Hz, 1H), 7.20 - 7.08 (m, 2H), 6.91 (t, J = 8.3 Hz, 1H), 6.86 (d, J= 2.1 Hz, 1H), 6.60 (d, J= 8.1 Hz, 1H), 6.47 (d, J= 8.3 Hz, 1H), 6.28 (d, J= 2.3 Hz, 1H), 5.18 (d, J = 6.4 Hz, 1H), 3.88 (s, 3H), 3.56 - 3.40 (m, 2H), 3.17 - 3.01 (m, 2H), 2.75 - 2.62 (m, 1H), 2.45 - 2.29 (m, 2H), 2.23 - 1.68 (m, 10H), 1.26 (d, J= 6.6 Hz, 3H); LCMS [M+1]+= 519.2.

[0419] Reductive Amination (RA-4)

[0420] Example 2-7:

[0421] 7V-(2-chl oro-3 -((5)-( 1 -methyl- 1 H-pyrazol-3 -yl)( 1 -((5)- 1 -(oxetan-3 -yl)ethyl)piperidin-4- yl)methoxy)phenyl)benzofuran-7-amine

[0422]

[0423] Step 1: To a solution of Example 2-2 (200 mg, 458 μmol, 1.00 eq) and 1-(oxetan-3-yl)ethanone (55.0 mg, 549 μmol, 1.20 eq) in tetrahydrofuran (4.00 mL) was added triethylamine (46.3 mg, 458 pmol, 63.7 μL, 1.00 eq), dibutyldichlorostannane (230 mg, 757 μmol, 1.65 eq) and phenylsilane (49.5 mg, 458 μmol, 56.5 μL, 1.00 eq), then the mixture was stirred at 90 °C for 12 hours. The reaction mixture was diluted with water (30.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with brine (30.0 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150x25 mm x 10 pm; mobile phase: [water (0.1% formic acid)-ACN]; gradient: 18%-48% B over 10 mins) to giveA-(2-chloro-3-((5)-(l-methyl-U / -pyrazol-3-yl)(l-((5)-l-(oxetan-3-yl)ethyl)piperidin-4-yl)methoxy)phenyl)benzofuran-7-amine (90.0 mg, 173 μmol, 38% yield) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ = 7.71 (d, J= 2.0 Hz, 1H), 7.55 - 7.49 (m, 1H), 7.30 (dd, J= 1.2, 7.6 Hz, 1H), 7.18 - 7.08 (m, 2H), 6.93 - 6.86 (m, 1H), 6.84 (d, J= 2.4 Hz, 1H), 6.60 (dd, J= 1.2, 8.4 Hz, 1H), 6.47 (d, J= 7.6 Hz, 1H), 6.25 (d, J= 2.4 Hz, 1H), 5.13 (d, J= 6.8 Hz, 1H), 4.72 (td, J= 6.8, 18.4 Hz, 2H), 4.64 - 4.50 (m, 2H), 3.88 - 3.83 (m, 3H), 3.49 - 3.38 (m, 2H), 3.27 - 3.04 (m, 2H), 2.95 - 2.56 (m, 2H), 2.36 - 2.12 (m, 2H), 1.86 - 1.59 (m, 3H), 1.19 (br d, J= 5.6 Hz, 3H); LCMS [M+1]+= 521.3.

[0424] Step 2: The residue was further separated by SFC ((column: DAICEL CHIRALPAK AD(250mm x 30 mm x 10 pm); mobile phase: [CO₂-EtOH (0.1%NH₃H₂O)]; B%: 35%, isocratic elution mode), to give A-(2-chl oro-3 -((5)-(l -methyl- U / -pyrazol-3-yl)(l -((5)- 1-(oxetan-3-yl)ethyl)piperidin-4-yl)methoxy)phenyl)benzofuran-7-amine (24.2 mg, 45.9 μmol, 27% yield, 99% purity) as a yellow solid. ¹H NMR (400 MHz, CD₃OD) δ = 7.70 (d, J= 1.6 Hz, 1H), 7.48 (d, J= 2.0 Hz, 1H), 7.28 (d, J= 6.8 Hz, 1H), 7.16 - 7.07 (m, 2H), 6.91 - 6.82 (m, 2H), 6.59 (d, J= 8.4 Hz, 1H), 6.47 (d, J= 8.0 Hz, 1H), 6.22 (d, J = 2.0 Hz, 1H), 5.09 (d, J= 7.2 Hz, 1H), 4.77 - 4.63 (m, 2H), 4.58 (t, J= 6.8 Hz, 1H), 4.48 (t, = 6.8 Hz, 1H), 3.83 (s, 3H), 3.31 - 3.26 (m, 1H), 3.21 (br d, J= 6.4 Hz, 1H), 3.00 (br d, J= 9.6 Hz, 2H), 2.54 (brt, J= 11.2 Hz, 1H), 2.38 (br t, J= 11.2 Hz, 1H), 2.19 (br d, J = 13.2 Hz, 1H), 2.07 (br dd, J= 3.6, 7.2 Hz, 1H), 1.72 - 1.58 (m, 2H), 1.57 - 1.44 (m, 1H), 1.07 (br d, = 6.4 Hz, 3H); LCMS [M+1]+= 521.3.

[0425] Table 2:

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438] General Scheme 3-1:

[0439]

[0440] General Procedures for Intermediates and Examples 3-1 to 3-30 for Table 3 Intermediate CA:

[0441] tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(4-chloropyrimidin-2- yl)methyl)piperidine- 1 -carboxylate

[0442]

[0443] Step 1: A mixture of 4-chloropyrimidin-2-amine (130 g, 1.00 mol, 1.00 eq), CH₂I₂ (403 g, 1.51 mol, 121 mL, 1.50 eq), Copper (I) iodide (382 g, 2.01 mol, 2.00 eq) and isopentyl nitrite (176 g, 1.51 mol, 203 mL, 1.50 eq) in tetrahydrofuran (1000 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 80 °C for 5 hours under a N₂ atmosphere. The mixture was diluted with water (500.0 mL) and extracted with ethyl acetate (1000 mL x 2). The organic layer was dried over sodium sulfate and concentrated and purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give the 4-chloro-2-iodopyrimidine (160 g, 625 mmol, 62% yield) as a yellow solid; LCMS [M+1]+=241.0.

[0444] Step 2: To a solution of 4-chloro-2-iodo-pyrimidine (143 g, 595 mmol, 1.00 eq.) in tetrahydrofuran (1000 mL) was added dropwise ethyl magnesium bromide (3 M, 218 mL, 1.10 eq.) at -78 °C. After addition, the mixture was stirred at this temperature for 1 hour, and then tert-butyl 4-formylpiperidine-l -carboxylate (127 g, 595 mmol, 1.00 eq.) in tetrahydrofuran (300 mL) was added dropwise at -78 °C. The resulting mixture was stirred at 0 °C for 1 hour. The mixture was quenched by addition water 400 mL at 0 °C, concentrated and purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give the tert-butyl 4-((4-chloropyrimidin-2-yl)(hydroxy)methyl)piperidine-l -carboxylate (110 g, 319 mmol, 54% yield) as a yellow oil; ¹H NMR (400 MHz, CDCl₃) δ = 8.62 (d, J= 5.6 Hz, 1H), 7.29 (d, J= 5.6 Hz, 1H), 4.68 (dd, J= 4.0, 6.3 Hz, 1H), 4.25 - 4.05 (m, 3H), 3.75 (br d, J= 6.4 Hz, 1H), 2.80 - 2.54 (m, 3H), 2.14 - 2.05 (m, 1H), 1.44 (s, 9H), 1.24 - 1.17 (m, 1H).

[0445] Step 3: To a solution of tert-butyl 4-[(4-chloropyrimidin-2-yl)-hydroxy-methyl]piperidine-l -carboxylate (60.0 g, 183 mmol, 1.00 eq.) and Intermediate AA (42.8 g, 165 mmol, 0.90 eq) in toluene (500 mL) was added (3E)-3-(dimethylcarbamoylimino)- 1,1 -dimethylurea (47.3 g, 274 mmol, 1.5 eq) and triphenylphosphine (72.0 g, 274 mmol, 1.50 eq) and then the mixture was stirred at 70 °C for 2 hours. The mixture was filtered and purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 20 / 1 to 4 / 1) to give the Intermediate BA (53.0 g, 87.5 mmol, 48% yield, 94% purity) as a yellow solid; ¹H NMR (400 MHz, CDCl₃) δ = 8.64 (d, J= 5.6 Hz, 1H), 7.62 (d, J= 2.0 Hz, 1H), 7.30 - 7.28 (m, 1H), 7.23 - 7.13 (m, 2H), 6.90 (br d, J= 8.0 Hz, 1H), 6.88 - 6.83 (m, 1H), 6.79 (d, J= 2.0 Hz, 1H), 6.54 (s, 1H), 6.29 (br d, J= 8.0 Hz, 1H), 5.30 (s, 1H), 5.08 (br d, J= 7.2 Hz, 1H), 4.13 (br d, J= 7.2 Hz, 2H), 2.85 - 2.65 (m, 2H), 2.51 - 2.36 (m, 1H), 2.14 (br d, J= 13.2 Hz, 1H), 1.60 - 1.52 (m, 2H), 1.47 (s, 9H), 1.33 (br d, J= 11.2 Hz, 1H); LCMS [M-55]+=513.1.

[0446] Example 3-1:

[0447] 2-((2-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-(cyclobutylmethyl)piperidin-4- yl)methyl)pyrimidin-4-yl)amino)ethan- 1 -ol

[0448]

[0449] Step 4: To a solution of Intermediate CA (300 mg, 527 pmol, 1.00 eq) in N, N-Dimethylformamide (3.00 mL) was added diisopropylethylamine (204 mg, 1.58 mmol, 275 pL, 3.00 eq) and 2-aminoethan-l-ol (48.3 mg, 790 pmol, 47.7 pL, 1.50 eq). The mixture was stirred at 40 °C for 3 hours. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=l / l to 0 / 1) to give tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(4-((2-hydroxyethyl)amino)pyrimidin-2-yl)methyl)piperidine-1-carboxylate (240 mg, 404 pmol, 77% yield) as a yellow oil. LCMS [M+l]+= 594.3 Step 6: To a solution of tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(4-((2-hydroxyethyl)amino)pyrimidin-2-yl)methyl)piperidine-l-carboxylate (40 mg, 67.3 pmol, 1.00 eq in di chloromethane (1.00 mL) was added trifluoroacetic acid (307 mg, 2.69 mmol, 0.200 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (0.1% formic acid)-ACN]; gradient: 10%-37% B over 9 min) to give 2-((2-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(piperidin-4-yl)methyl)pyrimidin-4-yl)amino)ethan-l-ol (20.4 mg, 40.9 pmol, 61% yield, 99% purity) as an off-white solid. 'HNMR (400 MHz, CD3OD) δ = 8.47 - 8.33 (m, 1H), 8.00 (br d, J= 5.2 Hz, 1H), 7.74 (d, J= 2.0 Hz, 1H), 7.33 (dd, J= 1.6, 7.2 Hz, 1H), 7.24 - 7.11 (m, 2H), 6.95 - 6.89 (m, 1H), 6.87 (d, J= 2.0 Hz, 1H), 6.63 (dd, J= 1.2, 8.4 Hz, 1H), 6.44 (br d, J= 1.6 Hz, 1H), 6.34 (d, J= 8.0 Hz, 1H), 4.96 (br s, 1H), 3.78 - 3.54 (m, 3H), 3.54 - 3.42 (m, 3H), 3.16 - 2.97 (m, 2H), 2.50 (br dd, J= 4.4, 8.8 Hz, 1H), 2.30 (br d, J= 14.0 Hz, 1H), 1.98 - 1.78 (m, 3H) LCMS [M+l]+= 494.3.

[0450] Step 6: To a solution of 2-((2-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(piperidin-4-yl)methyl)pyrimidin-4-yl)amino)ethan-l-ol (30.0 mg, 60.7 pmol, 1.00 eq) in N, N-dimethylformamide (1.00 mL) was added cyclobutanecarbaldehyde (5.62 mg, 66.8 pmol, 1.10 eq.) at 25 °C. After addition, the mixture was stirred at this temperature for 10 minutes, and then sodium triacetoxyborohydride (14.2 mg, 66.8 pmol, 1.10 eq) was added. The resulting mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 × 25mm × 10 μm; mobile phase: [water (0.1% formic acid)-ACN]; gradient: 20%-44% B over 10 min) to give 2-((2-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-(cyclobutylmethyl)piperidin-4-yl)methyl)pyrimidin-4-yl)amino)ethan-l-ol (15.5 mg, 27.2 pmol, 45% yield, 99% purity) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ = 8.08 (s, 1H), 8.06 - 7.87 (m, 1H), 7.72 (d, J= 2.0 Hz, 1H), 7.32 (dd, J= 1.2, 7.6 Hz, 1H), 7.21 - 7.10 (m, 2H), 6.91 (t, J= 8.4 Hz, 1H), 6.86 (d, J= 2.0 Hz, 1H), 6.61 (d, J= 8.4 Hz, 1H), 6.55 - 6.40 (m, 1H), 6.32 (br d, J= 8.0 Hz, 1H), 5.06 - 4.95 (m, 1H), 3.68 - 3.50 (m, 5H), 3.16 (br d, J= 7.2 Hz, 2H), 3.07 - 2.90 (m, 2H), 2.84 - 2.71 (m, 1H), 2.54 - 2.37 (m, 1H),

[0451] 2.29 - 2.17 (m, 3H), 2.12 - 1.75 (m, 8H); LCMS [M+1]+= 562.3.

[0452] Table 3:

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482] General Schem 4-1

[0483]

[0484] General Methods for the Preparation of Examples 4-1 to 4-14

[0485] Intermediate CB:

[0486] N-(2-chloro-3-((4-chloropyrimidin-2-yl)(piperidin-4-yl)methoxy)phenyl)benzofuran-7-amine

[0487]

[0488] Step 1: To a stirring solution of Intermediate CA (1.01 g, 1.77 mmol) in DCM (10 mL) was added HCl in 1,4-dioxane (517 mg, 14.2 mmol, 4M solution). The reaction stirred at room temperature. The resulting precipitated solid was filter and rinsed with DCM (20 mL). The solid was dried under high vacuum to give Intermediate CB (780 mg, 1.54 mmol, HC1 salt, 87% yield) as a yellow solid. 1H NMR (400 MHz, CD3OD, 298 K) 6 (ppm) = 8.73 (d, J= 5.4 Hz, 1H), 7.72 (d, J= 2.1 Hz, 1H), 7.54 (d, J= 5.4 Hz, 1H), 7.32 (dd, J= 1.1, 7.4 Hz, 1H), 7.21 - 7.10 (m, 2H), 6.92 - 6.83 (m, 2H), 6.60 (d, J= 7.8 Hz, 1H), 6.26 (d, J= 7.9 Hz, 1H), 5.26 (d, J= 6.1 Hz, 1H), 3.55 - 3.41 (m, 2H), 3.10 - 3.00 (m, 2H), 2.65 - 2.52 (m, 1H), 2.25 (br d, J= 13.9 Hz, 1H), 1.99 - 1.78 (m, 3H); LCMS [M+1]+= 562.3.

[0489] Example 4-1:

[0490] N-(2-chloro-3-((4-chloropyrimidin-2-yl)(1-isobutylpiperidin-4-yl)methoxy)phenyl)benzofuran-7-amine

[0491]

[0492] Step 2: A solution of Intermediate CB (1.01 g, 1 eq, 2.00 mmol), DCM (20 mL) and isobutyraldehyde (432 mg, 3 eq, 5.99 mmol) were stirred together for 30 minutes at which time sodium triacetoxyborohydride (1.69 g, 4 eq, 7.99 mmol) was added. The reaction was stirred at room temperature overnight. The reaction was diluted with DCM to 100 mL and washed with saturated aqueous sodium bicarbonate (100 mL). The organics were washed further with saturated sodium chloride (75 mL), dried over sodium sulfate and concentrated in vacuo. The crude oil was purified by normal phase chromatography (Column: 100 g, NH-silica, mobile phase: 0% EtOAc / 100% Heptane gradient to 100% EtOAc / 0% Heptane) to give N-(2-chloro-3-((4-chloropyrimidin-2-yl)(l-isobutylpiperidin-4-yl)methoxy)phenyl)benzofuran-7-amine (0.720 g, 1.37 mmol, 69% yield) as foam.1H NMR (400 MHz, CD3OD) δ ppm 1.04 - 1.14 (m, 6 H) 1.76 - 1.92 (m, 1 H) 1.95 - 2.10 (m, 2 H) 2.10 - 2.27 (m, 1 H) 2.33 (br d, J= 14.5 Hz, 1 H) 2.51 - 2.76 (m, 1 H) 2.95 - 3.10 (m, 4 H) 3.60 - 3.79 (m, 2 H) 5.24 - 5.50 (m, 1 H) 6.28 (d, J= 8.0 Hz, 1 H) 6.62 (d, J= 7.8 Hz, 1 H) 6.85 - 6.96 (m, 2 H) 7.11 - 7.24 (m, 2 H) 7.35 (dd, J=7.5, 1.00 Hz, 1 H) 7.56 (d, J= 5.4 Hz, 1 H) 7.74 (d, J=2.1 Hz, 1 H) 8.75 (d, J= 5.3 Hz, 1 H); LCMS [M+1]+= 525.2

[0493] Example 4-2:

[0494] (l-(2-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-isobutylpiperidin-4- yl)methyl)pyrimidin-4-yl)azetidin-3-yl)methanol

[0495]

[0496] A stirring solution of A-(2-chloro-3-((4-chloropyrimidin-2-yl)(l-isobutylpiperidin-4-yl)methoxy)phenyl)benzofuran-7-amine (40.0 mg, 0.076 mmol), azetidine-3-ylmethanol hydrochloride (24.0 mg, 0.19 mmol), DMSO (0.5 mL) and diisopropylethylamine (39 mg, 53 pL, 0.30 mmol) was heated to 100 °C. After 30 minutes, the reaction was diluted with water (15 mL) and extracted with iPrOAc (3 x 15 mL). The combined organics were washed with saturated sodium chloride (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give a crude oil. Purification by -HPLC (Acidic Conditions, Column: Phenomenex Gemini® 5uM NX-C18 110 A; 150 x 30 mm; gradient: 5% acetonitrile (0.035% TFA) / 95% water (0.05% TFA) to 95% acetonitrile (0.035% TFA) / 5% water (0.05% TFA) gave (l-(2-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-isobutylpiperidin-4-yl)methyl)pyrimidin-4-yl)azetidin-3-yl)methanol (12 mg, 0.019 mmol, 25% yield) as a white solid. 1H NMR (400 MHz, CD3OD, 298 K) 8 (ppm) = 8.06 (d, J= 6.1 Hz, 1H), 7.72 (d, J= 2.1 Hz, 1H), 7.30 (dd, J= 1.4, 7.3 Hz, 1H), 7.21 - 7.08 (m, 2H), 6.92 - 6.82 (m, 2H), 6.61 (dd, J= 0.9, 8.3 Hz, 1H), 6.33 (d, J= 8.3 Hz, 1H), 6.24 (d, J= 6.1 Hz, 1H), 4.83 (br s, 1H), 4.13 (br t, J= 8.7 Hz, 2H), 3.86 (br dd, J= 5.4, 9.1 Hz, 2H), 3.73 (d, J= 6.1 Hz, 2H), 3.28 - 3.11 (m, 2H), 2.99 - 2.86 (m, 1H), 2.50 - 2.15 (m, 6H), 1.95 (td, J = 6.3, 13.0 Hz, 1H), 1.84 - 1.68 (m, 2H), 1.51 (br d, J = 13.6 Hz, 1H), 0.97 (d, J = 6.5 Hz, 6H); LCMS [M+1]+= 576.3

[0497] Table 4:

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510] Purifications Methods (PM) for Tables 1 - 4

[0511] PM-1: Prep-HPLC (Acidic Conditions, Column: Phenomenex Gemini® 5uM NX-C18 110 Å; 150 x 30 mm; gradient: 5% acetonitrile (0.035% TFA) / 95% water (0.05% TFA) over 20 min)

[0512] PM-2: Prep-HPLC (neutral condition; Column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 29%-59% B over 10 min)

[0513] PM-3: / ric -HPLC (ACN and H₂O with 0.05% NH₄HCO₃ as mobile phase)

[0514] PM-4: Prep-HPLC (ACN and H2O with 0.2% TFA as mobile phase)

[0515] PM-5: Prep-HPLC (ACN and H2O with 0.2% Formic acid as mobile phase) PM-6: SFC ((column: DAICEL CHIRALPAK AD (250mm*30mm,10um); mobile phase:

[0516] [CO2-EtOH (0.1% NH3H2O)]; B%: 35%, isocratic elution mode)

[0517] PM-7: prep-HPLC (column: Phenomenex luna C18 150 × 25mm × 10 μm; mobile phase:

[0518] [water (0.1% formic acid)-ACN]; gradient: 20%-44% B over 10 min)

[0519] PM-8: prep-HPLC (column: Phenomenex luna C18 150×25mm× 10 μm; mobile phase:

[0520] [water (0.1% formic acid)-ACN]; gradient: 15%-35% B over 10 min)

[0521] PM-9: prep-HPLC (column: Phenomenex luna C18 150 × 25mm × 10 μm; mobile phase:

[0522] [water (0.1% formic acid)-ACN]; gradient: 12%-42% B over 10 min)

[0523] PM-10: prep-HPLC (column: Phenomenex luna C18 150 × 25mm × 10 μm; mobile phase: [ water (0.1% formic acid) – ACN]; gradient: 11% - 41% B over 10 min)

[0524] PM-11: prep-HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (0.1% formic acid) - ACN]; gradient: 10%-40% B over 9 min)

[0525] PM-12: prep-HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (0.1% formic acid)- ACN]; gradient: 15%-45% B over 9 min)

[0526] PM-13: prep-HPLC (FA condition; column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (0.1% formic acid)-ACN]; gradient: 5%-45% B over 9 min) PM-14: prep-HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (0.1% formic acid)-ACN]; gradient: 19%-43% B over 8 min)

[0527] PM-15: prep-HPLC (FA condition; column: Phenomenex luna C18 150×25 mm× 10 μm; mobile phase: [water (0.1% formic acid)-ACN]; gradient: 14%-34% B over 10 min) PM-16: prep-HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (0.1% formic acid)-ACN]; gradient: 17%-47% B over 10 min)

[0528] PM-17: SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 pm); mobile phase: [CO2-i-PrOH (0.1% NH3H2O)]; B%: 45%, isocratic elution mode)

[0529] PM-18: prep-HPLC (FA condition; column: Phenomenex luna C18 150×25 mm× 10 μm; mobile phase: [water (0.1% formic acid)-ACN]; gradient: 14%-44% B over 10 min) PM-19: prep- HPLC (column: Phenomenex luna C18 150 * 25 mm * 10 u μm; mobile phase: [water (0.1% formic acid)-ACN]; gradient: 11%-44% B over 11 min) PM-20: Normal phase chromatography (Column: 100 gNH-silica, mobile phase: 0% EtOAc / 100% Heptane gradient to 100% EtOAc / 0% Heptane)

[0530] PM-21: prep-TLC (SiO2, petroleum ether / ethyl acetate = 0:1)

[0531] General Scheme 5-1

[0532]

[0533] Intermediate DA:

[0534] tert-butyl 4-(hydroxy(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methyl)piperidine-1-carboxylate

[0535] Boc

[0536]

[0537] Step 1: To a solution of l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole (10.0 g, 65.7 mmol,

[0538] 1.00 eq) in tetrahydrofuran (200 mL) was added n-butyllithium (2.50 M, 39.4 mL, 1.50 eq) at -78 °C dropwise. The mixture was stirred at -78 °C for 0.5 hour, then tert-butyl 4-formylpiperidine-1-carboxylate (14.0 g, 65.7 mmol, 1.00 eq) was added dropwise at -78

[0539] °C, the mixture was stirred at -68 °C under nitrogen atmosphere for 1 hour. The mixture was quenched with water (8.00 mL) at 0°C, stirred for 0.5 hour, then extracted with ethyl acetate 450 mL (150 mL ×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash ® Silica Flash Column, Eluent of 0 ~ 80 % Ethyl acetate / Petroleum ether gradient @ 150 mL / min) to give tert-butyl 4-(hydroxy(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl)methyl)piperidine-l-carboxylate (12.0 g, 28.8 mmol, 44% yield, 87.6% purity) as a yellow gum.1H NMR (400 MHz, CDC13) 6 = 7.58 - 7.42 (m, 1H), 6.30 - 6.14 (m, 1H), 5.51 (ddd, J= 2.0, 9.6, 15.2 Hz, 1H), 4.65 - 4.40 (m, 1H), 4.31 - 3.92 (m, 4H), 3.78 - 3.54 (m, 1H), 2.99 - 2.58 (m, 3H), 2.58 - 2.33 (m, 1H), 2.25 - 2.05 (m, 3H), 2.02 - 1.86 (m, 1H), 1.75 - 1.68 (m, 2H), 1.46 (s, 9H), 1.36 - 1.29 (m, 1H), 1.20 - 1.02 (m, 1H); LCMS [M+l] + = 366.3

[0540] Step 2: A mixture of tert-butyl 4-(hydroxy(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl)methyl)piperidine-l -carboxylate (12.0 g, 32.8 mmol, 1.00 eq), l-bromo-2-chl oro-3 -fluoro-benzene (8.94 g, 42.7 mmol, 1.30 eq and potassium tert-butoxide (5.53 g, 49.3 mmol, 1.50 eq) in tetrahydrofuran (150 mL) was stirred at 80 °C for 3 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash Silica Flash Column, Eluent of 0-60% Ethyl acetate / Petroleum ether gradient @ 200 mL / min) to give tert-butyl 4-((3-bromo-2-chlorophenoxy)(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl)methyl)piperidine-l -carboxylate (13 g, 22.6 mmol, 69% yield, 96.4% purity) as a yellow oil. 'H NMR (400 MHz, CDCh) 6 = 7.49 (dd, J= 1.6, 14.0 Hz, 1H), 7.20 (ddd, J = 1.2, 8.0, 13.2 Hz, 1H), 6.91 (dt, J= 6.4, 8.4 Hz, 1H), 6.86 - 6.59 (m, 1H), 6.34 - 6.16 (m, 1H), 5.65 - 5.25 (m, 1H), 5.15 (d, J= 7.2 Hz, 1H), 4.30 - 4.11 (m, 2H), 4.10 - 3.89 (m, 1H), 3.76 - 3.46 (m, 1H), 2.81 - 2.56 (m, 2H), 2.55 - 2.31 (m, 1H), 2.24 - 2.06 (m, 3H), 1.89 - 1.60 (m, 4H), 1.47 (d, J = 1.2 Hz, 9H), 1.42 - 1.29 (m, 2H); LCMS [M+l] + = 556.2

[0541] Step 3: A mixture of tert-butyl 4-((3-bromo-2-chlorophenoxy)(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl)methyl)piperidine-l-carboxylate (5.00 g, 9.01 mmol, 1.00 eq benzofuran-7-amine (1.92 g, 14.4 mmol, 1.60 eq., cesium carbonate (8.81 g, 27.0 mmol, 3.00 eq.) and BrettPhos Pd G3 (817 mg, 901 pmol, 0.10 eq.) in dioxane (50.0 mL) as degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 90 °C for 17 hours under nitrogen atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash ® Silica Flash Column, Eluent of 0-70% Ethyl acetate / Petroleum ether gradient @ 120 mL / min) to give Intermediate DA (4.20 g, 5.88 mmol, 65% yield, 85.0% purity) as a yellow solid. 'H NMR (400 MHz, CDC13) 6 = 7.63 (d, J = 2.0 Hz, 1H), 7.56 - 7.45 (m, 1H), 7.31 - 7.28 (m, 1H), 7.23 - 7.13 (m, 2H), 6.98 - 6.84 (m, 2H), 6.81 (s, 1H), 6.50 - 6.45 (m, 1H), 6.34 - 6.21 (m, 1H), 5.18 (d, J= 7.6 Hz, 1H), 4.35 - 4.17 (m, 1H), 4.09 - 3.91 (m, 1H), 3.79 - 3.44 (m, 1H), 2.85 - 2.38 (m, 3H), 2.30 - 2.02 (m, 4H), 1.92 - 1.57 (m, 5H), 1.49 - 1.46 (m, 9H), 1.45 - 1.29 (m, 3H); LCMS [M+l] + = 607.4.

[0542] Intermediate DB:

[0543] N-(2-chloro-3-(piperidin-4-yl(1H-pyrazol-5-yl)methoxy)phenyl)benzofuran-7-amine

[0544]

[0545] To a solution of Intermediate DA (50.0 mg, 95.6 pmol, 1.00 eq.) in dichloromethane (1.00 mL) was added trifluoroacetic acid (109 mg, 956 pmol, 71.0 pL, 10.0 eq.). The mixture was stirred at 20 °C for 1 hour. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by / c -HPLC (column: Phenomenex luna C18 150 x 25mm x 10 pm; mobile phase: [water (0.1% formic acid) - ACN]; gradient: 18%-48% B over 10 min) to give Intermediate DB (18.6 mg, 39.6 pmol, 41% yield, 99.6% purity, HCOOH) as an off-white gum. 1H NMR (400 MHz, CD3OD) δ = 8.55 (s, 1H), 7.72 (d, J= 2.0 Hz, 1H), 7.63 (d, J= 2.0 Hz, 1H), 7.30 (dd, J= 1.2, 7.6 Hz, 1H), 7.19 - 7.14 (m, 1H), 7.13 - 7.08 (m, 1H), 6.90 (t, J= 8.4 Hz, 1H), 6.85 (d, J= 2.0 Hz, 1H), 6.67 - 6.55 (m, 1H), 6.46 (d, J= 8.0 Hz, 1H), 6.34 (d, J= 2.4 Hz, 1H), 5.26 (d, J = 6.4 Hz, 1H), 3.59 - 3.34 (m, 2H), 3.09 - 2.91 (m, 2H), 2.42 - 2.22 (m, 2H), 1.93 - 1.57 (m, 3H); LCMS [M+l]+= 423.2

[0546] Example 5-1:

[0547] N-(2-chloro-3-((1-(cyclobutylmethyl)piperidin-4-yl)(1H-pyrazol-3-yl)methoxy)phenyl)benzofuran-7-amine

[0548]

[0549] A mixture of Intermediate DB (50.0 mg, 118 pmol, 1.00 eq), cyclobutanecarbaldehyde (29.8 mg, 355 pmol, 3.00 eq) in DMF (2.00 mL) was stirred for 10 mins, then sodium triacetoxyborohydride (75.2 mg, 355 pmol, 3.00 eq) was added, the mixture was stirred at 20 °C for 1 hour under nitrogen atmosphere. The mixture was filtered to give the filtrate. The filtrate was purified by / c -HPLC (column: Phenomenex Luna C18 150 * 25 mm x 10 pm; mobile phase: [water (0.1% formic acid) - ACN]; gradient: 20% - 50% B over 10 min) to give N-(2-chloro-3-((1-(cyclobutylmethyl)piperidin-4-yl)(1H-pyrazol-3-yl)methoxy)phenyl)benzofuran-7-amine (15.8 mg, 28.7 pmol, 24% yield, 97.9% purity, HCOOH) as an off-white solid. ¹H NMR (400 MHz, CD3OD) δ = 8.55 (s, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.67 - 7.54 (m, 1H), 7.30 (dd, J= 1.2, 7.6 Hz, 1H), 7.19 - 7.14 (m, 1H), 7.13 - 7.08 (m, 1H), 6.96 - 6.88 (m, 1H), 6.85 (d, J = 2.0 Hz, 1H), 6.65 - 6.55 (m, 1H), 6.50 - 6.41 (m, 1H), 6.32 (d, J= 2.4 Hz, 1H), 5.22 (br d, J= 6.8 Hz, 1H), 3.27 - 3.11 (m, 2H), 2.84 - 2.65 (m, 3H), 2.59 - 2.39 (m, 2H), 2.26 - 2.11 (m, 4H), 2.01 - 1.94 (m, 1H), 1.91 - 1.74 (m, 4H), 1.72 - 1.65 (m, 2H); LCMS [M+l]+= 491.3

[0550] General Scheme 5-2

[0551]

[0552] Intermediate DC:

[0553] 2-(3-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(piperidin-4-yl)methyl)-1H-pyrazol-1-yl)ethan-1-ol

[0554]

[0555] Step 1: A mixture of tert-butyl 4-[[3-(benzofuran-7-ylamino)-2-chloro-phenoxy]-(2-tetrahydropyran-2-ylpyrazol-3-yl)methyl]piperidine-1-carboxylate (500 mg, 824 μmol,

[0556] 1.00 eq. p-toluene sulphonic acid (284 mg, 1.65 mmol, 2.00 eq.) in ethyl alcohol (50.0 mL) was stirred at 20 °C for 1 hour. The mixture was adjusted to pH=8 by diisopropylethylamine, then concentrated under reduced pressure to give a residue to give tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(17 / -pyrazol-3- yl)methyl)piperidine-l -carboxylate (500 mg, crude) as a yellow oil. 'H NMR (400 MHz, CDCl₃) δ = 7.67 - 7.62 (m, 1H), 7.55 (d, J= 2.4 Hz, 1H), 7.25 - 7.15 (m, 2H), 6.98 - 6.90 (m, 1H), 6.89 - 6.84 (m, 1H), 6.82 (d, J= 2.0 Hz, 1H), 6.56 - 6.43 (m, 2H), 6.34 (d, J = 2.4 Hz, 1H), 5.19 (d, J= 6.8 Hz, 1H), 4.29 - 4.15 (m, 2H), 2.88 - 2.57 (m, 2H), 2.22 - 2.13 (m, 1H), 1.59 (br d, J= 13.2 Hz, 2H), 1.48 (s, 9H), 1.43 - 1.31 (m, 2H); LCMS [M+l]+= 523.1.

[0557] Step 2: To a solution of tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(lH-pyrazol-3-yl)methyl)piperidine-l -carboxylate (180 mg, 344 pmol, 1.00 eq.) and 2-bromoethoxy-tert-butyl-dimethyl-silane (247 mg, 1.03 mmol, 3.00 eq.) in acetonitrile (5.00 mL) was added cesium carbonate (336 mg, 1.03 mmol, 3.00 eq.). The mixture was stirred at 20 °C for 17 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash Silica Flash Column, Eluent of 0 - 30 % Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-IT / -pyrazol-3-yl)methyl)piperidine-l -carboxylate (50.0 mg, 70.0 pmol, 20% yield, 95.4% purity) as a yellow oil. LCMS [M+l]+= 681.4

[0558] Step 3: A mixture of tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-lH-pyrazol-3-yl)methyl)piperidine-l-carboxylate (45.0 mg, 66.1 pmol, 1.00 eq.), cesium fluoride (100 mg, 660 pmol, 10.0 eq.) in Dimethyl Formamide (2.00 mL) was stirred at 20 °C for 1 hour. The mixture was extracted with ethyl acetate 45.0 mL (15.0 mL *3), dired over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)( l-(2-hydroxyethyl)- IT / -pyrazol-3-yl)methyl)piperidine- l -carboxylate (30 mg, crude) as a yellow oil. LCMS [M-55]+= 511.2

[0559] Step 4: To a solution of tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-(2-hydroxyethyl)-lH-pyrazol-3-yl)methyl)piperidine-l-carboxylate (30.0 mg, 52.9 pmol, 1.00 eq.) in dichloromethane (6.00 mL) was added TFA(60.3 mg, 529 pmol, 39.3 pL, 10.0 eq.). The mixture was stirred at 20 °C for 1 hour. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150 * 25 mm x 10 pm; mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient: 16 % - 46 % B over 10 min) to give Intermediate DC (8.53 mg, 18.3 pmol, 35% yield, 99.9% purity) as a yellow gum. 'H NMR (400 MHz, CD3OD) δ = 8.57 (br s, 1H), 7.74 (d, J= 2.2 Hz, 1H), 7.64 (d, J= 2.3 Hz, 1H), 7.33 (dd, J = 1.2, 7.5 Hz, 1H), 7.21 - 7.15 (m, 1H), 7.15 - 7.10 (m, 1H), 6.93 (t, J = 8.3 Hz, 1H), 6.87 (d, J= 2.1 Hz, 1H), 6.62 (dd, J= 1.1, 8.3 Hz, 1H), 6.51 (dd, J= 1.0, 8.3 Hz, 1H), 6.31 (d, J= 2.2 Hz, 1H), 5.22 (d, J= 6.5 Hz, 1H), 4.23 (t, J= 5.4 Hz, 2H), 3.88 (t, J= 5.4 Hz, 2H), 3.53 - 3.38 (m, 2H), 3.02 (dq, J=2.8, 13.1 Hz, 2H), 2.35 (br d, J= 11.6 Hz, 2H), 1.93 - 1.64 (m, 3H); LCMS [M+l]+= 467.3

[0560] Example 5-2:

[0561] 2-(3-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-(cyclobutylmethyl)piperidin-4- yl)methyl)- 17 / -pyrazol - 1 -yl)ethan- 1 -ol

[0562]

[0563] To a solution of Intermediate DC and cyclobutanecarbaldehyde (7.21 mg, 85.7 pmol, 1.00 eq.) in dimethyl formamide (1.00 mL) was stirred for 10 mins, then sodium triacetoxyborohydride (54.5 mg, 257 pmol, 3.00 eq.) added. The mixture was stirred at 20 °C for 1 hour. The mixture was filtered to give a filtrate. The filtrated was purified by / c -HPLC (column: Phenomenex Luna C18 150 * 25 mm x 10 pm; mobile phase: [water (0.1% formic acid) - ACN]; gradient: 21% - 51% B over 10 min) to give 2-(3-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-(cyclobutylmethyl)piperidin-4-yl)methyl)- U / -pyrazol-l-yl)ethan-l-ol (7.33 mg, 12.5 pmol, 15% yield, 99.4% purity, HCOOH) as a light brown solid. 'H NMR (400 MHz, CD3OD) δ = 8.54 (s, 1H), 7.72 (d, J= 2.0 Hz, 1H), 7.62 - 7.46 (m, 1H), 7.30 (br d, J= 7.2 Hz, 1H), 7.19 - 7.09 (m, 2H), 6.94 - 6.87 (m, 1H), 6.85 (br d, J= 2.0 Hz, 1H), 6.65 - 6.57 (m, 1H), 6.55 - 6.45 (m, 1H), 6.32 - 6.23 (m, 1H), 5.51 - 5.13 (m, 1H), 4.21 (br t, J= 5.6 Hz, 2H), 3.92 - 3.80 (m, 2H), 2.86 - 2.73 (m, 2H), 2.72 - 2.43 (m, 4H), 2.27 - 2.22 (m, 1H), 2.16 (br d, J= 8.8 Hz, 3H), 2.03 - 1.92 (m, 2H), 1.87 - 1.77 (m, 4H), 1.75 - 1.68 (m, 2H); LCMS [M+l]+= 535.4.

[0564] Example 5-3:

[0565] 2-(3-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-isobutylpiperidin-4-yl)methyl)-lH- pyrazol- 1 -yl)ethan- 1 -ol

[0566]

[0567] A mixture of Intermediate DC (55.0 mg, 118 pmol, 1.00 eq), isobutyraldehyde (25.5 mg, 353 pmol, 32.3 pL, 3.00 eq) in dimethyl formamide (1.00 mL) was stirred for 10 min, then sodium borohydride acetate (74.9 mg, 353 pmol, 3.00 eq) added, the mixture was stirred at 20 °C for Ihour under nitrogen atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 25 mm x 10 pm; mobile phase: [water (0.1% formic acid) - ACN]; gradient: 20% - 50% B over 10 min) to give 2-(3-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-isobutylpiperidin-4-yl)methyl)-lH-pyrazol-l-yl)ethan-l-ol (7.65 mg, 13.3 pmol, 11% yield, 98.7% purity, HCOOH) as a light brown solid.

[0568] 'H NMR (400 MHz, CD3OD) δ = 8.54 (br s, 1H), 7.72 (d, J= 2.0 Hz, 1H), 7.66 - 7.45 (m, 1H), 7.36 - 7.25 (m, 1H), 7.22 - 7.07 (m, 2H), 6.99 - 6.88 (m, 1H), 6.85 (d, J= 2.0 Hz, 1H), 6.64 - 6.57 (m, 1H), 6.56 - 6.46 (m, 1H), 6.38 - 6.15 (m, 1H), 5.54 - 5.09 (m, 1H), 4.44 - 4.16 (m, 2H), 4.00 - 3.77 (m, 2H), 3.51 - 3.34 (m, 2H), 2.81 - 2.41 (m, 4H), 2.37 - 2.16 (m, 2H), 2.13 - 1.96 (m, 1H), 1.92 - 1.57 (m, 3H), 1.21 - 0.77 (m, 6H);

[0569] LCMS [M+l]+= 523.3

[0570] General Scheme 5-3

[0571]

[0572] Intermediate DD:

[0573] A-(2-chloro-3-((l-isopropyl-lH-pyrazol-3-yl)(piperidin-4- yl)methoxy)phenyl)benzofuran-7-amine

[0574]

[0575] Step 1: To a solution of 3-bromo-lH-pyrazole (5.00 g, 34.0 mmol, 1.00 eq) in DMF (30.0 mL) was added dropwise sodium hydride (2.04 g, 51.0 mmol, 60% dispersion in mineral oil, 1.50 eq) at 0 °C. After addition, the mixture was stirred at this temperature for 0.5 hours, and then isopropyl iodide (6.94 g, 40.8 mmol, 4.07 mL, 1.20 eq) was added

[0576] dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 3 hours. After completion the reaction mixture was quenched with ammonium chloride (aq., 2.00 mL) and diluted with ethyl acetate (45.0 mL). The resulting mixture was washed with brine (50.0 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiCh, petroleum ether / ethyl acetate

[0577] =20:1) to give 3-bromo-l-isopropyl-lH-pyrazole (3.00 g, 11.1 mmol, 33% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ = 7.32 (d, J= 2.0 Hz, 1H), 6.24 (d, J= 2.0 Hz, 1H), 4.47 (td, J= 6.8, 13.4 Hz, 1H), 1.50 (s, 3H), 1.49 (s, 3H); LCMS [M+l]+= 191.1 Step 2: To a solution of tert-butyl 4-formylpiperidine-l -carboxylate (1.22 g, 5.72 mmol, 1.00 eq and 3-bromo-l-isopropyl-lH-pyrazole (1.30 g, 6.86 mmol, 1.20 eq. in tetrahydrofuran (12.0 mL) was added n-butyllithium (2.50 M, 2.75 mL, 1.20 eq. The mixture was stirred at -78 °C for 2 hours. After completion the reaction mixture was cooled to 25 °C and diluted with ethyl acetate (30.0 mL). The resulting mixture was washed with brine (15.0 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiC>2, dichloromethane: methyl alcohol = 20:1) to give tert-butyl 4-(hydroxy(l-isopropyl-U / -pyrazol-3-yl)methyl)piperidine-l-carboxylate (500 mg, 1.08 mmol, 19% yield) as a yellow solid.; LCMS [M-55]+= 268.2.

[0578] Step 3: A mixture of tert-butyl 4-(hydroxy(l -isopropyl -17 / -pyrazol -3-yl)methyl)piperidine-l -carboxylate (240 mg, 742 pmol, 1.50 eq, Intermediate AA (128 mg, 495 pmol, 1.00 eq, triphenylphosphine (169 mg, 643 pmol, 1.30 eq and (3E)-3-(dimethylcarbamoylimino)- 1,1 -dimethylurea (102 mg, 594 pmol, 1.20 eq in toluene (2.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 60 °C for 2 hours under N2 atmosphere. After completion the reaction mixture was cooled to 25 °C and diluted with ethyl acetate (30.0 mL). The resulting mixture was washed with brine (15.0 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiC>2, petroleum ether: ethyl acetate = 5:1) to give tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l -isopropyl- U / -pyrazol-3 -yl)methyl)piperidine- 1 -carboxylate (50.0 mg, 44.2 pmol, 9% yield) as a red solid.; LCMS [M+l]+= 565.2.

[0579] Step 4: To a solution of tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-isopropyl-U / -pyrazol-3-yl)methyl)piperidine-l-carboxylate (26.0 mg, 46.0 pmol, 1.00 eq in di chloromethane (0.500 mL) was added trifluoroacetic acid (52.5 mg, 460 pmol, 34 pL, 10.0 eq. The mixture was stirred at 25 °C for 1 hour after completion the reaction mixture was cooled to 25 °C and diluted with ethyl acetate (30.0 mL), the resulting mixture was washed with brine (15.0 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiCh, dichloromethane: methanol = 10: 1) and then further purified by prep- HPLC (FA condition, column: Phenomenex Luna C18 150 × 25 mm × 10 μm; mobile phase: [water (0.1% formic acid)-CAN]; B%: 20%-50%, 9 min) to give Intermediate DD (4.00 mg, 8.52 μmol, 19% yield) as an off-white solid.; ¹H NMR (400 MHz, CDCl₃) δ = 8.59 (br s, 1H), 7.63 (d, J= 2.0 Hz, 1H), 7.36 (d, J= 2.0 Hz, 1H), 7.27 (s, 1H), 7.24 – 7.20 (m, 1H), 7.20 – 7.14 (m, 1H), 6.97 - 6.90 (m, 1H), 6.89 - 6.84 (m, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.56 - 6.48 (m, 2H), 6.21 (d, J= 2.0 Hz, 1H), 5.15 (d, J= 7.2 Hz, 1H), 4.54 - 4.42 (m, 1H), 3.54 - 3.36 (m, 2H), 2.97 - 2.77 (m, 2H), 2.40 - 2.18 (m, 2H), 1.90 -1.80 (m, 1H), 1.79 - 1.68 (m, 2H), 1.50 (d, J = 2.0 Hz, 3H), 1.49 (d, J= 1.6 Hz, 3H); LCMS [M+l]+= 465.2.

[0580] Example 5-4:

[0581] N-(2-chloro-3-((l-isobutylpiperidin-4-yl)(l-isopropyl-lH-pyrazol-3- yl)methoxy)phenyl)benzofuran-7-amine

[0582]

[0583] To a solution of Intermediate DD (60.0 mg, 129 pmol, 1.00 eq) in DMF (1.00 mL) were added sodium triacetoxyborohydride (82.0 mg, 387 pmol, 3.00 eq) and isobutyraldehyde (27.9 mg, 387 pmol, 35.3 pL, 3.00 eq). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (Formic acid)-ACN];gradient:27%-57% B over 10 min) to give 7V-(2-chloro-3-((l-isobutylpiperidin-4-yl)(l-isopropyl-U7-pyrazol-3-yl)methoxy)phenyl)benzofuran-7-amine (19.4 mg, 36.2 pmol, 28% yield, 97% purity) as a yellow gum.; ¹H NMR (400 MHz, CD3OD) δ = 8.55 (s, 1H), 7.71 (d, J= 2.0 Hz, 1H), 7.57 (d, J= 2.4 Hz, 1H), 7.28 (dd, J= 1.6, 7.3 Hz, 1H), 7.17 – 7.12 (m, 1H), 7.11 (d, J = 1.2 Hz, 1H), 6.88 (t, J= 8.4 Hz, 1H), 6.84 (d, J= 2.0 Hz, 1H), 6.61 (dd, J= 1.2, 8.4 Hz, 1H), 6.49 (d, J= 8.4 Hz, 1H), 6.23 (d, J= 2.4 Hz, 1H), 5.10 (d, J= 7.2 Hz, 1H), 4.48 (td, J= 6.8, 13.4 Hz, 1H), 3.10 - 2.96 (m, 2H), 2.26 - 2.12 (m, 3H), 2.10 - 1.97 (m, 3H), 1.86 (td, J= 6.8, 13.6 Hz, 1H), 1.66 - 1.51 (m, 3H), 1.46 (d, J= 6.8 Hz, 6H), 0.92 (d, J= 6.8 Hz, 6H); LCMS [M+l]+= 521.3.

[0584] Example 5-5:

[0585] 7V-(2-chloro-3-((l-(cyclobutylmethyl)piperidin-4-yl)(l-isopropyl-U / -pyrazol-3- yl)methoxy)phenyl)benzofuran-7-amine

[0586]

[0587] To a solution of Intermediate DD (20.0 mg, 43.0 pmol, 1.00 eq) in DMF (1.00 mL) was added 51265-1 (10.9 mg, 129 pmol, 3.00 eq) and sodium triacetoxyborohydride (18.2 mg, 86.0 pmol, 2.00 eq). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water(Formic acid)-ACN];gradient:29%-59% B over 10 min) to give 7V-(2-chloro-3-((l-(cyclobutylmethyl)piperidin-4-yl)(l-isopropyl-U / -pyrazol-3-yl)methoxy)phenyl)benzofuran-7-amine (6.80 mg, 12.5 pmol, 29% yield, 98% purity) as an off-white solid.; ¹H NMR (400 MHz, CD3OD) δ = 8.55 (s, 1H), 7.71 (d, J= 2.0 Hz, 1H), 7.57 (d, J= 2.4 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.18 - 7.07 (m, 2H), 6.93 - 6.82 (m, 2H), 6.64 - 6.58 (m, 1H), 6.48 (d, J= 8.4 Hz, 1H), 6.22 (d, J= 2.4 Hz, 1H), 5.11 (d, J = 7.2 Hz, 1H), 4.48 (td, J= 6.8, 13.6 Hz, 1H), 3.12 - 2.96 (m, 2H), 2.64 - 2.50 (m, 3H), 2.24 - 2.02 (m, 6H), 1.97 - 1.87 (m, 1H), 1.83 - 1.70 (m, 3H), 1.65 - 1.52 (m, 3H), 1.46 (d, J= 6.8 Hz, 6H); LCMS [M+l]+= 533.3.

[0588] General Scheme 5-4

[0589]

[0590] Intermediate DE:

[0591] 7V-(2-chloro-3-((l-ethyl-lJ7-pyrazol-3-yl)(piperidin-4-yl)methoxy)phenyl)benzofuran-7- amine

[0592]

[0593] Step 1: To a solution of 3-bromo-IT / -pyrazole (3.00 g, 20.4 mmol, 1.00 eq) in dimethyl formamide (30.0 mL) was added dropwise sodium hydride (1.22 g, 30.6 mmol, 60%

[0594] purity, 1.50 eq) at 0 °C. After addition, the mixture was stirred at this temperature for 0.5 hours, and then iodoethane (5.09 g, 32.7 mmol, 2.61 mL, 1.60 eq) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 3 hours. After completion the reaction mixture was quenched with ammonium chloride (2.00 mL) and diluted with ethyl acetate (45.0 mL). The resulting mixture was washed with brine (50.0 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by / v -TLC (SiCh, petroleum ether / ethyl acetate =20:1) to give 3-bromo- 1 -ethyl- UT-pyrazole (1.50 g, 7.71 mmol, 38% yield) as an orange solid. LCMS [M+l]+= 176.8 Step 2: To a solution of tert-butyl 4-formylpiperidine-l -carboxylate (500 mg, 2.34 mmol, 1.00 eq) and 3 -bromo- 1 -ethyl- Irt-pyrazole (492 mg, 2.81 mmol, 1.20 eq.) in tetrahydrofuran (5.00 mL) at -68 °C. After addition, the mixture was stirred at this temperature for 1 hour, and then n-Butyllithium (2.50 M, 1.13 mL, 1.20 eq) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 1 hour. After completion the reaction mixture was cooled to 25 °C and diluted with ethyl acetate (30.0 mL). The resulting mixture was washed with brine (15.0 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by / v -TLC (SiCh, di chloromethane: methyl alcohol = 20:1) to give tert-butyl 4-((l-ethyl-lH-pyrazol-3-yl)(hydroxy)methyl)piperidine-l-carboxylate (200 mg, 452 pmol, 19 % yield) as a yellow solid. LCMS [M-55]+= 254.2

[0595] Step 3: A mixture of tert-butyl 4-((l-ethyl-lH-pyrazol-3-yl)(hydroxy)methyl)piperidine-1-carboxylate (80.0 mg, 259 pmol, 1.50 eq), Intermediate AA (44.8 mg, 172 pmol, 1.00 eq), triphenylphosphine (58.8 mg, 224 pmol, 1.30 eq.), N, N, N, N-Tetramethylazodicarboxamide (35.6 mg, 207 pmol, 1.20 eq.) in toluene (1.00 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 60 °C for 1 hour under a nitrogen atmosphere. After completion the reaction mixture was cooled to 25 °C and diluted with ethyl acetate (30.0 mL). The resulting mixture was washed with brine (15.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by / v -TLC (SiCh, petroleum ether: ethyl acetate = 5:1) to give tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-ethyl-lH-pyrazol-3-yl)methyl)piperidine-l-carboxylate (70.0 mg, 127 pmol, 74% yield) as a red solid. LCMS [M+l]+= 551.3

[0596] Step 4: To a solution of tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-ethyl-lH-pyrazol-3-yl)methyl)piperidine-l-carboxylate (40.0 mg, 43.6 pmol, 1.00 eq) in dichloromethane (0.500 mL) was added trifluoroacetic acid (49.7 mg, 436 pmol, 32.4 pL, 10.0 eq). The mixture was stirred at 25 °C for 1 hour after completion the reaction mixture was cooled to 25 °C and diluted with ethyl acetate (30.0 mL), the resulting mixture was washed with brine (15.0 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiO2, dichloromethane: methanol = 10: 1) and then further purified by prep-HPLC (Formic acid condition, column: Phenomenex Luna C18 150 x 25 mm x 10 pm; mobile phase: [water (0.1% formic acid)-ACN]; B%: 20%-50%, 9 min) to give Intermediate DE (10.0 mg, 21.1 pmol, 48% yield) as a brown gum. ¹H NMR (400 MHz, CDCl₃) δ = 8.57 (s, 1H), 7.62 (d, J= 2.0 Hz, 1H), 7.32 (d, J= 2.0 Hz, 1H), 7.27 (s, 1H), 7.23 - 7.19 (m, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.97 - 6.90 (m, 1H), 6.88 - 6.82 (m, 1H), 6.79 (d, J= 2.0 Hz, 1H), 6.57 - 6.43 (m, 2H), 6.21 (d, J= 2.0 Hz, 1H), 5.13 (d, J= 7.2 Hz, 1H), 4.14 (q, J= 7.2 Hz, 2H), 3.53 - 3.35 (m, 2H), 2.96 - 2.78 (m, 2H), 2.43 - 2.10 (m, 2H), 1.95 - 1.60 (m, 3H), 1.46 (t, J= 7.2 Hz, 3H); LCMS [M+l]+= 451.4.

[0597] Example 5-6:

[0598] 7V-(2-chloro-3-((l-(cyclobutylmethyl)piperidin-4-yl)(l-ethyl-lH-pyrazol-3- yl)methoxy)phenyl)benzofuran-7-amine

[0599]

[0600] To a solution of Intermediate DE (80.0 mg, 177 pmol, 1.00 eq.) and cyclobutanecarbaldehyde (22.4 mg, 266 pmol, 1.50 eq) in DMF (1.00 mL) was added sodium triacetoxyborohydride (75.2 mg, 355 pmol, 2.00 eq). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCh, dichloromethane: methanol = 10: 1) and then further purified by prep-HPLC (Formic acid condition, column: Phenomenex Luna C18 150 * 25 mm x 10 pm; mobile phase: [water (0.1% formic acid)-can]; B%: 30%-50%, 9 min) to give N-(2-chloro-3-((1-(cyclobutylmethyl)piperidin-4-yl)(1-ethyl-1H-pyrazol-3-yl)methoxy)phenyl)benzofuran-7-amine (25.1 mg, 47.8 pmol, 27% yield) as a yellow solid. 'H NMR (400 MHz, CDCh) 6 = 7.63 (br d, J= 2.0 Hz, 1H), 7.31 (d, J= 2.0 Hz, 1H), 7.26-7.28 (m, 1H), 7.19-7.24 (m, 1H), 7.12-7.19 (m, 1H), 6.90-6.97 (m, 1H), 6.83-6.88 (m, 1H), 6.80 (d, J= 2.0 Hz, 1H), 6.45-6.54 (m, 2H), 6.20 (d, J= 2.4 Hz, 1H), 5.15 (br d, J= 6.8 Hz, 1H), 4.14 (q, J= 7.2 Hz, 2H), 3.34 (br s, 2H), 2.78-2.89 (m, 2H), 2.67-2.77 (m, 1H), 2.35-2.62 (m, 2H), 2.16- 2.28 (m, 2H), 2.11-2.16 (m, 2H), 1.88-2.01 (m, 2H), 1.83-1.88 (m, 1H), 1.81 (br s, 2H), 1.72-1.78 (m, 2H), 1.46 ppm (t, J= 7.2 Hz, 3H); LCMS [M+1]+= 519.2.

[0601] Example 5-7

[0602] N-(2-chloro-3-((l-ethyl-lH-pyrazol-3-yl)(l-isobutylpiperidin-4- yl)methoxy)phenyl)benzofuran-7-amine

[0603]

[0604] To a solution of Intermediate DE (80.0 mg, 177 pmol, 1.00 eq) and isobutyraldehyde (22.4 mg, 266 pmol, 1.50 eq) in DMF (1.00 mL) was added Sodium triacetoxyborohydride (75.2 mg, 355 pmol, 2.00 eq). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, dichloromethane: methanol = 10: 1) and then further purified by / c -HPLC (column: Phenomenex Luna C18 150 * 25 mm x 10 pm; mobile phase: [water (0.1% formic acid)-ACN]; B%: 30%-50%, 9 min) to give7V-(2-chloro-3-((l-ethyl-lH-pyrazol-3-yl)(l-isobutylpiperidin-4-yl)methoxy)phenyl)benzofuran-7-amine (25.1 mg, 47.8 pmol, 27% yield) as a yellow solid. 'H NMR (400 MHz, CDCh) 3 = 7.63 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.26-7.28 (m, 1H), 7.19-7.23 (m, 1H), 7.12-7.19 (m, 1H), 6.90-6.97 (m, 1H), 6.83-6.88 (m, 1H), 6.80 (d, J= 2.0 Hz, 1H), 6.46-6.55 (m, 2H), 6.21 (d, J= 2.4 Hz, 1H), 5.16 (br d, J= 6.4 Hz, 1H), 4.15 (q, J= 7.2 Hz, 2H), 3.38 (dt, J= 2.8, 1.4 Hz, 2H), 2.59 (br d, J= 1.6 Hz, 2H), 2.37-2.53 (m, 1H), 2.17-2.34 (m, 2H), 2.08 (br s, 1H), 1.86-2.02 (m, 2H), 1.62- 1.85 (m, 2H), 1.46 (t, J = 7.2 Hz, 3H), 1.01 (s, 3H), 1.00 ppm (s, 3H); LCMS [M+l]+= 507.2

[0605] General Scheme 5-5

[0606]

[0607] Example 5-8

[0608] A-(3-((l-((3-aminocyclopentyl)methyl)piperidin-4-yl)(l-methyl-777-pyrazol-3- yl)methoxy)-2-chlorophenyl)benzofuran-7-amine

[0609] Step 1: To a solution of Example 2-1 (50.0 mg, 114 pmol, 1.00 eq.) and (3-((tert-butoxycarbonyl)amino)cyclopentyl)methyl 4-methylbenzenesulfonate (46.5 mg, 126

[0610] pmol, 1.10 eq) in DMF (0.500 mL) was added cesium carbonate (74.6 mg, 229 pmol,

[0611] 2.00 eq) and sodium iodide (25.7 mg, 172 pmol, 1.50 eq). The mixture was stirred at 50

[0612] °C for 12 hours. After completion the reaction mixture was quenched with aqueous ammonium chloride (2.00 mL) and diluted with ethyl acetate (45.0 mL). The resulting mixture was washed with brine (50.0 mL x 3), dried over anhydrous sodium sulfate,

[0613] filtered and concentrated under vacuum to give a residue. The residue was purified by

[0614] / vc -TLC (SiC>2, petroleum ether / ethyl acetate =3:1) to give Zc / V-butyl (3-((4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-methyl-777-pyrazol-3-yl)methyl)piperidin-l-yl)methyl)cyclopentyl)carbamate (15.0 g, 48.2 mmol, 49% yield) as a yellow oil. LCMS [M+l]+= 634.4

[0615] Step 2: To a solution of tert-butyl (3-((4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l -methyl- lH-pyrazol-3 -yl)methyl)piperidin- 1 -yl)methyl)cyclopentyl)carbamate (70.0 mg, 110 pmol, 1.00 eq) in dichloromethane (1.00 mL) was added trifluoroacetic acid (126 mg, 1.10 mmol, 82.0 pL, 10.0 eq). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by / c -HPLC (column:

[0616] Phenomenex Luna C18 150 x 25 mm x 10 pm; mobile phase: [water (Formic acid)-ACN]; B%: 11%-41%, 9 min) to give A-(3-((l-((3-aminocyclopentyl)methyl)piperidin-4-yl)(l -methyl- lH-pyrazol-3-yl)methoxy)-2-chlorophenyl)benzofuran-7-amine (12.2 mg, 22.6 pmol, 20% yield) as a white solid. 'H NMR (400 MHz, CD3OD) 6 = 8.54 (s, 1H),

[0617] 7.72 (d, J= 2.0 Hz, 1H), 7.52 (d, J= 2.0 Hz, 1H), 7.30 (dd, J= 1.2, 7.5 Hz, 1H), 7.20 - 7.08 (m, 2H), 6.95 - 6.83 (m, 2H), 6.61 (dd, J= 0.8, 8.3 Hz, 1H), 6.48 (d, J= 8.4 Hz, 1H), 6.25 (d, = 2.4 Hz, 1H), 5.12 (d, J= 7.2 Hz, 1H), 3.87 (s, 3H), 3.67 - 3.51 (m, 1H), 3.14 (br dd, J= 10.4, 12.0 Hz, 2H), 2.66 - 2.45 (m, 2H), 2.40 - 2.28 (m, 2H), 2.26 (br d, J = 11.2 Hz, 2H), 2.19 - 2.07 (m, 2H), 2.07 - 1.87 (m, 2H), 1.75 - 1.64 (m, 2H), 1.58 (br s, 2H), 1.55 (br s, 1H), 1.33 - 1.20 (m, 1H); LCMS [M+l]+= 534.4.

[0618] General Scheme 5-6

[0619]

[0620] Intermediate AA Example 5-9

[0621] Example 5-9:

[0622] (5)-N-(2-chloro-3-(l-(pyrimidin-2-yl)ethoxy)phenyl)benzofuran-7-amine

[0623]

[0624] To a stirring solution of 3-benzofuran-7-ylamino)-2-chlorophenol (30.0 mg, 1 Eq, 116 pmol), (R)-l-(pyrimidin-2-yl)ethan-l-ol (21.5 mg, 1.5 Eq, 173 pmol), triphenylphosphine (polymer bound @ 1.6 mmol / g) (245 mg, 392 pmol) and THF (1.5 mL. To the stirring reaction mixture was added diisopropylazadicarboxylate (35 mg, 33.7 pL, 173 pmol). The reaction was stirred overnight. The reaction mixture was filtered washing with DCM and concentrated in vacuo. The crude material was purified by prep-HPLC (Shimadzu Prep-HPLC; Column: Phenomenex Gemini® 5uMNX-C18 110 A; 150 x 30 mm; gradient: 5% acetonitrile (0.035% TFA) / 95% water (0.05% TFA) to 95% acetonitrile (0.035% TFA) / 5% water (0.05% TFA)) to give (S)-N-(2-chloro-3-(l-(pyrimidin-2-yl)ethoxy)phenyl)benzofuran-7-amine as an oil.1H NMR (400 MHz, DMSO-d6 ) 6 ppm 1.65 - 1.74 (m, 3 H) 5.50 - 5.58 (m, 1 H) 6.26 - 6.31 (m, 1 H) 6.36 - 6.40 (m, 1 H) 6.85 - 6.92 (m, 1 H) 6.93 - 6.97 (m, 1 H) 7.02 - 7.07 (m, 1 H) 7.14 - 7.21 (m, 1 H) 7.32 - 7.37 (m, 1 H) 7.43 - 7.48 (m, 1 H) 7.58 - 7.62 (m, 1 H) 7.90 - 7.94 (m, 1 H) 8.82 - 8.87 (m, 2 H); LCMS [M+l]+= 366.1

[0625] General Scheme 5-7

[0626]

[0627] Example 5-10:

[0628] 7V-(2-chloro-3-((l -methyl- lH-pyrazol-3-yl)(piperi din-3-yl)methoxy)phenyl)benzofuran-7- amine

[0629]

[0630] Step 1: A mixture of tert-butyl 3 -formylpiperidine- 1 -carboxylate (700 mg, 3.28 mmol, 1.00 eq and 3-bromo-l-methyl-pyrazole (1.06 g, 6.56 mmol, 2.00 eq) in tetrahydrofuran (20.0 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was cooled to -65°C and stirred at -65 °C for 10 minutes under a nitrogen atmosphere. Then n-BuLi (2.50 M, 2.63 mL, 2.00 eq was added dropwise at -65°C and the reaction was stirred at -65°C for 1.5 hours. The mixture was quenched with water (0.500 mL) at 0°C and stirred for 10 minutes. Then the mixture was extracted with ethyl acetate (30.0 mL x 3), washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and purified by column chromatography (SiCh, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give tert-butyl 3-(hydroxy(l-methyl-lH-pyrazol-3-yl)methyl)piperidine-l-carboxylate (350 mg, 1.09 mmol, 33% yield, 92% purity) as a yellow oil. LCMS [M+l]+= 296.1 Step 2: A mixture of tert-butyl 3-(hydroxy(l-methyl-lH-pyrazol-3-yl)methyl)piperidine-1-carboxylate (125 mg, 424 pmol, 1.10 eq), Intermediate AA (100 mg, 385 pmol, 1.00 eq and diisopropyl azodi carb oxy late (140 mg, 693 pmol, 1.80 eq) in toluene (2.00 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was cooled to 0 °C. Then tributylphosphane (140 mg, 693 pmol, 171 pL, 1.80 eq was added dropwise and the mixture was stirred at 50°C for 1 hour. The mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed phase / c -HPLC (0.1% Formic acid condition) to give tert-butyl 3-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l -methyl- lH-pyrazol-3 -yl)methyl)piperidine- 1 -carboxylate (55.0 mg, 23% yield, 86% purity) as a yellow solid. LCMS [M+l]+= 537.3

[0631] Step 3: To a solution of tert-butyl 3-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-m ethyl- UT-pyrazol-3 -yl)m ethyl)piperi dine- 1 -carboxylate (45.0 mg, 83.8 pmol, 1.00 eq in dichloromethane (3.00 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1.00 mL, 161 eq. The mixture was stirred at 15 °C for 3hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by / c -HPLC (column: Phenomenex Luna C18 150 x 25 mm x 10 pm; mobile phase: [water(0.1% formic acid)-ACN]; gradient:22%-52% B over 9 min) to give A-(2-chloro-3-((l-methyl-lH-pyrazol-3-yl)(piperidin-3-yl)methoxy)phenyl)benzofuran-7-amine (5.00 mg, 11.2 pmol, 13% yield, 98% purity, HCOOH) as a yellow solid.1H NMR (400 MHz, CD3OD) δ = 8.53 (s, 1H), 7.72 (d, J= 1.2 Hz, 1H), 7.58 (s, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.20 - 7.14 (m, 1H), 7.14 - 7.09 (m, 1H), 6.91 (t, J= 8.4 Hz, 1H), 6.86 (d, J= 2.4 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 6.47 (t, J = 9.2 Hz, 1H), 6.29 (dd, J= 2.4, 10.1 Hz, 1H), 5.38 - 5.13 (m, 1H), 3.89 (s, 3H), 3.49 - 3.32 (m, 2H), 3.14 - 2.84 (m, 2H), 2.55 - 2.38 (m, 1H), 2.31 -1.75 (m, 2H), 1.75 - 1.43 (m, 2H); LCMS [M+1]+= 437.2.

[0632] General Scheme 5-8

[0633]

[0634] Example 5-11:

[0635] 7V-(2-chloro-3-((2-methyl-3H-imidazo[4,5-c]pyridin-4-yl)(piperidin-4- yl)methoxy)phenyl)benzofuran-7-amine

[0636]

[0637] Step 1: To a solution of 2-bromopyridine-3,4-diamine (4.00 g, 21.3 mmol, 1.00 eq) and 1,1,1 -trimethoxy ethane (7.67 g, 63.8 mmol, 8.02 mL, 3.00 eq) in tetrahydrofuran (40.0 mL) and methanol (40.0 mL) was added / ?-toluenesulfonic acid (405 mg, 2.13 mmol, 0.10 eq). The mixture was stirred at 70 °C for 2 hours. After completion of the reaction, the reaction was cooled to 25 °C. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1) to give 4-bromo-2-methyl-lH-imidazo[4,5-c]pyridine (1.17 g, 4.97 mmol, 23% yield, 90% purity) as a yellow solid. LCMS [M+l]+= 211.9

[0638] Step 2: To a solution of 4-bromo-2-methyl-LH-imidazo[4,5-c]pyridine (1.17 g, 5.52 mmol, 1.00 eq) in tetrahydrofuran (10.0 mL) and methanol (10.0 mL) was added di-tert- butyl dicarbonate (2.41 g, 11.0 mmol, 2.54 mL, 2.00 eq) and triethylamine (1.67 g, 16.6 mmol, 2.30 mL, 3.00 eq). The mixture was stirred at 40 °C for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, Petroleum ether / Ethyl acetate=10 / l to 5 / 1) to give tert-butyl 4-bromo-2-methyl-IT / -imidazo[4,5-c]pyridine-l -carboxylate (0.94 g, 3.01 mmol, 54% yield, 99.9% purity) as an off-white solid. LCMS [M+l]+= 312.0

[0639] Step 3: A mixture of tert-butyl 4-bromo-2-methyl-17 / -imidazo[4,5-c]pyridine-l-carboxylate (0.50 g, 1.60 mmol, 1.00 eq) and n-butyllithium (2.50 M, 1.28 mL, 2.00 eq) in tetrahydrofuran (10.0 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at -70 °C for 0.5 hours under nitrogen atmosphere. Then the reaction was added tert-butyl 4-formylpiperidine-l -carboxylate (512 mg, 2.40 mmol, 1.50 eq.). The mixture was stirred at -70 °C for 1.5 hours. After completion of the reaction, the reaction mixture was quenched by water (50.0 mL), and then extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with brine (30.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, dichloromethane / methanol =1 / 0 to 10 / 1) to give tert-butyl 4-(hydroxy(2-methyl- IT / -imidazo[4,5-c]pyridin-4-yl)methyl)piperidine-l -carboxylate (90.0 mg, 221 pmol, 14% yield, 85% purity) as a yellow solid. LCMS [M+l]+= 347.1

[0640] Step 4: To a solution of tert-butyl 4-(hydroxy(2-methyl-lH-imidazo[4,5-c]pyridin-4-yl)methyl)piperidine-l -carboxylate (30.0 mg, 86.6 pmol, 1.00 eq) in tetrahydrofuran (1.00 mL) was added di-tert-butyl dicarbonate (18.9 mg, 86.6 pmol, 19.9 pL, 1.00 eq) and triethylamine (26.3 mg, 260 pmol, 36.2 pL, 3.00 eq). The mixture was stirred at 40 °C for 2 hours. After completion of the reaction, the reaction was cooled to 25 °C. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether: ethyl acetate = 2:1) to give tert-butyl 4-((l-(tert-butoxycarbonyl)piperidin-4-yl)(hydroxy)methyl)-2-methyl-U / -imidazo[4,5-c]pyridine-l-carboxylate (15.0 mg, 33.6 pmol, 39% yield) as a white solid. LCMS [M+l]+= 447.2

[0641] Step 5: To a solution tert-butyl 4-((l-(tert-butoxycarbonyl)piperidin-4-yl)(hydroxy)methyl)-2-methyl-lH-imidazo[4,5-c]pyridine-l -carboxylate (13.0 mg, 29.1 pmol, 1.00 eq) and Intermediate AA (11.3 mg, 43.7 pmol, 1.50 eq) in Toluene (0.50 mL) was added N,N,N,N-tetramethylazodicarboxamide (10.0 mg, 58.2 pmol, 2.00 eq) and triphenyl phosphine (15.3 mg, 58.2 pmol, 2.00 eq). The mixture was stirred at 60 °C for 2 hours. After completion of the reaction, the reaction was cooled to 25 °C. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by / vc -TLC (silicon dioxide, petroleum ether: ethyl acetate = 2 / 1) to give tertbutyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-2-methyl-lH-imidazo[4,5-c]pyridine-l-carboxylate (8.00 mg, 10.8 pmol, 37% yield, 93% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ = 8.54 (d, J = 5.6 Hz, 1H), 7.72 (d, J= 5.6 Hz, 1H), 7.61 (d, J= 2.0 Hz, 1H), 7.25 (dd, J= 1.2, 7.6 Hz, 1H), 7.20 - 7.10 (m, 2H), 6.85 - 6.76 (m, 3H), 6.51 (s, 1H), 6.46 (dd, J= 3.2, 6.4 Hz, 1H), 5.71 (d, = 8.8 Hz, 1H), 4.30 - 4.16 (m, 1H), 4.09 - 3.92 (m, 1H), 2.90 (s, 3H), 2.69 -2.56 (m, 2H), 2.41 (br d, J = 13.6 Hz, 1H), 1.72 (s, 13H), 1.45 (s, 9H); LCMS [M+l]+= 688.3

[0642] Step 6: To a solution tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-2-methyl-lH-imidazo[4,5-c]pyridine-l-carboxylate (6.00 mg, 8.72 pmol, 1.00 eq) in dichloromethane (0.10 mL) was added trifluoroacetic acid (92.1 mg, 808 pmol, 60.0 pL, 92.7 eq). The mixture was stirred at 25 °C for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: YMC-Actus Triart C18 150 x 30mm x 7um; mobile phase: [water (0.1% formic acid)- acetonitrile]; gradient: 13%- 43% B over 10 min) to give A-(2-chloro-3-((2-methyl-3H-imidazo[4,5-c]pyridin-4-yl)(piperidin-4-yl)methoxy)phenyl)benzofuran-7-amine (1.61 mg, 2.99 pmol, 34.3% yield, 99.3% purity, formic acid salt) as a white solid. 'HNMR (400 MHz, CD3OD) 6 = 8.55 (s, 1H), 8.29 (d, J= 5.6 Hz, 1H), 7.71 (s, 1H), 7.51 (d, = 5.6 Hz, 1H), 7.30 (d, J= 7.6 Hz, 1H), 7.18 - 7.12 (m, 1H), 7.11 - 7.07 (m, 1H), 6.84 (s, 1H), 6.77 (t, J= 8.4 Hz, 1H), 6.55 (d, J= 8.4 Hz, 1H), 6.25 (d, J= 8.4 Hz, 1H), 5.63 (br d, J= 7.6 Hz, 1H), 3.47 (br d, J= 12.0 Hz, 1H), 3.35 - 3.33 (m, 1H), 3.04 -2.95 (m, 1H), 2.92 - 2.82 (m, 1H), 2.69 (s, 3H), 2.64 (br dd, J= 2.8, 11.6 Hz, 1H), 2.51 (br d, J= 14.4 Hz, 1H), 1.91 - 1.78 (m, 1H), 1.77 - 1.65 (m, 1H), 1.45 (br d, J= 13.6 Hz, 1H); LCMS [M+l]+= 488.1

[0643] General Scheme 5-9

[0644]

[0645] Intermediate DF

[0646] Step 1: To a solution of 4-methylthiazole (1.03 g, 10.4 mmol, 942 pL, 1.30 eq.) in tetrahydrofuran (10.0 mL) was added dropwise n-Butyllithium (2.50 M, 3.19 mL, 1.00 eq.) at -78 °C. After addition, the mixture was stirred at this temperature for 45 minutes, and then tert-butyl 4-formylpiperidine-l -carboxylate (1.70 g, 7.97 mmol, 1.00 eq.) in tetrahydrofuran (10.0 mL) was added dropwise at -78 °C. The resulting mixture was stirred at 0 °C for 3 hours under nitrogen atmosphere. The reaction mixture was quenched by addition of aqueous ammonium chloride (5.00 mL) at 0 °C and extracted with ethyl acetate (50.0 mL x 3). The combined organic layers were washed with brine (50.0 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=2 / l to 1 / 1) to give tert-butyl 4-(hydroxy(4-methylthiazol-2-yl)methyl)piperidine-l -carboxylate (1.36 g, 4.35 mmol, 55% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ = 6.81 (d, J= 0.8 Hz, 1H), 4.70 (d, = 5.6 Hz, 1H), 4.10 (br d, J= 7.2 Hz, 1H), 2.63 (br s, 2H), 2.38 (d, J= 0.8 Hz, 3H), 1.97 - 1.86 (m, 1H), 1.69 -1.63 (m, 1H), 1.46 (br d, J= 5.6 Hz, 2H), 1.42 (s, 9H), 1.38 - 1.01 (m, 3H); LCMS [M+l]+= 275.2

[0647] Step 2: A mixture of tert-butyl 4-(hydroxy(4-methylthiazol-2-yl)methyl)piperidine-l-carboxylate (300 mg, 960 pmol, 1.30 eq), 4-methylthiazole (192 mg, 739 pmol, 1.00 eq., triphenylphosphine (388 mg, 1.48 mmol, 2.00 eq.) and diisopropyl azodicarboxylate (299 mg, 1.48 mmol, 286 pL, 2.00 eq.) in tetrahydrofuran (3.00 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 25 °C for 2 hours under nitrogen atmosphere. The reaction mixture was quenched with water (20.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The combined organic layers were washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether / ethyl acetate=2 / 1) to give tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(4-methylthiazol-2-yl)methyl)piperidine-1-carboxylate (280 mg, 505 pmol, 68% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ = 7.63 (d, J= 2.0 Hz, 1H), 7.29 (dd, J= 1.2, 7.6 Hz, 1H), 7.25 - 7.13 (m, 2H), 6.98 - 6.92 (m, 1H), 6.90 - 6.85 (m, 2H), 6.80 (d, J= 2.0 Hz, 1H), 5.35 (d, J= 6.0 Hz, 1H), 2.47 (d, J= 0.8 Hz, 3H), 2.05 (s, 9H), 1.64 (br s, 8H), 0.94 - 0.75 (m, 3H); LCMS [M+l]+= 554.3.

[0648] Step 3: To a solution of tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(4-methylthiazol-2-yl)methyl)piperidine-l -carboxylate (150 mg, 271 pmol, 1.00 eq.) in methylene chloride (2.00 mL) was added trifluoroacetic acid (308 mg, 2.71 mmol, 201 pL, 10.0 eq.). The mixture was stirred at 25 °C for 1 hour. The mixture was filtered. The filtrate was purified with / c -HPLC (column: Phenomenex luna C18 150 x 25 mm x 10 pm; mobile phase: [water (Formic acid)-ACN];gradient:27%-47% B over 10 min) and further purified with / c -HPLC (column: Waters xbridge 150 x 25mm 10um;mobile phase: [water(ammonium hydrogen carbonate)- ACN];gradi ent: 62%-82% B over 8 min) to give Intermediate DF (15.2 mg, 33.2 pmol, 12% yield, 99% purity) as a brown solid. 'H NMR (400 MHz, CD3OD) 6 = 7.71 (d, J= 2.4 Hz, 1H), 7.31 (dd, J= 1.2, 7.2 Hz, 1H), 7.18 - 7.09 (m, 3H), 6.91 (t, J= 8.4 Hz, 1H), 6.84 (d, J= 2.0 Hz, 1H), 6.60 (dd, J= 1.2, 8.4 Hz, 1H), 6.43 (d, J = 7.6 Hz, 1H), 5.38 (d, J= 6.4 Hz, 1H), 3.10 (br dd, J= 14.0, 16.4 Hz, 2H), 2.69 - 2.54 (m, 2H), 2.42 (d, J= 0.8 Hz, 3H), 2.28 - 2.13 (m, 1H), 2.03 (br d, J = 13.2 Hz, 1H), 1.64 - 1.46 (m, 3H); LCMS [M+l]+= 454.1.

[0649] Example 5-12

[0650] A-(2-chloro-3-((l-(cyclobutylmethyl)piperidin-4-yl)(4-methylthiazol-2- yl)methoxy)phenyl)benzofuran-7-amine

[0651]

[0652] To a solution of Intermediate DF (40.0 mg, 88.1 pmol, 1.00 eq.) and cyclobutanecarbaldehyde (8.15 mg, 96.9 pmol, 1.10 eq.) in N, N-dimethylformamide (1.00 mL) was added at 25 °C. The mixture was stirred at this temperature for 10 minutes, and then sodium borohydride acetate (20.5 mg, 96.9 pmol, 1.10 eq.) was added. The resulting mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna Cl 8 150 x 25mm x 10um; mobile phase: [water(Formic acid)-ACN];gradient:27%-57% B over 10 min) to give N-(2-chl oro-3 -((l-(cy cl obutylmethyl)piperidin-4-yl)(4-methylthiazol-2-yl)methoxy)phenyl)benzofuran-7-amine (8.10 mg, 17% yield, 99% purity) as a pink solid.

[0653] 1HNMR (400 MHz, CD3OD) 6 = 8.54 (s, 1H), 7.72 (d, J= 2.0 Hz, 1H), 7.32 (dd, J = 1.2, 7.2 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 7.14 - 7.10 (m, 2H), 6.93 (t, J= 8.4 Hz, 1H), 6.85 (d, J= 2.0 Hz, 1H), 6.63 - 6.56 (m, 1H), 6.43 (d, J= 8.4 Hz, 1H), 5.44 (d, J= 6.4 Hz, 1H), 3.18 - 3.06 (m, 2H), 2.63 (br s, 3H), 2.42 (s, 3H), 2.36 - 2.23 (m, 2H), 2.19 - 2.05 (m, 4H), 1.99 - 1.91 (m, 1H), 1.85 - 1.66 (m, 6H); LCMS [M+l]+= 522.3

[0654] Example 5-13

[0655] 7V-(2-chloro-3-((l-isobutylpiperidin-4-yl)(4-methylthiazol-2- yl)methoxy)phenyl)benzofuran-7-amine

[0656]

[0657] To a solution of Intermediate DF (40.0 mg, 88.1 pmol, 1.00 eq.) and isobutyraldehyde (6.99 mg, 96.9 pmol, 1.10 eq. in N, N-dimethylformamide (1.00 mL) was added at 25 °C. The mixture was stirred at this temperature for 10 minutes, and then sodium borohydride acetate (20.5 mg, 96.9 pmol, 1.10 eq.) wa added thereto. The resulting mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered to give a residue. The residue was purified by / c -HPLC (column: Phenomenex luna Cl 8 150 x 25mm x lOum; mobile phase: [water (Formic acid)-ACN];gradient:30%-54% B over 8 min) and further purified by prep-HPLC (column: Waters xbridge 150 x 25mm 10um;mobile phase: [water( NH4HC03)-ACN];gradient:90%-100% B over 8 min) to give N-(2-chloro-3-((l-isobutylpiperidin-4-yl)(4-methylthiazol-2-yl)methoxy)phenyl)benzofuran-7-amine (6.24 mg, 12.1 pmol, 14% yield, 99% purity) as a yellow gum.JH NMR (400 MHz, CD3OD) 8 = 7.72 (d, J = 2.0 Hz, 1H), 7.32 (dd, J = 1.6, 7.2 Hz, 1H), 7.20 - 7.09 (m, 3H), 6.92 (t, J= 8.4 Hz, 1H), 6.85 (d, J= 2.0 Hz, 1H), 6.61 (d, J= 8.4 Hz, 1H), 6.44 (d, J= 8.0 Hz, 1H), 5.39 (d, J= 6.4 Hz, 1H), 3.04 - 2.92 (m, 2H), 2.42 (s, 3H), 2.13 (d, J= 7.2 Hz, 2H), 2.08 - 2.00 (m, 2H), 2.00 - 1.88 (m, 2H), 1.83 (td, J= 6.8, 13.2 Hz, 1H), 1.74 - 1.60 (m, 2H), 1.58 - 1.52 (m, 1H), 0.91 (d, J= 6.4 Hz, 6H); LCMS [M+l]+= 510.3.

[0658] General Scheme 5-10

[0659]

[0660] Example 5-14

[0661] A-(3-((lH-benzo[d]imidazol-7-yl)(piperidin-4-yl)methoxy)-2-chlorophenyl)benzofuran- 7-amine

[0662]

[0663] Step 1: To a solution of 4-bromo-lH-benzo[d]imidazole (2.00 g, 10.2 mmol, 1.00 eq.) in tetrahydrofuran (20.0 mL) was added 3,4-dihydro-2H-pyran (4.27 g, 50.8 mmol, 4.64

[0664] mL, 5.00 eq.) and p-toluene sulfonic acid (175 mg, 1.02 mmol, 0.100 eq.). The mixture was stirred at 70 °C for 12 hours. After completion, the reaction mixture was quenched with ammonium chloride (aq., 2.00 mL) and diluted with ethyl acetate (45.0 mL). The resulting mixture was washed with brine (50.0 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was

[0665] purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 1 / 1) to give 4-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-benzo[d]imidazole (2.80 g, 8.96 mmol,

[0666] 88% yield) as a white solid. LCMS [M-83]+= 197.1 Step 2: To a solution of 4-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-benzo[d]imidazole (1.00 g, 3.56 mmol, 1 eq.) in tetrahydrofuran (10.0 mL) was added dropwise n-butyllithium (2.50 M, 1.57 mL, 1.10 eq.) at -68 °C. After addition, the mixture was stirred at this temperature for 1 hour, and then 1,1,1,2,2,2-hexachloroethane (1.09 g, 4.62 mmol, 524 pL, 1.30 eq.) in tetrahydrofuran (10.0 mL) was added dropwise at -68 °C. The resulting mixture was stirred at -68 °C for 1 hour. After completion the reaction mixture was quenched with ammonium chloride (aq., 2.00 mL) and diluted with ethyl acetate (45.0 mL). The resulting mixture was washed with brine (50.0 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by / v -TLC (SiCh, petroleum ether / ethyl acetate =2 / 1) to give 4-bromo-2-chloro-l-(tetrahydro-2H-pyran-2-yl)-lH-benzo[d]imidazole (1.00 g, 2.85 mmol, 80% yield) as a yellow oil. LCMS [M-83]+= 232.9.

[0667] Step 3: To a solution of n-butyllithium (2.50 M, 989 pL, 1.50 eq.) and isopropyl magnesium bromide (1.00 M, 2.47 mL, 1.50 eq.) in tetrahydrofuran (0.500 mL) was added dropwise 4-bromo-2-chloro-l-(tetrahydro-2H-pyran-2-yl)-lH-benzo[d]imidazole (520 mg, 1.65 mmol, 1.00 eq.) at -68 °C. After addition, the mixture was stirred at this temperature for 1 hour, and then tert-butyl 4-formylpiperidine-l -carboxylate (1.05 g, 4.94 mmol, 3.00 eq.) in tetrahydrofuran (0.500 mL) was added dropwise at -68 °C. The resulting mixture was stirred at -68 °C for 1 hour. After completion the reaction mixture was quenched with ammonium chloride (aq., 2.00 mL) and diluted with ethyl acetate (45.0 mL). The resulting mixture was washed with brine (50.0 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiCh, petroleum ether / ethyl acetate =1 / 1) to give tertbutyl 4-((2-chloro-l-(tetrahydro-2H-pyran-2-yl)-lH-benzo[d]imidazol-4-yl)(hydroxy)methyl)piperidine-l -carboxylate (250 mg, 500 pmol, 30% yield) as a yellow oil. LCMS [M+l]+= 450.2

[0668] Step 4: To a solution of tert-butyl 4-((2-chloro-l-(tetrahydro-2H-pyran-2-yl)-lH-benzo[d]imidazol-4-yl)(hydroxy)methyl)piperidine-l -carboxylate (200 mg, 444 pmol, 1.00 eq.) in triethylamine (0.280 mL), tetrahydrofuran (10.0 mL) and ethyl acetate (10.0 mL) was added Pd / C (120 mg, 1.13 mmol, 50% purity, 2.54 eq.) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen for 5 times. The mixture was stirred under hydrogen (15 Psi) at 25 °C for 1 hour. Then the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by / v -TLC (SiCh, petroleum ether / ethyl acetate =0 / 1) to give tertbutyl 4-(hydroxy(l-(tetrahydro-2H-pyran-2-yl)-lH-benzo[d]imidazol-4-yl)methyl)piperidine-l -carboxylate (200 mg, 433 pmol, 97% yield) as a yellow oil.

[0669] LCMS [M+l]+= 416.2.

[0670] Step 5: To a solution of tert-butyl 4-(hydroxy(l-(tetrahydro-2H-pyran-2-yl)-lH-benzo[d]imidazol-4-yl)methyl)piperidine-l -carboxylate (180 mg, 433 pmol, 1.30 eq.) in tetrahydrofuran (1.00 mL) was added potassium;2-methylpropan-2-olate;oxolane (184 mg, 999 pmol, 3.00 eq.) and l-bromo-2-chloro-3-fluorobenzene (69.8 mg, 333 pmol, 1.00 eq.). The mixture was stirred at 80 °C for 2 hours. Then the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether / ethyl acetate =0 / 1) to give tert-butyl 4-((3-bromo-2-chlorophenoxy)(l-(tetrahydro-2H-pyran-2-yl)-lH-benzo[d]imidazol-4-yl)methyl)piperidine-l -carboxylate (50.0 mg, 74.4 pmol, 22% yield) as a yellow oil. LCMS [M+l]+= 605.1.

[0671] Step 6: A mixture of tert-butyl 4-((3-bromo-2-chlorophenoxy)(l-(tetrahydro-2H-pyran-2-yl)-lH-benzo[d]imidazol-4-yl)methyl)piperidine-l-carboxylate (30.0 mg, 49.6 pmol, 1.00 eq.), benzofuran-7-amine (7.26 mg, 54.6 pmol, 1.10 eq.), cesium carbonate (32.3 mg, 99.2 pmol, 2.00 eq.) and RuPhos Pd G3 (8.30 mg, 9.92 pmol, 0.200 eq.) in toluene (0.500 mL) was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by / vc -TLC (SiCh, petroleum ether / ethyl acetate =1:1) to give tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-(tetrahydro-2H-pyran-2-yl)-lH-benzo[d]imidazol-4-yl)methyl)piperidine-l -carboxylate (30.0 mg, 45.7 pmol, 92% yield) as a yellow oil. LCMS [M+l]+= 658.2.

[0672] Step 7: To a solution of tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-(tetrahydro-2H-pyran-2-yl)-lH-benzo[d]imidazol-4-yl)methyl)piperidine-l-carboxylate (15.0 mg, 22.8 pmol, 1.00 eq.) in methyl alcohol (1.00 mL) and water (0.200 mL) was added p-toluene sulphonic acid (11.8 mg, 68.5 pmol, 3.00 eq.). The mixture was stirred at 80 °C for 1.5 hours. After completion, the reaction mixture was cooled to 25 °C and diluted with ethyl acetate (30.0 mL), the resulting mixture was washed with brine (15.0 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by / c -HPLC (Formic acid condition, column: Phenomenex Luna C18 150 * 25 mm x 10 pm; mobile phase: [water (Formic acid)-ACN]; B%: 14%-44%, 9 min) to give N-(3-((lH-benzo[d]imidazol-7-yl)(piperidin-4-yl)methoxy)-2-chlorophenyl)benzofuran-7-amine (5.88 mg, 11.8 pmol, 51% yield) as a yellow solid. 'H NMR (400 MHz, CDC13, 25°C): 8 = 8.59 (br d, J= 4.8 Hz, 1H), 8.08 (br s, 1H), 7.73 (br d, J= 7.2 Hz, 1H), 7.54-7.64 (m, 2H), 7.26 (br s, 1H), 7.17-7.24 (m, 2H), 7.14 (br s, 2H), 6.77 (s, 1H), 6.73 (br s, 2H), 6.46 (s, 1H), 6.16-6.33 (m, 1H), 5.44-5.66 (m, 1H), 3.29-3.42 (m, 2H), 2.69-2.84 (m, 2H), 2.34 (br s, 1H), 2.29 (br s, 2H), 1.71-1.95 (m, 2H), 1.36-1.55 ppm (m, 1H); LCMS [M+l]+= 473.2.

[0673] General Scheme 5-11

[0674]

[0675] Example 5-15

[0676] A-(2-chloro-3-(2-(l-(cyclobutylmethyl)piperidin-4-yl)-l-(l-methyl-lH-pyrazol-3- yl)ethoxy)phenyl)benzofuran-7-amine

[0677]

[0678] Step 1: To a solution of 3-iodo-l-methyl-pyrazole (9.20 g, 44.2 mmol, 1.20 eq.) in tetrahydrofuran (100 mL) was added n-BuLi (2.5 M, 19.2 mL, 1.30 eq.) at -60°C, stirred at -60 °C for 0.5 hours, then tert-butyl 4-(2-oxoethyl) piperidine- 1 -carboxylate (10.9 g, 47.9 mmol, 1.30 eq.) was added dropwise at -60°C. The mixture was stirred at -60 °C for 1.5 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-10% DCM / MeOH ether gradient @ 100 mL / min) to give tert-butyl 4-(2-hydroxy-2-(l-methyl-lH-pyrazol-3-yl)ethyl)piperidine-l-carboxylate (10.0 g, 22.6 mmol, 61% yield, 70% purity) as a yellow oil. LCMS [M+Na]+= 332.3 Step 2: To a solution of l-bromo-2-chl oro-3 -fluor obenzene (1.35 g, 6.46 mmol, 2.00 eq.) and tert-butyl 4-(2-hydroxy-2-(l-methyl-lH-pyrazol-3-yl)ethyl)piperidine-l-carboxylate (1.00 g, 3.23 mmol, 1.00 eq.) in tetrahydrofuran (10.0 mL) was added potassium tert-butoxide (725 mg, 6.46 mmol, 2.00 eq.). The mixture was stirred at 80 °C for 2 hours. The mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase prep-HPLC (0.1% Formic acid condition) to give tert-butyl 4-(2-(3-bromo-2-chlorophenoxy)-2-(l -methyl- lH-pyrazol-3-yl)ethyl)piperidine-l -carboxylate (1.00 g, 1.96 mmol, 61% yield, 98% purity) as a yellow oil. 'HNMR (400 MHz, CDC13) 8 = 7.27 - 7.26 (m, 1H), 7.16 (dd, J= 2.8, 6.4 Hz, 1H), 6.98 - 6.91 (m, 2H), 6.21 (d, J= 2.4 Hz, 1H), 5.37 (dd, J= 4.4, 9.2 Hz, 1H), 4.11 - 3.94 (m, 2H), 3.87 (s, 3H), 2.83 - 2.54 (m, 2H), 2.22 - 2.11 (m, 1H), 1.80 - 1.76 (m, 2H), 1.71 -1.62 (m, 2H), 1.45 (s, 9H), 1.24 - 1.12 (m, 2H); LCMS [M+l] += 500.2

[0679] Step 3: A mixture of tert-butyl 4-(2-(3-bromo-2-chlorophenoxy)-2-(l-methyl-lH-pyrazol-3 -yl)ethyl)piperidine-l -carboxylate (500 mg, 1.00 mmol, 1.00 eq.), benzofuran-7-amine (400 mg, 3.01 mmol, 3.00 eq.), cesium carbonate (980 mg, 3.01 mmol, 3.00 eq.), 2,2’-bis(diphenylphosphino)-l,l’-binaphthalene (12.0 mg, 200 pmol, 0.20 eq.) and tris(dibenzylideneacetone)dipalladium (91.8 mg, 100 pmol, 0.10 eq.) in toluene (10.0 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 17 hours under nitrogen atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-45% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to give tert-butyl 4-(2-(3-(benzofuran-7- ylamino)-2-chlorophenoxy)-2-(l-methyl-lH-pyrazol-3-yl)ethyl)piperidine-l-carboxylate (400 mg, 654 pmol, 65% yield, 90.1% purity) as a yellow oil. LCMS [M+l]+= 551.3

[0680] Step 4: To a solution of tert-butyl 4-(2-(3-(benzofuran-7-ylamino)-2-chlorophenoxy)-2-(l-methyl-lH-pyrazol-3-yl)ethyl)piperidine-l-carboxylate (55.0 mg, 99.8 pmol, 1.00 eq.) in dichloromethane (1.00 mL) was added trifluoroacetic acid (153 mg, 1.35 mmol, 0.10 mL, 13.5 eq.) at 0 °C. The mixture was stirred at 20 °C for 1 hour. The mixture was concentrated under reduced pressure to give N-(2-chloro-3-(l-(l-methyl-lH-pyrazol-3-yl)-2-(piperidin-4-yl)ethoxy)phenyl)benzofuran-7-amine (60.0 mg, crude) as a yellow

[0681] gum which was used into the next step without further purification. LCMS [M+l]+=

[0682] 451.3

[0683] Step 5: To a solution of N-(2-chloro-3-(l-(l-methyl-lH-pyrazol-3-yl)-2-(piperidin-4-yl)ethoxy)phenyl)benzofuran-7-amine (50.0 mg, 111 pmol, 1.00 eq.) and cyclobutanecarbaldehyde (28.0 mg, 333 pmol, 3.00 eq.) in dimethyl formamide (0.50

[0684] mL) stirred for 10 minutes, then sodium borohydride acetate (70.5 mg, 333 pmol, 3.00 eq.) was added. The mixture was stirred at 20 °C for 1 hour. The mixture was filtered to give the filtrate. The filtrate was purified by / c -HPLC (column: Phenomenex luna Cl 8

[0685] 150 x 25mm x 10um; mobile phase: [water (Formic acid) - ACN]; gradient: 28% - 58% B over 10 min) to give N-(2-chl oro-3 -(2-(l-(cy cl obutylmethyl)piperidin-4-yl)-l-(l-methyl-lH-pyrazol-3-yl)ethoxy)phenyl)benzofuran-7-amine (9.89 mg, 19.0 pmol, 17% yield,

[0686] 99.5% purity) as an off-white gum. 'H NMR (400 MHz, CD3OD) 8 = 7.72 (d, J= 2.4 Hz, 1H), 7.52 (d, J= 2.4 Hz, 1H), 7.31 (dd, J= 1.2, 7.6 Hz, 1H), 7.20 - 7.14 (m, 1H), 7.13 -7.08 (m, 1H), 6.92 (t, J= 8.4 Hz, 1H), 6.86 (d, J= 2.4 Hz, 1H), 6.61 (dd, J= 1.2, 8.4 Hz, 1H), 6.56 - 6.48 (m, 1H), 6.28 (d, J= 2.4 Hz, 1H), 5.44 (dd, J= 4.8, 8.8 Hz, 1H), 3.87 (s, 3H), 3.59 - 3.36 (m, 2H), 3.12 (br d, J= 6.8 Hz, 2H), 3.02 - 2.84 (m, 2H), 2.76 (td, J =

[0687] 7.6, 15.2 Hz, 1H), 2.23 - 2.15 (m, 3H), 2.14 - 1.93 (m, 4H), 1.92 - 1.84 (m, 4H), 1.69 -1.44 (m, 2H); LCMS [M+l]+= 519.3.

[0688] General Scheme 5-12

[0689]

[0690] Example 5-16 (5)-A-(2-chloro-3-((l-methyl-lH-pyrazol-4-yl)(piperidin-4- yl)methoxy)phenyl)benzofuran-7-amine

[0691]

[0692] Step 1: A mixture of tert-butyl 4-formylpiperidine-l -carboxylate (10 g, 46.9 mmol, 1.00 eq) and 4-iodo-l -methyl- LH-pyrazole (11.7 g, 56.3 mmol, 1.20 eq) in tetrahydrofuran (100 mL) was degassed and purged with nitrogen 3 times. After addition, the mixture was stirred at -78 °C for 10 mins, and then n-butyllithium (2.5 M, 37.5 mL, 2.00 eq) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 1 hour under nitrogen atmosphere. The reaction mixture was quenched by addition ammonium chloride aqueous solution (100 mL) at 0 °C under nitrogen, and then diluted with water (100 mL) and extracted with the mixed solvent (chloroform: isopropyl alcohol=4:l) (200 mL x 3). The combined organic layers were washed with brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase HPLC (0.1% FA condition) to give tert-butyl 4-(hydroxy(l-methyl-lH-pyrazol-4-yl)methyl)piperidine-l-carboxylate (2.75 g, 8.38 mmol, 18% yield) as an orange oil. 'H NMR (400 MHz, CDC13) 8 = 7.41 (s, 1H), 7.30 (s, 1H), 4.43 (d, J= 7.2 Hz, 1H), 4.27 - 4.04 (m, 2H), 3.89 (s, 3H), 2.79 - 2.57 (m, 2H), 1.92 (br d, J= 13.2 Hz, 2H), 1.72 (td, J= 4.0, 7.6 Hz, 1H), 1.46 - 1.44 (m, 9H), 1.37 - 1.04 (m, 3H) Step 2: To a solution of tert-butyl 4-(hydroxy(l-methyl-lH-pyrazol-4-yl)methyl)piperidine-l -carboxylate (2.75 g, 9.31 mmol, 1.00 eq), Intermediate AA (2.42 g, 9.31 mmol, 1.00 eq), triphenylphosphine (3.66 g, 14.0 mmol, 1.50 eq) and A, N, N, N-tetramethylazodicarboxamide (2.40 g, 14.0 mmol, 1.50 eq) in toluene (30.0 mL) was degassed and purged with nitrogen for 3 times, the mixture was stirred at 60 °C for 2 hours under nitrogen atmosphere. The reaction mixture was diluted with water 50 mL and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with brine (50.0 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase / vc -HPLC (0.1% Formic acid condition) to give tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l -methyl- lH-pyrazol-4-yl)methyl)piperidine-l -carboxylate (1.65 g, 2.92 mmol, 31% yield) as a yellow oil.1H NMR (400 MHz, CDC13) 8 = 7.63 (d, J= 2.0 Hz, 1H), 7.44 (s, 1H), 7.31 - 7.27 (m, 2H), 7.25 - 7.14 (m, 2H), 6.98 - 6.91 (m, 1H), 6.88 -6.83 (m, 1H), 6.81 (d, J= 2.0 Hz, 1H), 6.51 (s, 1H), 6.39 (d, J= 8.0 Hz, 1H), 5.01 (br d, J = 6.0 Hz, 1H), 4.18 (br s, 2H), 3.87 (s, 3H), 2.71 (br d, J= 12.0 Hz, 2H), 2.05 (br s, 1H), 1.66 (br d, J = 12.4 Hz, 2H), 1.47 (s, 9H), 1.43 - 1.38 (m, 1H), 1.33 (br dd, J= 4.4, 12.7 Hz, 1H); LCMS [M+23]+= 559.3

[0693] Step 3: To a solution of tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-methyl-lH-pyrazol-4-yl)methyl)piperidine-l -carboxylate (1.35 g, 2.51 mmol, 1.00 eq in dichloromethane (7.00 mL) was added trifluoroacetic acid (2.07 g, 18.2 mmol, 1.35 mL, 7.23 eq) dissolve in dichloromethane (7 mL) dropwise at 0 °C and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with dichloromethane 10.0 mL and added sodium bicarbonate solution (15.0 mL) to adjust pH =7. Then the mixture was extracted with dichloromethane (50.0 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude N-(2-chloro-3-((l-methyl-lH-pyrazol-4-yl)(piperidin-4-yl)methoxy)phenyl)benzofuran-7-amine (1.26 g, crude) as a yellow oil. LCMS [M+1]+= 437.2.

[0694] Step 4: A mixture of N-(2-chloro-3-((l-methyl-lH-pyrazol-4-yl)(piperidin-4-yl)methoxy)phenyl)benzofuran-7-amine (600 mg, 1.37 mmol, 1.00 eq and cyclobutanecarbaldehyde (173 mg, 2.06 mmol, 1.50 eq in N, A-dimethylformamide (6.00 mL) was stirred at 25 °C for 10 mins. Ant then sodium triacetoxyborohydride (436 mg, 2.06 mmol, 1.50 eq was added to the mixture and stirred at 25 °C for 50 mins. The reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with brine (30.0 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150x25 mmx 10 pm; mobile phase: [water (Formic acid)-ACN]; gradient: 24%-54% B over 10 minutes) to give 51332-6 (122 mg, 232 pmol, 17% yield) as a light yellow solid. 'H NMR (400 MHz, CDC13) 6 = 7.63 (d, J= 2.0 Hz, 1H), 7.45 (s, 1H), 7.32 - 7.28 (m, 2H), 7.24 - 7.14 (m, 2H), 6.98 - 6.90 (m, 1H), 6.85 (d, J= 7.2 Hz, 1H), 6.80 (d, J= 2.0 Hz, 1H), 6.48 (s, 1H), 6.38 (d, J= 7.2 Hz, 1H), 4.98 (d, J= 7.0 Hz, 1H), 3.86 (s, 3H), 3.41 - 3.28 (m, 2H), 2.85 -2.69 (m, 3H), 2.52 - 2.32 (m, 3H), 2.31 - 2.23 (m, 2H), 2.15 (br d, J= 8.8 Hz, 2H), 1.84 - 1.74 (m, 6H); LCMS [M+l]+= 505.3.

[0695] Step 5: The residue was further separated by SFC (column: DAICEL CHIRALPAK AD(250mmx30mm,10um);mobile phase: [CO2-EtOH(0.1%NH3H2O)]; B%: 50%, isocratic elution mode) to give (S)-N-(2-chl oro-3 -((l-(cy cl obutylmethyl)piperidin-4-yl)(l-methyl-lH-pyrazol-4-yl)methoxy)phenyl)benzofuran-7-amine (12.4 mg, 24.4 pmol, 10% yield, 99.2% purity) as an off-white solid. 'HNMR (400 MHz, CDC13) 6 = 7.63 (d, J= 2.0 Hz, 1H), 7.44 (s, 1H), 7.29 (s, 2H), 7.24 - 7.14 (m, 2H), 6.98 - 6.91 (m, 1H), 6.88 -6.83 (m, 1H), 6.80 (d, J= 2.0 Hz, 1H), 6.50 (s, 1H), 6.40 (d, J= 8.0 Hz, 1H), 4.98 (br d, J = 6.8 Hz, 1H), 3.85 (s, 3H), 3.19 - 2.91 (m, 2H), 2.68 - 2.43 (m, 3H), 2.25 - 1.97 (m, 6H), 1.95 - 1.87 (m, 2H), 1.81 (br d, J= 8.8 Hz, 1H), 1.72 (br d, J= 9.2 Hz, 2H), 1.34 - 1.25 (m, 2H); LCMS [M+l]+= 505.3

[0696] General Scheme 5-13

[0697]

[0698] Intermediate DG

[0699] Step 1: To a solution of tert-butyl 4-formylpiperidine-l -carboxylate (200 mg, 938 pmol, 1.00 eq.) in tetrahydrofuran (4.00 mL) was added dropwise z-PrMgCl-LiCl (1.30 M, 866 pL, 1.20 eq.) at -78 °C. After addition, the mixture was stirred at this temperature for 0.5 hours, and then 2-iodopyrimidine (232 mg, 1.13 mmol, 1.20 eq.) in tetrahydrofuran (4.00 mL) was added dropwise at 20 °C. The resulting mixture was stirred at 20 °C for 12 hours. After completion the reaction mixture was quenched with ammonium chloride (aq., 2.00 mL) and diluted with ethyl acetate (45.0 mL). The resulting mixture was washed with brine (50.0 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiC>2, petroleum ether / ethyl acetate =0:1) to give tert-butyl 4-(hydroxy(pyrimidin-2-yl)methyl)piperidine-l -carboxylate (100 mg, 307 pmol, 33% yield) as an orange solid. LCMS [M-55]+= 238.0

[0700] Step 2: A mixture of tert-butyl 4-(hydroxy(pyrimidin-2-yl)methyl)piperidine-l-carboxylate (90.0 mg, 307 pmol, 1.00 eq.), TosCl (87.7 mg, 460 pmol, 1.50 eq.), TEA (93.1 mg, 920 pmol, 128 pL, 3.00 eq.) in dichloromethane (0.500 mL) was stirred at 25 °C for 1 hour. After completion the reaction mixture was cooled to 25 °C and diluted with ethyl acetate (30.0 mL). The resulting mixture was washed with brine (15.0 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiO2, dichloromethane: methyl alcohol = 20:1) to give tert-butyl 4-(pyrimidin-2-yl(tosyloxy)methyl)piperidine-l -carboxylate (50.0 mg, 112 pmol, 36% yield) as a yellow solid. LCMS [M-55]+= 392.1.

[0701] Step 3: A mixture of tert-butyl 4-(pyrimidin-2-yl(tosyloxy)methyl)piperidine-l-carboxylate (50.0 mg, 112 pmol, 1.00 eq.), Intermediate AA (43.5 mg, 168 pmol, 1.50 eq.) and potassium carbonate (61.8 mg, 447 pmol, 4.00 eq.) in DMF (0.500 mL)was stirred at 80 °C for 12 hours. After completion the reaction mixture was cooled to 25 °C and diluted with ethyl acetate (30.0 mL). The resulting mixture was washed with brine (15.0 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether: ethyl acetate = 5: 1) to give Intermediate DG (50.0 mg, 74.8 pmol, 67% yield) as a red solid. LCMS [M-55]+= 479.2.

[0702] Example 5-17

[0703] N-(2-chloro-3-(piperidin-4-yl(pyrimidin-2-yl)methoxy)phenyl)benzofuran-7-amine

[0704]

[0705] Step 4: To a solution of Intermediate DG (50.0 mg, 93.5 pmol, 1.00 eq.) in dichloromethane (0.500 mL) was added trifluoroacetic acid (107 mg, 935 pmol, 69.4 pL, 10.0 eq.). The mixture was stirred at 25 °C for 1 hour after completion the reaction mixture was cooled to 25 °C and diluted with ethyl acetate (30.0 mL), the resulting mixture was washed with brine (15.0 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiO2, dichloromethane: methanol = 10: 1) and then further purified by prep-HPLC (FA condition, column: Phenomenex Luna Cl 8 150 x 25 mm x 10 pm; mobile phase: [water (Formic acid)-ACN]; B%: 20%-50%, 9 min) to give N-(2-chl oro-3 -(piperidin-4-yl(pyrimidin-2-yl)methoxy)phenyl)benzofuran-7-amine (9.90 mg, 22.6 pmol, 24% yield) as a light yellow solid.JH NMR (400 MHz, DMSO-d6) d = 8.86 (d, J = 4.8 Hz, 2H), 8.40 (s, 1H), 7.91 (d, J= 2.0 Hz, 1H), 7.62 (s, 1H), 7.46 (t, J= 4.8 Hz, 1H), 7.35 (d, = 7.6 Hz, 1H), 7.17 (t, J= 7.6 Hz, 1H), 7.05 (d, = 7.6 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 6.85 (t, J= 8.4 Hz, 1H), 6.26 (br d, J = 8.4 Hz, 2H), 5.15 (d, J = 6.8 Hz, 1H), 3.28 - 3.08 (m, 2H), 2.84 - 2.62 (m, 2H), 2.46 - 2.30 (m, 2H), 2.07 - 1.95 (m, 1H), 1.69 -1.49 (m, 2H), 1.38 (br d, J= 12.4 Hz, 1H); LCMS [M+l]+= 435.2.

[0706] General Scheme 5-14

[0707]

[0708] Example 5-18

[0709] (5)-N-(2-chloro-3-(piperidin-4-yl(pyrimidin-2-yl)methoxy)phenyl)benzofuran-7-amine

[0710]

[0711] Step 1: Intermediate DG (70.0 mg, 105 pmol, 1.00 eq.) was purified by prep-SFC (column: DAICEL CHIRALCEL OD(250mm x 30mm,10um);mobile phase: [CO2-MeOH(0.1%NH3H2O)]; B%:40%, isocratic elution mode) to give tert-butyl (S)-4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(pyrimidin-2-yl)methyl)piperidine-l-carboxylate (25.0 mg, 46.7 pmol, 36% yield) as a white solid. LCMS [M-55]+= 479.2.

[0712] Step 2: To a solution of tert-butyl (S)-4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(pyrimidin-2-yl)methyl)piperidine-l -carboxylate (25.0 mg, 46.7 pmol, 1.00 eq.) in dichloromethane (0.500 mL) was added trifluoroacetic acid (53.3 mg, 467 pmol, 10.0 eq.). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was cooled to 25 °C and diluted with ethyl acetate (30.0 mL), the resulting mixture was washed with brine (15.0 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiC>2, dichloromethane: methanol = 10: 1) and then further purified by prep-HPLC (Formic acid condition, column: Phenomenex Luna C18 150 × 25 mm × 10 μm; mobile phase: [water (Formic acid)-ACN]; B%: 20%-50%, 9 min) to give (S)-N-(2-chl oro-3 -(piperidin-4-yl(pyrimidin-2-yl)methoxy)phenyl)benzofuran-7-amine (12 mg, 27.56 pmol, 59% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 6 = 8.86 (d, J= 4.8 Hz, 2H), 8.40 (s, 1H), 7.91 (d, J= 2.0 Hz, 1H), 7.62 (s, 1H), 7.46 (t, J= 4.8 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.17 (t, J= 7.6 Hz, 1H), 7.05 (d, J= 7.6 Hz, 1H), 6.95 (d, J= 2.0 Hz, 1H), 6.85 (t, J= 8.4 Hz, 1H), 6.26 (br d, J= 8.4 Hz, 2H), 5.15 (d, J= 6.8 Hz, 1H), 3.28 - 3.08 (m, 2H), 2.84 - 2.62 (m, 2H), 2.46 - 2.30 (m, 2H), 2.07 - 1.95 (m, 1H), 1.69 - 1.49 (m, 2H), 1.38 (br d, J= 12.4 Hz, 1H); LCMS [M+l]+= 435.2.

[0713] Example 5-19

[0714] (A)-N-(2-chloro-3-(piperidin-4-yl(pyrimidin-2-yl)methoxy)phenyl)benzofuran-7-amine

[0715]

[0716] Step 1: Intermediate DG (70.0 mg, 105 pmol, 1.00 eq.) was purified by prep-SFC (column: DAICEL CHIRALCEL OD(250mm x 30mm,10um);mobile phase: [CO2-MeOH(0.1%NH3H2O)]; B%:40%, isocratic elution mode) to give tert-butyl (S)-4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(pyrimidin-2-yl)methyl)piperidine-l-carboxylate (25.0 mg, 46.7 pmol, 36% yield) as a white solid. LCMS [M-55]+= 479.2 Step 2: To a solution of tert-butyl (S)-4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(pyrimidin-2-yl)methyl)piperidine-l -carboxylate (22.0 mg, 41.1 pmol, 1.00 eq.) in dichloromethane (0.500 mL) was added trifluoroacetic acid (46.9 mg, 411 pmol, 30.5 pL, 10.0 eq.). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with ethyl acetate (30.0 mL), the resulting mixture was washed with brine (15.0 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCh, dichloromethane: methanol = 10: 1) and then further purified by prep-HPLC (Formic acid condition, column: Phenomenex Luna Cl 8 150 x 25 mm x 10 pm; mobile phase: [water (Formic acid)-ACN]; B%: 20%-50%, 9 min) to give (R)-N-(2-chl oro-3 -(piperidin-4-yl(pyrimidin-2-yl)methoxy)phenyl)benzofuran-7-amine (12.0 mg, 27.3 pmol, 66% yield) as a white solid. 'HNMR (400 MHz, DMSO-d6) 6 = 8.86 (d, J= 4.8 Hz, 2H), 8.40 (s, 1H), 7.91 (d, J= 2.0 Hz, 1H), 7.62 (s, 1H), 7.46 (t, J= 4.8 Hz, 1H), 7.35 (d, J= 7.6 Hz, 1H), 7.17 (t, J= 7.6 Hz, 1H), 7.05 (d, J= 7.6 Hz, 1H), 6.95 (d, J= 2.0 Hz, 1H), 6.85 (t, J = 8.4 Hz, 1H), 6.26 (br d, J= 8.4 Hz, 2H), 5.15 (d, J= 6.8 Hz, 1H), 3.28 - 3.08 (m, 2H), 2.84 - 2.62 (m, 2H), 2.46 - 2.30 (m, 2H), 2.07 - 1.95 (m, 1H), 1.69 - 1.49 (m, 2H), 1.38 (br d, J= 12.4 Hz, 1H); LCMS [M+l]+= 435.2.

[0717] General Scheme 5-15

[0718]

[0719] Intermediate DH

[0720] Step 1: To a solution of (S)-pyrrolidin-3-ol (2.00 g, 22.9 mmol, 1.86 mL, 1.00 eq. in DMF (10.0 mL) was added dropwise Diisopropylethylamine (5.93 g, 45.9 mmol, 8.00 mL, 2.00 eq.) at 0 °C over 0.5 hour and then 2,4-dibromopyrimidine (5.46 g, 22.96 mmol, 1.00 eq.) in DMF (10.0 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 1.5 hour. The residue was diluted with water 80 mL and extracted with ethyl acetate (100 mL x 5). The combined organic layers were washed with salt solution (50 mL x 4), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a (S)-l-(2-bromopyrimidin-4-yl)pyrrolidin-3-ol (6.00 g, 17.2 mmol, 75% yield, 70% purity) as a white solid. LCMS [M+l]+= 243.9

[0721] Step 2: To a solution of (S)-l-(2-bromopyrimidin-4-yl)pyrrolidin-3-ol (6.00 g, 24.5 mmol, 1.00 eq.) in dichloromethane (50.0 mL) was added tert-butyldimethylsilyl chloride (5.56 g, 36.8 mmol, 4.54 mL, 1.50 eq.) and imidazole (5.02 g, 73.7 mmol, 3.00 eq.). The mixture was stirred at 25 °C for 2 hours The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=10 / l to 3 / 1) to give (S)-2-bromo-4-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)pyrimidine (6.60 g, 17.8 mmol, 73% yield, 97.1% purity) as a white solid. LCMS [M+l]+= 358.1.

[0722] Step 3: To a solution of (S)-2-bromo-4-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)pyrimidine (4.00 g, 11.2 mmol, 1.00 eq.) in tetrahydrofuran (50.0 mL) was added dropwise w-butyllithium (2.5 M, 6.70 mL, 1.50 eq.) at -78 °C. After addition, the mixture was stirred at this temperature for 1 hour, and then tert-butyl 4-formylpiperidine-l-carboxylate (3.57 g, 16.7 mmol, 1.50 eq.) in tetrahydrofuran (10.0 mL) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 1 hour. The reaction mixture was quenched by addition ammonium chloride 20 mL at 0 °C, and then diluted with water 40.0 mL and extracted with (100 mL x 3). The combined organic layers were washed with salt solution (50 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 1 / 2) to give tertbutyl 4-((4-((S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)pyrimidin-2-yl)(hydroxy)methyl)piperidine-l -carboxylate (4.20 g, 5.97 mmol, 53% yield, 70.1% purity) as a white solid. LCMS [M+l]+= 493.4.

[0723] Step 4: A mixture of tert-butyl 4-((4-((S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)pyrimidin-2-yl)(hydroxy)methyl)piperidine-l -carboxylate (1.00 g, 2.03 mmol, 1.00 eq.), l-bromo-2-chl oro-3 -fluoro-benzene (467 mg, 2.23 mmol, 1.10 eq), potassium tert-butoxide (455 mg, 4.06 mmol, 2.00 eq.) in tetrahydrofuran (15.0 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 60 °C for 2 hours under nitrogen atmosphere. The residue was diluted with water 30 mL and extracted with ethyl acetate (30.0 mL x 3). The combined organic layers were washed with salt solution (20.0 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 1 / 1) to give tert-butyl 4-((3-bromo-2-chlorophenoxy)(4-((S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)pyrimidin-2-yl)methyl)piperidine-l -carboxylate (340 mg, 408 pmol, 20% yield, 82.2% purity) as a white solid. LCMS [M+l]+= 683.2.

[0724] Step 5: A mixture of tert-butyl 4-((3-bromo-2-chlorophenoxy)(4-((S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin- 1 -yl)pyrimidin-2-yl)methyl)piperidine- 1 -carboxylate (340 mg, 498.42 pmol, 1.00 eq.), benzofuran-7-amine (132.73 mg, 996.83 pmol, 2.00 eq.), BrettPhos Pd G3 (45.18 mg, 49.84 pmol, 0.100 eq.) and cesium carbonate (487.18 mg, 1.50 mmol, 3.00 eq.) in dioxane (10 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 90 °C for 1 hour under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 2: 1) to give Intermediate DH (305 mg, 374 pmol, 75% yield, 90.2% purity) as a white solid. LCMS [M+l]+= 734.9.

[0725] Example 5-20

[0726] (5)-l-(2-((A)-(3-(benzofuran-7-ylamino)-2-chlorophenoxy)(piperidin-4- yl)methyl)pyrimidin-4-yl)pyrrolidin-3-ol

[0727]

[0728] Step 6: A mixture of Intermediate DH (305 mg, 415 pmol, 1.00 eq.) cesium fluoride (630.86 mg, 4.15 mmol, 10.0 eq.) in N. A-Dimethylformamide (5.00 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 25 °C for 12 hours under nitrogen atmosphere. The residue was diluted with water 20 mL and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with salt solution (30 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(4-((S)-3-hydroxypyrrolidin-l-yl)pyrimidin-2-yl)methyl)piperidine-l -carboxylate (252 mg, 371 pmol, 89% yield, 91.5% purity) as a white solid.

[0729] Step 7: To a solution of tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(4-((S)-3-hydroxypyrrolidin-l-yl)pyrimidin-2-yl)methyl)piperidine-l -carboxylate (250 mg, 403 pmol, 1.00 eq.) in dichloromethane (3.00 mL) was added Trifluoroacetic Acid (229 mg, 2.02 mmol, 149 pL, 5.00 eq.), the mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (Formic acid condition; column: Phenomenex luna C18 150×25mm× 10 μm; mobile phase: [water (Formic acid)-ACN];gradient:15%-35% B over 10 min) to give (3S)-l-(2-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(piperidin-4-yl)methyl)pyrimidin-4-yl)pyrrolidin-3-ol (140 mg, 266 pmol, 66% yield, 99.1% purity) as a white solid. LCMS [M+l]+= 520.3.

[0730] Step 8: (3 S)- 1 -(2-((3 -(benzofuran-7-ylamino)-2-chlorophenoxy)(piperidin-4-yl)methyl)pyrimidin-4-yl)pyrrolidin-3-ol was further separated by SFC (condition: column: DAICEL CHIRALPAK IG (250mmx30mm,10um); mobile phase: [CO2-ACN / i-PrOH (0.1%IPAm)]; B%:55%, isocratic elution mode) to give (S)-l-(2-((S)-(3-(benzofuran-7-ylamino)-2-chlorophenoxy)(piperidin-4-yl)methyl)pyrimidin-4-yl)pyrrolidin-3-ol (5.35 mg, 10.3 pmol, 4% yield, 97.5% purity) was obtained as a white solid.XH NMR (400 MHz, CDC13) 6 ppm 1.26 (s, 1 H) 1.38 - 1.68 (m, 4 H) 2.07 - 2.19 (m, 3 H) 2.29 - 2.40 (m, 1 H) 2.57 - 2.72 (m, 2 H) 3.06 - 3.20 (m, 2 H) 3.36 - 3.84 (m, 4 H) 4.62 (br s, 1 H) 4.88 (d, J=7.2 Hz, 1 H) 6.15 (br d, J=5.6 Hz, 1 H) 6.45 (d, J=8.0 Hz, 1 H) 6.53 (s, 1 H) 6.79 (d, J=2.0 Hz, 1 H) 6.82 - 6.86 (m, 1 H) 6.90 (d, J=8.0 Hz, 1 H) 7.16 (d, J=7.6 Hz, 1 H) 7.20 - 7.23 (m, 1 H) 7.25 (s, 1 H) 7.63 (d, J=2.0 Hz, 1 H) 8.18 (d, J=6.0 Hz, 1 H). LCMS [M+l]+= 520.3.

[0731] General Scheme 5-16

[0732]

[0733] Example 5-21

[0734] l-(2-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-(cyclobutylmethyl)piperidin-4- yl)methyl)pyrimidin-4-yl)pyrrolidin-3-ol

[0735] Step 1: To a solution of Intermediate DH (307 mg, 418 pmol, 1.00 eq) in

[0736] dichloromethane (6.00 mL) was added trifluoroacetic acid (461 mg, 4.04 mmol, 0.300

[0737] mL, 9.66 eq dropwise and the mixture was stirred at 25 °C for 1 hour under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to remove the solvents. The reaction mixture was quenched by addition sodium bicarbonate solution to adjust pH=7, and then extracted with dichloromethane (10.0 mL x 3). The combined

[0738] organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude N-(3-((4-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)pyrimidin-2-yl)(piperidin-4-yl)methoxy)-2-chlorophenyl)benzofuran-7-amine (215

[0739] mg, crude) as a yellow oil. LCMS [M+l]+= 634.4

[0740] Step 2: A mixture of N-(3-((4-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)pyrimidin-2-yl)(piperidin-4-yl)methoxy)-2-chlorophenyl)benzofuran-7-amine (215 mg, 339 pmol,

[0741] 1.00 eq) and cyclobutanecarbaldehyde (31.4 mg, 377 pmol, 1.10 eq inN, N-dimethylformamide (3.00 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 25 °C for 10 minutes under nitrogen atmosphere. Then

[0742] sodium triacetoxyborohydride (79.0 mg, 373 pmol, 1.10 eq) was added to the mixture and stirred at 25 °C for 50 minutes. The reaction mixture was quenched by addition

[0743] ammonium chloride solution (20.0 mL) at 0 °C, and then extracted with ethyl acetate

[0744] (20.0 mL x 3). The combined organic layers were washed with brine (20.0 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude

[0745] product N-(3-((4-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)pyrimidin-2-yl)(l- (cyclobutylmethyl)piperidin-4-yl)methoxy)-2-chlorophenyl)benzofuran-7-amine (215

[0746] mg, crude) as a brown oil. LCMS [M+l]+= 702.7

[0747] Step 3: To a solution of N-(3-((4-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)pyrimidin-2-yl)(l-(cyclobutylmethyl)piperidin-4-yl)methoxy)-2-chlorophenyl)benzofuran-7-amine (215 mg, 306 pmol, 1.00 eq in DMF (2.50 mL) was added cesium fluoride (465 mg, 3.06 mmol, 10.0 eq) and the mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water 10.0 mL and extracted with ethyl acetate (10.0 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. Then the mixture was dissolved in DMF (2.00 mL). The residue was purified by prep-HPLC (column:

[0748] Phenomenex luna C18 150x25 mmx 10 pm; mobile phase: [water(Formic acid)-ACN];gradient:12%-42% B over 10 min) to give compound 1-(2-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(1-(cyclobutylmethyl)piperidin-4-yl)methyl)pyrimidin-4-yl)pyrrolidin-3-ol (63.7 mg, 107 pmol, 35% yield, 99% purity) as a white solid. 'H NMR (400 MHz, CDC13) 8 = 8.47 (s, 1H), 8.16 (dd, J= 3.2, 6.0 Hz, 1H), 7.63 (d, J= 2.0 Hz, 1H), 7.25 (br s, 1H), 7.23 - 7.12 (m, 2H), 6.95 - 6.88 (m, 1H), 6.87 - 6.83 (m, 1H), 6.80

[0749] (d, J= 2.4 Hz, 1H), 6.51 (s, 2H), 6.16 (br d, J = 5.2 Hz, 1H), 4.93 (br d, J = 6.8 Hz, 1H), 4.61 (br s, 1H), 3.65 - 3.52 (m, 2H), 3.34 - 3.20 (m, 2H), 2.73 (br s, 4H), 2.48 - 2.24 (m, 7H), 1.99 - 1.89 (m, 3H), 1.86 - 1.69 (m, 6H); LCMS [M+l]+= 588.5.

[0750] General Scheme 5-19

[0751]

[0752] Example 5-22

[0753] 2-((2-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-(cyclobutylmethyl)piperidin-4- yl)methyl)pyrimidin-4-yl)oxy)ethan- 1 -ol Step 1: To a solution of ethylene glycol (13.1 mg, 211 pmol, 11.8 pL, 1.20 e.) inN, N-dimethylformamide (0.500 mL) was added dropwise sodium hydride (8.43 mg, 211 pmol, 60% dispersion in mineral oil, 1.20 eq.) at 0 °C. After addition, the mixture was stirred at this temperature for 30 min, and then Intermediate CA (100 mg, 175 pmol, 1.00 eq.) in N, N-dimethylformamide (1.00 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with water (20.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The combined organic layers were washed with brine (50.0 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCh, petroleum ether / ethyl acetate=2 / l) to give tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(4-(2-hydroxyethoxy)pyrimidin-2-yl)methyl)piperidine-l -carboxylate (100 mg, 168 pmol, 96% yield) as a white solid. LCMS [M+l]+= 595.3.

[0754] Step 2: To a solution of tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(4-(2-hydroxyethoxy)pyrimidin-2-yl)methyl)piperidine-l -carboxylate (50 mg, 84.0 pmol, 1.00 eq.) in dichloromethane (1.00 mL) was added trifluoroacetic acid (307 mg, 2.69 mmol, 0.200 mL, 32.0 eq.). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give crude 2-((2-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(piperidin-4-yl)methyl)pyrimidin-4-yl)oxy)ethan-l-ol, which was used for the next step without further purification. LCMS [M+l]+= 495.2.

[0755] Step 3: To a solution of 2-((2-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(piperidin-4-yl)methyl)pyrimidin-4-yl)oxy)ethan-l-ol (30.0 mg, 60.6 pmol, 1.00 eq.) in DMF (1.00 mL) was added dropwise to sodium triacetoxyborohydride (15.4 mg, 72.7 pmol, 1.20 eq.) at 25 °C. After the addition was complete, the mixture was stirred at this temperature for 10 min and then cyclobutanecarbaldehyde (6.12 mg, 72.7 pmol, 1.20 eq.) was added dropwise at 25 °C. The resulting mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered, concentrated and purified by prep-HPLC (column: Phenomenex luna C18 150 x 25mm x 10 urn; mobile phase: [water(Formic acid)-ACN];gradient:22%-52% B over 10 min) to give 2-((2-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-(cyclobutylmethyl)piperidin-4-yl)methyl)pyrimidin-4-yl)oxy)ethan-l-ol (20.4 mg, 35.8 pmol, 59% yield, 99% purity) as a yellow solid.1H NMR (400 MHz, CD3OD) δ = 8.54 (br s, 1H), 8.45 (d, J= 6.0 Hz, 1H), 7.72 (d, J= 2.0 Hz, 1H), 7.31 (dd, J= 1.2, 7.6 Hz, 1H), 7.21 - 7.09 (m, 2H), 6.90 - 6.83 (m, 2H), 6.80 (d, J= 6.0 Hz, 1H), 6.58 (dd, J= 1.2, 8.4 Hz, 1H), 6.29 (dd, J= 1.2, 8.4 Hz, 1H), 5.19 (d, J= 6.0 Hz, 1H), 4.51 - 4.36 (m, 2H), 3.89 - 3.73 (m, 2H), 3.46 (br dd, J= 13.6, 16.4 Hz, 2H), 3.06. (d, J= 7.2 Hz, 2H), 2.95 -2.82 (m, 2H), 2.76 (td, J= 7.6, 15.2 Hz, 1H), 2.54 - 2.43 (m, 1H), 2.23 - 2.13 (m, 3H), 2.07 - 1.95 (m, 2H), 1.93 - 1.77 (m, 5H); LCMS [M+l]+= 563.3.

[0756] General Scheme 5-18

[0757]

[0758] Example 5-23

[0759] N-(2-chl oro-3 -((l-(cy cl obutylmethyl)piperidin-4-yl)(4-methylpyrimidin-2- yl)methoxy)phenyl)benzofuran-7-amine

[0760] Step 1: A mixture of Intermediate CA (250 mg, 439 pmol, 1.00 eq.), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (551 mg, 2.19 mmol, 614 pL, 50% purity, 5.00 eq.), Pd(dppf)C12 (64.2 mg, 87.8 pmol, 0.200 eq.) and potassium carbonate (121 mg, 878 pmol, 2.00 eq.) in dioxane (2.00 mL) was degassed and purged with nitrogen for 3 times, then the mixture stirred at 80 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was quenched with water (20.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The combined organic layers were washed with brine (50.0 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated and purified by prep-TLC (SiCh, petroleum ether / ethyl acetate=2 / l) to give tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(4-methylpyrimidin-2-yl)methyl)piperidine-l -carboxylate (220 mg, 401 pmol, 91% yield) as a white solid. LCMS [M-55]+= 493.2.

[0761] Step 2: To a solution of tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(4-methylpyrimidin-2-yl)methyl)piperidine-l -carboxylate (60.0 mg, 109 pmol, 1.00 eq.) in dichloromethane (1.00 mL) was added trifluoroacetic acid (307 mg, 2.69 mmol, 0.200 mL, 24.6 eq.). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give crude N-(2-chl oro-3 -((4-methylpyrimidin-2-yl)(piperidin-4-yl)methoxy)phenyl)benzofuran-7-amine, which was used for the next step without further purification. LCMS [M+l]+= 499.2. Step 3: To a solution of N-(2-chl oro-3 -((4-m ethylpyrimidin-2 -yl)(piperidin-4-yl)methoxy)phenyl)benzofuran-7-amine (40 mg, 89.1 pmol, 1.00 eq.) inN, N-dimethylformamide (1.00 mL) was added dropwise sodium borohydride acetate (28.3 mg, 134 pmol, 1.50 eq.) at 25 °C. After addition, the mixture was stirred at this temperature for 10 mins and then cyclobutanecarbaldehyde (11.2 mg, 134 pmol, 1.50 eq.) was added dropwise at 25 °C. The resulting mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered, concentrated and purified by prep-HPLC (column: Phenomenex luna C18 150 × 25mm × 10 um; mobile phase: [water (FA)-ACN]; gradient: 24%-54% B over 10 mins) to give N-(2-chl oro-3 -((l-(cy cl obutylmethyl)piperidin-4-yl)(4-methylpyrimidin-2-yl)methoxy)phenyl)benzofuran-7-amine (11.1 mg, 21.3 pmol, 24% yield, 99% purity) as a white solid.1H NMR (400 MHz, CD3OD) δ = 8.65 (d, J = 5.1 Hz, 1H), 8.54 (br s, 1H), 7.73 (d, J= 2.0 Hz, 1H), 7.36 - 7.30 (m, 2H), 7.22 - 7.11 (m, 2H), 6.91 - 6.83 (m, 2H), 6.60 (dd, J= 0.8, 8.4 Hz, 1H), 6.28 - 6.22 (m, 1H), 5.18 (d, J= 6.4 Hz, 1H), 3.60 - 3.43 (m, 2H), 3.13 (br d, J= 7.2 Hz, 2H), 2.96 (q, J= 12.0 Hz, 2H), 2.79 (td, J= 7.2, 14.8 Hz, 1H), 2.57 (s, 3H), 2.55 - 2.46 (m, 1H), 2.31 (br d, J= 14.4 Hz, 1H), 2.25 - 2.16 (m, 2H), 2.11 - 1.96 (m, 2H), 1.94 - 1.85 (m, 4H), 1.73 (br d, J= 14.4 Hz, 1H); LCMS [M+l]+= 517.3.

[0762] General Scheme 5-19

[0763]

[0764] Example 5-24

[0765] N-(2-chloro-3-((1-(cyclobutylmethyl)piperidin-4-yl)(4-(2-methoxyethoxy)pyrimidin-2-yl)methoxy)phenyl)benzofuran-7-amine

[0766] Step 1: To a solution of 2-methoxyethanol (16.0 mg, 211 pmol, 1.20 eq.) in N, N-dimethylformamide (0.500 mL) was added dropwise sodium hydride (8.43 mg, 211 pmol, 60% dispersion in mineral oil, 1.20 eq.) at 0 °C. After addition, the mixture was stirred at this temperature for 30 min, and then Intermediate CA (100 mg, 175 pmol, 1.00 eq) in N, N-dimethylformamide (1.00 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with water (20.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The combined organic layers were washed with brine (50.0 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCh, petroleum ether / ethyl acetate=2 / l) to give tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chl orophenoxy)(4-(2 -methoxy ethoxy )pyrimidin-2-yl)methyl)piperi dine- 1 -carboxylate (100 mg, 164 pmol, 94% yield) as a white solid. LCMS [M+l]+= 609.3.

[0767] Step 2: To a solution of tert-butyl 4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(4-(2-methoxyethoxy)pyrimidin-2-yl)methyl)piperidine-l -carboxylate (50 mg, 82.1 pmol, 1.00 eq.) in dichloromethane (1.00 mL) was added trifluoroacetic acid (307 mg, 2.69 mmol, 0.200 mL, 32.8 eq.). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give crude N-(2-chl oro-3 -((4-(2-methoxyethoxy)pyrimidin-2-yl)(piperidin-4-yl)methoxy)phenyl)benzofuran-7-amine. The crude was used for the next step without further purification. LCMS [M+l]+= 509.2. Step 3: To a solution of N-(2-chloro-3-((4-(2-methoxyethoxy)pyrimidin-2-yl)(piperidin-4-yl)methoxy)phenyl)benzofuran-7-amine (30.0 mg, 58.9 pmol, 1.00 eq.) in DMF (1.00 mL) was added dropwise sodium triacetoxyborohydride (15.0 mg, 70.7 pmol, 1.20 eq.) at 25 °C. After addition, the mixture was stirred at this temperature for 10 mins and then cyclobutanecarbaldehyde (5.95 mg, 70.7 pmol, 1.20 eq.) was added dropwise at 25 °C. The resulting mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered, concentrated and purified by prep-HPLC (column: Phenomenex luna C18 150 × 25mm × 10 μm; mobile phase: [water(Formic acid)-ACN];gradient: 26%-56% B over 10 mins) to give N-(2-chloro-3-((l-(cyclobutylmethyl)piperidin-4-yl)(4-(2-methoxyethoxy)pyrimidin-2-yl)methoxy)phenyl)benzofuran-7-amine (23.6 mg, 40.4 pmol, 69 yield, 99% purity) as a yellow solid. 'H NMR (400 MHz, CD3OD) 6 = 8.55 (s, 1H), 8.44 (d, J= 6.0 Hz, 1H), 7.72 (d, J= 2.4 Hz, 1H), 7.31 (dd, J= 1.2, 7.6 Hz, 1H), 7.20 - 7.09 (m, 2H), 6.90 - 6.83 (m, 2H), 6.76 (d, J= 6.0 Hz, 1H), 6.59 (dd, J= 1.2, 8.4 Hz, 1H), 6.28 (dd, J= 1.2, 8.4 Hz, 1H), 5.16 (d, J= 6.0 Hz, 1H), 4.57 - 4.42 (m, 2H), 3.71 - 3.53 (m, 2H), 3.30 (s, 3H), 3.24 (br dd, J= 13.6, 17.2 Hz, 2H), 2.79 (d, J= 6.8 Hz, 2H), 2.68 (td, J= 7.6, 14.9 Hz, 1H), 2.59 - 2.44 (m, 2H), 2.42 - 2.29 (m, 1H), 2.22 - 2.05 (m, 3H), 2.03 - 1.92 (m, 1H), 1.90 - 1.64 (m, 6H); LCMS [M+l]+= 577.3. General Scheme 5-20

[0768]

[0769] Example 5-25

[0770] N-(2-chloro-3-((1-(cyclobutylmethyl)piperidin-4-yl)(pyrimidin-2-yl)methoxy)phenyl)benzofuran-7-amine

[0771] To a solution of Example 5-17 (20.0 mg, 45.9 pmol, 1.00 eq. cyclobutanecarbaldehyde (7.74 mg, 91.9 pmol, 2.00 e.) in methanol (2.00 mL) was added sodium

[0772] cyanoborohydride (288 pg, 4.60 pmol, 0.10 eg.) and acetic acid (276 pg, 4.60 pmol,

[0773] 2.63e-l pL, 0.1 eg.). The mixture was stirred at 25 °C for 1 hour. After completion of the reaction, the reaction was poured into water (10.0 mL) and extracted with ethyl acetate

[0774] (20.0 mL><3). The combined organic phase was washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna Cl 8 150 x 25 mm x 10 pm; mobile phase: [water (FA)-MeCN]; gradient: 22%-52% B over 9 mins) to give N-(2-chl oro-3 -((l-(cy cl obutylmethyl)piperi din-4-yl)(pyrimidin-2-yl)methoxy)phenyl)benzofuran-7-amine (6.00 mg, 11.8 pmol, 25.8% yield, 99.7% purity) as a yellow solid. 'H NMR (400 MHz, CDC13) 8 = 8.78 (d, J= 4.8 Hz, 2H), 7.62 (s, 1H), 7.27 - 7.15 (m, 3H), 6.91 - 6.83 (m, 2H), 6.80 (s, 1H), 6.51 (s, 1H), 6.34 - 6.33(m, 1H),

[0775] 5.15 (br d, J= 4.0 Hz, 1H), 3.30 - 3.12 (m, 2H), 2.80 - 2.63 (m, 3H), 2.37 - 2.33(m, 3H), 2.13 - 2.11 (m, 3H), 1.97 - 1.75 (m, 7H); LCMS [M+l]+= 503.2.

[0776] General Scheme 5-21

[0777]

[0778] Example 5-26:

[0779] N-(3-((1-((3-aminocyclopentyl)methyl)piperidin-4-yl)(1-methyl-1H-pyrazol-3-yl)methoxy)-2-chlorophenyl)benzofuran-7-amine Step 1: To a solution of Example 2-1 (50.0 mg, 114 pmol, 1.00 eq.) and (3-((tert-butoxycarbonyl)amino)cyclopentyl)methyl 4-methylbenzenesulfonate (46.5 mg, 126 pmol, 1.10 eq.) in dimethyl formamide (0.500 mL) was added cesium carbonate (74.6 mg, 229 pmol, 2.00 eq.) and sodium iodide (25.7 mg, 172 pmol, 1.50 eq.). The mixture was stirred at 50 °C for 12 hours. After completion the reaction mixture was quenched with ammonium chloride (aq., 2.00 mL) and diluted with ethyl acetate (45.0 mL). The resulting mixture was washed with brine (50.0 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiCh, petroleum ether / ethyl acetate =3:1) to give tert-butyl (3-((4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(1-methyl-1H-pyrazol-3-yl)methyl)piperidin-1-yl)methyl)cyclopentyl)carbamate (15.0 mg, 22.6 μmol, 49% yield) as a yellow oil. LCMS [M+l]+= 634.4.

[0780] Step 2: To a solution of tert-butyl (3-((4-((3-(benzofuran-7-ylamino)-2-chlorophenoxy)(l-methyl-lH-pyrazol-3-yl)methyl)piperidin-l-yl)methyl)cyclopentyl)carbamate (70.0 mg, 110 pmol, 1.00 eq.) in dichloromethane (1.00 mL) was added trifluoroacetic acid (126 mg, 1.10 mmol, 82.0 pL, 10.0 eq.). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Formic acid condition, column: Phenomenex Luna C18 150 x 25 mm x 10 pm; mobile phase: [water (Formic acid)-ACN]; B%: 11%-41%, 9 min) to give N-(3-((l-((3-aminocyclopentyl)methyl)piperidin-4-yl)(l-methyl-lH-pyrazol-3-yl)methoxy)-2-chlorophenyl)benzofuran-7-amine (12.2 mg, 22.6 pmol, 20% yield) as a white solid. 'H NMR (400 MHz, CD3OD) 6 = 8.54 (s, 1H), 7.72 (d, J= 2.0 Hz, 1H), 7.52 (d, J= 2.0 Hz, 1H), 7.30 (dd, J= 1.2, 7.5 Hz, 1H), 7.20 - 7.08 (m, 2H), 6.95 - 6.83 (m, 2H), 6.61 (dd, J= 0.8, 8.3 Hz, 1H), 6.48 (d, J= 8.4 Hz, 1H), 6.25 (d, J= 2.4 Hz, 1H), 5.12 (d, J= 7.2 Hz, 1H), 3.87 (s, 3H), 3.67 - 3.51 (m, 1H), 3.14 (br dd, J= 10.4, 12.0 Hz, 2H), 2.66 - 2.45 (m, 2H), 2.40 - 2.28 (m, 2H), 2.26 (br d, J= 11.2 Hz, 2H), 2.19 - 2.07 (m, 2H), 2.07 - 1.87 (m, 2H), 1.75 - 1.64 (m, 2H), 1.58 (br s, 2H), 1.55 (br s, 1H), 1.33 - 1.20 (m, 1H); LCMS [M+l]+= 534.4.

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

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[0789]

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[0965]

[0966] SOS1 Inhibition Assay

[0967] This Example illustrates that exemplary compounds of the present invention bind to SOS1 and prevent a labeled tracer ligand from occupying the SOS1 binding site.

[0968] The ability of a provided compounds to bind to SOS1 was measured using a HTRF displacement assay. A recombinant human SOS1 polypeptide (corresponding to amino acids 560-1049, expressed in E. Coli with N-terminal His-TEV-AviTag-SOS1 (MW=59.4 kDa) and lanthanide labeled streptavidin (CisBio) was incubated with an exemplary provided compounds (in a DMSO stock solution) in buffer (25 mM HEPES pH 7.5, 25 mM NaCl, 1 mM DTT, 0.01% Brij 35, 0.02% BSA, 0.1% DMSO). After a 10-15 minute incubation at room temperature, a solution comprised of a custom-made Cy5 labelled tracer and MAb Anti-6HIS Tb cryptate Gold (Cisbio 61HI2TLA) in buffer was added to the solution containing the SOS1 polypeptide and exemplary provided compounds. After a 1-hour incubation at room temperature, the HTRF signal was measured using Clairostar plate reader (BMG Labtech) according to the manufacturer’s instructions. Excitation filter EX-TR was used, and emission 1 was detected at 650-610 nm and emission 2 detected at 620-610 nm. The HTRF ratio was calculated using the formula: [emission 1 / emission 2]*10000.

[0969] Background signals were calculated from well with a 10pM inhibitor, known to inhibit 100% at that concentration. The background subtracted signals were converted to % binding relative to DMSO controls. Data were analyzed using XLFIT software (IDBS) using a Morrison equation for competitive binding and Ki’s were generated for provided compounds.

[0970] Thus, exemplary compounds of the present invention potently inhibited the binding of a SOS1 labeled tracer to SOS1 protein.

[0971] Table A. GDP Exchange HTRF SOS1 Assay Data

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979] GDP Exchange HTRF SOS2 Assay Data

[0980] An HTRF displacement assay was utilized to measure the amount of binding between provided compounds and SOS2. A recombinant SOS2 polypeptide (corresponding to amino acids 558-1047 with 6-His-TEV-AviTag-SOS2 (MW=61.4 kDa) and lanthanide labeled streptavidin (CisBio) was incubated with compounds (in a DMSO stock solution) in buffer (50 mM HEPES pH 7.5, 5 mM MgCl2, 0.2 mg / mL BSA, 1 mM TCEP, 1.0% DMSO, 2 nM SOS2, 100 nM GTP-Cy5). After 15 minutes of incubation at room temperature, 30 nM of KRAS4B and 0.5 nM of Terbium-Streptavidin in buffer (50 mM HEPES pH 7.5, 5 mM MgCl2, 0.2 mg / mL BSA, 1 mM TCEP, 1.0% DMSO, 30 nM of KRAS4B and 0.5 nM of Terbium-Streptavidin) was added to the solution containing the SOS2 polypeptide, tracer, and compound. After a 30-minute incubation at room temperature, the HTRF signal was measured using the Clariostar plate reader (BMG Labtech) according to the manufacturer’s instructions. Excitation filter EX-TR was used, and emission 1 was detected at 665-610 nm and emission 2 detected at 620-610 nm. The HTRF ratio was calculated using the formula: [emission 1 / emission 2]* 10000. Background signals were calculated from wells with a 10 uM inhibitor, known to inhibit 100% at that concentration. The background subtracted signals were converted to % binding relative to DMSO controls. Data was analyzed using XLFIT software (IDBS) using a Morrison equation for competitive binding and Ki’s were generated for provided compounds.

[0981] Table B

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989] MKN1 pERK In Cell Western Assay Data

[0990] To prepare assay plates for the pERK In-Cell Western (ICW) assay, cells were trypsinized, resuspended in fresh media, and viable cells were counted utilizing a Cellometer Mini (Nexcelom Bioscience, Lawrence, MA) and trypan blue exclusion. All cell lines were diluted in complete growth media and seeded at 30,000 cells / well in 96-well black walled, clear bottom assay plates (Corning Cat. #3904). PBS was added to the outer wells of each 96-well plate. Cells were incubated for 24 hours at 37 °C, 5% CO2, 100% humidity to adhere prior to treatment. MRTX0902 was serially diluted (1:3) in DMSO. A 10X dosing plate was prepared from the DMSO serial dilutions using an intermediate dilution (1: 100) into complete growth media without serum. Cells were dosed with 10 pl of the 10X intermediate drug dilutions added to the 96-well cell plates. Six vehicle (DMSO) wells were included on each assay plate. After a 30-minute drug treatment, cells were fixed by adding freshly prepared 4% formaldehyde to each well and incubated for 20 minutes at room temperature. Formaldehyde was removed and cells were permeabilized with ice-cold methanol for 30 minutes at -20 °C. Following permeabilization, methanol was removed from each well and blocking buffer (Odyssey Blocking Buffer Cat. #927-50000; LLCOR, Lincoln, NE) with 0.05% Tween-20, was added to each well and incubated for 1 hour at room temperature. Blocking buffer was removed and the pERK (Cell signaling Technology #9101L; Rabbit, 1:500 in blocking buffer) and GapDH (Millipore #MAB374; Mouse; 1:5000 in blocking buffer) primary antibodies were added and incubated overnight at 4 °C on a rocking platform. Plates were then washed three times with PBS+0.1%Tween 20 (PBST) and incubated with IRDye® 800CW Goat anti-Rabbit IgG Secondary Antibody (LI-COR Biosciences Cat. #926-32211) and IRDye® 680RD Goat anti-Mouse IgG Secondary Antibody (LI-COR Biosciences Cat. #926-68070) (1:800 in blocking buffer) for 1.5 hours at room temperature. Plates were washed three times with PBS-T and then imaged using LICOR Odyssey CLx Imaging system (LI-COR, Lincoln, NE) set to Plate Acquisition format for both the 700 and 800 wavelength channels to measure the signal intensities from each well for the IRDye® 680RD Goat anti-Mouse IgG Secondary Antibody and IRDye® 800CW Goat anti-Rabbit IgG secondary antibodies, respectively. The signal output for both channels was exported to excel for further quantitative analysis.

[0991] For the ICW assay, the fluorescence intensities for both pERK and GapDH proteins were quantified in each selected vehicle or drug-treated well. A normalized value for pERK (versus GapDH) was calculated, divided by the average fluorescence in vehicle treated wells, and multiplied by 100 to yield the “percent (%) of vehicle control” value. “Percent (%) of vehicle control” values were plotted as log(inhibitor) vs. response -Variable slope (four parameters) for curve fitting and IC50 value determination in GraphPad Prism.

[0992] Table C

[0993]

[0994]

[0995]

[0996]

[0997]

[0998]

[0999]

[1000] sp|Q07889|SOS1_HUMAN Son of sevenless homolog 1 OS=Homo sapiens OX=9606 GN=SOS1 PE=1 SV=1

[1001] Seq ID #1:

[1002] MQAQQLPYEFFSEENAPKWRGLLVPALKKVQGQVHPTLESNDDALQYVEELILQLLNMLCQAQPRSASDVEE RVQKSFPHPIDKWAIADAQSAIEKRKRRNPLSLPVEKIHPLLKEVLGYKIDHQVSVYIVAVLEYISADILKL VGNYVRNIRHYEITKQDIKVAMCADKVLMDMFHQDVEDINILSLTDEEPSTSGEQTYYDLVKAFMAEIRQYI RELNLIIKVFREPFVSNSKLFSANDVENIFSRIVDIHELSVKLLGHIEDTVEMTDEGSPHPLVGSCFEDLAE ELAFDPYESYARDILRPGFHDRFLSQLSKPGAALYLQSIGEGFKEAVQYVLPRLLLAPVYHCLHYFELLKQL EEKSEDQEDKECLKQAITALLNVQSGMEKICSKSLAKRRLSESACRFYSQQMKGKQLAIKKMNEIQKNIDGW EGKDIGQCCNEFIMEGTLTRVGAKHERHIFLFDGLMICCKSNHGQPRLPGASNAEYRLKEKFFMRKVQINDK DDTNEYKHAFEIILKDENSVIFSAKSAEEKNNWMAALISLQYRSTLERMLDVTMLQEEKEEQMRLPSADVYR FAEPDSEENIIFEENMQPKAGIPIIKAGTVIKLIERLTYHMYADPNFVRTFLTTYRSFCKPQELLSLIIERF EIPEPEPTEADRIAIENGDQPLSAELKRFRKEYIQPVQLRVLNVCRHWVEHHFYDFERDAYLLQRMEEFIGT VRGKAMKKWVESITKIIQRKKIARDNGPGHNITFQSSPPTVEWHISRPGHIETFDLLTLHPIEIARQLTLLE SDLYRAVQPSELVGSVWTKEDKEINSPNLLKMIRHTTNLTLWFEKCIVETENLEERVAVVSRIIEILQVFQE LNNFNGVLEVVSAMNSSPVYRLDHTFEQIPSRQKKILEEAHELSEDHYKKYLAKLRSINPPCVPFFGIYLTN ILKTEEGNPEVLKRHGKELINFSKRRKVAEITGEIQQYQNQPYCLRVESDIKRFFENLNPMGNSMEKEFTDY LFNKSLEIEPRNPKPLPRFPKKYSYPLKSPGVRPSNPRPGTMRHPTPLQQEPRKISYSRIPESETESTASAP NSPRTPLTPPPASGASSTTDVCSVFDSDHSSPFHSSNDTVFIQVTLPHGPRSASVSSISLTKGTDEVPVPPP VPPRRRPESAPAESSPSKIMSKHLDSPPAIPPRQPTSKAYSPRYSISDRTSISDPPESPPLLPPREPVRTPD VFSSSPLHLQPPPLGKKSDHGNAFFPNSPSPFTPPPPQTPSPHGTRRHLPSPPLTQEVDLHSIAGPPVPPRQ STSQHIPKLPPKTYKREHTHPSMHRDGPPLLENAHSS

[1003] sp|Q07890|SOS2_HUMAN Son of sevenless homolog 2 OS=Homo sapiens OX=9606 GN=SOS2 PE=1 SV=2

[1004] Seq ID #2: MQQAPQPYEFFSEENSPKWRGLLVSALRKVQEQVHPTLSANEESLYYIEELIFQLLNKLC MAQPRTVQDVEERVQKTFPHPIDKWAIADAQSAIEKRKRRNPLLLPVDKIHPSLKEVLGYKVDYHVSLYIVA VLEYISADILKLAGNYVFNIRHYEISQQDIKVSMCADKVLMDMFDQDDIGLVSLCEDEPSSSGELNYYDLVR TEIAEERQYLRELNMIIKVFREAFLSDRKLFKPSDIEKIFSNISDIHELTVKLLGLIEDTVEMTDESSPHPL AGSCFEDLAEEQAFDPYETLSQDILSPEFHEHFNKLMARPAVALHFQSIADGFKEAVRYVLPRLMLVPVYHC WHYFELLKQLKACSEEQEDRECLNQAITALMNLQGSMDRIYKQYSPRRRPGDPVCPFYSHQLRSKHLAIKKM NEIQKNIDGWEGKDIGQCCNEFIMEGPLTRIGAKHERHIFLFDGLMISCKPNHGQTRLPGYSSAEYRLKEKF VMRKIQICDKEDTCEHKHAFELVSKDENSIIFAAKSAEEKNNWMAALISLHYRSTLDRMLDSVLLKEENEQP LRLPSPEVYRFVVKDSEENIVFEDNLQSRSGIPIIKGGTVVKLIERLTYHMYADPNFVRTFLTTYRSFCKPQ ELLSLLIERFEIPEPEPTDADKLAIEKGEQPISADLKRFRKEYVQPVQLRILNVFRHWVEHHFYDFERDLEL LERLESFISSVRGKAMKKWVESIAKIIRRKKQAQANGVSHNITFESPPPPIEWHISKPGQFETFDLMTLHPI EIARQLTLLESDLYRKVQPSELVGSVWTKEDKEINSPNLLKMIRHTTNLTLWFEKCIVEAENFEERVAVLSR IIEILQVFQDLNNFNGVLEIVSAVNSVSVYRLDHTFEALQERKRKILDEAVELSQDHFKKYLVKLKSINPPC VPFFGIYLTNILKTEEGNNDFLKKKGKDLINFSKRRKVAEITGEIQQYQNQPYCLRIEPDMRRFFENLNPMG SASEKEFTDYLFNKSLEIEPRNCKQPPRFPRKSTFSLKSPGIRPNTGRHGSTSGTLRGHPTPLEREPCKISF SRIAETELESTVSAPTSPNTPSTPPVSASSDLSVFLDVDLNSSCGSNSIFAPVLLPHSKSFFSSCGSLHKLS EEPLIPPPLPPRKKFDHDASNSKGNMKSDDDPPAIPPRQPPPPKVKPRVPVPTGAFDGPLHSPPPPPPRDPL PDTPPPVPLRPPEHFINCPFNLQPPPLGHLHRDSDWLRDISTCPNSPSTPPSTPSPRVPRRCYVLSSSQNNL AHPPAPPVPPRQNSSPHLPKLPPKTYKRELSHPPLYRLPLLENAETPQ

Claims

1. WE CLAIM:

1. A compound having the structure of formula (I):

4. 6.or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers thereof; Wherein, n is 0, 1 or 2;7.Cyl is selected from Ce-io aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R100;8.Cy2 is selected from C3-7 monocyclic cycloalkyl, C7-10 fused bicyclic cycloalkyl, C7-10 spirocyclic cycloalkyl, C5-10 bridged bicyclic cycloalkyl, 4-7 membered monocyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, 8-10 membered fused bicyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, 7-10 membered spriocyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, and 6-10 membered bridged bicyclic heterocyclyl, containing 1 to 4 heteroatoms selected from N, O, and S, each independently optionally substituted with one to four R100;9.R1is selected from hydrogen, halo, oxo, hydroxy, amino, -C(O)Ra, -C(O)ORb, -C(O)NRaRb, -N(Ra)C(O)Rb, -S(O)NRaRb, -S(O)2NRaRb, -S(O)Rg, -S(O)2Rg, -NRaRb, - ORa, -SRb, -C1-6 alkyl, 4-6 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, 5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl is optionally substituted with one to four R100; R2is selected from hydrogen, halo, oxo, hydroxy, amino, -C(O)Ra, -C(O)ORb, -C(O)NRaRb, -N(Ra)C(O)Rb, -S(O)NRaRb, -S(O)2NRaRb, -S(O)Rg, -S(O)2Rg, -NRaRb, -ORa, -SRb, -C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-7 membered monocyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, 5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered fused bicyclic heterocyclyl and 8-10 membered fused bicyclic heteroaryl is optionally substituted with one to four R100;10.R3is selected from hydrogen, halo and -C1-6 alkyl;11.R4is selected from hydrogen, halo, hydroxy, amino and -C1-6 alkyl;12.Each R5and R6is independently selected from hydrogen, halo, hydroxy, amino, -CN, -C(O)Ra, -C(O)ORb, -C(O)NRaRb, -N(Ra)C(O)Rb, -N(Ra)C(O)NRaRb, -N(Ra)SO2NRaRb, -S(O)NRaRb, -S(O)2NRaRb, -N(Ra)S(O)2Rb, -S(O)Rg, -S(O)2Rg, -NRaRb, -ORa, -SRb, -OC(O)Ra, -OC(O)NRaRb, C1-6 alkyl; C2-6 alkenyl, C2-6 alkynyl and C3-8 cycloalkyl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C3-8 cycloalkyl is optionally substituted with one to four R100;13.each Raand Rbis independently selected from absent, hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-7 membered monocyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S,, 5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, 8-10 membered fused bicyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; 8-10 membered fused bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered fused bicyclic heterocyclyl and 8-10 membered fused bicyclic heteroaryl is optionally substituted with one to four R200; alternatively, Raand Rbtogether with the atom(s) to which they are attached may form a spiro, fused or bridged ring, optionally substituted with one to four R200; each R100is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -N(Rc)C(O)Rd, -S(O)NRcRd, -S(O)2NRcRd, -S(O)Rh, -S(O)2Rh, -NRcRd, -ORC, -SRC, Ci-6 alkyl, C2-6alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R201; alternatively two R100groups together with the atoms to which they are attached may form a C3-8 cycloalkyl or 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, each optionally substituted with one to four R201.14.each Rcand Rdis independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; alternatively, Rcand Rdtogether with the atom(s) to which they are attached may form a spiro, fused or bridged ring, optionally substituted with one to four R300;15.each R200and R201is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)Re, -C(O)ORe, -C(O)NReRf, -N(Re)C(O)Rf, -S(O)NReRf, -S(O)2NReRf, -S(O)R‘, -S(O)2Ri, -NReRf, -ORe, -SRe, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R300;16.each Rg, Rhand Riis independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, is optionally substituted with one to four R300;17.wherein each R300is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)Re, -C(O)ORe, -C(O)NReRf, -N(Re)C(O)Rf, -S(O)NReRf, - S(O)2NReRf, -NReRf, S(O)Re, -S(O)2Re, -NReRf, -ORe, -SRe, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;18.each Reand Rfis independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl; C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R400;19.each R400is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, S(O)NRkR1, -S(O)2NRkR‘, -20.

21. 6 alkyl, C2-6 alkenyl and C2-6 alkynyl;22.each Rkand Rlis independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl; C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S.

2. A compound of claim 1, having the structure of Formula (II):

27. 29.Formula (II)30.or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers thereof.

3. A compound of claim 1, having the structure of Formula (III):

32. 34.Formula (III)35.or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers thereof.

4. A compound of claim 1, having the structure of Formula (IVa) or (IVb):

39.

40. or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers thereof.

5. A compound having the structure of Formula (V):

42. 44.Formula (V)45.or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers thereof; Wherein, n is 0, 1 or 2;46.L1is selected from -N(Ra)-[(CH2)2-O]x-(CH2)2N(Ra)C(O)-(CH2)y-; wherein each x and y is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;47.Cy2 is selected from C3-7 monocyclic cycloalkyl, C7-10 fused bicyclic cycloalkyl, C7-10 spirocyclic cycloalkyl, C5-10 bridged bicyclic cycloalkyl, 4-7 membered monocyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, 8-10 membered fused bicyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, 7-10 membered spriocyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, and 6-10 membered bridged bicyclic heterocyclyl, containing 1 to 4 heteroatoms selected from N, O, and S, each independently optionally substituted with one to four R100; R2is selected from hydrogen, halo, oxo, hydroxy, amino, -C(O)Ra, -C(O)ORb, -C(O)NRaRb, -N(Ra)C(O)Rb, -S(O)NRaRb, -S(O)2NRaRb, -S(O)Rg, -S(O)2Rg, -NRaRb, -ORa, -SRb, -C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-7 membered monocyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, 5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered fused bicyclic heterocyclyl and 8-10 membered fused bicyclic heteroaryl is optionally substituted with one to four R100;48.R3is selected from hydrogen, halo and -C1-6 alkyl;49.R4is selected from hydrogen, halo, hydroxy, amino and -C1-6 alkyl;50.Each R5and R6is independently selected from hydrogen, halo, hydroxy, amino, -CN, -C(O)Ra, -C(O)ORb, -C(O)NRaRb, -N(Ra)C(O)Rb, -N(Ra)C(O)NRaRb, -N(Ra)SO2NRaRb, -S(O)NRaRb, -S(O)2NRaRb, -N(Ra)S(O)2Rb, -S(O)Rg, -S(O)2Rg, -NRaRb, -ORa, -SRb, -OC(O)Ra, -OC(O)NRaRb, C1-6 alkyl; C2-6 alkenyl, C2-6 alkynyl and C3-8 cycloalkyl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C3-8 cycloalkyl is optionally substituted with one to four R100;51.each Raand Rbis independently selected from absent, hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-7 membered monocyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S,, 5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, 8-10 membered fused bicyclic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; 8-10 membered fused bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered fused bicyclic heterocyclyl and 8-10 membered fused bicyclic heteroaryl is optionally substituted with one to four R200; alternatively, Raand Rbtogether with the atom(s) to which they are attached may form a spiro, fused or bridged ring, optionally substituted with one to four R200;52.each R100is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -N(Rc)C(O)Rd, -S(O)NRcRd, -S(O)2NRcRd, -S(O)Rh, -S(O)2Rh, -NRcRd, -ORC, -SRC, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R201; alternatively two R100groups together with the atoms to which they are attached may form a C3-8 cycloalkyl or 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S, each optionally substituted with one to four R201.53.each Rcand Rdis independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; alternatively, Rcand Rdtogether with the atom(s) to which they are attached may form a spiro, fused or bridged ring, optionally substituted with one to four R300;54.each R200and R201is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)Re, -C(O)ORe, -C(O)NReRf, -N(Re)C(O)Rf, -S(O)NReRf, -S(O)2NReRf, -S(O)R‘, -S(O)2Ri, -NReRf, -ORe, -SRe, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R300;55.each Rg, Rhand Riis independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, is optionally substituted with one to four R300;56.wherein each R300is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)Re, -C(O)ORe, -C(O)NReRf, -N(Re)C(O)Rf, -S(O)NReRf, -S(O)2NReRf, -NReRf, S(O)Re, -S(O)2Re, -NReRf, -ORe, -SRe, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;57.each Reand Rfis independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl; C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R400;58.each R400is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)Rk, -C(O)ORk, -C(O)NRkR1, -N(Rk)C(O)Rl, -S(O)NRkR1, -S(O)2NRkRl, -NRkR‘, S(O)Rk, -S(O)2Rk, -NRkR‘, -ORk, -SRk, Ci-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;59.each Rkand R1is independently selected from hydrogen, Ci-6 alkyl, C2-6 alkenyl and C2-6 alkynyl; C3-8 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S.

6. A compound according to any of claims 1-2 and 5 wherein R3is -Cl.

7. A compound according to any of claims 1-6 wherein R1is selected from:62.-(CH2)mOH, -N(CH3)CH2C(O)NH2, -N(CH3)CH2C(OH)CH3, -N(CH3)CH2C(O)N(H)CH2CH3, -N(Ra)(C(Ra)(Rb))mOH, -N(Ra)(C(Ra)(Rb))mC(O)NH2, -N(Ra)(C(Ra)(Rb))mH, -N(Ra)(C(Ra)(Rb))mC(O)NH2,64.

66. 68.Wherein m is 0, 1, 2, 3 or 4; and,69.R7is selected from -H, halo, oxo, -OH, -CN, -NH2, -C(O)NH2, -(CH2)OH, -C(O)OH, C1-6alkyl optionally substituted with one to four R100.

8. A compound according to any of claims 1-6 wherein R4is -H and R5is -H.

9. A compound of claim 1, selected from the Table I or a pharmaceutically acceptable salt thereof;73.

76.

78.

80.

82.

84.

87.

89.

92.

94.

96.

98.

100.

102.

105.

108.

111.

113.

115.

117.

119.

122.

124.

141.

143.

145.

147.

150.

152.

154.

157.

159.

161.

177.

191.

193.

195.

197.

199.

201.

203.

205.

208.

211.

213.

215.

217.

219.

222.

224.

226.

229.

231.

241.

243.

246.

248.

250.

265.

267.

269.

271.

273.

275.

277.

280.

282.

284.

287.

290.

292.

294.

296.

299.

326.

328.

330.

332.

338.

340.

342.

344.

347.

350.

352.

376.

378.

380.

396.

398.

400.

402.

404.

406.

408.

410.

412.

414.

417.

433.

450.

469.

483.

500.

518.

520.

522.

10. A pharmaceutical composition comprising one or more compounds according to any of the above claims and a pharmaceutically acceptable carrier or diluent.

11. A method for inhibiting SOS1 or SOS2 activity in a cell, comprising contacting the cell in which inhibition of SOS1 activity is desired with an effective amount of the compound according to any of claims 1-9 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim.

12. A method for treating cancer comprising administering a therapeutically effective amount of a compound according to claims 1-9 or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

13. The method according to claim11, wherein the cancer is selected from the group consisting of Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);528.Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.

14. The method according to any of claims 11-13, further comprising administering at least one additional anticancer agent or therapy.

15. A method of modulating the heterodimerization of son of sevenless (SOS) protein with the catalytic domain of Ras protein comprising the step of binding a compound to one ore more residues of SOS1 selected from Glu792, Leu795, Tyr796, Leu821, Met824, Ile825, His827, Thr828, Asn869, Glu873, Val927, Pro928, Phe929, Phe930, Gly931, and Leu934; or one or more residues of SOS2 selected from Glu790, Leu793, Tyr794, Leu819, Met822, Ile823, His825, Thr826, Asn867, Glu871, Val925, Pro926, Phe927, Phe928, Gly929, and Leu932.

16. A method of modulating the heterodimerization of son of sevenless (SOS) protein with the catalytic domain of Ras protein comprising the step of binding a compound in the pockets created by SOS1 residues Glu792, Leu795, Tyr796, Leu821, Met824, Ile825, His827, Thr828, Asn869, Glu873, Val927, Pro928, Phe929, Phe930, Gly931, and Leu934; or SOS2 residues Glu790, Leu793, Tyr794, Leu819, Met822, Ile823, His825, Thr826, Asn867, Glu871, Val925, Pro926, Phe927, Phe928, Gly929, and Leu932.

17. The method according to claims 15 or 16 wherein said compound is a compound according to any of claims 1-10.

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