(2,6-naphthyridin-1-yl)amine derivatives as BFL-1 inhibitors for the treatment of cancer

Abstract

The present invention is directed to naphthyridine derivatives of formula (I) as BFL-1 inhibitors for use in methods of treatment of leukemias, lymphomas and other cancers.

Description

[0001] NAPHTHYRIDINE DERIVATIVES USEFUL AS A BFL-1 INHIBITORS

[0002] Cross-Reference to Related Applications

[0003] This application claims priority from United States Provisional Application Serial No. 63 / 706,812 filed October 14, 2024, the contents of which is incorporated by reference in its entirety.

[0004] Field of the Invention

[0005] The present invention is directed naphthyridine derivatives, stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing said compounds, and the use of said compounds in the treatment of leukemias, lymphomas and other cancers.

[0006] Background of the Invention

[0007] Non-Hodgkin lymphoma (NHL) is a heterogeneous group of malignancies, from B- or T-cell origin, accounting for about 4% of all malignancies in the US (BIBIKOVA et al., Blood. 2019; 134 (Supplement^ : 2571 ). Worldwide, diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of NHL, accounting for 30% to 40% of all newly diagnosed cases (SEHN LH & GASCOYNE RD, Blood. 2015;125(1):22-32). DLBCL typically presents as an aggressive lymphoma, evolving over months and resulting in symptomatic disease that is fatal without treatment (Ibid).

[0008] Outcomes in DLBCL have improved dramatically over the last decade with the addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (R CHOP). This regimen remains the current standard of care. However, R CHOP treatment fails in about 30% to 50% of patients with DLBCL (COIFFiER B & Sarkozy C,. Hematology Am Soc Hematol Educ Program. 2016;2016(1 ):366-378). Less than half of these patients can be cured with stem cell transplantation (GISSELBRECHT et al., J Clin Oncol. 2010; 28(27): 4184-4190), and those who are not cured will typically die from their disease (CRUMP et al., Blood. 2017; 130(16): 1800-1808). Since the best chance for cure is front-line treatment, there have been many attempts to improve upon R CHOP but so far, these treatments have failed to significantly improve outcomes (GOYA., J Clin Oncol. 2017;35(31):3519-3522). Recently, several studies have explored the addition of targeted agents to R CHOP in front-line treatment. Promising signs of activity in some of these studies encourage the further exploration of combinations that may improve cure rate of targeted agents in select patients (CHIAPPELLA et a!., Hematological Oncology. 2017;35(S2):419-428 & YOUNES et a!., Lancet Oncol. 2014;15(9):1019-1026). Thus, optimization of front-line therapy, as well as the development of more effective salvage strategies, remains an important objective.

[0009] Follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MOL) and Waldenstrom macroglobulinemia (WM) are considered largely incurable lymphomas that require therapies throughout the course of disease. Currently, there are limited lines of therapy available for these diseases, and treatments are needed that avoid the use of cytotoxic chemotherapy.

[0010] Acute myelogenous leukemia (AML) is a clonal disease of the blood and bone marrow resulting from mutations that occur in normal hematopoietic stem cells. AML is a heterogenous disease in that it presents with a range of cytogenetic, morphological and immunophenotypic features, and is characterized by an accumulation of clonal, abnormal myeloid progenitor cells, known as myeloblasts. These cells demonstrate disruption of normal myeloid differentiation and excessive proliferation, resulting in the decreased formation of hematopoietic cells. Disease remission can be achieved with standard induction chemotherapy, but refractory and relapsed disease remains a challenge due to persistence of leukemic stem cells. Patients refractory to salvage therapy are treated pal liatively, as current treatment options are extremely limited. These patients have a median survival of 2 months. Therefore, AML represents an unmet medical need with >20,000 new cases per year in the US with 5-year overall survival below 30% (STEIN ET etal., Health Qual Life Outcomes. 2018; 16: 193).

[0011] In addition, patients with newly diagnosed intermediate or higher-risk myelodysplastic syndrome (MDS) and those who relapse after standard care have a poor prognosis and high risk of progression to AML. Therefore, there is an urgent need for new treatment modalities for relapsed / refractory (R / R) AML and MDS patients, newly diagnosed AML patients ineligible for induction chemotherapy based on age and comorbidities, and newly diagnosed intermediate / high / very high risk MDS patients.

[0012] Intrinsic apoptosis (programmed cell death) is regulated by the B Cell lymphoma 2 (BCL-2) protein family. Anti-apoptotic family members sequester their pro-apoptotic counterparts through a highly conserved BH3 binding groove. Disruption of this balance will lead to mitochondrial pore formation and subsequent cell death. To evade apoptosis, tumors often upregulate the expression of one or more anti-apoptotic family members. As such anti-apoptotic family members have become attractive targets for anti-cancer drug development. The most advanced small molecule inhibitor targeting the anti-apoptotic protein BCL-2, Venetoclax, effectively improves clinical outcomes in newly diagnosed, relapsed and refractory acute myeloid leukemia (AML) patients, with complete response rates (with and without complete blood count recovery) ranging between 34-90% and 21-33%, respectively. (GRIFFIOEN et al., Cancers. 2022; 14 (14): 3456)

[0013] BFL-1 (‘Bcl-2 related gene expressed in fetal liver’ (Choi et al., Oncogene. 1995; 11 : 1693-1698), gene name BCL2A1 (B-cell lymphoma 2-related protein A1 )) is a lesser-known anti-apoptotic family member, physiologically mainly expressed in the hematopoietic system. BFL-1 was found to be a direct transcriptional target of nuclear factor-KB (NF-KB) (LEE et al., PNAS. 1999; 96: 9136-9141 ). Two BFL-1 isoforms are reported; the full length BFL-1 containing 175 amino acids and a shorter 163 amino acids BFL-1 isoform (as a result of alternative splicing of the BFL-1 gene), BFL-1 S, predominantly expressed in the lymph nodes (KO et al., Oncogene. 2003; 22: 2457- 2465).

[0014] In comparative transcriptome analysis of acute myeloid leukaemia (AML) patient samples, BCL2A1 (BFL-1) was identified as the most differentially expressed gene, enriched in samples resistant to Venetoclax treatment (ZHANG et al., Nature Cancer. 2020; 1 : 826-839 & BISAILLON et al., Leukemia. 2020; 34: 63-74).

[0015] BFL-1 overexpression has been reported in many types of B cell lymphoma. Diffuse large B cell lymphoma (DLBCL) patient sample analysis shows, with regards to expression of anti-apoptotic family members, expression levels of BFL-1 are second only to MCL-1 (REDDY et al., Cell. 2017; 171 , 481-494). Expression of BFL-1 was shown to be upregulated in MYC / BCL2 double hit lymphoma cell lines treated with Venetoclax in vivo (ESTEVE-ARENYS et al., Oncogene. 2018; 37: 1830-1844). BFL-1 positive lymphomas are also shown to be less sensitive to inhibition of BCL-2 and MCL- 1 (BOIKO et al., Blood. 2021 ; 137 (21): 2947-2957). Targeting BFL-1 is therefore a possible strategy for the treatment of cancers such as AML, MDS, and DLBCL.

[0016] There remains a need for inhibitors of the BFL-1 receptor, which may be useful for the treatment of cancer, more particularly for the treatment of leukemias, lymphomas and related cancers.

[0017] Summary of the Invention

[0018] The present invention is directed to compounds of formula (I) wherein

[0019] R1is hydrogen;

[0020] R2is selected from the group consisting of hydroxy substituted Ci-4alkyl, -C(O)- NRARB, -C(O)-NRA-(C3-6cycloalkyl) and 4 to 8 membered heterocycloalkyl; wherein the 4 to 8 membered heterocycloalkyl or Ca ecycloalkyl, whether alone or as part of a substituent group is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, Ci-4alkyl, fluorinated Ci-2alkyl, and cyano; and wherein RAand RBare each independently selected from the group consisting of hydrogen and Ci-4alkyl;

[0021] R3is selected from the group consisting of phenyl, 5 to 6 membered heteroaryl and 4-(trifluoromethyl)-bicyclo[2.2.2]octan-1 -yl; wherein the phenyl or 5 to 6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-4alkyl, fluorinated Ci-4alkyl, nitro, -NRCRD, -NRc-C(O)-(Ci-4alkyl), -NRc-C(O)-(fluorinated Ci- 4alkyl), and -NRc-C(O)-(C2-4alkenyl); and wherein Rcand RDare each independently selected form the group consisting of hydrogen and Ci-4alkyl;

[0022] R4is phenyl; wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci-4alkyl, fluorinated Ci-4alkyl, hydroxy substituted Ci 4alkyl, Ci-4alkoxy, -NRERF, and -C(O)- NRERF; wherein REand RFare each independently selected from the group consisting of hydrogen, and Ci-4alkyl;

[0023] R5is selected from the group consisting of nitrogen bound, 5 to 6 membered heterocycloalkyl and nitrogen bound, 9 to 10 membered bicyclic heterocycloalkyl; wherein the nitrogen bound, 5 to 6 membered heterocycloalkyl is optionally substituted with one or more halogen; wherein the nitrogen bound 5 to 6 membered heterocycloalkyl is further optionally substituted with phenyl or 5 to 6 membered heterocyclyl; wherein the phenyl or 5 to 6 membered heterocyclyl is further optionally substituted with halogen, hydroxy, oxo, Ci-4alkyl, fluorinated Ci-2alkyl, Ci-4alkoxy, fluorinated Ci-2alkoxy,-SO2-(Ci-2alkyl), - SO2-(fluorinated Ci-2alkyl), -SO2-NRGRH, and -SO(NH2)-CH3; wherein RGand RHare each independently selected from the group consisting of hydrogen and Ci-4alkyl; and wherein the nitrogen bound, 9 to 10 membered bicyclic heterocycloalkyl contains at least one ring S, said ring S is optionally substituted with one to two oxo groups; and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0024] The present invention is further directed to a compound of formula (II)

[0025] also known as (2R)-N-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 - carbonyl]-7-(2,4,5-trimethyl-3-thienyl)-2,6-naphthyridin-1 -yl]amino]-3-[4- (trifluoromethyl)phenyl]propenamide; and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0026] The present invention is further directed to processes for the preparation of the compounds of formula (I) and formula (II). The present invention is further directed to a product prepared according to the process described herein.

[0027] The present invention is further directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product prepared according to any of the process(es) described herein. The present invention is further directed to a pharmaceutical composition made by mixing the product prepared according to any of the process(es) described herein and a pharmaceutically acceptable carrier. The present invention is further directed to a process for making a pharmaceutical composition comprising mixing the product prepared according to any of the process(es) described herein and a pharmaceutically acceptable carrier.

[0028] Exemplifying the invention are methods of treating a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is a leukemia (selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), (acute) T-cell leukemia, acute monocytic leukemia, acute promyelocytic leukemia (APL), bisphenotypic B myelomonocytic leukemia, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia, and myelodysplastic syndrome (MDS)) comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.

[0029] Exemplifying the invention are methods of treating a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is a lymphoma (selected from the group consisting of AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell DLBCL, double-hit lymphoma, double-expressor lymphoma, anaplastic large cell lymphoma, marginal B cell lymphoma, primary mediastinal B-cell lymphoma, immunoblastic large cell lymphoma, Burkitt lymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoplasmatic lymphoma, precursor B - lymphoblastic lymphoma, lymphoma of the central nervous system, small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia (CLL), precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma, sarcoma of the soft tissue, gliosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma, breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma) comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.

[0030] In an embodiment, the present invention is directed to a compound of formula (I) for use as a medicament. In an embodiment, the present invention is directed to a compound of formula (II) for use as a medicament.

[0031] In another embodiment, the present invention is directed to a compound of formula (I) or a compound of formula (II) for use in the treatment of a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is a leukemia (selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), (acute) T-cell leukemia, acute monocytic leukemia, acute promyelocytic leukemia (APL), bisphenotypic B myelomonocytic leukemia, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia, and myelodysplastic syndrome (MDS)).

[0032] In another embodiment, the present invention is directed to a compound of formula (I) or a compound of formula (II) for use in the treatment of a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is a lymphoma (selected from the group consisting of AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell DLBCL, double-hit lymphoma, double-expressor lymphoma, anaplastic large cell lymphoma, marginal B cell lymphoma, primary mediastinal B-cell lymphoma, immunoblastic large cell lymphoma, Burkitt lymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoplasmatic lymphoma, precursor B - lymphoblastic lymphoma, lymphoma of the central nervous system, small lymphocytic lymphoma (SLL), lymphocytic leukemia (CLL), T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma, sarcoma of the soft tissue, gliosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma, breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma).

[0033] In another embodiment, the present invention is directed to a composition comprising a compound of formula (I) or a compound of formula (II) for the treatment of a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is a leukemia (selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), (acute) T-cell leukemia, acute monocytic leukemia, acute promyelocytic leukemia (APL), bisphenotypic B myelomonocytic leukemia, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia, and myelodysplastic syndrome (MDS)).

[0034] In another embodiment, the present invention is directed to a composition comprising a compound of formula (I) or a compound of formula (II) for the treatment of a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is a lymphoma (selected from the group consisting of AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T- NHL), Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell DLBCL, double-hit lymphoma, double-expressor lymphoma, anaplastic large cell lymphoma, marginal B cell lymphoma, primary mediastinal B-cell lymphoma, immunoblastic large cell lymphoma, Burkitt lymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoplasmatic lymphoma, precursor B -lymphoblastic lymphoma, lymphoma of the central nervous system, small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia (CLL), precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma; sarcoma of the soft tissue, gliosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma, breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma).

[0035] Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating: (a) acute lymphoblastic leukemia (ALL), (b) acute myeloid leukemia (AML), (c) (acute) T-cell leukemia, (d) acute monocytic leukemia, (e) acute promyelocytic leukemia (APL), (f) bisphenotypic B myelomonocytic leukemia, (g) chronic myeloid leukemia (CML), (h) chronic myelomonocytic leukemia (CMML), (i) large granular lymphocytic leukemia, (j) plasma cell leukemia, or (k) myelodysplastic syndrome (MDS), in a subject in need thereof.

[0036] Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating: (a) AIDS-related lymphoma, (b) Hodgkin lymphoma, (c) non-Hodgkin's lymphoma (NHL), (d) T-non-Hodgkin lymphoma (T-NHL), (e) Diffuse Large Cell Lymphoma (DLBCL), (f) activated B-cell DLBCL, (g) germinal center B-cell DLBCL, (h) double-hit lymphoma, (i) double-expressor lymphoma, (j) anaplastic large cell lymphoma, (k) marginal B cell lymphoma, (I) primary mediastinal B-cell lymphoma, (m) immunoblastic large cell lymphoma, (n) Burkitt lymphoma, (o) follicular lymphoma, (p) hairy cell leukemia, (q) Hodgkin's disease, (r) mantle cell lymphoma (MCL), (s) lymphoplasmatic lymphoma, (t) precursor B - lymphoblastic lymphoma, (u) lymphoma of the central nervous system, (v) small lymphocytic lymphoma (SLL), (w) chronic lymphocytic leukemia (CLL), (x) precursor T- lymphoblastic lymphoma / leukemia, (y) peripheral T-cell lymphoma (PTCL), (z) cutaneous T-cell lymphoma (CTCL), (aa) angioimmunoblastic T-cell lymphoma, (ab) extranodal natural killer T-cell lymphoma, (ac) enteropathy type T-cell lymphoma, (ad) subcutaneous panniculitis-like T-cell lymphoma, (ae) anaplastic large cell lymphoma, (af) sarcoma of the soft tissue, (ag) gliosarcoma, (ah) osteosarcoma, (ai) malignant fibrous histiocytoma, (aj) lymphosarcoma, (ak) rhabdomyosarcoma, (al) breast cancer, (am) colorectal carcinoma, (an) gastric cancer, (ao) gliosarcoma, (ap) head & neck cancer, (aq) hepatocellular carcinoma, (ar) lung cancer, (as) multiple myeloma, (at) neuroblastoma, (au) ovarian cancer, (av) pancreatic cancer, (aw) prostate cancer, or (ax) renal cell carcinoma, in a subject in need thereof.

[0037] In another example, the present invention is directed to a compound as described herein for use in a method for treating a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is a leukemia selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), (acute) T-cell leukemia, acute monocytic leukemia, acute promyelocytic leukemia (APL), bisphenotypic B myelomonocytic leukemia, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia, and myelodysplastic syndrome (MDS), in a subject in need thereof.

[0038] In another example, the present invention is directed to a compound as described herein for use in a method for treating a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is a lymphoma selected from the group consisting of AIDS-related lymphoma, Hodgkin lymphoma, nonHodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), subtypes of NHL such as Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B- cell DLBCL, double-hit lymphoma and double-expressor lymphoma; anaplastic large cell lymphoma, marginal B cell lymphoma and primary mediastinal B-cell lymphoma, immunoblastic large cell lymphoma, Burkitt lymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoplasmatic lymphoma, precursor B -lymphoblastic lymphoma, lymphoma of the central nervous system, small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL); T- cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma; sarcomas including but not limited to sarcoma of the soft tissue, gliosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma; and other cancers, such as solid tumors, including but not limited to breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma, in a subject in need thereof.

[0039] Detailed Description of the Invention

[0040] The present invention is directed to compounds of formula (I) wherein R1, R2, R3, R4, and R5are as herein defined, and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. The compounds of the present invention are useful for the treatment of cancers mediated by the BFL-1 receptor, including, leukemias, lymphomas and related cancers.

[0041] The present invention is further directed to a compound of formula (II) and stereoisomers and pharmaceutically acceptable salt thereof; useful for the treatment of cancers mediated by the BFL-1 receptor, including, leukemias, lymphomas and related cancers.

[0042] In some embodiments, the present invention is directed to compounds of formula (I) wherein

[0043] R1is hydrogen;

[0044] R2is selected from the group consisting of hydroxy substituted Ci-4alkyl, -C(O)- NRARB, and -C(O)-NRA-(C3-4cycloalkyl); wherein RAand RBare each independently selected from the group consisting of hydrogen and Ci-2alkyl; and wherein the C3- 4cycloalkyl is optionally substituted with one to two substituents independently selected from the group consisting of hydroxy, Ci-2alkyl, and cyano;

[0045] R3is selected from the group consisting of phenyl and 6 membered heteroaryl; wherein the phenyl or 6 membered heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of fluorinated Ci-2alkyl, nitro, -NRCRD, -NRc-C(O)-(Ci-2alkyl), -NRc-C(O)-(fluorinated Ci-2alkyl) and -NRc-C(O)- (C2-4alkenyl); wherein Rcand RDare each independently selected form the group consisting of hydrogen and Ci-2alkyl;

[0046] R4is phenyl; wherein the phenyl is optionally substituted with one to three substituents independently selected from the group consisting of chloro, fluoro, Ci- 2alkyl, fluorinated Ci-2alkyl, hydroxy substituted Ci-4alkyl, and Ci-2alkoxy;

[0047] R5is selected from the group consisting of nitrogen bound, 6 membered heterocycloalkyl and nitrogen bound, 10 membered bicyclic heterocycloalkyl; wherein the nitrogen bound 6 membered heterocycloalkyl is optionally substituted with one to two halogen;wherein the nitrogen bound, 6 membered heterocycloalkyl is further optionally substituted with phenyl or 6 membered heteroaryl; wherein the phenyl or 6 membered heteroaryl is optionally substituted with -SO2-Ci-2alkyl; and wherein the nitrogen bound, 10 membered bicyclic heterocycloalkyl contains at least one ring S, said ring S is optionally substituted with one to two oxo groups; and stereoisomers and pharmaceutically acceptable salt thereof.

[0048] In some embodiments, the present invention is directed to compounds of formula (I) wherein

[0049] R1is hydrogen;

[0050] R2is selected from the group consisting of R-(1 -hydroxy-isopropyl), R-(methyl- amino-carbonyl), R-(1 -cyano-cycloprop-1 -yl-amino-carbonyl), and R-(3-hydroxy-3- methyl-cyclobutyl-amino-carbonyl);

[0051] R3is selected from the group consisting of 4-(trifluoro-methyl)-phenyl, 2-(difluoro- methyl)-4-(trifluoro-methyl)-phenyl, 2-nitro-4-(trifluoro-methyl)-phenyl, 2-amino-4- (trifluoro-methyl)-phenyl, 3-(methyl-amino)-4-(trifluoro-methyl)-phenyl, 2-(dimethyl- amino)-4-(trifluoro-methyl)-phenyl, 2-(methyl-carbonyl-amino)-4-(trifluoro-methyl)- phenyl, 2-(vinyl-carbonyl-amino)-4-(trifluoro-methyl)-phenyl, 3-(vinyl-carbonyl-(methyl- amino))-4-(trifluoro-methyl)-phenyl, 2-(trifluoro-methyl-carbonyl-amino)-4-(trifluoro- methyl)-phenyl, 5-(trifluoro-methyl)-pyrimidin-2-yl, 2-(trifluoro-methyl)-pyrimidin-5-yl, 6- (trifluoro-methyl)-pyridin-3-yl, and 4-amino-6-(trifluoro-methyl)-pyridin-3-yl;

[0052] R4is selected from the group consisting of 2,5-dimethyl-phenyl, 2,3,6-trimethyl- phenyl, and 2-methoxy-3,6-dimethyl-phenyl;

[0053] R5is selected from the group consisting of 4-(4-methyl-sulfonyl)-phenyl)- piperidi n-1 -yl, 4-(6-methyl-su If onyl)-py rid in-3-yl)-pi peridin- 1 -yl, 4-(6-(methyl-sulfonyl)- pyridin-3-y l)-3 ,3-dif luoro-pi peridin- 1 -yl, 4-(4-methyl-sulfonyl)-phenyl)-piperazin-1 -yl, 4-(6- methyl-sulfonyl)-pyridin-3-yl)-piperazin-1 -yl, morpholin-4-yl, (S*)-8- octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2-dioxide, and (R*)-8-octahydropyrazino[2,1 - c][1 ,4]thiazin-8-yl 2,2-dioxide; and stereoisomers and pharmaceutically acceptable salt thereof.

[0054] In some embodiments, the present invention is directed to compounds of formula (I) wherein

[0055] R1is hydrogen;

[0056] R2is selected from the group consisting of R-(1 -hydroxy-isopropyl), R-(methyl- amino-carbonyl), R-(1 -cyano-cycloprop-1 -yl-amino-carbonyl), and R-(3-hydroxy-3- methyl-cyclobutyl-amino-carbonyl);

[0057] R3is selected from the group consisting of 4-(trifluoro-methyl)-phenyl, 2-(difluoro- methyl)-4-(trifluoro-methyl)-phenyl, 2-nitro-4-(trifluoro-methyl)-phenyl, 2-amino-4- (trifluoro-methyl)-phenyl, 3-(methyl-amino)-4-(trifluoro-methyl)-phenyl, 2-(dimethyl- amino)-4-(trifluoro-methyl)-phenyl, 2-(methyl-carbonyl-amino)-4-(trifluoro-methyl)- phenyl, 2-(vinyl-carbonyl-amino)-4-(trifluoro-methyl)-phenyl, 3-(vinyl-carbonyl-(methyl- amino))-4-(trifluoro-methyl)-phenyl, 2-(trifluoro-methyl-carbonyl-amino)-4-(trifluoro- methyl)-phenyl, 2-(trifluoro-methyl)-pyrimidin-5-yl, 6-(trifluoro-methyl)-pyridin-3-yl, and 4- amino-6-(trifluoro-methyl)-pyridin-3-yl;

[0058] R4is selected from the group consisting of 2,5-dimethyl-phenyl, 2,3,6-trimethyl- phenyl, and 2-methoxy-3,6-dimethyl-phenyl;

[0059] R5is selected from the group consisting of 4-(6-(methyl-sulfonyl)-pyridin-3-yl)- piperidi n-1 -yl, 4-(6-(methyl-su If ony l)-py ridin-3-y l)-3 ,3-difl uoro-pi peridin-1 -yl, 4-(4-(methyl- sulfonyl)-phenyl)-piperazin-1 -yl, and (S*)-8-octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2- dioxide; and stereoisomers and pharmaceutically acceptable salt thereof.

[0060] In some embodiments, the present invention is directed to compounds of formula (I) wherein

[0061] R1is hydrogen;

[0062] R2is R-(methyl-amino-carbonyl), R-(1 -cyano-cycloprop-1 -yl-amino-carbonyl) or R-(3-hydroxy-3-methyl-cyclobutyl-amino-carbonyl);

[0063] R3is selected from the group consisting of 4-(trifluoro-methyl)-phenyl, 2-amino-4- (trifluoro-methyl)-phenyl, 2-(vinyl-carbonyl-amino)-4-(trifluoro-methyl)-phenyl, 2- (trifluoro-methyl)-pyrimidin-5-yl, 6-(trifluoro-methyl)-pyridin-3-yl, and 4-amino-6-(trifluoro- methyl)-pyridin-3-yl ;

[0064] R4is 2,3,6-trimethyl-phenyl;

[0065] R5is selected from the group consisting of 4-(6-(methyl-sulfonyl)-pyridin-3-yl)- 3 ,3-difl uoro-piperid in-1 -yl , and 4-(4-(methyl-sulfonyl)-phenyl)-piperazin-1 -yl; and stereoisomers and pharmaceutically acceptable salt thereof.

[0066] In some embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of hydroxy substituted Ci-4alkyl, - C(O)-NRARB, and -C(O)-NRA-(C3-4cycloalkyl); wherein RAand RBare each independently selected from the group consisting of hydrogen and Ci-2alkyl; and wherein the C3-4cycloalkyl is optionally substituted with one to two substituents independently selected from the group consisting of hydroxy, Ci-2alkyl, and cyano.

[0067] In some embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of R-(1 -hydroxy-isopropyl), R- (methyl-amino-carbonyl), R-(1 -cyano-cycloprop-1 -yl-amino-carbonyl), and R-(3-hydroxy- 3-methyl-cyclobutyl-amino-carbonyl). In some embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of R-(1 -hydroxy-isopropyl), R-(methyl-amino-carbonyl), R-(1 -cyano-cycloprop-1 -yl-amino- carbonyl), and R-(3-hydroxy-3-methyl-cyclobutyl-amino-carbonyl). In some embodiments, the present invention is directed to compounds of formula (I) wherein R2is R-(methyl-amino-carbonyl), R-(1 -cyano-cycloprop-1 -yl-amino-carbonyl) or R-(3- hydroxy-3-methyl-cyclobutyl-amino-carbonyl).

[0068] In some embodiments, the present invention is directed to compounds of formula (I) wherein R3is selected from the group consisting of phenyl and 6 membered heteroaryl; wherein the phenyl or 6 membered heteroaryl is optionally substituted with one to three (preferably one to two) substituents independently selected from the group consisting of fluorinated Ci-2alkyl, nitro, -NRCRD, -NRc-C(O)-(Ci-2alkyl), -NRc-C(O)- (fluorinated Ci-2alkyl) and -NRc-C(O)-(C2-4alkenyl); wherein Rcand RDare each independently selected form the group consisting of hydrogen and Ci-2alkyl.

[0069] In some embodiments, the present invention is directed to compounds of formula (I) wherein R3is selected from the group consisting of 4-(trifluoro-methyl)-phenyl, 2- (difluoro-methyl)-4-(trifluoro-methyl)-phenyl, 2-nitro-4-(trifluoro-methyl)-phenyl, 2-amino- 4-(trifluoro-methyl)-phenyl, 3-(methyl-amino)-4-(trifluoro-methyl)-phenyl, 2-(dimethyl- amino)-4-(trifluoro-methyl)-phenyl, 2-(methyl-carbonyl-amino)-4-(trifluoro-methyl)- phenyl, 2-(vinyl-carbonyl-amino)-4-(trifluoro-methyl)-phenyl, 3-(vinyl-carbonyl-(methyl- amino))-4-(trifluoro-methyl)-phenyl, 2-(trifluoro-methyl-carbonyl-amino)-4-(trifluoro- methyl)-phenyl, 5-(trifluoro-methyl)-pyrimidin-2-yl, 2-(trifluoro-methyl)-pyrimidin-5-yl, 6- (trifluoro-methyl)-pyridin-3-yl, and 4-amino-6-(trifluoro-methyl)-pyridin-3-yl.

[0070] In some embodiments, the present invention is directed to compounds of formula (I) wherein R3is selected from the group consisting of 4-(trifluoro-methyl)-phenyl, 2- (difluoro-methyl)-4-(trifluoro-methyl)-phenyl, 2-nitro-4-(trifluoro-methyl)-phenyl, 2-amino- 4-(trifluoro-methyl)-phenyl, 3-(methyl-amino)-4-(trifluoro-methyl)-phenyl, 2-(dimethyl- amino)-4-(trifluoro-methyl)-phenyl, 2-(methyl-carbonyl-amino)-4-(trifluoro-methyl)- phenyl, 2-(vinyl-carbonyl-amino)-4-(trifluoro-methyl)-phenyl, 3-(vinyl-carbonyl-(methyl- amino))-4-(trifluoro-methyl)-phenyl, 2-(trifluoro-methyl-carbonyl-amino)-4-(trifluoro- methyl)-phenyl, 2-(trifluoro-methyl)-pyrimidin-5-yl, 6-(trifluoro-methyl)-pyridin-3-yl, and 4- amino-6-(trifluoro-methyl)-pyridin-3-yl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R3is selected from the group consisting of R3is selected from the group consisting of 4-(trifluoro-methyl)-phenyl, 2-amino-4- (trifluoro-methyl)-phenyl, 2-(vinyl-carbonyl-amino)-4-(trifluoro-methyl)-phenyl, 2- (trifluoro-methyl)-pyrimidin-5-yl, 6-(trifluoro-methyl)-pyridin-3-yl, and 4-amino-6-(trifluoro- methyl)-pyridin-3-yl.

[0071] In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is phenyl; wherein the phenyl is optionally substituted with one to three substituents independently selected from the group consisting of chloro, fluoro, Ci- 2alkyl, fluorinated Ci-aalkyl, hydroxy substituted Ci-4alkyl, and Ci-2alkoxy. In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of 2,5-dimethyl-phenyl, 2,3,6-trimethyl-phenyl, and 2-methoxy-3,6-dimethyl-phenyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of 2,5- dimethyl-phenyl, 2,3,6-trimethyl-phenyl, and 2-methoxy-3,6-dimethyl-phenyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is 2,3,6-trimethyl-phenyl.

[0072] In some embodiments, the present invention is directed to compounds of formula (I) wherein R5is selected from the group consisting of nitrogen bound, 6 membered heterocycloalkyl and nitrogen bound, 10 membered bicyclic heterocycloalkyl; wherein the nitrogen bound 6 membered heterocycloalkyl is optionally substituted with one to two halogen; wherein the nitrogen bound, 6 membered heterocycloalkyl is further optionally substituted with phenyl or 6 membered heteroaryl; wherein the phenyl or 6 membered heteroaryl is optionally substituted with -SO2-Ci-2alkyl; and wherein the nitrogen bound, 10 membered bicyclic heterocycloalkyl contains at least one ring S, said ring S is optionally substituted with one to two oxo groups.

[0073] In some embodiments, the present invention is directed to compounds of formula (I) wherein R5is selected from the group consisting of 4-(4-methyl-sulfonyl)-phenyl)- piperidi n-1 -yl, 4-(6-methyl-su If onyl)-py rid in-3-yl)-pi peridin- 1 -yl, 4-(6-(methyl-sulfonyl)- pyridin-3-y l)-3 ,3-dif luoro-pi peridin- 1 -yl, 4-(4-methyl-sulfonyl)-phenyl)-piperazin-1 -yl, 4-(6- methyl-sulfonyl)-pyridin-3-yl)-piperazin-1 -yl, morpholin-4-yl, (S*)-8- octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2-dioxide, and (R*)-8-octahydropyrazino[2,1 - c][1 ,4]thiazin-8-yl 2,2-dioxide. In some embodiments, the present invention is directed to compounds of formula (I) wherein R5is selected from the group consisting of 4-(6- (methyl-sulfonyl)-pyridin-3-yl)-piperidin-1 -yl, 4-(6-(methyl-sulfonyl)-pyridin-3-yl)-3,3- difluoro-piperidin-1 -yl, 4-(4-(methyl-sulfonyl)-phenyl)-piperazin-1 -yl, and (S*)-8- octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2-dioxide. In some embodiments, the present invention is directed to compounds of formula (I) wherein R5is selected from the group consisting of 4-(6-(methyl-sulfonyl)-pyridin-3-yl)-3 ,3-dif luoro-pi peridin- 1 -yl, and 4-(4-(methyl-sulfonyl)-phenyl)-piperazin-1 -yl.

[0074] Additional embodiments of the present invention, include those wherein the substituents selected for one or more of the variables defined herein (i.e. a, R1, R2, R3, R4, and R5) are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein.

[0075] In additional embodiments, the present invention is directed to any single compound or subset of compounds independently selected from the representative compounds listed in Table 1 , below.

[0076] In additional embodiments, the present invention is directed to methods of treating a leukemia or lymphoma comprising administering a therapeutically effective amount of any single compound or subset of compounds independently selected from the representative compounds listed in Table 1 , below.

[0077] Representative compounds of formula (I) of the present invention are as listed in Table 1 , below. Wherein the compound contains at least on stereo-center, stereochemistry at the stereo-center(s) is as noted in the name. Unless otherwise noted, wherein a stereogenic center is present in the listed compound (e.g. as denoted by the symbol in the structure at the head of the table), the compound was prepared as a mixture of stereo-configurations (for example, as a racemate). The “S*”- and “R*- “ or “*S-“ and “*R-“ designations in the name are intended to indicate that the compound was prepared in an enantiomeric excess of one stereo-isomer, although the exact stereo-configuration was not determined; whereas the “S-“ and “R-“ designations in the name are intended to indicate that the compound was prepared in an enantiomeric excess of the corresponding S- or R- stereo-isomer.

[0078] In certain embodiments, the present invention is directed to one or more compounds of formula (I), independently selected from the group consisting of the compounds listed in Table 1 , below.

[0079] Table 1 : Representative Compounds of Formula (I)

[0080] In certain embodiments, the present invention is directed to one or more compounds of formula (I) independently selected from the group consisting of and stereoisomers and pharmaceutically acceptable salts thereof.

[0081] In certain embodiments, the present invention is directed to one or more compounds of formula (I) independently selected from the group consisting of (2R)-N-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl]amino]-3-[2-(prop-2-enoylamino)-4- (trifluoromethyl)phenyl]propanamide;

[0082] (2R)-N-methyl-3-[3-[methyl(prop-2-enoyl)amino]-4-(trifluoromethyl)phenyl]-2-[[5- [4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6-trimethylphenyl)-2,6- naphthyridin-1 -yl]amino]propanamide;

[0083] (2R)-N-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl]amino]-3-[4-(trifluoromethyl)phenyl]propanamide;

[0084] (2R)-N-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl]amino]-3-[6-(trifluoromethyl)-3- pyridyl]propanamide;

[0085] (2R)-N-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl]amino]-3-[4-(trifluoromethyl)phenyl]propanamide; and stereoisomers, isotopomers and pharmaceutically acceptable salts thereof.

[0086] In certain embodiments, the present invention is directed to compounds of formula (I) which, when tested for BFL-1 receptor inhibition according to the procedure as described in Biological Example 1 or 2, which follows hereinafter, exhibit a Ki of less than or equal to about 1 pM, preferably less than or equal to about 500 nM, more preferably less than or equal to about 250 nM, more preferably less than or equal to about 100 nM, more preferably less than or equal to about 50 nM, more preferably less than or equal to about 10 nM, more preferably less than or equal to about 5 nM, more preferably less than or equal to about 1 nM, more preferably less than or equal to about 0.5 nM, more preferably less than or equal to about 0.2 nM, more preferably less than or equal to about 0.1 nM.

[0087] Definitions and Abbreviations

[0088] Abbreviations used in the specification, for example in the Schemes, Synthesis Examples and Biological Examples, are as listed in the Table A, below:

[0089] Table A: Abbreviations

[0090]

[0091] As used herein, unless otherwise noted, “halogen” shall mean chloro, bromo, fluoro and iodo; for example bromo, fluoro or chloro; for example, fluoro or chloro; for example bromo, chloro or iodo. As used herein, unless otherwise noted, the term “oxo” shall mean a functional group of the structure =0 (i.e. a substituent oxygen atom connected to another atom by a double bond). One skilled in the art will recognize that when the oxo substituent is bound to a carbon atom, the oxygen atom is bound to the carbon atom through a double bond. One skilled in the art will recognize that wherein the oxo group is bound to a ring nitrogen or a nitrogen substituted with two non-hydrogen substituent groups (e.g. a secondary nitrogen), the result will be a N-oxide bond (i.e. >N+-0 ).

[0092] As used herein, unless otherwise noted, the term “Cx-Yalkyl” wherein X and Y are integers, whether used alone or as part of a substituent group, include straight and branched chains containing between X and Y carbon atoms. For example, Ci 4alkyl radicals include straight and branched chains of between 1 and 4 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl. As used herein, unless otherwise noted, the term “fluorinated Cx-valkyl” shall mean any Cx-yalkyl group as defined above substituted with one or more fluoro groups, preferably one to three fluoro group. Suitable examples include, but are not limited to, - CH2F, -CHF2, -CF3J-CH2CF3, -CF2CH3, -CH-CH2F, -CH2CH2CF3, -CH2CH2CHF2, - CH2CH2CH2F, -CH2CH2CF3, -C(CH3)2CF3, -C(CF3)3and the like.

[0093] As used herein, unless otherwise noted, the term “hydroxy substituted Cx-valkyl” shall mean any Cx-valkyl group as defined above substituted with one or more hydroxy (-OH) groups, preferably one to three, more preferably one to two hydroxy groups. Suitable examples include, but are not limited to, -CH2OH, -CH2CH2OH, -CH(OH)CH3, - CH2CH(OH)CH3, -CH(OH)CH2OH, -CH2CH2CH2OH, -C(CH2OH)3, -CH2C(OH)(CH3)2, - CH(CH3)CH2OH and the like.

[0094] As used herein, unless otherwise noted, the terms “Cx-valkenyl” wherein X and Y are integers, whether used alone or as part of a substituent group, include straight and branched chains containing between X and Y carbon atoms, further containing one or more, preferably one to two, more preferably one, carbon-carbon double bond. For example, a C2-4alkenyl shall include -CH=CH2, -CHCCH2, -CH2CH=CH2, - CH2CH2CH=CH2, -CH=CHCH2CH3, -CH=CHCH=CH2and the like.

[0095] As used herein, unless otherwise noted, “Cx-valkoxy” wherein X and Y are integers, shall mean an oxygen ether radical of the above described straight or branched chain Cx-valkyl groups containing between X and Y carbon atoms. For example, Ci- 4alkoxy shall include methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy, iso-butyloxy, sec-butyloxy and tert-butyloxy.

[0096] As used herein, unless otherwise noted, the term “fluorinated Cx-valkoxy” shall mean any Cx-valkoxy oxygen ether radical as defined above, substituted with one or more fluoro groups, preferably one to three fluoro groups. Suitably examples include, but are not limited to -CH2F, CHF2, -CF3, -CH2-CF3, -CF2-CH3, -CH2-CH2-CH2F, -CH2- CH2-CF3, -C(CH3)2CF3, -C(CF3)3, and the like.

[0097] As used herein, unless otherwise noted, the term “Cx-vcycloalkyl”, wherein X and Y are integers, shall mean any stable X- to Y-membered monocyclic, bicyclic, polycyclic, bridged or spiro-cyclic saturated ring system, preferably a monocyclic, bicyclic, bridged or spiro-cyclic saturated ring system. For example, the term “C3- scycloalkyl” includes, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1 ]hept-2-yl, cyclooctyl, bicyclo[2.2.2]octan-2-yl, and the like.

[0098] As used herein, unless otherwise noted, the term “4 to 8 membered heterocycloal kyl” shall denote any four to eight membered monocyclic saturated or partially unsaturated (preferably saturated) ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S. Unless otherwise noted, the 4 to 8 membered heterocycloalkyl may be bound through any ring atom which results in a stable structure. Suitably examples include, but are not limited to piperidinyl, 1 ,4-dioxanyl, morpholinyl, 1 ,4-dithianyl, thiomorpholinyl, piperazinyl, trihianyl, 2,5-dihydro-1 ,2,4-oxadiazolyl, 1 ,4,5,6-tetrahydropyridazinyl, and the like.

[0099] As used herein, unless otherwise noted, the term “nitrogen bound 5 to 6 membered heterocycloal kyl” shall denote any five or six membered monocyclic saturated or partially unsaturated (preferably saturated) ring structure containing at least one N, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; wherein the nitrogen bound 5 to 6 membered heterocycloalkyl is bound through any ring nitrogen atom which results in a stable structure. Suitably examples include, but are not limited to piperidin-1 -yl, morpholin-4-yl, 1 ,4-dithian-1 -yl, thiomorpholine-4-yl, piperazin-1 -yl, 1 ,4,5,6-tetrahydropyridazin-1-yl, and the like.

[0100] As used herein, unless otherwise noted, the term “nitrogen bound 9 to 10 bicyclic membered heterocycloalkyl” shall denote any nine to ten membered bicyclic, saturated or partially unsaturated (preferably saturated) ring structure containing at least one N, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; wherein the nitrogen bound 9 to 10 membered bicyclic heterocycloalkyl is bound through any ring nitrogen atom which results in a stable structure. Suitable examples include, but are not limited to (S*)-8-octahydropyrazino[2,1 - c][1 ,4]thiazin-8-yl 2,2-dioxide, and (R*)-8-octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2- dioxide.

[0101] As used herein, unless otherwise noted, the term “5 to 6 membered heteroaryl” shall denote any five or six membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S. Unless otherwise noted, the 5 to 6 membered heteroaryl may be bound through any ring atom which results in a stable structure. Suitably examples include, but are not limited to furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thidiazolyl, tetrazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, dioxinyl, oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl, and the like.

[0102] As used herein, unless otherwise noted, the term “5 to 6 membered heterocyclyl” shall denote any five to six membered monocyclic, saturated, partially unsaturated or aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S. The 5 to 6 membered heterocyclyl may be bound through any ring atom which results in a stable structure. Suitable examples include, but are not limited to furyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, isothiazolyl, dioxolanyl, pyrazolidinyl, thiadiazolyl, pyranyl, pyridinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, triazinyl, oxazinyl, isoxazinyl, oxathiazinyl, and the like.

[0103] When a particular group is "substituted" (e.g. Cx-yalkyl, Cx-ycycloalkyl, heterocyclyl, heterocycloalkyl, benzo-fused carbocyclyl, benzo-fused heterocyclyl, etc.), said group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents. With reference to substituents, the term “independently” means that when more than one substituent is possible, such substituents may be the same or different from each other.

[0104] One skilled in the art will recognize that any of the compounds of formula (I) or formula (II) of the present invention may exist as crystalline forms. Some of the crystalline forms for the compounds of the present invention may further exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.

[0105] In some embodiments, the present invention is directed to pharmaceutically acceptable salts of the compounds of formula (I) and formula (II).

[0106] For use in medicine, the salts of the compounds of the present invention refer to non-toxic “pharmaceutically acceptable salts”. Other salts may, however, be useful in the preparation of the compounds of the present invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.

[0107] Thus, representative pharmaceutically acceptable salts include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

[0108] Representative acids which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: acids including acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L- aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)- camphoric acid, camphorsulfonic acid, (+)-(1 S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1 ,2-disu Ifonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D- glucoronic acid, L-glutamic acid, oc-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (±)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1 ,5-disulfonic acid, 1 -hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid.

[0109] Representative bases which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1 H-imidazole, L-lysine, magnesium hydroxide, 4-(2- hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1 -(2-hydroxyethyl)- pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

[0110] It is further intended that the present invention includes the compounds of formula (I) and compounds of formula (II) described herein, including all isomers thereof (including, but not limited to stereoisomers, enantiomers, diastereomers, tautomers, isotopologues, isotopomers, and the like).

[0111] As used herein, the symbol or notation shall denote the presence of a stereogenic center.

[0112] Where the compounds of the present invention contain at least one chiral center, they may accordingly exist as enantiomers. Where the compounds of the present invention contain two or more chiral centers, they may additionally exist as diastereomers or stereoisomers. It is to be understood that all such isomers I stereoisomers and mixtures thereof are encompassed within the scope of the present invention. It is further understood that atropisomers (a specific type of stereoisomer resulting from steric or other hinderances to rotation) are also encompassed within the scope of the present invention.

[0113] Preferably, wherein a compound of the present invention is present as an enantiomer, the enantiomer is present at an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%. Similarly, wherein a compound of the present invention is present as a diastereomer or stereoisomer, the diastereomer or stereoisomer is present at a diastereomeric or stereoisomeric excess of greater than or equal to about 80%, more preferably, at a diastereomeric or stereoisomeric excess of greater than or equal to about 90%, more preferably still, at a diastereomeric or stereoisomeric excess of greater than or equal to about 95%, more preferably still, at a diastereomeric or stereoisomeric excess of greater than or equal to about 98%, most preferably, at a diastereomeric or stereoisomeric excess of greater than or equal to about 99%.

[0114] Throughout the specification and claims, wherein a compound or substituent group is drawn or named, the “*S” and “*R” or “S*” and “R*” designations associated with a given stereo-center indicate that although the compound or substituent group is present in an excess of one stereo-orientation at said stereo-center, the exact stereoconfiguration has not been determined. Further, wherein a compound or substituent group is drawn or named, the “S” and “R” designations indicate that the stereoorientation at said stereo-center was measured / determined and that the compound or group is present in an excess of the corresponding “S” or “R” stereo-orientation.

[0115] Wherein a compound or substituent group contains two stereo-centers which are drawn using “ and I or > "HI “ bond symbols, and which are the further denoted as “RS”, it is intended to indicate that the compound is present in an excess of either the “cis” or “trans” orientation of said two stereo-centers, although the exact stereo-configuration has not been determined. In some embodiments, the present invention is directed to compounds of formula (I) or formula wherein the stereocenter denoted with a “*” is present in the R- stereoorientation. In some embodiments, the present invention is directed to compounds of formula (I) wherein the stereocenter denoted with a is present in an S- stereoorientation.

[0116] As used herein, unless otherwise noted, the term “isotopologues” shall mean molecules that differ only in their isotopic composition. More particularly, an isotopologue of a molecule differs from the parent molecule in that it contains at least one atom which is an isotope (i.e. has a different number of neutrons from its parent atom). For example, isotopologues of water include, but are not limited to, "light water" (HOH or H2O), "semi-heavy water" with the deuterium isotope in equal proportion to protium (HDO or1H2HO), “heavy water” with two deuterium isotopes of hydrogen per molecule (c / 2O or2H2O), "super-heavy water" or tritiated water (T2O or3H2O), where the hydrogen atoms are replaced with tritium (3H) isotopes, two heavy-oxygen water isotopologues (H218O and H217O) and isotopologues where the hydrogen and oxygen atoms may each independently be replaced by isotopes, for example the doubly labeled water isotopologue c / 218O.

[0117] As used herein, unless otherwise noted, the term “isotopomer” shall mean isomers with isotopic atoms, having the same number of each isotope of each element but differing in their position. Isotopomers include both constitutional isomers and stereoisomers solely based on isotopic location. For example, CHsCHDCHsand CH3CH2CH2D are a pair of constitutional isotopomers of n-propane; whereas (F?)-CH3CHDOH and (S)-CH3CHDOH or (Z)-CH3CH=CHD and (E)-CH3CH=CHD are examples of isotopic stereoisomers of ethanol and n-propene, respectively.

[0118] The present invention is further directed to compounds of formula (I) and compounds of formula (II) wherein any one or more element(s) (atoms) comprise all isotopes and isotopic mixtures of said element(s), either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, a reference to hydrogen includes within its scope1H,2H (D), and3H (T). Similarly, references to carbon and oxygen include within their scope respectively12C,13C and14C and16O and18O. The isotopes may be radioactive or non-radioactive. Radiolabelled compounds of formula (I) and compounds of formula (II) may comprise one or more radioactive isotope(s) selected from the group of3H,11C,18F,122l,123l,125l, 1311,75Br,76Br,77Br and82Br. Preferably, the radioactive isotope is selected from the group of3H,11C and18F.

[0119] Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a “phenyl-(Ci-C6alkylene)-amino-carbonyl- (Ci-Cealkylene)-” substituent refers to a group of the formula

[0120] One skilled in the art will recognize that in the chemical structures provided

[0121] _S _ _c _ CH herein, a methyl substituent group may be denoted as “ ”, as “3” or as . For example, a 4-methyl-pyridin-2-yl substituent may be drawn as

[0122] As used herein, unless otherwise noted, the term “isolated form” shall mean that the compound is present in a form which is separate from any solid mixture with another compound(s), solvent system or biological environment. In an embodiment of the present invention, the compound of formula (I) is present in an isolated form. In an embodiment of the present invention, the compound of formula (II) is present in an isolated form.

[0123] As used herein, unless otherwise noted, the term “substantially pure form” shall mean that the mole percent of impurities in the isolated compound is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably, less than about 0.1 mole percent. In an embodiment of the present invention, the compound of formula (I) is present as a substantially pure form. In an embodiment of the present invention, the compound of formula (II) is present as a substantially pure form.

[0124] As used herein, unless otherwise noted, the term “substantially free of a corresponding salt form(s)” when used to described a compound of the present invention shall mean that mole percent of the corresponding salt form(s) in the isolated free acid or free base of said compound, is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably less than about 0.1 mole percent. In an embodiment of the present invention, the compound of formula (I) is present in a form which is substantially free of corresponding salt form(s). In an embodiment of the present invention, the compound of formula (II) is present in a form which is substantially free of corresponding salt form(s).

[0125] General Synthesis Schemes

[0126] Compounds of formula (I) of the present invention wherein R1is hydrogen, may be prepared by coupling three substituent groups onto a central 1 -C(O)-substituted naphthyridine scaffold of the following structure (A) wherein the numbering indicates ring atoms around said naphthyridine scaffold. More specifically, the compounds of the present invention may be prepared by coupling the following substituent groups, at the noted positions:

[0127] (a) an -R4group (herein referred to as the “bottom" substituent) directly to the carbon atom at the 3-position of the naphthyridine scaffold;

[0128] (b) an -NH-C(R2)-CH3-R3group (herein referred to as the “right hand side” substituent), at the 5-position of the naphthyridine scaffold; and

[0129] (c) an -R5group (herein referred to as the “left hand side” substituent), to the - C(O)- at the 1 -position of the naphthyridine scaffold.

[0130] One skilled in the art will recognize that the “bottom”, “right hand side” and “left hand side” substituent groups may be introduced / coupled onto the central naphthyridine scaffold in any order, and in either a single coupling step or in multiple steps. One skilled in the art will further recognize that depending on the order in which the “bottom”, “right hand side” and “left hand side” substituent groups are introduced I coupled onto the naphthyridine scaffold, reactive terminal groups and I or substituents may be protected at a suitable or desired step prior to the coupling step, and deprotected at any suitable subsequent step, according to known methods.

[0131] The Schemes which follow herein describe methods for coupling the “bottom”, “right hand side” and “left hand side” substituents onto the naphthyridine scaffold, starting from a suitably substituted compound of formula (V) wherein A1is Ci 4alkyl , preferably methyl or ethyl and LG1is a suitably selected leaving group such as halogen, preferably Br.

[0132] The compound of formula (V) may be prepared as described in Scheme 1 , below.

[0133] Scheme 1

[0134] Accordingly, 2-fluoro-4-iodopyridine, a known compound, is reacted with for example ethyl formate, a known compound; in the presence of a suitably selected base such as LDA, n-BuLi, LiHMDS, and the like; in a suitably selected solvent such as THF, hexanes, diethyl ether, and the like; at a temperature in the range of -70°C to about 50°C; to yield the corresponding 2-fluoro-4-iodonicotinaldehyde.

[0135] The 2-fluoro-4-iodonicotinaldehyde is reacted with a suitably selected alkylating agent such as sodium methoxide (for introducing a methyl group), sodium ethoxide (for introducing an ethyl group), and the like; in a suitably selected solvent such as methanol, THF, and the like; at a temperature below room temperature, for example at about 10°C; to yield the corresponding compound of formula (M1) wherein A1is the corresponding alkyl group.

[0136] The compound of formula (M1 ) is reacted with a suitably selected reducing agent such as NaBH4, UAIH4, DIBAL, and the like; in a suitably selected solvent such as methanol, ethanol, THF, and the like; at a temperature below room temperature, for example at about 0°C; to yield the corresponding compound of formula (M2).

[0137] The compound of formula (M2) is reacted with a suitably selected chlorinating agent such as mesyl chloride, thionyl chloride, CCk, and the like; in the presence of a suitably selected organic base such as TEA, DIPEA, pyridine, and the like; in a suitably selected solvent such as DCM, DMF, THF, and the like; at a temperature in the range of from about 0°C to about 20°C (about room temperature); to yield the corresponding compound of formula (M3).

[0138] The compound of formula (M3) is reacted with a suitably selected source of -CN such as TMSCN, NaCN, KCN, and the like; wherein the suitably selected source of -CN will selectively reacted with the chloro group on the compound of formula (M3); in the presence of a suitably selected additive such as TBAF, KI, , and the like; in a suitably selected solvent such as acetonitrile, DMSO, DMF, and the like; at an elevated temperature, for example at about 80°C (about solvent reflux temperature); to yield the corresponding compound of formula (M4).

[0139] The compound of formula (M4) is reacted with a second source of cyanide such as Zn(CN)2, K4Fe(CN)6, TMSCN, NaCN and the like; wherein the suitably selected source of -CN will selectively reacted with the iodo group on the compound of formula (M4); in the presence of a suitably selected coupling agent such as Pd(PPh3)4, CU2O, Pd(t-BuXPhos), and the like; in the presence of a suitably selected additive such as NaCIO (sodium hypochloride), K2CO3, and the like; in the presence of a suitably selected drying agent such as 4A° MS and the like; in a suitably selected solvent or mixture of solvents such as DMF, DMA, THF / H2O, and the like; at an elevated temperature, for example at about 120°C; to yield the corresponding compound of formula (M5).

[0140] The compound of formula (M5) is reacted to effect ring closure, for example with HBr; in the presence of a suitably selected additive such as acetic acid, NaHCOs, and the like; at a reduced temperature, for example at about 0°C; to yield the corresponding compound of formula (M6).

[0141] The compound of formula (M6) is reacted with carbon monoxide (for example, 50 psi CO gas); in the presence of a suitably selected catalyst such as Pd(OAc)2, PdCl2, PdCl2(PPh3)2, and the like; in the presence of a suitably selected ligand such as XantPhos, PPhs, dppf, and the like; in the presence of a suitably selected base such as TEA, DIPEA, pyridine, K2CO3, and the like; in a suitable solvent or mixture of solvents for example, a mixture of MeOH and DMF, ACN, DMA, and the like; at an elevated temperature, for example at about 70°C; to yield the corresponding compound of formula (M7).

[0142] The compound of formula (M7) is reacted with a suitably selected nitrous acid precursor such as tert-butyl nitrile (tBuONO), NaNO2, and the like; in the presence of a suitably selected source of halogen such as CuBr2, HBr, HCI, CuCl2, and the like; in a suitably selected solvent such as 2-methyl-THF, H2O, ACN, and the like; at an elevated temperature, for example at about 60°C; to yield the corresponding compound of formula (M8), wherein LG1is the correspond halogen (for example when the source of halide is CuBr2, then LG1is Br). The compound of formula (M8) is reacted with a suitably selected base such as aqueous LiOH, aqueous NaOH, and the like; in a suitably selected solvent such as THF, 1 ,4-dioxane, MeOH, and the like; at about room temperature; to yield the corresponding compound of formula (V).

[0143] Compounds of formula (I) of the present invention may be prepared by coupling the “left hand side”, “bottom” and “right hand side” substituent groups, in this sequence, as described in Scheme 2, below.

[0144] Scheme 2

[0145] Accordingly, a suitably substituted compound of formula (V), wherein LG1is halogen, preferably Br, prepared for example as described in Scheme 1 above, is reacted with a suitably substituted compound of formula (VI), a known compound or compound prepared by known methods; in the presence of a suitably selected coupling agent such as HATU, T3P®, BOP, PyBOP and the like; in the presence of a suitably selected organic base such as TEA, DIPEA, pyridine, and the like; in a suitably selected organic solvent such as DMF, DMA, THF, ACN, and the like; at about room temperature; to yield the corresponding compound of formula (VI).

[0146] The compound of formula (VI) is reacted with a suitably substituted compound of formula (VIII) wherein -B(R)2 is a boronic acid wherein each R is OH, a dialkyl boronic ester wherein each R is -O-Ci-4alkyl, or a cyclic boronic ester of the formula (wherein the two R groups are taken together with the boron atom to which they are bound), a known compound or compound prepared by known methods; in the presence of a suitably selected coupling agent such as CataCXium A Pd G3, Pd(dppf)Cl2, Pd(PPh3)4, and the like; in the presence of a suitably selected base such as K3PO4, CS2CO3, Na2CO3, and the like; in a suitably selected solvent or mixture of solvents such as a mixture of DMF and water, a mixture of dioxane and water, a mixture of THF and water, and the like; at an elevated temperature, for example at about 80°C; to yield the corresponding compound of formula (IX).

[0147] The compound of formula (IX) is reacted with a suitably selected deprotection reagent such as Nal, HCI, BBrs, and the like; possibly in the presence of a suitably selected additive such as TMSCI, KOtBu, and the like; in a suitably selected solvent such as acetonitrile, dioxane, DCM, CHCI3, THF and the like; from about room temperature to 50°C; to yield the corresponding compound of formula (X).

[0148] The compound of formula (X) is reacted with a suitably selected source of halogen such as a suitably selected source of chlorine such as POCI3, SOCI2, PCI5, and the like; in a suitably selected solvent such as ACN, toluene, and the like; at elevated temperature, for example at about 100°C; to yield the corresponding compound of formula (XI), wherein LG2is the corresponding halogen (for example when the source of halogen is POCI3, then LG2is Cl).

[0149] The compound of formula (XI) is reacted with a suitably substituted compound of formula (XII), a known compound or compound prepared by known methods, in the presence of a suitably selected coupling agent such as rac-BINAP Pd G4, SPhos Pd G3, XPhos Pd G3, XantPhos Pd G3, and the like; in the presence of a suitably selected base such as K3PO4, CS2CO3, NaOtBu, and the like; in a suitably selected solvent such as dioxane, THF, toluene, and the like; at an elevated temperature, for example at about 90°C; to yield the corresponding compound of formula (XI).

[0150] Compounds of formula (VI) are known compounds or compounds prepared by known methods. For example, 4-(4-(methyl-sulfonyl)-phenyl)-piperazine may be prepared by reacting 1 -bromo-4-(methylsulfonyl)benzene, a known compound with piperazine, a known compound; in the presence of a coupling agent such as Pd2(dba)3, and the like; in the presence of ligand such as BINAP, and the like; in the presence of a base such as NaOtBu, and the like; in a solvent such as toluene, and the like; at an elevated temperature, for example at about 100°C.

[0151] One skilled in the art will recognize that various substituent groups and I or functional groups on said substituent groups (for example -OH, -NH2, -C(O)OH, etc.) may be protected prior to any reaction step, and then de-protected at a later step in the synthesis, as would be desirable or necessary, according to methods well known to those skilled in the art.

[0152] As more extensively provided in this written description, terms such as “reacting” and “reacted” are used herein in reference to a chemical entity that is any one of: (a) the actually recited form of such chemical entity, and (b) any of the forms of such chemical entity in the medium in which the compound is being considered when named.

[0153] One skilled in the art will recognize that, where not otherwise specified, the reaction step(s) is performed under suitable conditions, according to known methods, to provide the desired product. One skilled in the art will further recognize that, in the specification and claims as presented herein, wherein a reagent or reagent class / tvoe (e.g. base, solvent, etc.) is recited in more than one step of a process, the individual reagents are independently selected for each reaction step and may be the same of different from each other. For example, wherein two steps of a process recite an organic or inorganic base as a reagent, the organic or inorganic base selected for the first step may be the same or different than the organic or inorganic base of the second step. Further, one skilled in the art will recognize that wherein a reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems. One skilled in the art will recognize that wherein a reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.

[0154] One skilled in the art will further recognize that the reaction or process step(s) as herein described are allowed to proceed for a sufficient period of time until the reaction is complete, as determined by any method known to one skilled in the art, for example, chromatography (e.g. HPLC), thin layer chromatography (TLC), etc. In this context a “completed reaction or process step” shall mean that the reaction mixture contains a diminished amount of the starting material(s) I reagent(s) and an increased amount of the desired product(s), as compared to the amounts of each present at the beginning of the reaction.

[0155] To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about”. It is understood that whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and / or measurement conditions for such given value.

[0156] To provide a more concise description, some of the quantitative expressions herein are recited as a range from about amount X to about amount Y. It is understood that wherein a range is recited, the range is not limited to the recited upper and lower bounds, but rather includes the full range from about amount X through about amount Y, or any amount or range therein.

[0157] Examples of suitable solvents, bases, reaction temperatures, and other reaction parameters and components are provided in the detailed descriptions which follow herein. One skilled in the art will recognize that the listing of said examples is not intended, and should not be construed, as limiting in any way the invention set forth in the claims which follow thereafter.

[0158] As used herein, unless otherwise noted, the term “leaving group” shall mean a charged or uncharged atom or group which departs during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like.

[0159] During any of the processes for preparation of the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective , John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

[0160] As used herein, unless otherwise noted, the term “nitrogen protecting group” shall mean a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction. Suitable nitrogen protecting groups include, but are not limited to carbamates - groups of the formula -C(O)O-R wherein R is for example methyl, ethyl, t-butyl, benzyl, phenylethyl, CH2=CH-CH2-, and the like; amides - groups of the formula -C(O)- R’ wherein R’ is for example methyl, phenyl, trifluoromethyl, and the like; N-sulfonyl derivatives - groups of the formula -SO2-R” wherein R” is for example tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogen protecting groups may be measured in texts such as T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 .

[0161] As used herein, unless otherwise noted, the term “oxygen protecting group” shall mean a group which may be attached to an oxygen atom to protect said oxygen atom from participating in a reaction and which may be readily removed following the reaction. Suitable oxygen protecting groups include, but are not limited to, acetyl, benzoyl, t-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, THP, and the like. Other suitable oxygen protecting groups may be measured in texts such as T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

[0162] Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartaric acid and / or (+)-d i-p-tol uoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.

[0163] Additionally, chiral HPLC against a standard may be used to determine percent enantiomeric excess (%ee). The enantiomeric excess may be calculated as follows [ (Rmoles-Smoles) / (Rmoles+Smoles) ] X 100% where Rmoles and Smoles are the R and S mole fractions in the mixture such that Rmoles+Smoles = 1 . The enantiomeric excess may alternatively be calculated from the specific rotations of the desired enantiomer and the prepared mixture as follows: ee = ([oc-obs] I [oc-max]) X 100.

[0164] Methods of Treatment I Disorders Mediated by BFL-1 Receptor

[0165] The present invention is further directed to methods of treating a cancers mediated by the BFL-1 receptor (including, but not limited to leukemias and lymphomascomprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I) or compound of formula (II).

[0166] As used herein, unless otherwise noted the term “cancer mediated by the BFL-1 receptor” shall include leukemias and lymphomas. Leukemias include, but are not limited to, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), (acute) T-cell leukemia, acute monocytic leukemia, acute promyelocytic leukemia (APL), bisphenotypic B myelomonocytic leukemia, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia, myelodysplastic syndrome (MDS) (which can develop into an acute myeloid leukemia). Lymphomas include, but are not limited to, AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), subtypes of NHL such as Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell DLBCL, double-hit lymphoma and double-expressor lymphoma; anaplastic large cell lymphoma, marginal B cell lymphoma and primary mediastinal B-cell lymphoma, immunoblastic large cell lymphoma, Burkitt lymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoplasmatic lymphoma, precursor B -lymphoblastic lymphoma, lymphoma of the central nervous system, small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL); T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma; sarcomas including but not limited to sarcoma of the soft tissue, gliosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma; and other cancers, such as solid tumors, including but not limited to breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma.

[0167] In certain embodiments, the cancer mediated by the BFL-1 receptor is a leukemia. In certain embodiments, the cancer mediate by the BFL-1 receptor is a leukemia selected from the group consisting of acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS). In certain embodiments, the cancer mediated by the BFL-1 receptor is a leukemia is acute myeloid leukemia (AML).

[0168] In certain embodiments, the cancer mediated by the BFL-1 receptor is a lymphoma. In certain embodiments, the cancer mediated by the BFL-1 receptor is a lymphoma selected from the group consisting of AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), subtypes of NHL such as Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell DLBCL, double-hit lymphoma and double-expressor lymphoma; anaplastic large cell lymphoma, marginal B cell lymphoma and primary mediastinal B-cell lymphoma, immunoblastic large cell lymphoma, Burkitt lymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoplasmatic lymphoma, precursor B -lymphoblastic lymphoma, lymphoma of the central nervous system, small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL). In certain embodiments, the cancer mediated by the BFL- 1 receptor is a lymphoma selected from the group consisting of T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma. In certain embodiments, the cancer mediated by the BFL-1 receptor is a sarcoma selected from the group consisting sarcoma of the soft tissue, gliosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma. In certain embodiments, the cancer mediated by the BFL-1 receptor is a solid tumor, selected from the group consisting of breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma. In certain embodiments, the cancer mediated by the BFL-1 receptor is a leukemia is Diffuse Large Cell Lymphoma (DLBCL).

[0169] As used herein, unless otherwise noted, the terms “treating”, “treatment” and the like, shall include the management and care of a subject or patient, preferably a mammal, more preferably a human, for the purpose of combating a disease, condition, or disorder and includes the administration of any of the compounds of the present invention to prevent the onset of symptoms or complications, alleviate symptoms or complications, slow the progression of the disease or disorder, or eliminate the disease, condition, or disorder. The terms "treating" or "treatment" further include: (a) inhibiting the disease-state, i.e. , arresting its development; and / or (b) relieving the disease-state, i.e. , causing regression of the disease state. As used herein, "risk reduction" includes treatment which lowers the incidence of development or progression of a disease, disorder or condition. The terms “subject” and “patient” as used herein, refers to an animal, preferably a mammal, most preferably a human, who is the object of treatment, observation, clinical trial or experiment. Preferably, the subject or patient has experienced and I or exhibited at least one symptom of the disease, disorder or condition to be treated.

[0170] The term “therapeutically effective amount” as used herein, means the amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. Preferably, the therapeutically effective amount results in the alleviation of at least one symptom of the disease, disorder or condition being treated.

[0171] Pharmaceutical Compositions

[0172] The present invention is further directed to pharmaceutical compositions comprising, consisting of, or consisting essentially of a compound of formula (I), or a compound of formula (II) as described herein. The present invention is further directed to pharmaceutical compositions comprising, consisting of, or consisting essentially of a compound of formula (I), or a compound of formula (II) as described herein and one or more pharmaceutically acceptable carriers or excipients.

[0173] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

[0174] As used herein, the terms "combination" and "pharmaceutical combination" refer to either: 1 ) a fixed dose combination in one dosage unit form; or 2) a non-fixed dose combination, optionally packaged together for combined administration.

[0175] The present invention further comprises pharmaceutical compositions containing a compound of formula (I), or compound of formula (II) with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing one or more of the compounds of the present invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral). Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption. For parenteral administration, the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.

[0176] To prepare the pharmaceutical compositions of this invention, one or more compounds of the present invention as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules, caplets, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 0.01 mg to about 1000 mg or any amount or range therein, and may be given at a dosage of from about 0.05 mg / day to about 1000 mg / day, or any amount or range therein, about 0.1 mg / day to about 500 mg / day, or any amount or range therein, preferably from about 1 mg / day to about 250 mg / day, or any amount or range therein.

[0177] The dosages, however, may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.

[0178] Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these pre-formulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid pre- formulation composition is then subdivided into unit dosage forms of the type described above containing from about 0.01 mg to about 1 ,000 mg, or any amount or range therein, of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form yielding the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

[0179] The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

[0180] The method of the treatment of the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.01 mg and about 1000 mg of the compound, or any amount or range therein, preferably from about 0.05 mg to about 500 mg of the compound, or any amount or range therein, more preferably from about 0.1 mg to about 500 mg of the compound, or any amount or range therein, more preferably from about 0.1 mg to about 500 mg of the compound, or any amount or range therein, more preferably from about 10 mg to about 500 mg of the compound, or any amount or range therein; and may be constituted into any form suitable for the mode of administration selected. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

[0181] Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

[0182] For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders; lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

[0183] The liquid forms may include suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.

[0184] To prepare a pharmaceutical composition of the present invention, a compound of formula (I), or compound of formula (II) as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be measured in The Handbook of

[0185] Pharmaceutical , published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain. Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical

[0186] Dosage Forms: Tablets, Second Edition, Revised and , Volumes 1 -3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1 - 2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1 -2, edited by Lieberman et al; published by Marcel Dekker, Inc.

[0187] Compounds of the present invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of cancers mediated by BFL-1 (including leukemias and lymphomas) is reguired.

[0188] The daily dosage of the products may be varied over a wide range from about 0.01 mg to about 1 ,000 mg per adult human per day, or any amount or range therein. For oral administration, the compositions are preferably provided in the form of tablets containing, 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug may be ordinarily supplied at a dosage level of from about 0.005 mg / kg to about 10 mg / kg of body weight per day, or any amount or range therein. Preferably, the range is from about 0.01 to about 5.0 mg / kg of body weight per day, or any amount or range therein, more preferably, from about 0.1 to about 1 .0 mg / kg of body weight per day, or any amount or range therein, more preferably, from about 0.1 to about 0.5 mg / kg of body weight per day, or any amount or range therein. The compounds may be administered on a regimen of 1 to 4 times per day.

[0189] Examples

[0190] The following Examples are set forth to aid in the understanding of the invention and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.

[0191] Unless otherwise indicated in the examples, all temperature is expressed in Centigrade (°C). All reactions were conducted under an inert atmosphere at ambient temperature unless otherwise noted. Unless otherwise specified, reaction solutions were stirred at room temperature under a N2(g) or Ar<g) atmosphere. Reagents employed without synthetic details are commercially available or made according to known methods, for example according to literature procedures. When solutions were “concentrated to dryness”, they were concentrated using a rotary evaporator under reduced pressure; when solutions were dried, they were typically dried over a drying agent such as MgSC or Na2SO4. Where a synthesis product is listed as having been isolated as a residue, it will be understood by those skilled in the art that the term “residue” does not limit the physical state in which the product was isolated and may include, for example, a solid, an oil, a foam, a gum, a syrup, and the like.

[0192] In obtaining the compounds described in the examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.

[0193] LC-MS: Unless otherwise indicated, the analytical LC-MS system used consisted of one of the following: 1 ) Shimadzu LCMS-2020 with electrospray ionization (ESI) in positive ion detection mode with a HALO C18 column, 30 x 5.0 mm, 2.7 pm. Mobile phase A was water containing 0.05% TFA and mobile phase B was acetonitrile containing 0.05% TFA with a flow rate of 1 .5 mL / min. 2) Agilent 1260 Inifinity II with electrospray ionization (ESI) in positive ion detection mode with an InfinityLab Poroshell 120 EC-C18 column, 50 x 2.1 mm, 2.7 pm. Mobile phase A was water containing 0.1% TFA and mobile phase B was acetonitrile containing 0.1% TFA with a flow rate of 1 .2 mL / min. Mobile phase gradients were optimized for the individual compounds. Calculated mass corresponds to the exact mass.

[0194] Normal phase flash chromatography: Unless otherwise noted, normal phase flash column chromatography (FCC) was performed on silica gel with pre-packaged silica gel columns (such as RediSep®).

[0195] NMR: Unless otherwise noted,1H NMR and19F NMR spectra were acquired using 600 MHz spectrometers, 400 MHz spectrometers, 356 MHz spectrometers or 300 MHz spectrometers in a suitably selected deuterated solvent such as Dimethyl Sulfoxide-de, Chloroform-d, Methanol-d4, Deuterium Oxide, Acetic Acid-d4, Acetone-de, Acetonitrile-da, Benzene-de, Cyclohexane-di2, N, N-Dimethyl-formamide-d?, 1 ,4- Dioxane-ds, Ethanol-de, Methylene Chloride-d2, Pyridine-ds, 1 ,1 ,2,2-Tetrachloroethane- d2, Tetrahydrofuran-ds, Toluene-ds, Trifluoroacetic Acid-d, Trifluoroethanol-da, and the like. NMR data are reported in parts per million (5) and are referenced to the residual solvent signal of the deuterated solvent or TMS (Trimethylsilane). Coupling constants (J) are reported in hertz (Hz). The nature of the shifts as to multiplicity is reported as s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (double of triplets), td (triplet of doublets), dq (doublet of quartets), tt (triplet of triplets), tdd (triplet of doublet of doublets), dtd (doublet of triplet of doublets), ddt (doublet of doublet of triplets), qd (quartet of doublets), qt (quartet of triplets), m (multiplet), br (broad). It will be understood that for compounds comprising an exchangeable proton, said proton may or may not be visible on an NMR spectrum depending on the choice of solvent used for running the NMR spectrum and the concentration of the compound in the solution.

[0196] Intermediate Synthesis Examples

[0197] Intermediate A: 3-Bromo-5-methoxy-2,6-naphthyridine-1 -carboxylic acid.

[0198] Step A: 2-Fluoro-4-iodonicotinaldehyde. To a solution of 2-fluoro-4-iodopyridine (1 .50 kg, 6.73 mol) in THF (15.0 L) was added LDA (2 M, 3.70 L) at -78 °C under N2. The reaction mixture was stirred at -78 °C for 30 minutes under N2, then ethyl formate (1 .49 kg, 20.2 mol, 1 .62 L) was added. The reaction mixture was allowed to warm to 25 °C and stirred for 30 minutes under N2. The reaction was quenched with saturated aqueous solution of ammonium chloride (20.0 L) and the mixture was then stirred at 25 °C for 10 minutes. The aqueous phase was extracted with ethyl acetate (7.00 L x 3). The combined organic layers were washed with brine (7.00 L x 3), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 0 -10%) to yield the title compound as a yellow solid.1H NMR (400 MHz, CDCI3) 6 10.14 (d, J= 1 .2 Hz, 1 H), 7.97 (d, J = 5.2 Hz, 1 H), 7.87 (d, J = 5.2 Hz, 1 H).

[0199] Step B: 4-lodo-2-methoxynicotinaldehyde. A solution of 2-fluoro-4- iodonicotinaldehyde (300 g x 6, 1 .20 mol) in MeOH (3.00 L) was stirred at 10 °C for 30 minutes under N2, then NaOCHa (103 g, 1 .91 mol) was added at 20 °C under N2. The reaction mixture was stirred at 20 °C for 4 hours then concentrated under vacuum. To the residue was added H2O (5.00 L) and the mixture was extracted with ethyl acetate (5.00 L x 3). The combined organic layers were washed with brine (5.00 L x 2), dried with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 0 ~5%) and re-purified by re-crystallization from petroleum ether I ethyl acetate =10:1 (3.00 L) at 20 °C to yield the title compound as a light yellow solid.1H NMR (400 MHz, CDCI3) 5 10.20 (s, 1 H), 7.85 (d, J = 5.2 Hz, 1 H), 7.53 (d, J = 5.2 Hz, 1 H), 4.05 (s, 3H).

[0200] Step C: (4-lodo-2-methoxypyridin-3-yl)methanol. To a solution of 4-iodo-2- methoxynicotinaldehyde (300 g, 1.14 mol) in MeOH (3.00 L) cooled to 0 °C was added NaBH4 (51 .8 g, 1 .37 mol) under N2. The mixture was stirred at 0 °C for 30 minutes, the reaction was then quenched with water (2.00 L) and concentrated in vacuum. The aqueous phase was extracted with ethyl acetate (3.00 L x 3). The combined organic layers were washed with brine (2.00 L x 3), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum to yield the title compound as a white solid, which was used in the next step without further purification. MS (ESI): mass calculated for C7H8INO2, 265.0; m / z measured, 265.9 [M+H]+.1H NMR (400 MHz, CDCI3) 5 7.69 (d, J = 5.2 Hz, 1 H), 7.33 (d, J = 5.2 Hz, 1 H), 4.81 (s, 2H), 3.97 (s, 3H), 2.60 - 2.28 (m, 1 H).

[0201] Step D: 3-(Chloromethyl)-4-iodo-2-methoxypyridine. To a solution of (4-iodo-2- methoxypyridin-3-yl)methanol (210 g, 792.31 mmol) and TEA (165.4 mL, 1 .190 mol) in DCM (2000 mL) cooled to 0 °C, was added MsCI (117.99 g, 1.03 mol, 79.72 mL) dropwise. The mixture was stirred at 25 °C for 5 hours. The reaction was quenched with aqueous NaHCOs (-10%, 2000 mL) to adjust the value of pH ~ 8, then extracted with DCM (500 mL x 2). The combined organic layers were washed with water (1000 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield the title compound as a yellow solid. MS (ESI): mass calculated for C7H7CIINO, 282.9; m / z measured, 283.9 [M+H]+.1H NMR (400 MHz, CDCI3) 5 7.73 (d, J = 5.2 Hz, 1 H), 7.36 (d, J = 5.2 Hz, 1 H), 4.77 (s, 2H), 4.00 (s, 3H).

[0202] Step E: 2-(4-lodo-2-methoxypyridin-3-yl)acetonitrile. To a solution of 3- (chloromethyl)-4-iodo-2-methoxypyridine (225 g, 793.67 mmol) in MeCN (2000 mL) was added TBAF (1 M, 793.67 mL) and TMSCN (157.47 g, 1 .59 mol, 198.58 mL). The reaction mixture was stirred at 80 °C for 2 hours, then concentrated in vacuum. The residue was diluted with EtOAc (2000 mL) and the organic phase was washed with water (800 mL x 3). The combined aqueous layers were extracted with ethyl acetate (300 mL x 2). The combined organic layers were washed with brine (1000 mL x 2), then dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=5 / 1 ) to yield the title compound as a white solid.1H NMR (400 MHz, CDCI3) 5 7.77 (d, J = 5.4 Hz, 1 H), 7.37 (d, J - 5.4 Hz, 1 H), 4.01 (s, 3H), 3.87 (s, 2H).

[0203] Step F: 3-(Cyanomethyl)-2-methoxyisonicotinonitrile. A solution of 2-(4-iodo-2- methoxypyridin-3-yl)acetonitrile (229 g, 835.59 mmol), Zn(CN)2 (98.12 g, 835.59 mmol, 53.04mL) and Pd(PPh3)4 (19.31 g, 16.71 mmol) in DMF (1500 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 120 °C for 2 hours under N2 atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure then poured into saturated Na2COs (3000 mL). The aqueous phase was extracted with EtOAc (1000 mL x 3) and the combined organic layers were washed with brine (1000 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=20%) to yield the title compound as a white solid.1H NMR (400 MHz, CDCI3) 5 8.33 (d, J = 5.2 Hz, 1 H), 7.15 (d, J = 5.2 Hz, 1 H), 4.09 (s, 3H), 3.86 (s, 2H).

[0204] Step G: 1 -Bromo-5-methoxy-2,6-naphthyridin-3-amine. HBr / AcOH (894.00 g, 3.65 mol, 600 mL, 33% purity) was added to 3-(cyanomethyl)-2- methoxyisonicotinonitrile (60 g, 346.48 mmol) at 0 °C then the mixture was stirred at 0 °C for 30 minutes. The reaction mixture was added to ice-water 5000 mL and stirred for 30 minutes at 20 °C, then filtered and dried in vacuum. The cake was collected and triturated with sat. aq. NaHCOs (5000 mL) after that the mixture was extracted with ethyl acetate (3000 mL x 2), dried with Na2SO4, filtered, and concentrated to yield the title as a yellow solid. MS (ESI): mass calculated for CgHsBrNsO, 253.0; m / z measured, 253.9 [M+H]+.1H NMR (400 MHz, CDCI3) 5 7.72 (d, J = 6.0 Hz, 1 H), 7.19 (dd, J= 0.8, 6.1 Hz, 1 H), 6.88 (d, J= 0.8 Hz, 1 H), 6.66 (s, 2H), 4.01 (s, 3H).

[0205] Step H: Methyl 3-amino-5-methoxy-2,6-naphthyridine-1 -carboxylate. To a solution of 1 -bromo-5-methoxy-2,6-naphthyridin-3-amine (220 g, 865.86 mmol), Xantphos (20.04 g, 34.63 mmol) and TEA (262.85 g, 2.60 mol, 361 .55 mL) in DMF (3000 mL) and MeOH (1000 mL) was added Pd(OAc)2 (3.89 g, 17.32 mmol) under N2, then the mixture was stirred under CO (865.86 mmol) (50 psi) at 70 °C for 18 hours. The reaction mixture was filtered and concentrated in vacuum. The residue was poured into H2O (3000 mL) and the aqueous phase was extracted with ethyl acetate (1000 mL x 3). The combined organic layers were washed with brine (1000 mL), dried over anhydrous Na2SO4, concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 3 / 1 ) to yield the titled compound as a yellow solid. MS (ESI): mass calculated for C11H11N3O3, 233.1 ; m / z measured, 234.1 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 6 7.69 (d, J = 6.4 Hz, 1 H), 7.61 (dd, J = 0.8, 6.3 Hz, 1 H), 7.15 (d, J - 0.8 Hz, 1 H), 6.60 (s, 2H), 4.02 (s, 3H), 3.92 (s, 3H).

[0206] Step I: Methyl 3-bromo-5-methoxy-2,6-naphthyridine-1 -carboxylate. To a solution of methyl 3-amino-5-methoxy-2,6-naphthyridine-1 -carboxylate (70.0 g, 300.14 mmol) in 2-methyl-tetrahydrofuran (1200 mL) was added CuBr2 (134.07 g, 600.28 mmol, 28.11 mL) at 25 °C. The reaction mixture was stirred at 60 °C for 30 minutes then tert-butyl nitrate (46.4 g, 450 mmol, 53.55 mL) was added portion wise over 30 minutes. The reaction mixture was stirred at 60 °C for 3 hours, filtered and concentrated in vacuum. The residue was poured into H2O (2000 mL) and the aqueous phase was extracted with ethyl acetate (1000 mL x 3). The combined organic layers were washed with brine (2000 mL x 2), dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 15%) to yield the title compound as a yellow solid. MS (ESI): mass calculated for CuHgBrlShOs, 296.0; m / z measured, 296.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 8.45 (s, 1 H), 8.28 (d, J = 6.4 Hz, 1 H), 7.98 (dd, J = 0.8, 6.2 Hz, 1 H), 4.11 (s, 3H), 4.00 (s, 3H).

[0207] Step J: 3-Bromo-5-methoxy-2,6-naphthyridine-1 -carboxylic acid. To a solution of methyl 3-bromo-5-methoxy-2,6-naphthyridine-1 -carboxylate (73.0 g, 246 mmol) in THF (1800 mL) was added LiOH (1 M, 491 mL), then the mixture was stirred at 25 °C for 3 hours. The reaction mixture was concentrated under vacuum and extracted with ethyl acetate (300 mL x 2). The aqueous phase was adjusted to pH ~ 4 with 1 M aq HCI and a solid precipitated. The solid was filtrated and collected. The filtrate was extracted with ethyl acetate (300 mL x 3) and the combined organic layers were washed with brine (500 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to yield the title compound as a light yellow solid. MS (ESI): mass calculated for CioH7BrN203, 282.0; m / z measured, 284.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.36 (d, J = 0.8 Hz, 1 H), 8.24 (d, J = 6.4 Hz, 1 H), 7.95 (dd, J = 0.8, 6.4 Hz, 1 H), 4.09 (s,

[0208] 3H).

[0209] Intermediate B: 1 -(4-(Methylsulfonyl)phenyl)piperazine.

[0210] A suspension of 1 -bromo-4-(methylsulfonyl)benzene (200 g, 851 mmol), piperazine (733 g, 8.51 mol), Pd2(dba)3 (23 g, 26 mmol), BINAP (21 g, 34 mmol) and t- BuONa (123 g, 1 .28 mol) in toluene (2 L) was degassed and purged with N2 three times, and the mixture was stirred at 110 °C for 12 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (5 L) and acidified with HCI to pH 3~4. The aqueous mixture was extracted twice with DCM (5 L). The aqueous layer was then adjusted to pH -10-11 with Na2COs and extracted twice with DCM (5 L). The combined organic layers were washed twice with brine (10 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound as a yellow solid. MS (ESI): mass calculated for C11H16N2O2S, 240.1 ; m / z measured, 241.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 7.69 - 7.62 (m, 2H), 7.05 (d, J = 9.2 Hz, 2H), 3.27 - 3.20 (m, 4H), 3.08 (s, 3H), 2.84 - 2.78 (m, 4H).

[0211] Intermediate C: (5-Chloro-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone. Step A: (3-Bromo-5-methoxy-2,6-naphthyridin-1 -yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone. To a solution of 3-bromo-5-methoxy-

[0212] 2.6-naphthyridine-1 -carboxylic acid compound (Intermediate A, 15.0 g, 53.0 mmol) in DMF (50 mL) was added HATU (44.3 g, 117 mmol) and EtsN (21.5 g, 212 mmol, 29.5 mL). The reaction mixture was stirred at 25 °C for 30 minutes then 1 -(4- (methylsulfonyl)phenyl)piperazine (Intermediate B, 12.7 g, 53.0 mmol, 1.00 eq) was added, and the reaction mixture was stirred at 25 °C for 2 hours. The mixture was diluted with water (150 mL) and a solid precipitated. The solid was filtered to yield the title compound as a yellow solid, which was used in the next without further purification. MS (ESI): mass calculated for C2iH2iBrN4O4S, 504.1 ; m / z measured, 505.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.29 (s, 1 H), 8.24 (d, J = 6.1 Hz, 1 H), 7.70 (d, J = 9.0 Hz, 2H), 7.41 (dd, J = 6.1 , 0.6 Hz, 1 H), 7.09 (d, J = 9.0 Hz, 2H), 4.11 (s, 3H), 3.90 (br d, J = 5.8 Hz, 2H), 3.55-3.62 (m, 2H), 3.31 (br s, 2H), 3.29 (br s, 2H), 3.09 ppm (s, 3H).

[0213] Step B: (5-Methoxy-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone. To a solution of (3-bromo-5-methoxy-

[0214] 2.6-naphthyridin-1 -yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1 -yl)methanone (26.0 g, 51. 5 mmol) and 4,4,5,5-tetramethyl-2-(2,3,6-trimethylphenyl)-1 ,3,2-dioxaborolane (15.2 g, 61 .7 mmol) in DMF (702 mL) and H2O (78 mL) was added K3PO4 (32.8 g, 154 mmol) at 25 °C. The mixture was degassed with N2 for 1 minute, then CataCXium® A Pd G3 (3.75 g, 5.14 mmol) was added and the mixture stirred at 80 °C for 12 hours. The reaction mixture was cooled to 25 °C, filtered, diluted with water (1500 mL). The precipitated solid was filtered, then was dissolved into DCM, diluted with water (1000 mL), extracted with DCM (500 mL x 3). The combined organic layers were washed with brine (1000 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 0-30% Ethyl acetate / DCM). The residue was then triturated with MTBE at 25 °C for 1 hour then filtered to yield the title as a yellow solid. MS (ESI): mass calculated for C30H32N4O4S, 544.2; m / z measured, 545.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.24 (d, J - 6.0 Hz, 1 H), 7.88 (d, J - 0.8 Hz, 1 H), 7.68 (d, J = 9.0 Hz, 2H), 7.45 (dd, J = 6.1 , 0.8 Hz, 1 H), 7.16 (d, J= 7.8 Hz, 1 H), 7.03-7.12 (m, 3H), 4.10 (s, 3H), 3.87-3.94 (m, 2H), 3.53-3.60 (m, 2H), 3.31 (br d, J= 6.5 Hz, 4H), 3.09 (s, 3H), 2.26 (s, 3H), 1 .94 (s, 3H), 1 .88 ppm (s, 3H).

[0215] Step C: (5-Hydroxy-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl) (4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone. To a mixture of Nal (25.3 g, 169 mmol) in ACN (690 mL) was added TMSCI (18.4 g, 169 mmol, 21 .4 mL) at 25 °C. The mixture was stirred at 25 °C for 5 minutes, then (5-methoxy-3-(2,3,6-trimethylphenyl)- 2,6-naphthyridin-1 -yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1 -yl)methanone (23.0 g, 42.2 mmol) was added and the mixture was stirred at 25 °C for 1 hour. The reaction was quenched with sat. aq. Na2SOs (1000 mL) and the mixture extracted with DCM / MeOH = 10:1 (500 mL x 3). The combined organic layers were washed with brine (1000 mL), dried with Na2SO4, filtered, and concentrated under vacuum to yield the title compound as an off-white solid, which was used in the next step without further purification. MS (ESI): mass calculated for C29H30N4O4S, 530.2; m / z measured, 531.3 [M+H]+.

[0216] Step D: (5-Chloro-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone. To (5-hydroxy-3-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1 - yl)methanone (12.0 g, 22.6 mmol) was added POCI3 (119 g, 775 mmol, 72.0 mL) at 25 °C. The mixture was stirred at 100 °C for 1 hour. The reaction was cooled to 15 °C and the POCI3 was removed by reduced pressure distillation. The residue was dissolved in DCM (150 mL) and poured slowly into warm water (150 mL) at 15-20 °C. The solution was stirred for until no more gas was released. The content of the flask was transferred to a separatory funnel and the organic layer was separated. The aqueous phase was extracted with DCM (500 mL). The combined organic layers were washed with H2O (100 mLx3), brine (100 mL), dried with Na2SO4, filtered and the solvent was removed in vacuo. The residue was triturated with MTBE at 25 °C for 1 hour and filtered to yield the title compound as a purple solid. MS (ESI): mass calculated for C29H29CIN4O3S, 548.2; m / z measured, 549.2 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 6 8.56 (d, J = 5.8 Hz, 1 H), 7.96-8.03 (m, 2H), 7.69 (d, J = 9.0 Hz, 2H), 7.19 (d, J = 7.8 Hz, 1 H), 7.08 (d, J = 9.1 Hz, 3H), 3.92 (br s, 2H), 3.58 (br s, 2H), 3.30 (br s, 4H), 3.09 (s, 3H), 2.27 (s, 3H), 1.97 (s, 3H), 1.91 ppm (s, 3H).

[0217] Intermediate D: (R)-2-Amino- / V-((1 s,3S)-3-hydroxy-3-methylcyclobutyl)-3-(4- (trifluoromethyl)phenyl)propanamide HCI.

[0218]

[0219] Step A: tert-Butyl (( / =?)- 1 -(((1 s,3S)-3-hydroxy-3-methylcyclobutyl)amino)-1 -oxo-3- (4-(trifluoromethyl)phenyl)propan-2-yl)carbamate. HATU (2.6 g, 6.8 mmol) was added to a mixture of (R)-2-((tert-butoxycarbonyl)amino)-3-(4-(trifluoromethyl)phenyl)propanoic acid (1.9 g, 5.7 mmol), (1 s,3s)-3-amino-1 -methylcyclobutan-1 -ol hydrochloride (950 mg, 6.90 mmol) and EtsN (2.8 g, 27.67 mmol) in DMF (38 mL). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with H2O (50 mL) and filtered. The filter cake was washed with H2O (10 mL x 3), collected and dried in vacuo to yield the title compound as a white solid. MS (ESI): mass calculated for C20H27F3N2O4, 416.2; m / z measured, 361.3 [M-56+H]+(loss of tert-butyl group).1H NMR (400 MHz, CDCI3) 5 7.56 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 6.04 (d, J=7.7 Hz, 1 H), 4.98 (s, 1 H), 4.29 (d, J=7.4 Hz, 1 H), 3.93 (sxt, J=7.8 Hz, 1 H), 3.21 - 3.02 (m, 2H), 2.55 - 2.39 (m, 2H), 1 .97 - 1 .78 (m, 2H), 1 .41 (s, 9H), 1 .37 (s, 3H).19F NMR (376 MHz, CDCI3) 5 -62.50 (s, 1 F).

[0220] Step B: (F?)-2-Amino- / V-((1 s,3S)-3-hydroxy-3-methylcyclobutyl)-3-(4- (trifluoromethyl)phenyl)propanamide HCI. 4 M HCI / 1 ,4-dioxane (42 mL) was added to a mixture of tert-butyl ((F?)-1 -(((1 s,3S)-3-hydroxy-3-methylcyclobutyl)amino)-1 -oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)carbamate (2.2 g, 5.28 mmol) in DCM (84 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness in vacuo to yield the title compound as a white solid. MS (ESI): mass calculated for C15H19F3N2O2, 316.1 ; m / z measured, 317.3 [M+H]+.1H NMR (400 MHz, DMSO-ofe) 5 8.81 - 8.72 (m, 1 H), 8.36 (br s, 3H), 7.69 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 5.03 (br s, 1 H), 3.96 (br s, 1 H), 3.73 (qd, J=7.9, 15.9 Hz, 1 H), 3.11 (br d, J=6.9 Hz, 2H), 2.25 - 2.08 (m, 2H), 1 .97 - 1 .87 (m, 1 H), 1 .73 - 1 .66 (m, 1 H), 1 .20 (s, 3H).19F NMR (376 MHz, DMSO-d6) 5 -60.87 (s, 1 F).

[0221] Intermediate E: (F?)-3-Amino-2-methyl-4-(4-(trifluoromethyl)phenyl)butan-2-ol HCI.

[0222] Step A: Ethyl (F?)-2-((tert-butoxycarbonyl)amino)-3-(4- (trifluoromethyl)phenyl)propanoate. A mixture of Boc-4-(trifluoromethyl)-D-phenylalanine (10 g, 30 mmol) and CS2CO3 (29.3 g, 90.0 mmol) in DMF (200 mL) was stirred at room temperature for 15 minutes before iodoethane (3.6 mL, 45 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered, and the filter cake was washed with EtOAc (300 mL). The filtrate was washed with brine (3x 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by chromatography (FCC, silica gel, 0-60% EtOAc in petroleum ether) yielded the title compound as a white solid. MS (ESI): mass calculated for C17H22F3NO4, 361 .2; m / z measured, 262.2 [M-100+H]+(loss of Boc group).1H NMR (400 MHz, CDCI3) 5 7.57 (br d, J = 7.8 Hz, 2H), 7.33 - 7.25 (m, 2H), 5.05 (br s, 1 H), 4.61 (br d, J = 6.8 Hz, 1 H), 4.24 - 4.12 (m, 2H), 3.26 - 3.05 (m, 2H), 1.43 (s, 9H), 1.25 (br t, J = 7.2 Hz, 3H).19F NMR (376 MHz, CDCI3) 5 -62.52 (br s, 1 F).

[0223] Step B: tert-Butyl (F?)-(3-hydroxy-3-methyl-1 -(4-(trifluoromethyl)phenyl)butan-2- yl)carbamate. To a mixture of ethyl (F?)-2-((tert-butoxycarbonyl)amino)-3-(4- (trifluoromethyl)phenyl)propanoate (100 mg, 271 pmol) in THF (3 mL) was added CHsMgBr (3 M solution in ether, 0.45 mL, 1 .35 mmol) at 0 °C under N2. The mixture was stirred at 0 °C for 2 hours then sat. aq. NH4CI (15 mL) was added to the mixture dropwise at 0 °C. The mixture was extracted with ethyl acetate (15 mL x 3). The combined organic layers were separated, washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 60% ethyl acetate in petroleum ether) to yield the title compound as a white solid. MS (ESI): mass calculated for C17H24F3NO3, 347.2; m / z measured, 248.0 [M-100+H]+(loss of Boc group).1H NMR (400 MHz, CDCI3) 5 7.54 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 4.55 (br d, J=9.3 Hz, 1 H), 3.77 - 3.68 (m, 1 H), 3.19 - 3.11 (m, 1 H), 2.73 - 2.64 (m, 1 H), 2.13 (br s, 1 H), 1.34 (s, 3H), 1.31 (s, 3H), 1 .27 (s, 9H).19F NMR (376 MHz, CDCI3) 6 -62.42 (s, 1 F).

[0224] Step C: (R)-3-Amino-2-methyl-4-(4-(trifluoromethyl)phenyl)butan-2-ol HCI. 4 M HCI / 1 ,4-dioxane (2 mL) was added to a solution of tert-butyl (F?)-(3-hydroxy-3-methyl-1 - (4-(trifluoromethyl)phenyl)butan-2-yl)carbamate (65.0 mg, 181 pmol) in DCM (2 mL). The mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum to yield the title compound as a yellow oil, which was used in the next step without further purification. MS (ESI): mass calculated for C12H16F3NO, 247.1 ; m / z measured, 248.0 [M+H]+.

[0225] Intermediate F: (R)-3-Amino-2-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)butan-2-ol HCI.

[0226] Step A: Methyl (F?)-2-((tert-butoxycarbonyl)amino)-3-(6-(trifluoromethyl)pyridin-3- yl)propanoate. To a solution of methyl (R)-2-amino-3-(6-(trifluoromethyl)pyridin-3- yl)propanoate (1 .0 g, 3.5 mmol) in DCM (35 mL) was added DIPEA (0.73 mL, 4.2 mmol) and BOC2O (0.83 mL, 3.9 mmol). The reaction mixture was stirred at 60 °C overnight, then the volatiles were evaporated. The residue was taken up in EtOAc and the organic phase was washed with a sat. aq. NaHCOs, brine and concentrated to yield the title compound as colorless oil, which was used in the next step without further purification. MS (ESI): mass calculated for C15H19F3N2O4, 348.1 ; m / z measured, 349.1 [M+H]+.

[0227] Step B: tert-Butyl (F?)-(3-hydroxy-3-methyl-1 -(6-(trifluoromethyl)pyridin-3-yl)butan- 2-yl)carbamate. To a solution of methyl (F?)-2-((tert-butoxycarbonyl)amino)-3-(6- (trifluoromethyl)pyridin-3-yl)propanoate (1 .0 g, 2.9 mmol) in THF (14 mL) cooled to 0 °C was added methylmagnesium bromide (3.4M in methyl-THF, 3.4 mL, 11 mmol) and the reaction mixture was stirred for 4 hours. To the reaction mixture was added sat. ammonium chloride and the aqueous phase was extracted with EtOAc. The residue was purified by silica gel flash chromatography (eluent 50% EtOAc / Heptane) to yield the title compound as a white solid. MS (ESI): mass calculated for C16H23F3N2O3, 348.2; m / z measured, 349.1 [M+H]+.

[0228] Step C: (F?)-3-Amino-2-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)butan-2-ol HCI. To a solution of tert-butyl (F?)-(3-hydroxy-3-methyl-1 -(6-(trifluoromethyl)pyridin-3-yl)butan-2- yl)carbamate (950 mg, 2.73 mmol) in DCM (5.4 mL) was added 4M HCI in 1 ,4-dioxane (6.8 mL, 27 mmol) and the reaction mixture was stirred for 1 hour. To the reaction mixture was added diethyl ether and a solid precipitated. The solid was filtered to yield the title compound as a yellow solid, which was used in the next step without further purification. MS (ESI): mass calculated for C11H15F3N2O, 248.1 ; m / z measured, 249.0 [M+H]+.

[0229] Intermediate G: (R)-2-Amino- / V-methyl-3-(4-(trifluoromethyl)phenyl)propanamide HCI.

[0230] Step A: tert-Butyl (F?)-(1 -(methylamino)-1 -oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)carbamate. To a solution of (R)-2-((tert- butoxycarbonyl)amino)-3-(4-(trifluoromethyl)phenyl)propanoic acid (10 g, 30 mmol), methylamine hydrochloride (3.04 g, 45.0 mmol) and triethylamine (20.9 mL, 150 mmol) in DMF (100 mL) at 0°C was added HATU (13.7 g, 36.0 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water (100 mL) was added, and the reaction mixture was extracted with EtOAc (1000 mL). The combined organic extracts were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with DCM / petroleum ether (20 / 1 , 220 mL) at room temperature and the solid was collected by filtration to yield the title compound. MS (ESI): mass calculated for C16H21F3N2O3, 346.2; m / z measured, 291.1 [M-56+H]+(loss of tert-butyl group).1H NMR (400 MHz, CDCI3) 5 7.56 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 7.8 Hz, 2H), 5.90 (br s, 1 H), 5.00 (br s, 1 H), 4.34 (br d, J = 7.5 Hz, 1 H), 3.23-3.14 (m, 1 H), 3.12-3.03 (m, 1 H), 2.76 (d, J = 4.8 Hz, 3H), 1.39 (s, 9H).

[0231] Step B: (R)-2-Amino- / V-methyl-3-(4-(trifluoromethyl)phenyl)propanamide HCI. To a solution of tert-butyl (F?)-(1 -(methylamino)-1 -oxo-3-(4-(trifluoromethyl)phenyl)propan-2- yl)carbamate (9.7 g, 28 mmol) in DCM (100 mL) was added HCI (4M in 1 ,4-dioxane, 28.0 mL, 112 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was filtered and the solid was dried under vacuum to yield the title compound as the hydrochloride salt, which was used directly in the next step. MS (ESI): mass calculated for C11H13F3N2O, 246.1 ; m / z measured, 247.1 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 8.41 (br d, J= 4.3 Hz, 1 H), 8.21 (br s, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.45 (d, J= 8.0 Hz, 2H), 3.96 (t, J= 7.0 Hz, 1 H), 3.18-3.10 (m, 1 H), 3.09-3.01 (m, 1 H), 2.61 (d, J= 4.5 Hz, 3H).19F NMR (376 MHz, DMSO-d6) 5 -60.86 (s, 1 F).

[0232] Intermediate H: (R)-2-Amino-N-methyl-3-(2-nitro-4- (trifluoromethyl)phenyl)propanamide.

[0233] To a mixture of (R)-2-amino- / V-methyl-3-(4-(trifluoromethyl)phenyl)propanamide HCI (Intermediate G, 500 mg, 2.00 mmol) in cone. H2SO4 (5 mL) was added KNO3 (350 mg, 3.46 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The mixture was poured into ice-water (50 mL), basified with 50% aq. NaOH (15 mL) and extracted with ethyl acetate (30 mL x 3). The combined extract was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to yield the title compound as yellow oil, which was used in the next step without further purification. MS (ESI): mass calculated for C11H12F3N3O3, 291.1 ; m / z measured, 292.1 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.20 (s, 1 H), 7.86 - 7.79 (m, 1 H), 7.63 (d, J=8.0 Hz, 1 H), 7.02 (br s, 1 H), 3.71 (br dd, J=5.1 , 7.7 Hz, 1 H), 3.55 (dd, J=4.8, 13.6 Hz, 1 H), 3.13 (dd, J=8.0, 13.6 Hz, 1 H), 2.83 (d, J=4.8 Hz, 3H).19F NMR (376 MHz, CDCI3) 5 -62.90 (s, 1 F).

[0234] Intermediate I: (R)-2-Amino- / V-(1 -cyanocyclopropyl)-3-(4- (trifluoromethyl)phenyl)propanamide.

[0235]

[0236] To a suspension of (F?)-2-((tert-butoxycarbonyl)amino)-3-(4- (trifluoromethyl)phenyl)propanoic acid (590 mg, 1 .77 mmol) in acetonitrile (7 mL) was added 1 -aminocyclopropane-1 -carbonitrile (163 mg, 1 .99 mmol), T3P® (50% solution in EtOAc, 2.1 mL, 3.5 mmol) and DIPEA (1.1 mL, 6.4 mmol). The reaction mixture was stirred at room temperature overnight, then the volatiles were evaporated. The residue was resuspended in 1 ,4-dioxane (6.5 mL) and HCI (4M in 1 ,4-dioxane, 5.3 mL, 21 mmol). The reaction mixture was stirred at room temperature for 16 hours, then the volatiles were evaporated. To the residue was added a saturated aqueous solution of NaHCOa. The layers were separated, and the aqueous phase was extracted three times with EtOAc. The combined organic layers were washed with water, dried over MgSO4, filtered and evaporated to yield the title compound as an orange oil. MS (ESI): mass calculated for C14H14F3N3O, 297.1 ; m / z measured, 298.0 [M+H]+.1H NMR (400 MHz, CDCI3) 5 7.85 (br s, 1 H), 7.59 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 3.66 (dd, J = 8.6, 4.2 Hz, 1 H), 3.26 (dd, J= 13.9, 4.2 Hz, 1 H), 2.92 (dd, J= 13.7, 8.3 Hz, 1 H), 1.62- 1.36 (m, 4H), 1.26-1.12 (m, 2H).

[0237] Intermediate J: (F?)-2-Amino- / V-methyl-3-(5-(trifluoromethyl)pyrimidin-2- yl)propanamide.

[0238] Step A: Methyl (F?)-2-((tert-butoxycarbonyl)amino)-3-(5-(trifluoromethyl)pyrimidin- 2-yl)propanoate. To the activated Zn powder (830 mg, 12.7 mmol) was added DMF (7 mL) and I2 (50.0 mg, 197.00 umol) under N2 at room temperature. After stirring for 20 minutes, a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (1 .2 g, 3.7 mmol) in DMF (4 mL) was added. The reaction mixture was stirred for 30 minutes. To the above mixture was added a mixture of 2-bromo-5-(trifluoromethyl)pyrimidine (1 .0 g, 4.4 mmol), Pd2(dba)3 (100.0 mg, 109.2 pmol) and SPhos (75.0 mg, 183 pmol) in DMF (14 mL). The reaction mixture was stirred at 50 °C overnight. The mixture was quenched with sat. aq. Na2SOs (50 mL) then filtered over Celite®, and the solid was rinsed with ethyl acetate (100 mL). The filtrate was washed with 3% aq. LiCI (100 mL x 4), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 30% ethyl acetate in petroleum ether) to yield title compound as a colorless oil. MS (ESI): mass calculated for C14H18F3N3O4, 349.1 ; m / z measured, 249.7 [M-100+H]+(loss of Boc group).1H NMR (400 MHz, CDCI3) 5 8.91 (s, 2H), 5.68 (br d, J=8.1 Hz, 1 H), 4.98 - 4.79 (m, 1 H), 3.72 (d, J=1 .9 Hz, 3H), 3.69 - 3.51 (m, 2H), 1 .43 (s, 9H).19F NMR (376 MHz, CDCI3) 5 -62.40 (br s, 1 F).

[0239] Step B: tert-Butyl (F?)-(1 -(methylamino)-1 -oxo-3-(5-(trifluoromethyl)pyrimidin-2- yl)propan-2-yl)carbamate. 40% aq. CH3NH2 (1 .45 g, 18.7 mmol) was added to a mixture of methyl (F?)-2-((tert-butoxycarbonyl)amino)-3-(5-(trifluoromethyl)pyrimidin-2- yl)propanoate (430 mg, 1.23 mmol) in MeOH (14 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (12 mL), washed with H2O (12 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to yield the title compound as a yellow solid, which was used in the next step without further purification. MS (ESI): mass calculated for C14H19F3N4O3, 348.1 ; m / z measured, 248.7 [M-100+H]+(loss of Boc group).1H NMR (400 MHz, CDCI3) 5 8.91 (s, 2H), 6.62 - 6.42 (m, 1 H), 6.07 - 5.91 (m, 1 H), 4.91 - 4.64 (m, 1 H), 3.66 (dd, J=5.7, 16.5 Hz, 1 H), 3.48 (dd, J=5.4, 16.4 Hz, 1 H), 2.81 (d, J=4.9 Hz, 3H), 1.45 (s, 9H).19F NMR (376 MHz, CDCI3) 5 -62.39 (s, 1 F).

[0240] Step C: (R)-2-Amino- / V-methyl-3-(5-(trifluoromethyl)pyrimidin-2-yl)propanamide. 4 M HCI / 1 ,4-dioxane (7 mL) was added to the mixture of tert-butyl (F?)-(1 -(methylamino)- 1 -oxo-3-(5-(trifluoromethyl)pyrimidin-2-yl)propan-2-yl)carbamate (430 mg) in DCM (14 mL). The solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness in vacuo. The mixture was diluted with DCM (1 mL), and adjusted the pH to 9 by 25% aq. NH3. The mixture was concentrated to dryness in vacuo. The residue was purified by RP-HPLC (Stationary phase: Welch Xtimate C18, 5 pm, 150 x 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 5 - 35% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as yellow powder. MS (ESI): mass calculated for C9H11F3N4O, 248.1 ; m / z measured, 249.0 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.95 (s, 2H), 7.48 (br d, J=2.0 Hz, 1 H), 4.02 (br dd, J=3.9, 8.6 Hz, 1 H), 3.72 (dd, J=3.8, 15.7 Hz, 1 H), 3.31 (dd, J=8.7, 15.7 Hz, 1 H), 2.87 (d, J=5.0 Hz, 3H);19F NMR (376 MHz, CDCI3) 5 -62.34 (s, 1 F).

[0241] Intermediate K: (R)-2-Amino- / V-methyl-3-(2-(trifluoromethyl)pyrimidin-5- yl)propanamide.

[0242] Step A: Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(2-(trifluoromethyl)pyrimidin- 5-yl)propanoate. A mixture of 5-bromo-2-(trifluoromethyl)pyrimidine (3.55 g, 15.6 mmol), dtbbpy (405 mg, 1.51 mmol), NiBr2 (330 mg, 1.51 mmol), methyl (S)-2-((tert- butoxycarbonyl)amino)-3-iodopropanoate (5.0 g, 15 mmol) and Mn powder (2.5 g, 45 mmol) in a flask was exchanged with Ar, then DMA (80 mL) was added. After purging with Ar, the reaction mixture was placed in a pre-heated oil bath (50 °C) and stirred for 3 hours. The mixture was filtered through a pad of Celite® and the filter cake was rinsed with ethyl acetate (100 mL). The filtrate was diluted with sat. aq. NH4CI (120 mL) and extracted with ethyl acetate (120 mL x 3). The combined organic layers were washed with brine (150 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 100% ethyl acetate in petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C14H18F3N3O4, 349.1 ; m / z measured, 293.8 [M-56+H]+(loss of tert-butyl group).1H NMR (400 MHz, CDCI3) 5 8.70 (s, 2H), 5.18 (d, J=6.2 Hz, 1 H), 4.64 (d, J=5.8 Hz, 1 H), 3.80 (s, 3H), 3.35 (dd, J=5.2, 14.1 Hz, 1 H), 3.11 (dd, J=6.1 , 13.9 Hz, 1 H), 1.42 (s, 9H).19F NMR (376 MHz, CDCI3) 5 -70.26 (s, 1 F). Step B: tert-Butyl (F?)-(1 -(methylamino)-1 -oxo-3-(2-(trifluoromethyl)pyrimidin-5- yl)propan-2-yl)carbamate. To a solution of methyl (F?)-2-((tert-butoxycarbonyl)amino)-3- (2-(trifluoromethyl)pyrimidin-5-yl)propanoate (2.4 g, 6.7 mmol) in MeOH (48 mL) was added 40% aq. CH3NH2 (5.12 g, 65.9 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with H2O (25 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 60% ethyl acetate in petroleum ether) to yield the title compound as a white solid. MS (ESI): mass calculated for C14H19F3N4O3, 348.1 ; m / z measured, 247.9 [M-100+H]+(loss of Boc group).1H NMR (400 MHz, CDCI3) 6 8.76 (s, 2H), 6.27 (br s, 1 H), 5.21 (br s, 1 H), 4.51 - 4.37 (m, 1 H), 3.32 - 3.19 (m, 1 H), 3.02 (br dd, J=7.4, 13.9 Hz, 1 H), 2.81 (br d, J=4.3 Hz, 3H), 1.38 (s, 9H).19F NMR (376 MHz, CDCI3) 6 -70.24 (s, 1 F).

[0243] Step C: (R)-2-Amino- / V-methyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)propanamide. To a solution of tert-butyl (F?)-(1 -(methylamino)-1 -oxo-3-(2-(trifluoromethyl)pyrimidin-5- yl)propan-2-yl)carbamate (2.2 g, 6.2 mmol) in DCM (40 mL) was added 4 M HCI / 1 ,4- dioxane (17 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was directly concentrated to dryness in vacuo, then basified with 25% aq. NH3 to pH = 8 and purified by RP-HPLC (Stationary phase: Xtimate C18, 10 pm, 150 x 40 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 2 - 32% B in A over 8 min, flow rate: 55 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C9H11 F3N4O, 248.1 ; m / z measured, 248.8 [M+H]+.1H NMR (400 MHz, CDCI3) 6 8.78 (s, 2H), 7.12 (br s, 1 H), 3.70 (dd, J=4.6, 7.6 Hz, 1 H), 3.25 (dd, J=4.5, 14.2 Hz, 1 H), 3.04 (dd, J=7.5, 14.2 Hz, 1 H), 2.82 (d, J=5.0 Hz, 3H).19F NMR (376 MHz, CDCI3) 5 -70.20 (s, 1 F).

[0244] Intermediate L: (R)-2-Amino- / V-methyl-3-(2-(methylamino)-4- (trifluoromethyl)phenyl)propanamide.

[0245]

[0246] Step A: tert-Butyl (F?)-(1 -(methylamino)-3-(2-nitro-4-(trifluoromethyl)phenyl)-1 - oxopropan-2-yl)carbamate. To a mixture of (R)-2-amino- / V-methyl-3-(2-nitro-4- (trifluoromethyl)phenyl)propanamide (Intermediate H, 200 mg, 629 pmol) and EtsN (180 mg, 1 .78 mmol) in DCM (2 mL) was added BOC2O (203 mg, 930 pmol). The mixture was stirred at room temperature overnight. The mixture was diluted with H2O (5 mL) and extracted with DCM (5 mL x 3). The combined organic layers were dried with anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, 0 - 60% ethyl acetate in petroleum ether) to yield the title compound as yellow solid. MS (ESI): mass calculated for C16H20F3N3O5, 391.1 ; m / z measured, 291.9 [M-100+H]+(loss of Boc group).1H NMR (400 MHz, CDCI3) 6 8.29 (s, 1 H), 7.79 (d, J=7.8 Hz, 1 H), 7.58 (d, J=8.3 Hz, 1 H), 6.16 (s, 1 H), 5.36 (d, J=8.8 Hz, 1 H), 4.59 (s, 1 H), 3.60 (dd, J=4.1 , 13.4 Hz, 1 H), 3.15 - 3.03 (m, 1 H), 2.86 (d, J=4.8 Hz, 3H), 1 .28 ( s, 9H).19F NMR (376 MHz, CDCI3) 6 -62.97 (s, 1 F).

[0247] Step B: tert-Butyl (F?)-(3-(2-amino-4-(trifluoromethyl)phenyl)-1 -(methylamino)-1 - oxopropan-2-yl)carbamate. To a solution of tert-butyl (F?)-(1 -(methylamino)-3-(2-nitro-4- (trifluoromethyl)phenyl)-1 -oxopropan-2-yl)carbamate (270 mg, 536 pmol) in THF (15 mL) was added 10% wet Pd / C (918 mg) and 20% wet Pd(OH)2 / C (918 mg) under N2. The suspension was degassed in vacuo and purged with H2 several times. The mixture was stirred at room temperature under H2 (15 psi) for 3 hours. The mixture was filtered through a pad of Celite® and the filter cake was rinsed with MeOH (15 mL x 3). The filtrate was concentrated to dryness in vacuo to yield the title compound as a yellow solid, which was used in the next step without further purification. MS (ESI): mass calculated for C16H22F3N3O3, 361.2; m / z measured, 305.9 [M-56+H]+(loss of tert-butyl group).1H NMR (400 MHz, CDCI3) 6 7.03 (d, J=8.3 Hz, 1 H), 6.89 (s, 2H), 5.56 (s, 1 H), 5.40 (s, 1 H), 4.65 (s, 2H), 4.27 - 4.18 (m, 1 H), 3.09 (d, J=12.8 Hz, 1 H), 2.93 - 2.81 (m, 1 H), 2.73 (d, J=4.8 Hz, 3H), 1.45 (s, 9H).19F NMR (376 MHz, CDCI3) 6 -62.77 (s, 1 F). Step C: tert-Butyl (F?)-(1 -(methylamino)-3-(2-(methylamino)-4- (trifluoromethyl)phenyl)-1 -oxopropan-2-yl)carbamate. Pyridine (161 mg, 2.04 mmol) and methylboronic acid (92 mg, 1 .54 mmol) were added to a mixture of tert-butyl (F?)-(3-(2- amino-4-(trifluoromethyl)phenyl)-1 -(methylamino)-l -oxopropan-2-yl)carbamate (230 mg) and CU(OAC)2 (253 mg, 1.39 mmol) in 1 ,4-dioxane (12 mL). The reaction mixture was stirred at 105 °C for 1.5 hours. The mixture was quenched with sat. aq. NFUCI (10 mL) and extracted with DCM (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, 0 - 60% ethyl acetate in petroleum ether) and further purified by RP-HPLC (Stationary phase: Boston Prime C18, 5 pm, 150 x 30 mm; Mobile phase: (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 55 - 85% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C17H24F3N3O3, 375.2; m / z measured, 376.0 [M+H]+.1H NMR (400 MHz, CDCI3) 6 7.03 (d, J=7.8 Hz, 1 H), 6.88 (d, J=7.5 Hz, 1 H), 6.81 (s, 1 H), 5.59 (s, 1 H), 5.37 (s, 1 H), 4.17 (s, 1 H), 3.07 (d, J=12.5 Hz, 1 H), 2.94 (s, 3H), 2.92 - 2.82 (m, 1 H), 2.74 (d, J=4.8 Hz, 3H), 1.46 (s, 9H).19F NMR (376 MHz, CDCI3) 6 -62.68 (s, 1 F).

[0248] Step D: (R)-2-Amino- / V-methyl-3-(2-(methylamino)-4- (trifluoromethyl)phenyl)propanamide. To a solution of tert-butyl (F?)-(1 -(methylamino)-3- (2-(methylamino)-4-(trifluoromethyl)phenyl)-1 -oxopropan-2-yl)carbamate (50.0 mg, 118 pmol) in DCM (4 mL) was added 4 M HCI / 1 ,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was adjusted the pH to 8 with sat. aq. NaHCOs and then extracted with DCM (3 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to yield the title compound as a yellow oil, which was used in the next step without further purification. MS (ESI): mass calculated for C12H16F3N3O, 275.1 ; m / z measured, 275.9 [M+H]+.1H NMR (400 MHz, CDCI3) 6 7.40 (s, 1 H), 7.07 (d, J=7.8 Hz, 1 H), 6.89 (d, J=7.8 Hz, 1 H), 6.78 (s, 1 H), 3.59 (dd, J=3.4, 8.2 Hz, 1 H), 3.20 (dd, J=3.3, 14.6 Hz, 1 H), 2.89 (s, 3H), 2.84 (d, J=5.0 Hz, 3H), 2.67 (dd, J=8.3, 14.6 Hz, 1 H).19F NMR (376 MHz, CDCI3) 6 -62.65 (s, 1 F).

[0249] Intermediate M: (R)-2-Amino-3-(2-(difluoromethyl)-4-(trifluoromethyl)phenyl)- / V- methylpropanamide.

[0250]

[0251] Step A: 1 -Bromo-2-(difluoromethyl)-4-(trifluoromethyl)benzene. To a solution of 2- bromo-5-(trifluoromethyl)benzaldehyde (1 g, 4 mmol) in DCM (10 mL) at 0 °C was added dropwise a solution of DAST (1 .90 g, 11.8 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM (20 mL), carefully poured into sat. aq. NaHCOs (40 mL) at 0 °C, then extracted with DCM (40 mL x 3). The combined organic layers were dried with anhydrous NaaSC , filtered over a pad of silica gel and concentrated to dryness in vacuo at 0 °C to yield the title compound as a colorless oil.1H NMR (400 MHz, CDCI3) 6 7.99 - 7.89 (m, 1 H), 7.78 (d, J=8.3 Hz, 1 H), 7.61 (br d, J=8.3 Hz, 1 H), 7.10 - 6.75 (m, 1 H).

[0252] Step B: Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(2-(difluoromethyl)-4- (trifluoromethyl)phenyl)propanoate. To a mixture of methyl (S)-2-((tert- butoxycarbonyl)amino)-3-iodopropanoate (1.2 g, 3.7 mmol), 1 -bromo-2-(difluoromethyl)- 4-(trifluoromethyl)benzene (1.0 g, 3.6 mmol), dtbbpy (110 mg, 410 pmol), NiBra (80.0 mg, 366 pmol) and Mn powder (600 mg, 10.9 mmol) was added DMA (15 mL) under Ar. The mixture was stirred at 50 °C for 2 hours, then cooled to room temperature. The mixture was filtered over a pad of Celite®, and the solid was rinsed with ethyl acetate (50 mL). The filtrate was washed with 3% aq. LiCI (50 mL x 3), dried over anhydrous NaaSC , filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiOa, gradient elution: 0 - 15% ethyl acetate in petroleum ether) to yield the title compound as an off-white solid. MS (ESI): mass calculated for C17H20F5NO4, 397.1 ; m / z measured, 297.9 [M-100+H]+(loss of Boc group).1H NMR (400 MHz, CDCI3) 6 7.82 (s, 1 H), 7.67 (br d, J=7.9 Hz, 1 H), 7.41 (d, J=8.1 Hz, 1 H), 7.04 - 6.71 (m, 1 H), 5.14 (br d, J=7.5 Hz, 1 H), 4.62 (q, J=7.3 Hz, 1 H), 3.78 - 3.71 (m, 3H), 3.36 (dd, J=6.0, 14.3 Hz, 1 H), 3.16 (br dd, J=7.6, 14.0 Hz, 1 H), 1.38 (s, 9H).19F NMR (376 MHz, CDCI3) 6 -62.82 (s, 1 F), -110.56 (br d, J=292.7 Hz, 1 F). Step C: tert-Butyl (F?)-(3-(2-(difluoromethyl)-4-(trifluoromethyl)phenyl)-1 - (methylamino)-1 -oxopropan-2-yl)carbamate. 40% aq. CH3NH2 (1.27 g, 16.4 mmol) was added to a mixture of methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(2-(difluoromethyl)-4- (trifluoromethyl)phenyl)propanoate (360 mg, 753 pmol, 83% purity) in MeOH (7 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined extract was dried with anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to yield the title compound as an off-white solid, which was used in the next step without further purification. MS (ESI): mass calculated for C17H21 F5N2O3, 396.1 ; m / z measured, 397.0 [M+H]+.1H NMR (400 MHz, CDCI3) 6 7.81 (s, 1 H), 7.66 (br d, J=7.6 Hz, 1 H), 7.45 (d, J=8.0 Hz, 1 H), 7.11 - 6.79 (m, 1 H), 5.84 (br s, 1 H), 5.12 (br s, 1 H), 4.35 (br d, J=7.4 Hz, 1 H), 3.32 (br dd, J=6.0, 13.2 Hz, 1 H), 3.13 (br d, J=6.3 Hz, 1 H), 2.76 (d, J=4.8 Hz, 3H), 1.36 (s, 9H).19F NMR (376 MHz, CDCI3) 6 -62.81 (s, 1 F), - 101.35 - -122.14 (m, 1 F).

[0253] Step D: (R)-2-Amino-3-(2-(difluoromethyl)-4-(trifluoromethyl)phenyl)- / V- methylpropanamide. 4 M HCI / 1 ,4-dioxane (10 mL) was added to a solution of tert-butyl (F?)-(3-(2-(difluoromethyl)-4-(trifluoromethyl)phenyl)-1 -(methylamino)-1 -oxopropan-2- yl)carbamate (320 mg, 716 pmol) in DCM (20 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness in vacuo. The reaction mixture was diluted with H2O (10 mL), adjusted the pH to 8 with sat. aq. NaHCOs, then extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to yield the title compound as a yellow oil, which was used in the next step without further purification. MS (ESI): mass calculated for C12H13F5N2O, 296.1 ; m / z measured, 297.2 [M+H]+.1H NMR (400 MHz, CDCI3) 5 7.86 (s, 1 H), 7.71 (br d, J=7.9 Hz, 1 H), 7.49 (d, J=8.0 Hz, 1 H), 7.17 (br s, 1 H), 6.94 (t, J=54.8 Hz, 1 H), 3.63 (dd, J=4.4, 9.2 Hz, 1 H), 3.51 (dd, J=4.1 , 14.5 Hz, 1 H), 2.92 (dd, J=9.2, 14.2 Hz, 1 H), 2.84 (d, J=4.9 Hz, 3H).19F NMR (376 MHz, CDCI3) 6 -62.77 (s, 1 F), -110.34 (d, J=145.7 Hz, 1 F).

[0254] Intermediate N: (R)-2-Amino- / V-methyl-3-(4-(2,2,2-trifluoroacetamido)-6- (trifluoromethyl)pyridin-3-yl)propanamide HCI.

[0255]

[0256] Step A: / V-(5-Bromo-2-(trifluoromethyl)pyridin-4-yl)-2,2,2-trifluoroacetamide. A mixture of 5-bromo-2-(trifluoromethyl)pyridin-4-amine (300 mg, 1 .24 mmol) and EtsN (255 mg, 2.52 mmol) in THF (2 mL) was bubbled with N2 for 1 minute. Then a solution of TFAA (522 mg, 2.49 mmol) in THF (1 mL) was added to the above solution dropwise at 0 °C. The mixture was stirred at room temperature overnight. The mixture was directly concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 20% ethyl acetate in petroleum ether) to yield the title compound as a white solid. MS (ESI): mass calculated for CsHaBrFel^O, 335.9; m / z measured, 337.0 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.86 (s, 1 H), 8.75 (s, 1 H), 8.65 (br s, 1 H).19F NMR (376MHz, CDCI3) 5 -68.08 (s, 1 F), -75.79 (s, 1 F).

[0257] Step B: Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(4-(2,2,2-trifluoroacetamido)- 6-(trifluoromethyl)pyridin-3-yl)propanoate. A mixture of methyl (S)-2-((tert- butoxycarbonyl)amino)-3-iodopropanoate (300 mg, 912 pmol), / V-(5-bromo-2- (trifluoromethyl)pyridin-4-yl)-2,2,2-trifluoroacetamide (333 mg, 915 pmol), dtbbpy (27.0 mg, 101 pmol), NiBr2 (21 mg, 96 pmol) and Mn powder (150 mg, 2.73 mmol) was charged with Ar. The flask was sealed with a rubber septum and the atmosphere was exchanged with Ar balloon. Then DMA (4.5 mL) was added and the mixture was placed in a pre-heated oil bath (50 °C) and stirred for 2 hours, then cooled to room temperature. The reaction was quenched with sat. aq. NH4CI (30 mL) and the mixture extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 20% ethyl acetate in petroleum ether) to yield the title compound as a colorless oil. MS (ESI): mass calculated for C17H19F6N3O5, 459.1 ; m / z measured, 460.1 [M+H]+.1H NMR (400 MHz, CDCI3) 5 10.68 (br s, 1 H), 8.64 (s, 1 H), 8.47 (s, 1 H), 5.64 (br d, J=3.5 Hz, 1 H), 4.24 (ddd, J=2.4, 5.2, 9.2 Hz, 1 H), 3.79 (s, 3H), 3.33 (dd, J=2.1 , 14.7 Hz, 1 H), 3.08 (dd, J=9.3, 14.8 Hz, 1 H), 1.48 (s, 9H).19F NMR (376 MHz, CDCI3) 5 - 68.02 (s, 1 F), -74.80 (br s, 1 F).

[0258] Step C: tert-Butyl (F?)-(3-(4-amino-6-(trifluoromethyl)pyridin-3-yl)-1 - (methylamino)-1 -oxopropan-2-yl)carbamate. To a solution of methyl (F?)-2-((tert- butoxycarbonyl)amino)-3-(4-(2,2,2-trifluoroacetamido)-6-(trifluoromethyl)pyridin-3- yl)propanoate (500 mg, 940 pmol) in MeOH (5 mL) was added 40% aq. CH3NH2 (731 mg, 9.42 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with H2O (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried with anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 30% ethyl acetate in petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C15H21F3N4O3, 362.2; m / z measured, 363.2 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.06 (s, 1 H), 6.87 (s, 1 H), 5.59 (br s, 4H), 4.17 - 4.12 (m, 1 H), 3.06 (dd, J=2.5, 14.3 Hz, 1 H), 2.95 - 2.82 (m, 1 H), 2.79 (d, J=4.8 Hz, 3H), 1 .46 (s, 9H).19F NMR (376 MHz, CDCI3) 5 -68.38 (s, 1 F).

[0259] Step D: tert-Butyl (F?)-(1 -(methylamino)-1 -oxo-3-(4-(2,2,2-trifluoroacetamido)-6- (trifluoromethyl)pyridin-3-yl)propan-2-yl)carbamate. A solution of TFAA (358 mg, 1 .70 mmol) in THF (2.5 mL) was added dropwise to a mixture of tert-butyl (R)-(3-(4-amino-6- (trifluoromethyl)pyridin-3-yl)-1 -(methylamino)-1 -oxopropan-2-yl)carbamate (310 mg, 856 pmol) and EtsN (179 mg, 1 .77 mmol) in THF (7.5 mL) at 0 °C under N2. The mixture was stirred at room temperature overnight. The reaction was quenched with H2O (30 mL) and extracted with ethyl acetate (25 mL x 3). The combined extract was washed with brine (20 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 30% ethyl acetate in petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C17H20F6N4O4, 458.1 ; m / z measured, 459.3 [M+H]+.1H NMR (400 MHz, CDCI3) 5 11 .60 (s, 1 H), 8.62 - 8.48 (m, 1 H), 8.45 - 8.25 (m, 1 H), 6.54 (br d, J=4.4 Hz, 1 H), 5.30 (br d, J=9.2 Hz, 1 H), 4.54 (dt, J=2.7, 8.9 Hz, 1 H), 3.25 - 3.18 (m, 1 H), 3.14 - 3.05 (m, 1 H), 2.80 (d, J=4.9 Hz, 3H), 1 .49 (s, 9H).19F NMR (376 MHz, CDCI3) 5 -68.09 (s, 1 F), -75.57 (s, 1 F). Step E: (R)-2-Amino- / V-methyl-3-(4-(2,2,2-trifluoroacetamido)-6- (trifluoromethyl)pyridin-3-yl)propanamide HCI. 4 M HCI / 1 ,4-dioxane (8.0 mL, 32 mmol) was added to a solution of tert-butyl (R)-(1 -(methylamino)-1 -oxo-3-(4-(2,2,2- trifluoroacetamido)-6-(trifluoromethyl)pyridin-3-yl)propan-2-yl)carbamate (300 mg, 622 pmol) in DCM (8 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated to dryness in vacuo to yield the title compound as a yellow solid. MS (ESI): mass calculated for C12H12F6N4O2, 358.1 ; m / z measured, 359.0 [M+H]+.

[0260] Intermediate O: (R)-2-Amino-N-methyl-3-(3-(methylamino)-4- (trifluoromethyl)phenyl)propanamide.

[0261] Step A: 5-Bromo-2-(trifluoromethyl)aniline. To a mixture of 4-bromo-2-nitro-1 - (trifluoromethyl)benzene (1.0 g, 3.7 mmol), iron powder (1 .10 g, 19.7 mmol), NH4CI (1.19 g, 22.3 mmol) in MeOH / THF / F O (v / v / v, 1 / 2 / 1 , 20 mL) was added 1 M aq. HCI (0.1 mL, 0.1 mmol). The reaction mixture was stirred at 70 °C for 1 day. The hot mixture was directly filtered, the filter cake was washed with ethyl acetate (50 mL), and the filtrate was concentrated to dryness under vacuum. The residue was diluted with sat. aq. NaHCOa (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness under vacuum. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 3% ethyl acetate in petroleum ether) to yield the title compound as a yellow oil. MS (ESI): mass calculated for CyHsBrFaN, 239.0; m / z measured, 239.8 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 5 7.25 (d, J=8.5 Hz, 1 H), 7.03 (s, 1 H), 6.75 (d, J=8.5 Hz, 1 H), 5.89 (s, 2H).19F NMR (376 MHz, DMSO-d6) 5 -61 .81 (s, 1 F).

[0262] Step B: Methyl (F?)-3-(3-amino-4-(trifluoromethyl)phenyl)-2-((tert- butoxycarbonyl)amino)propanoate. A mixture of methyl (S)-2-((tert- butoxycarbonyl)amino)-3-iodopropanoate (770 mg, 2.34 mmol), 5-bromo-2- (trifluoromethyl)aniline (700 mg, 2.89 mmol), Mn powder (385 mg, 7.01 mmol), dtbbpy (77.0 mg, 287 gmol) and NiBr2 (62.0 mg, 284 gmol) in a 50 mL round bottom flask was exchanged with Ar, then DMA (15 mL) was added. After purging with Ar, the reaction mixture was placed in a pre-heated oil bath (50 °C) and stirred for 2 hours. The reaction mixture was filtered, and the filter cake was rinsed with ethyl acetate (10 mL). The filtrate was diluted with ethyl acetate (40 mL) and washed with 3% aq. LiCI (50 mL x 3). The organic phrase was dried with anhydrous Na2SO4, filtered and concentrated to dryness under vacuum. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 16% ethyl acetate in petroleum ether) to yield the title compound as a light yellow oil. MS (ESI): mass calculated for C16H21F3N2O4, 362.1 ; m / z measured, 263.2 [M-100+H]+(loss of Boc group).1H NMR (400 MHz, DMSO-ofe) 5 7.29 (d, J=8.0 Hz, 1 H), 7.23 (d, J=8.0 Hz, 1 H), 6.67 (s, 1 H), 6.50 (d, J=8.0 Hz, 1 H), 5.48 (s, 2H), 4.20 - 4.11 (m, 1 H), 3.62 (s, 3H), 2.95 - 2.84 (m, 1 H), 2.75 (dd, J=9.9, 13.4 Hz, 1 H), 1 .34 (s, 9H).19F NMR (376 MHz, DMSO-d6) 5 -61.10 (s, 1 F).

[0263] Step C: (F?)-3-(3-Amino-4-(trifluoromethyl)phenyl)-2-((tert- butoxycarbonyl)amino)propanoic acid. To a mixture of methyl (F?)-3-(3-amino-4- (trifluoromethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (600 mg, 1 .58 mmol) in MeOH / THF (v / v, 1 / 1 , 12 mL) was added 1 M aq. NaOH (1 .9 mL, 1 .9 mmol). The mixture was stirred at room temperature for 2 hours. 1 M aq. HCI was added to adjust pH to 6, then the mixture was diluted with brine (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried with anhydrous Na2SO4, filtered and concentrated to dryness under vacuum to yield the title compound as a light yellow oil. MS (ESI): mass calculated for C15H19F3N2O4, 348.1 ; m / z measured, 249.0 [M- 100+H]+(loss of Boc group).1H NMR (400 MHz, DMSO-cfe) 5 7.11 (d, J=8.1 Hz, 1 H), 6.60 (s, 1 H), 6.43 (d, J=8.0 Hz, 1 H), 5.88 (s, 1 H), 5.29 (s, 2H), 3.69 (s, 1 H), 2.96 - 2.86 (m, 1 H), 2.84 - 2.74 (m, 1 H), 1 .34 (s, 9H).19F NMR (376 MHz, DMSO-de) 5 -59.21 - - 64.28 (m, 1 F).

[0264] Step D: tert-Butyl (F?)-(3-(3-amino-4-(trifluoromethyl)phenyl)-1 -(methylamino)-1 - oxopropan-2-yl)carbamate. HATU (775 mg, 2.04 mmol) was added to a solution of (F?)- 3-(3-amino-4-(trifluoromethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (560 mg, 1 .57 mmol), CH3NH2*HCI (212 mg, 3.14 mmol) and EtsN (726 mg, 7.18 mmol) in DMF (11 mL). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (20 mL), then washed with 3% aq. LiCI (20 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated to dryness under vacuum. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 31% ethyl acetate in petroleum ether) to yield the title compound as yellow oil. MS (ESI): mass calculated for C16H22F3N3O3, 361 .2; m / z measured, 261.9 [M-100+H]+(loss of Boc group).1H NMR (400 MHz, DMSO-d6) 5 7.80 (d, J=4.4 Hz, 1 H), 7.20 (d, J=8.1 Hz, 1 H), 6.83 (d, J=8.5 Hz, 1 H), 6.64 (s, 1 H), 6.50 (d, J=8.1 Hz, 1 H), 5.43 (s, 2H), 4.11 - 4.04 (m, 1 H), 2.84 (dd, J=4.8, 13.5 Hz, 1 H), 2.65 - 2.60 (m, 1 H), 2.57 (d, J=4.4 Hz, 3H), 1 .31 (s, 9H).19F NMR (376 MHz, DMSO-d6) 5 -61.00 (s, 1 F).

[0265] Step E: tert-Butyl (F?)-(1 -(methylamino)-3-(3-(methylamino)-4- (trifluoromethyl)phenyl)-1 -oxopropan-2-yl)carbamate. A solution of tert-butyl (F?)-(3-(3- amino-4-(trifluoromethyl)phenyl)-1 -(methylamino)-l -oxopropan-2-yl)carbamate (500 mg, 1.25 mmol), methylboronic acid (180 mg, 3.01 mmol), pyridine (350 mg, 4.43 mmol) and CU(OAC)2 (566 mg, 3.12 mmol) in 1 ,4-dioxane (10 mL) was stirred at 105 °C overnight, then cooled to room temperature. The reaction mixture was diluted with H2O (10 mL), then extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried with anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (Stationary phase: Boston Prime C18, 5 pm, 150 x 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 30 - 60% B in A over 7 min, flow rate: 55 mL / min) to yield the title compound as a white powder. MS (ESI): mass calculated for C17H24F3N3O3, 375.2; m / z measured, 275.9 [M-100+H]+(loss of Boc group).1H NMR (400 MHz, DMSO-ofe) 5 7.86 (d, J=4.5 Hz, 1 H), 7.27 (d, J=8.0 Hz, 1 H), 6.90 (d, J=8.6 Hz, 1 H), 6.62 (s, 1 H), 6.54 (d, J=7.9 Hz, 1 H), 5.50 (d, J=4.4 Hz, 1 H), 4.12 (dt, J=4.4, 9.3 Hz, 1 H), 2.92 (dd, J=4.3, 13.6 Hz, 1 H), 2.77 (d, J=4.6 Hz, 3H), 2.71 - 2.65 (m, 1 H), 2.59 (d, J=4.5 Hz, 3H), 1.29 (s, 9H).19F NMR (376 MHz, DMSO-de) 5 -60.94 (s, 1 F).

[0266] Step F: (F?)-2-Amino-N-methyl-3-(3-(methylamino)-4- (trifluoromethyl)phenyl)propanamide. 4 M HCI / 1 ,4-dioxane (2.3 mL) was added to a solution of tert-butyl (F?)-(1 -(methylamino)-3-(3-(methylamino)-4-(trifluoromethyl)phenyl)- 1 -oxopropan-2-yl)carbamate (180 mg, 480 pmol) and DCM (3.5 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate (10 mL), adjusted pH to 7 with sat. aq. NaHCOs, and then extracted with ethyl acetate (10 mL x 5). The combined organic layers were dried with anhydrous NaaSC , filtered and concentrated to dryness under vacuum to yield the title compound as a yellow solid. MS (ESI): mass calculated for C12H16F3N3O, 275.1 ; m / z measured, 276.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 7.82 (d, J=4.5 Hz, 1 H), 7.28 (d, J=8.0 Hz, 1 H), 6.54 (s, 1 H), 6.50 (d, J=8.1 Hz, 1 H), 5.51 (d, J=4.6 Hz, 1 H), 3.40 - 3.35 (m, 1 H), 2.89 (dd, J=5.0, 13.1 Hz, 1 H), 2.75 (d, J=4.8 Hz, 3H), 2.62 - 2.54 (m, 4H).19F NMR (376 MHz, DMSO-d6) 5 -60.91 (s, 1 F).

[0267] Intermediate P: (R)-2-Amino- / V-methyl-3-(6-(trifluoromethyl)pyridin-3- yl)propanamide.

[0268] Step A: Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(6-(trifluoromethyl)pyridin-3- yl)propanoate. To a solution of methyl (F?)-2-amino-3-(6-(trifluoromethyl)pyridin-3- yl)propanoate HCI (600 mg, 2.11 mmol) and EtsN (640 mg, 6.32 mmol) in DCM (6 mL) was added BocaO (690 mg, 3.16 mmol) dropwise at room temperature. The mixture was stirred at room temperature overnight. The mixture was diluted with H2O (30 mL) and extracted with DCM (35 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness under vacuum. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 70% ethyl acetate in petroleum ether) to yield the title compound as a white solid. MS (ESI): mass calculated for C15H19F3N2O4, 348.1 ; m / z measured, 349.2 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.51 (s, 1 H), 7.71 - 7.67 (m, 1 H), 7.65 - 7.61 (m, 1 H), 5.10 (d, J=7.3 Hz, 1 H), 4.65 (d, J=6.8 Hz, 1 H), 3.77 (s, 3H), 3.29 (dd, J=5.3, 13.8 Hz, 1 H), 3.11 (br dd, J=6.3, 13.8 Hz, 1 H), 1.42 (s, 9H).19F NMR (376 MHz, CDCI3) 5 -67.86 (s, 1 F).

[0269] Step B: (F?)-2-((tert-Butoxycarbonyl)amino)-3-(6-(trifluoromethyl)pyridin-3- yl)propanoic acid. 1 M aq. NaOH (1 .9 mL, 1 .9 mmol) was added to a solution of methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(6-(trifluoromethyl)pyridin-3-yl)propanoate (700 mg, 1 .92 mmol) in MeOH (20 mL). The mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum to yield the title compound as a white solid, which was used in the next step without further purification. MS (ESI): mass calculated for C14H17F3N2O4, 334.1 ; m / z measured, 334.9 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 5 8.43 (s, 1 H), 7.75 (s, 2H), 5.86 (d, J=5.1 Hz, 1 H), 3.73 (d, J=5.2 Hz, 1 H), 3.21 - 3.13 (m, 2H), 3.01 (dd, J=5.2, 13.1 Hz, 1 H), 1.33 (s, 9H).19F NMR (376 MHz, DMSO-cfe) 5 -66.09 (s, 1 F).

[0270] Step C: tert-Butyl (F?)-(1 -(methylamino)-1 -oxo-3-(6-(trifluoromethyl)pyridin-3- yl)propan-2-yl)carbamate. DIEA (1 .71 g, 13.3 mmol) and HATU (1 .09 g, 2.87 mmol) were added to a mixture of (F?)-2-((tert-butoxycarbonyl)amino)-3-(6- (trifluoromethyl)pyridin-3-yl)propanoic acid (745 mg) and methylamine hydrochloride (186 mg, 2.76 mmol) in DMF (10 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The mixture reaction was diluted with H2O (25 mL) and extracted with DCM (30 mL x 3). The combined organic layers were dried with anhydrous Na2SO4, filtered and concentrated to dryness under vacuum. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 70% ethyl acetate in petroleum ether) to yield the title compound as a white solid. MS (ESI): mass calculated for C15H20F3N3O3, 347.1 ; m / z measured, 347.9 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.57 (s, 1 H), 7.78 - 7.71 (m, 1 H), 7.62 (d, J=8.1 Hz, 1 H), 6.18 (s, 1 H), 5.10 (d, J=7.3 Hz, 1 H), 4.39 (d, J=7.2 Hz, 1 H), 3.25 (dd, J=G.5, 13.9 Hz, 1 H), 3.05 (dd, J=7.3, 13.9 Hz, 1 H), 2.79 (d, J=4.8 Hz, 3H), 1 .38 (s, 9H).19F NMR (376MHz, CDCI3) 5 -67.82 (s, 1 F).

[0271] Step D: (F?)-2-Amino-N-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propanamide. 4 M HCI / 1 ,4-dioxane (3.8 mL) was added to a solution of tert-butyl (F?)-(1 -(methylamino)- 1 -oxo-3-(6-(trifluoromethyl)pyridin-3-yl)propan-2-yl)carbamate (700 mg) in DCM (15 mL). The mixture was stirred at room temperature for 3 hours. The mixture reaction was diluted with H2O (20 mL) and washed with DCM (40 mL). The aqueous layer was adjusted to pH 7~8 with sat. aq. NaHCOs, then extracted with ethyl acetate (200 mL x 5). The combined organic layers were dried with anhydrous Na2SO4, filtered and concentrated to dryness under vacuum. The residue was separated by SFC: (Column: DAICEL CHIRALPAKAD 250 x 30 mm, 10 pm; mobile phase: CO2(A) - EtOH (0.1 % NH3H2O) (B); isocratic elution: 45% B in A; flow rate: 80 mL / min; column temp.: 40 °C; ABPR: 100 bar) to yield the title compound as a white solid. MS (ESI): mass calculated for C10H12F3N3O, 247.1 ; m / z measured, 247.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.56 (s, 1 H), 7.89 - 7.75 (m, 3H), 3.36 (dd, J=5.1 , 8.2 Hz, 1 H), 2.98 (dd, J=5.0, 13.5 Hz, 1 H), 2.76 - 2.68 (m, 1 H), 2.55 (d, J=4.6 Hz, 3H).19F NMR (376 MHz, DMSO-d6) 5 - 66.02 - -66.17 (m, 1 F).

[0272] Intermediate Q: (5-Chloro-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(6- (methylsulfonyl)pyridin-3-yl)piperidin-1 -yl)methanone.

[0273] Step A: (3-Bromo-5-methoxy-2,6-naphthyridin-1 -yl)(4-(6-(methylsulfonyl)pyridin- 3-yl)piperidin-1 -yl)methanone. HATU (2.2 g, 5.79 mmol) was added to the solution of 3- bromo-5-methoxy-2,6-naphthyridine-1 -carboxylic acid (Intermediate A, 1.1 g, 3.9 mmol), 2-(methylsulfonyl)-5-(piperidin-4-yl)pyridine dihydrochloride (1.54 g, 4.92 mmol) and DIEA (2.2 g, 17.02 mmol) in DMF (22 mL). The solution was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (50 mL), then washed with 3% aq. LiCI (25 mL x 2). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 100% ethyl acetate in petroleum ether), then further triturated with petroleum ether / ethyl acetate (v / v, 2 / 1 , 30 mL) at room temperature overnight then filtered. The solid was washed with petroleum ether (10 mL x 2), collected, and dried in vacuo to yield the title compound as an off-white solid. MS (ESI): mass calculated for C2iH2iBrN4O4S, 506.0; m / z measured, 506.9 [M+H]+.1H NMR (400 MHz, DMSO-ofe) 5 8.75 (d, J=2.0 Hz, 1 H), 8.30 - 8.24 (m, 2H), 8.09 (dd, J=2.0, 8.0 Hz, 1 H), 7.99 (d, J=8.0 Hz, 1 H), 7.43 (d, J=6.0 Hz, 1 H), 4.78 (br d, J=13.1 Hz, 1 H), 4.10 (s, 3H), 3.37 (br s, 1 H), 3.26 (s, 3H), 3.25 - 3.17 (m, 1 H), 3.11 - 3.00 (m, 2H), 2.08 - 1 .98 (m, 1 H), 1 .95 - 1 .82 (m, 1 H), 1 .73 (br d, J=12.3 Hz, 1 H), 1.61 - 1 .46 (m, 1 H). Step B: (5-Methoxy-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(6- (methylsulfonyl)pyridin-3-yl)piperidin-1 -yl)methanone. Pd(dppf)Cl2 (150 mg, 205.00 pmol) was added to the mixture of (3-bromo-5-methoxy-2,6-naphthyridin-1 -yl)(4-(6- (methylsulfonyl)pyridin-3-yl)piperidin-1 -yl)methanone (1 g, 2 mmol), (2,3,6- trimethylphenyl)boronic acid (360 mg, 2.20 mmol) and CS2CO3 (2.0 g, 6.1 mmol) in 1 ,4- dioxane / H2O (v / v, 9 / 1 , 10 mL) under N2. The reaction mixture was stirred at 80 °C for 40 hours, then cooled to room temperature. The reaction mixture was filtered through a pad of Celite®, and the solid was rinsed with ethyl acetate (10 mL x 3). The filtrate was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 100% ethyl acetate in petroleum ether) to yield the title compound as a white solid. MS (ESI): mass calculated for C30H32N4O4S, 544.2; m / z measured, 545.1 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.60 (d, J=1.8 Hz, 1 H), 8.19 (d, J=6.0 Hz, 1 H), 8.05 (d, J=8.0 Hz, 1 H), 8.01 (s, 1 H), 7.79 (dd, J=2.1 , 8.2 Hz, 1 H), 7.44 (d, J=6.0 Hz, 1 H), 7.18 - 7.12 (m, 1 H), 7.07 (br s, 1 H), 5.11 (br d, J=13.6 Hz, 1 H), 4.15 (s, 3H), 3.64 (br d, J=12.8 Hz, 1 H), 3.23 (s, 4H), 3.07 - 2.93 (m, 2H), 2.30 (br s, 3H), 2.11 - 1.84 (m, 8H), 1.77 (br s, 2H).

[0274] Step C: (5-Hydroxy-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(6- (methylsulfonyl)pyridin-3-yl)piperidin-1 -yl)methanone. To the mixture of Nal (600 mg, 4.00 mmol) in MeCN (20 mL) was added TMSCI (440 mg, 4.05 mmol) at room temperature. After stirring for 15 minutes, (5-methoxy-3- (2,3,6-trimethylphenyl)-2,6- naphthyridin-1 -yl) (4-(6-(methylsulfonyl)pyridin-3-yl) pi peridin- 1 -yl)methanone (715 mg, 1 .31 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction was quenched with sat. aq. Na2SOs (30 mL) and the mixture extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 10% MeOH in ethyl acetate) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C29H30N4O4S, 530.2; m / z measured, 531.1 [M+H]+.1H NMR (400 MHz, CDCI3) 5 10.03 (br s, 1 H), 8.60 (d, J=1.5 Hz, 1 H), 8.17 (s, 1 H), 8.05 (d, J=8.1 Hz, 1 H), 7.79 (dd, J=2.0, 8.2 Hz, 1 H), 7.24 (br s, 1 H), 7.15 (d, J=7.6 Hz, 1 H), 7.05 (br d, <7=7.7 Hz, 1 H), 6.77 (d, J=7.2 Hz, 1 H), 5.07 (br d, J=13.4 Hz, 1 H), 3.70 (br d, J=12.9 Hz, 1 H), 3.31 - 3.25 (m, 1 H), 3.23 (s, 3H), 2.98 (br t, ^=11.8 Hz, 2H), 2.29 (s, 3H), 2.04 - 1 .91 (m, 6H), 1 .90 - 1 .79 (m, 2H), 1 .77 (br s, 1 H), 1 .58 - 1 .51 (m, 1 H).

[0275] Step D: (5-Chloro-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(6- (methylsulfonyl)pyridin-3-yl)piperidin-1 -yl)methanone. A mixture of (5-hydroxy-3-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(6- (methylsulfonyl) py rid in-3-yl) pi peridin- 1 - yl)methanone (665 mg, 1 .25 mmol) in POCI3 (10 mL) was stirred at 100 °C for 1 hour, then cooled to room temperature. The mixture was slowly added to sat. aq. Na2COs (10 mL) at 0 °C, then the resulting mixture was adjusted pH to 8 with sat. aq. Na2CO3. The aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 100% ethyl acetate in petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C29H29CIN4O3S, 548.2; m / z measured, 549.1 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 8.73 (d, J=1 .7 Hz, 1 H), 8.58 (d, J=5.7 Hz, 1 H), 8.07 (dd, J=2.1 , 8.2 Hz, 1 H), 8.02 - 7.95 (m, 3H), 7.18 (d, J=7.6 Hz, 1 H), 7.08 (br d, J=7.4 Hz, 1 H), 4.81 (br d, J=13.5 Hz, 1 H), 3.42 (br d, J=13.0 Hz, 1 H), 3.31 (s, 1 H), 3.25 (s, 3H), 3.24 - 3.18 (m, 1 H), 3.14 - 3.00 (m, 2H), 2.26 (s, 3H), 2.02 (br s, 1 H), 1.92 (br d, J=18.0 Hz, 6H), 1 .73 (br d, J=12.5 Hz, 1 H), 1 .58 - 1 .45 (m, 1 H).

[0276] Intermediate R: 5-(3,3-Dif luoropiperidin-4-yl)-2-(methylsulfonyl)pyridine TFA.

[0277] Step A: tert-Butyl 3 , 3-dif lu oro-4-( ((trif luoromethy l)su Ifonyl )oxy )-3 , 6- dihydropyridine-1 (2 H) -carboxyl ate. A solution of tert-butyl 3,3-difluoro-4-oxopiperidine-1 - carboxylate (1.0 g, 4.3 mmol) in THF (10 mL) was added to a solution of NaH (60% in mineral oil, 340 mg, 8.50 mmol) in THF (10 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 30 minutes, then PhNTf2 (2.3 g, 6.4 mmol) was added. The mixture was heated to 45 °C and stirred for 48 hours. The reaction mixture was quenched with sat. aq. NH4CI (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 40% ethyl acetate in petroleum ether) to yield the title compound as a yellow oil.1H NMR (400 MHz, CDCI3) 5 6.32 (br s, 1 H), 4.27 (br s, 2H), 3.99 (br t, J=10.4 Hz, 2H), 1 .51 (s, 9H).19F NMR (376 MHz, CDCI3) 5 - 73.41 (br s, 1 F), -108.36 (br d, J=5.7 Hz, 1 F).

[0278] Step B: tert-Butyl 3',3'-difluoro-6-(methylsulfonyl)-3',6'-dihydro-[3,4'-bipyridine]- 1 '(2'H)-carboxylate. PdCl2(dtbpf) (150 mg, 230 pmol) was added to a mixture of tertbutyl 3,3-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1 (2H)-carboxylate (860 mg, 2.34 mmol), (6-(methylsulfonyl)pyridin-3-yl)boronic acid (470 mg, 2.34 mmol) and K2CO3 (650 mg, 4.70 mmol) in 1 ,4-dioxane / H2O (v / v, 4 / 1 , 20 mL) under N2. The mixture was stirred at room temperature overnight. The mixture was diluted with H2O (30 mL), then extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 80% ethyl acetate in petroleum ether) to yield the title compound as a yellow oil. MS (ESI): mass calculated for C16H20F2N2O4S, 374.1 ; m / z measured, 375.0 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.80 (s, 1 H), 8.14 - 8.10 (m, 1 H), 8.10 - 8.05 (m, 1 H), 6.52 (br s, 1 H), 4.30 (br s, 2H), 4.00 (br t, J=11 .0 Hz, 2H), 3.27(s, 3H), 1 .53 (s, 9H).19F NMR (376 MHz, CDCI3) 5 -98.68 (br s, 1 F).

[0279] Step C: tert-Butyl 3,3-difluoro-4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1 - carboxylate. 10% wet. Pd / C (100 mg) was added to a solution of tert-butyl 3',3'-difluoro- 6-(methylsulfonyl)-3',6'-dihydro-[3,4'-bipyridine]-1 '(2'H)-carboxylate (535 mg, 1.16 mmol) in THF / MeOH (v / v, 1 / 1 , 10 mL) under N2. The reaction mixture was degassed in vacuo and purged with H2 several times. The mixture was stirred under H2 (15 psi) at room temperature for 36 hours. The mixture was filtered through a pad of Celite® and the filter cake was rinsed with MeOH (10 mL x 2). The filtrate was concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 80% ethyl acetate in petroleum ether) to yield the title compound as a white solid. MS (ESI): mass calculated for C16H22F2N2O4S, 376.1 ; m / z measured, 377.1 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.68 (s, 1 H), 8.11 (d, J=8.0 Hz, 1 H), 7.95 (br d, J=8.0 Hz, 1 H), 4.48 (br s, 2H), 3.33 - 3.16 (m, 4H), 3.15 - 2.79 (m, 2H), 2.24 (dq, J=4.3, 13.1 Hz, 1 H), 1 .94 (br d, J=13.6 Hz, 1 H), 1 .52 (s, 9H).19F NMR (376 MHz, CDCI3) 5 -105.22 (br d, <7=248.9 Hz, 1 F), -114.57 - -119.53 (m, 1 F).

[0280] Step D: 5-(3,3-Difluoropiperidin-4-yl)-2-(methylsulfonyl)pyridine TFA. TFA (4.62 g, 40.5 mmol) was added to a solution of tert-butyl 3,3-difluoro-4-(6- (methylsulfonyl)pyridin-3-yl)piperidine-1 -carboxylate (100 mg, 266 pmol) in DCM (6 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness in vacuo to yield the title compound as white solid. MS (ESI): mass calculated for C11H14F2N2O2S, 276.1 ; m / z measured, 277.0 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 5 8.72 (s, 1 H), 8.11 (s, 2H), 3.95 - 3.83 (m, 2H), 3.78 (td, J=3.8, 13.0 Hz, 1 H), 3.70 - 3.57 (m, 1 H), 3.46 (br d, J=12.0 Hz, 1 H), 3.22 - 3.09 (m, 3H), 2.32 - 2.26 (m, 1 H), 2.24 - 2.18 (m, 1 H).19F NMR (376 MHz, DMSO-d6) 5 -74.08 (s, 1 F), -102.31 (d, <7=252.5 Hz, 1 F), -110.14 (br d, J=252.5 Hz, 1 F).

[0281] Intermediate S: (R)-5-((3-Hydroxy-3-methyl-1 -(4-(trifluoromethyl)phenyl)butan-2- yl)amino)-3-(2, 3, 6-trimethylphenyl)-2,6-naphthyridine-1 -carboxylic acid.

[0282] Step A: Methyl 5-methoxy-3-(2,3,6-trimethylphenyl)-2,6-naphthyridine-1 - carboxylate. Pd(dppf)Cl2 (260 mg, 355 pmol) was added to a mixture of methyl 3- bromo-5-methoxy-2,6-naphthyridine-1 -carboxylate (Intermediate A, Step I, 1.0 g, 3.4 mmol), (2,3,6-trimethylphenyl)boronic acid (700 mg, 4.27 mmol) and CS2CO3 (3.3 g, 10 mmol) in 1 ,4-1 ,4-dioxane / H2O (v / v, 9 / 1 , 14 mL) under N2. The mixture was stirred at 80 °C overnight, then cooled to room temperature. The reaction mixture was filtered through a pad of Celite® and the filter cake was rinsed with ethyl acetate (20 mL x 3). The filtrate was diluted with H2O (30 mL), then extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 80% ethyl acetate in petroleum ether) to yield the title compound as an off-white solid. MS (ESI): mass calculated for C20H20N2O3, 336.1 ; m / z measured, 337.1 [M+H]+.1H NMR (400 MHz, DMSO-ofe) 6 8.29 (d, J=6.2 Hz, 1 H), 8.07 (d, J=0.8 Hz, 1 H), 8.01 (dd, J=0.8, 6.2 Hz, 1 H), 7.17 (s, 1 H), 7.09 (s, 1 H), 4.10 (s, 3H), 3.98 (s, 3H), 2.27 (s, 3H), 1.91 (s, 3H), 1.85 (s, 3H).

[0283] Step B: Methyl 5-hydroxy-3-(2,3,6-trimethylphenyl)-2,6-naphthyridine-1 - carboxylate. To a mixture of Nal (1.1 g, 7.3 mmol) in MeCN (40 mL) was added TMSCI (800 mg, 7.36 mmol) at room temperature, and the mixture was stirred for 15 minutes before methyl 5-methoxy-3-(2, 3, 6-trimethylphenyl)-2,6-naphthyridine-1 -carboxylate (810 mg, 2.41 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was quenched with sat. aq. Na2SOs (35 mL), then extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 50% ethyl acetate in petroleum ether) to yield the title compound as a white solid. MS (ESI): mass calculated for C19H18N2O3, 322.1 ; m / z measured, 322.9 [M+H]+.1H NMR (400 MHz, CDCI3) 5 10.16 (br d, J=1.8 Hz, 1 H), 8.33 (s, 1 H), 7.53 (d, J=7.5 Hz, 1 H), 7.26 - 7.23 (m, 1 H), 7.16 - 7.09 (m, 1 H), 7.07 - 6.99 (m, 1 H), 4.03 (s, 3H), 2.29 (s, 3H), 2.02 (s, 3H), 1.96 (s, 3H).

[0284] Step C: Methyl 5-chloro-3-(2,3,6-trimethylphenyl)-2,6-naphthyridine-1 - carboxylate. A mixture of methyl 5-hydroxy-3-(2,3,6-trimethylphenyl)-2,6-naphthyridine- 1 -carboxylate (300 mg, 931 pmol) in POCI3 (6 mL) was stirred at 100 °C for 3 hours, then cooled to room temperature. The reaction mixture was concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 20% ethyl acetate in petroleum ether) to yield the title compound as a yellow oil. MS (ESI): mass calculated for C19H17CIN2O2, 340.1 ; m / z measured, 340.9 [M+H]+.1H NMR (400 MHz, CDCI3) 6 8.62 (dd, J=1.0, 6.1 Hz, 1 H), 8.54 (d, J=6.1 Hz, 1 H), 8.26 (d, J=1.0 Hz, 1 H), 7.22 - 7.16 (m, 1 H), 7.10 (d, J=7.7 Hz, 1 H), 4.10 (s, 3H), 2.33 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H).

[0285] Step D: Methyl (R)-5-((3-hydroxy-3-methyl-1 -(4-(trifluoromethyl)phenyl)butan-2- yl)amino)-3-(2, 3, 6-trimethylphenyl)-2,6-naphthyridine-1 -carboxylate. BINAP Pd G4 (89 mg, 88 pmol) was added to the mixture of methyl 5-chloro-3-(2,3,6-trimethylphenyl)-2,6- naphthyridine-1 -carboxylate (300 mg, 880 pmol), (F?)-3-amino-2-methyl-4-(4- (trifluoromethyl)phenyl)butan-2-ol HCI (Intermediate E, 300 mg, 1.06 mmol) and CS2CO3 (885 mg, 2.72 mmol) in 1 ,4-dioxane (12 mL) under N2. The mixture was stirred at 100 °C overnight and cooled to room temperature. The mixture was filtered through a pad of Celite® and the filter cake was rinsed with ethyl acetate (30 mL). The filtrate was concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 25% ethyl acetate in petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C31H32F3N3O3, 551.2; m / z measured, 552.2 [M+H]+.

[0286] Step E: (F?)-5-((3-Hydroxy-3-methyl-1 -(4-(trifluoromethyl)phenyl)butan-2- yl)amino)-3-(2,3,6-trimethylphenyl)-2,6-naphthyridine-1 -carboxylic acid. 1.5 M aq. NaOH (380 pL, 570 pmol) was added to a solution of methyl (F?)-5-((3-hydroxy-3-methyl-1 -(4- (trifluoromethyl)phenyl)butan-2-yl)amino)-3-(2,3,6-trimethylphenyl)-2,6-naphthyridine-1 - carboxylate (105 mg) in THF / MeOH (v / v, 1 / 1 , 2 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with H2O (8 mL), then extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried with anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to yield the title compound as a yellow solid. MS (ESI): mass calculated for C30H30F3N3O3, 537.2; m / z measured, 538.2 [M+H]+.

[0287] Intermediate T: (5-Chloro-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 - yl)(morpholino)methanone.

[0288] Step A: (3-Bromo-5-methoxy-2,6-naphthyridin-1 -yl)(morpholino)methanone.

[0289] HATU (540 mg, 1.42 mmol) was added to a mixture of 3-bromo-5-methoxy-2,6- naphthyridine-1 -carboxylic acid (Intermediate A, 300 mg, 1.06 mmol), morpholine (300 mg, 3.44 mmol) and EtsN (540 mg, 5.34 mmol) in DMF (5 mL). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (10 mL), then washed with 3% aq. LiCI (10 mL x 3). The organic phase was dried with anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 35% ethyl acetate in petroleum ether) to yield the title compound as a brown solid. MS (ESI): mass calculated for CuHuBrNsOs, 351.0; m / z measured, 351 .9 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 5 8.25 (d, J=7.4 Hz, 2H), 7.38 (d, J=6.0 Hz, 1 H), 4.10 (s, 3H), 3.76 (s, 4H), 3.49 - 3.44 (m, 2H), 3.19 - 3.14 (m, 2H).

[0290] Step B: (5-Methoxy-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 - yl)(morpholino)methanone. CataCXium® A Pd G3 (72 mg, 99 pmol) was added to a mixture of (3-bromo-5-methoxy-2,6-naphthyridin-1 -yl)(morpholino)methanone (180 mg, 499 pmol), (2,3,6-trimethylphenyl)boronic acid (98.0 mg, 598 pmol) and K3PO4 (324 mg, 1 .53 mmol) in 1 ,4-dioxane / H2O (v / v, 9 / 1 , 9 mL) under N2. The reaction mixture was stirred at 70 °C overnight, then cooled to room temperature. The reaction mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 35% ethyl acetate in petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C23H25N3O3, 391.2; m / z measured, 392.1 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 5 8.24 (d, J=6.0 Hz, 1 H), 7.86 (s, 1 H), 7.42 (d, J=6.0 Hz, 1 H), 7.16 (d, J-7.7 Hz, 1 H), 7.06 (d, J=7.6 Hz, 1 H), 4.09 (s, 2H), 3.75 (d, J=5.Q Hz, 4H), 3.46 (t, J=4.6 Hz, 2H), 3.18 - 3.15 (m, 3H), 2.26 (s, 3H), 1.91 (s, 3H), 1.86 (s, 3H).

[0291] Step C: (5-Hydroxy-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 - yl)(morpholino)methanone. TMSCI (148 mg, 1.36 mmol) was added to a mixture of Nal (207 mg, 1 .38 mmol) in MeCN (3 mL), and the mixture was stirred at room temperature for 30 minutes. Then a solution of (5-methoxy-3-(2,3,6-trimethylphenyl)-2,6- naphthyridin-1 -yl)(morpholino)methanone (175 mg, 441 pmol) in MeCN (1 mL) was added at room temperature. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with sat. aq. Na2SOs (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to yield the title compound as a white solid which was used in the next step without further purification. MS (ESI): mass calculated for C22H23N3O3, 377.2; m / z measured, 400.1 [M+Na]+.1H NMR (400 MHz, DMS0-d6) 5 11.81 (d, J=5.Q Hz, 1 H), 7.85 (s, 1 H), 7.37 (dd, J=6.0, 7.3 Hz, 1 H), 7.14 (d, J=7.6 Hz, 1 H), 7.05 (d, J=7.6 Hz, 1 H), 6.51 (d, J=7.2 Hz, 1 H), 3.71 (d, J=3.2 Hz, 4H), 3.48 (t, J=4.6 Hz, 2H), 3.20 - 3.14 (m, 2H), 2.25 (s, 3H), 1.91 (s, 3H), 1.85 (s, 3H).

[0292] Step D: (5-Chloro-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 - yl)(morpholino)methanone. A solution of (5-hydroxy-3-(2,3,6-trimethylphenyl)-2,6- naphthyridin-1 -yl)(morpholino)methanone (160 mg, 424 pmol) in POCI3 (2 mL) was stirred at 100 °C for 1 hour, then cooled to room temperature. The mixture was adjusted pH to 8 with sat. aq. Na2COs at 0 °C, then extracted with ethyl acetate (10 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 30% DCM in ethyl acetate) to yield the title compound as a brown solid. MS (ESI): mass calculated for C22H22CIN3O2, 395.1 ; m / z measured, 396.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.57 (d, J=5.7 Hz, 1 H), 8.02 - 7.91 (m, 2H), 7.18 (d, J=7.7 Hz, 1 H), 7.08 (d, J=7.7 Hz, 1 H), 3.77 (d, J=4.4 Hz, 4H), 3.49 - 3.43 (m, 2H), 3.23 - 3.17 (m, 2H), 2.27 (s, 3H), 1.94 (s, 3H), 1.89 (s, 3H).

[0293] Intermediate U: (2-Methoxy-3,6-dimethylphenyl)boronic acid.

[0294] Step A: 2-Bromo-3,6-dimethylphenol. NBS (17.5 g, 98.2 mmol) was added to a solution of 2,5-dimethylphenol (10 g, 82 mmol) and diisopropylamine (828 mg, 8.18 mmol) in DCM (200 mL) at room temperature. The mixture was stirred at 70 °C for 12 hours. The mixture was diluted with H2O (50 mL), then extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (50 mL), dried with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 10% ethyl acetate in petroleum ether) to yield the title compound as a yellow solid.1H NMR (400 MHz, CDCI3) 5 6.96 (d, J=7.5 Hz, 1 H), 6.72 (d, J=7.5 Hz, 1 H), 5.67 (s, 1 H), 2.37 (s, 3H), 2.28 (s, 3H).

[0295] Step B: 2-bromo-3-methoxy-1 ,4-dimethylbenzene. CH3I (141 mg, 995 pmol) was added to a mixture of 2-bromo-3,6-dimethylphenol (100 mg, 497 gmol) and K2CO3 (206 mg, 1 .49 mmol) in THF (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The reaction was poured into water (10 mL), then extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried with Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 10% ethyl acetate in petroleum ether) to yield the title compound as a yellow solid.1H NMR (400 MHz, CDCI3) 5 7.01 (d, J=7.8 Hz, 1 H), 6.92 (d, J=7.8 Hz, 1 H), 3.80 (s, 3H), 2.38 (s, 3H), 2.31 (s, 3H).

[0296] Step C: (2-Methoxy-3,6-dimethylphenyl)boronic acid. Pd(Amphos)Cl2 (6.6 mg, 9.3 pmol) was added to the mixture of 2-bromo-3-methoxy-1 ,4-dimethylbenzene (200 mg, 930 pmol), hypodiboric acid (125 mg, 1 .39 mmol) and DIPEA (240 mg, 1 .86 mmol) in MeOH (1 .5 mL) and THF (1 .5 mL) under N2. The mixture was stirred at 55 °C overnight. The mixture was filtered through a pad of Celite® and the filter cake was washed with ethyl acetate (20 mL). The filtrate was diluted with H2O (20 mL), then extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with 1 M aq. HCI (25 mL x 2), brine (20 mL), dried with Na2SO4, filtered, and concentrated under vacuum to yield the title compound as a yellow solid.1H NMR (400 MHz, CDCI3) 5 7.14 (d, J=7.6 Hz, 1 H), 6.92 (d, J=7.6 Hz, 1 H), 5.87 (br d, J=4.6 Hz, 2H), 3.79 - 3.75 (m, 3H), 2.50 (s, 3H), 2.26 (s, 3H).

[0297] Intermediate V: (5-Chloro-3-(2-methoxy-3,6-dimethylphenyl)-2,6-naphthyridin-1 - yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1 -yl)methanone.

[0298] Step A: (3-Bromo-5-hydroxy-2,6-naphthyridin-1 -yl) (4- (4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone. To a mixture of Nal (53.0 mg, 352 pmol) in MeCN (5 mL) was added TMSCI (38.0 mg, 352 pmol) at room temperature. The mixture was stirred at room temperature for 5 minutes. Then (3-bromo-5-methoxy- 2,6-naphthyridin-1 -yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1 -yl)methanone (Intermediate C, Step A, 60.0 mg, 117 pmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with sat. aq. Na2SOs (10 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried with Na2SO4, filtered and concentrated under vacuum. The residue was triturated with petroleum ether / ethyl acetate (v / v, 10 / 1 , 10 mL) at room temperature for 5 minutes. The mixture was filtered, and the filter cake was dried under vacuum to yield the title compound as a brown solid. MS (ESI): mass calculated for C2oHi9BrN404S, 490.0; m / z measured, 493.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.91 (d, J=5.4 Hz, 1 H), 8.22 (s, 1 H), 7.71 (s, 1 H), 7.69 (s, 1 H), 7.37 (dd, J=5.9, 7.1 Hz, 1 H), 7.10 (s, 1 H), 7.08 (s, 1 H), 6.47 (d, J=7.2 Hz, 1 H), 3.92 - 3.81 (m, 2H), 3.59 - 3.48 (m, 2H), 3.37 - 3.33 (m, 2H), 3.31 (s, 2H), 3.09 (s, 3H).

[0299] Step B: (5-Hydroxy-3-(2-methoxy-3,6-dimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone. To a mixture of (3-bromo-5-hydroxy- 2,6-naphthyridin-1 -yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1 -yl)methanone (55.0 mg, 112 pmol) and (2-methoxy-3,6-dimethylphenyl)boronic acid (Intermediate U, 30.0 mg, 168 pmol) in DMF / H2O (v / v, 9 / 1 , 4 mL) was added K3PO4 (71 .0 mg, 336 umol) at room temperature. The mixture was degassed with N2 for 1 minute. CataCXium® A Pd G3 (8.20 mg, 11.2 pmol) was added and the mixture was stirred at 80 °C for 72 hours. The mixture was diluted with ethyl acetate (30 mL) and washed with brine (10 mL x 3). The organic layer was dried with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 100% ethyl acetate in DCM) to yield the title compound as light yellow solid. MS (ESI): mass calculated for C29H30N4O5S, 546.2; m / z measured, 547.1 [M+H]+.

[0300] Step C: (5-Chloro-3-(2-methoxy-3,6-dimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone. To (5-hydroxy-3-(2-methoxy-3,6- dimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1 - yl)methanone (25.0 mg, 36.7 pmol) was added POCI3 (0.8 mL) at room temperature. The mixture was stirred at 100 °C for 1 hour. The mixture was quenched with sat. aq. NaHCOs (10 mL), then extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried with Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 70% ethyl acetate in dichloromethane) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C29H29CIN4O4S, 564.2; m / z measured, 565.1 [M+H]+.

[0301] Intermediate W: (5-Chloro-3-(2,5-dimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(4- (methylsulfonyl)phenyl)piperidin-1 -yl)methanone.

[0302] Step A: 3-Bromo-2-methoxyisonicotinic acid. To a solution of 3-bromo-2- chloroisonicotinic acid (1 .0 g, 4.2 mmol) in MeOH (20 mL) was added NaOCHa (2.3 g, 42 mmol). The reaction mixture was stirred at 70 °C overnight. The mixture was concentrated. To the residue was added 1 N aq. HCI to adjust pH < 3 and filtered. The filtrate was extracted with ethyl acetate (30 mL x 3). The combined organic layers were concentrated to yield the title compound as a light yellow solid. MS (ESI): mass calculated for CyHeBrNOa, 230.9; m / z measured, 233.9 [M+H]+.1H NMR (400 MHz, DMSO-ok) 6 8.22 (d, J=5.0 Hz, 1 H), 7.16 (d, J=5.0 Hz, 1 H), 4.03 - 3.91 (m, 3H).

[0303] Step B: Methyl 3-bromo-2-methoxyisonicotinate. To a solution of 3-bromo-2- methoxyisonicotinic acid (915 mg, 3.95 mmol) in DCM / MeOH (v / v, 10 / 1 , 17.6 mL) at 0 °C was slowly added TMSCHN2 (2 M solution in hexane, 2.96 mL, 5.92 mmol). The mixture was stirred at 0 °C for 30 minutes. The mixture was quenched with AcOH (15 mL), diluted with H2O (6 mL), then extracted with DCM (25 mL x 3). The combined organic layers were washed with brine (15 mL x 3), dried with anhydrous NaaSC , filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 20% ethyl acetate in petroleum ether) to yield the title compound as a light brown solid. MS (ESI): mass calculated for CsHsBrNOs, 245.0; m / z measured, 248.0 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.15 (d, J=5.0 Hz, 1 H), 7.09 (d, J=5.0 Hz, 1 H), 4.04 (s, 3H), 3.97 (s, 3H).

[0304] Step C: Methyl 3-((2,5-dimethylphenyl)ethynyl)-2-methoxyisonicotinate. To a mixture of methyl 3-bromo-2-methoxyisonicotinate (700 mg, 2.85 mmol), 2-ethynyl-1 ,4- dimethylbenzene (740 mg, 4.95 mmol), and Cui (108 mg, 569 gmol) in DMF (8 mL) was added PdCl2 (50.4 mg, 284 pmol), / -Pr2NH (1.15 g, 11.4 mmol) and PPhs (149 mg, 569 pmol). After purging with argon, the mixture was stirred at 60 °C overnight. The reaction mixture was diluted with ethyl acetate (8 mL), then washed with 3% aq. LiCI (3 mL). The aqueous layer was extracted with ethyl acetate (8 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 50% ethyl acetate in petroleum ether) to yield the title compound as light brown solid. MS (ESI): mass calculated for C18H17NO3, 295.1 ; m / z measured, 296.1 [M+H]+.1H NMR (400 MHz, CDCI3) 6 8.16 (d, J=5.3 Hz, 1 H), 7.38 (s, 1 H), 7.33 (d, J=5.3 Hz, 1 H), 7.16 - 7.11 (m, 1 H), 7.11 - 7.04 (m, 1 H), 4.07 (s, 3H), 3.98 (s, 3H), 2.53 (s, 3H), 2.33 (s, 3H).

[0305] Step D: 3-(2,5-Dimethylphenyl)-5-methoxy-1 H-pyrano[4,3-c]pyridin-1-one. Methyl 3-((2,5-dimethylphenyl)ethynyl)-2-methoxyisonicotinate (700 mg, 2.37 mmol) was added to PPA (7 mL), then the mixture was stirred at 90 °C for 6 hours. To the reaction mixture was added ice water (30 mL), and the mixture was then extracted with ethyl acetate (80 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 50% ethyl acetate in petroleum ether) to yield the title compound as a light brown solid. MS (ESI): mass calculated for C17H15NO3, 281.1 ; m / z measured, 282.1 [M+H]+.1H NMR (400 MHz, CDCI3) 6 8.24 (d, J=5.3 Hz, 1 H), 7.65 (d, J=5.5 Hz, 1 H), 7.37 (s, 1 H), 7.18 (s, 2H), 6.90 (s, 1 H), 4.10 (s, 3H), 2.47 (s, 3H), 2.38 (s, 3H).

[0306] Step E: 3-(2-(2,5-Dimethylphenyl)-2-oxoethyl)-2-methoxyisonicotinamide. To a solution of 3-(2,5-dimethylphenyl)-5-methoxy-1 / - / -pyrano[4,3-c]pyridin-1 -one (600 mg, 2.13 mmol) in DMF (10 mL) was added ammonia solution (28% in water, 8 mL). The mixture was stirred at 80 °C overnight. The reaction mixture was diluted with 3% aq. LiCI (10 mL), then extracted with ethyl acetate (30 mL). The organic layer was dried with Na2SO4, filtered and concentrated under vacuum to yield the title compound as a light yellow gum, which was used in the next step without further purification. MS (ESI): mass calculated for C17H18N2O3, 298.1 ; m / z measured, 299.2 [M+H]+.

[0307] Step F: 3-(2,5-Dimethylphenyl)-5-methoxy-2,6-naphthyridin-1 (2H)-one. 3-(2-(2,5- Dimethylphenyl)-2-oxoethyl)-2-methoxyisonicotinamide (400 mg) was added to AcOH (8 mL). The mixture was stirred at 90 °C for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL) and sat. aq. NaHCOa (15 mL), then extracted with ethyl acetate (20 mL). The combined organic layers were dried with NaaSC , filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiOa, gradient elution: 0 - 70% ethyl acetate in petroleum ether) to yield the title compound as a light brown solid. MS (ESI): mass calculated for C17H16N2O2, 280.1 ; m / z measured, 281.1 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.96 (br s, 1 H), 8.17 (d, J=5.6 Hz, 1 H), 7.72 (d, J=5.6 Hz, 1 H), 7.22 - 7.18 (m, 3H), 6.80 (s, 1 H), 4.09 (s, 3H), 2.38 (s, 3H), 2.36 (s, 3H).

[0308] Step G: 3-(2,5-Dimethylphenyl)-5-methoxy-2,6-naphthyridin-1 -yl trifluoromethanesulfonate. To a solution of 3-(2,5-dimethylphenyl)-5-methoxy-2,6- naphthyridin-1 (2 / - / )-one (330 mg, 1.17 mmol), EtaN (357 mg, 3.53 mmol) in DCM (15 mL) was added Tf20 (996 mg, 3.53 mmol) at -78 °C by dropwise, then the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (30 mL) and sat. aq. NaHCOa (15 mL), and extracted with DCM (20 mL). The combined organic layers were dried with NaaSC , filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 50% ethyl acetate in petroleum ether) to yield the title compound as a light yellow solid. MS (ESI): mass calculated for C18H15F3N2O4S, 412.1 ; m / z measured, 413.1 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.26 (d, J=6.0 Hz, 1 H), 8.19 (d, J=1.0 Hz, 1 H), 7.44 (dd, J=0.8, 6.0 Hz, 1 H), 7.33 (s, 1 H), 7.24 - 7.20 (m, 1 H), 7.20 - 7.16 (m, 1 H), 4.19 (s, 3H), 2.43 (s, 3H), 2.40 (s, 3H).19F NMR (376 MHz, CDCI3) 5 -72.93 (s, 1 F).

[0309] Step H: Methyl 3-(2,5-dimethylphenyl)-5-methoxy-2,6-naphthyridine-1 - carboxylate. To a solution of 3-(2,5-dimethylphenyl)-5-methoxy-2,6-naphthyridin-1 -yl trifluoromethanesulfonate (320 mg, 760 pmol) in MeOH (6 mL) and DMF (6 mL) was added Pd(OAc)2 (17 mg, 76 pmol), DPPF (84.3 mg, 152 pmol) and EtaN (539 mg, 5.32 mmol). The reaction mixture was heated at 80 °C for 16 hours under CO (50 psi). The reaction mixture was diluted with ethyl acetate (30 mL) and washed with 3% aq. LiCI (15 mL). The aqueous layer was extracted with ethyl acetate (30 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 50% ethyl acetate in petroleum ether) to yield the title compound as a light yellow solid. MS (ESI): mass calculated for C19H18N2O3, 322.1 ; m / z measured, 323.1 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.33 (d, J=0.8 Hz, 1 H), 8.22 - 8.18 (m, 1 H), 8.16 - 8.11 (m, 1 H), 7.33 (d, J=1.5 Hz, 1 H), 7.23 - 7.19 (m, 1 H), 7.17 - 7.13 (m, 1 H), 4.17 (s, 3H), 4.08 (s, 3H), 2.39 (s, 6H).

[0310] Step I: 3-(2,5-Dimethylphenyl)-5-methoxy-2,6-naphthyridine-1 -carboxylic acid. To a solution of methyl 3-(2,5-dimethylphenyl)-5-methoxy-2,6-naphthyridine-1 -carboxylate (95.0 mg, 272 pmol) in THF (2 mL) and MeOH (2 mL) was added 1 M aq. NaOH (815 pL, 815 pmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (10 mL) and 1 M aq. HCI (1 mL), then extracted with ethyl acetate (10 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated under vacuum to yield the title compound as a light yellow gum, which was used in the next step without further purification. MS (ESI): mass calculated for C18H16N2O3, 308.1 ; m / z measured, 309.1 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.81 (d, J=6.2 Hz, 1 H), 8.50 (d, J=0.8 Hz, 1 H), 8.28 (d, J=6.2 Hz, 1 H), 7.31 (s, 1 H), 7.27 - 7.21 (m, 2H), 4.19 (s, 3H), 2.43 (s, 3H), 2.38 (s, 3H).

[0311] Step J: (3-(2,5-Dimethylphenyl)-5-methoxy-2,6-naphthyridin-1 -yl) (4- (4- (methylsulfonyl)phenyl)piperidin-1 -yl)methanone. To a solution of 3-(2,5- dimethylphenyl)-5-methoxy-2,6-naphthyridine-1 -carboxylic acid (100 mg) in DMF (3 mL) were added HATU (172 mg, 454 pmol) and EtsN (197 mg, 1.94 mmol), and the mixture was stirred at room temperature for 30 minutes. Then 4-(4- (methylsulfonyl)phenyl)piperidine (116 mg, 486 pmol) was added, and the mixture was stirred at room temperature overnight. Then another batch of HATU (135 mg, 357 pmol) was added to the mixture. After stirring at room temperature for 30 minutes, 4-(4- (methylsulfonyl)phenyl)piperidine (62.0 mg, 259 pmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (20 mL), and washed with 3% aq. LiCI (5 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 100% ethyl acetate in petroleum ether) to yield the title compound as a light yellow solid, which was used int the next without further purification. MS (ESI): mass calculated for C30H31N3O4S, 529.2; m / z measured, 530.2 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.19 - 8.15 (m, 2H), 7.90 (d, J=8.3 Hz, 2H), 7.43 (d, J=7.3 Hz, 3H), 7.30 (s, 1 H), 7.23 - 7.19 (m, 1 H), 7.18 - 7.14 (m, 1 H), 5.10 (br d, J=11.5 Hz, 1 H), 4.18 - 4.15 (m, 3H), 3.68 (br d, J=12.8 Hz, 1 H), 3.23 (br t, J=10.4 Hz, 1 H), 3.06 (s, 3H), 3.01 (br s, 2H), 2.38 (s, 6H), 2.10 (br s, 1 H), 1.96 - 1.85 (m, 1 H), 1.83 - 1.73 (m, 2H).

[0312] Step K: (3-(2,5-dimethylphenyl)-5-hydroxy-2,6-naphthyridin-1 -yl)(4-(4- (methylsulfonyl)phenyl)piperidin-1 -yl)methanone. To a solution of (3-(2,5- dimethylphenyl)-5-methoxy-2,6-naphthyridin-1 -yl)(4-(4-(methyl sulfonyl)phenyl)piperidin- 1 -yl)methanone (190 mg) in MeCN (10 mL) was added TMSCI (43.5 mg, 401 pmol) and Nal (60.0 mg, 401 pmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with sat. aq. NaHCOs (2 mL), then extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, petroleum ether / ethyl acetate = 10 / 1 ) to yield the title compound as a light brown solid. MS (ESI): mass calculated for C29H29N3O4S, 515.2; m / z measured, 516.1 [M+H]+.1H NMR (400 MHz, CDCI3 ) 5 9.68 (br s, 1 H), 8.36 (s, 1 H), 7.91 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.3 Hz, 2H), 7.32 (s, 1 H), 7.24 - 7.19 (m, 2H), 7.19 - 7.15 (m, 1 H), 6.77 (d, J=7.5 Hz, 1 H), 5.07 (br d, J=13.6 Hz, 1 H), 3.76 (br d, J=12.8 Hz, 1 H), 3.32 - 3.21 (m, 1 H), 3.06 (s, 3H), 3.03 - 2.90 (m, 2H), 2.41 (s, 3H), 2.37 (s, 3H), 2.09 (br s, 1 H), 1 .95 - 1 .74 (m, 3H).

[0313] Step L: (5-Chloro-3-(2,5-dimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(4- (methylsulfonyl)phenyl)piperidin-1 -yl)methanone. (3-(2,5-Dimethylphenyl)-5-hydroxy- 2,6-naphthyridin-1 -yl)(4-(4-(methylsulfonyl)phenyl)piperidin-1 -yl)methanone (140 mg, 272 pmol) was added to POCI3 (10 mL). The mixture was stirred at 100 °C for 6 hours. The reaction mixture was concentrated under reduced pressure. To the residue was slowly added sat. aq. NaHCOs (10 mL), then the mixture was extracted with ethyl acetate (40 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1 ) to yield the title compound as a light yellow gum. MS (ESI): mass calculated for C29H28CIN3O3S, 533.2; m / z measured, 534.1 [M+H]+.1H NMR (400MHz, CDCI3) 5 = 8.48 (d, J=5.8 Hz, 1 H), 8.24 (d, J=0.8 Hz, 1 H), 7.94 - 7.87 (m, 3H), 7.43 (d, J=8.3 Hz, 2H), 7.33 (s, 1 H), 7.26 - 7.19 (m, 2H), 5.11 (br d, J=13.6 Hz, 1 H), 3.71 (br d, J=14.3 Hz, 1 H), 3.32 - 3.21 (m, 1 H), 3.08 - 3.06 (m, 3H), 3.04 (s, 1 H), 3.02 - 2.91 (m, 1 H), 2.40 (s, 6H), 2.10 (br d, J=6.0 Hz, 1 H), 1 .96 - 1 .75 (m, 3H).

[0314] Intermediate X: (5-Chloro-3-(2,5-dimethylphenyl)-2,6-naphthyridin-1 -y I) (4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone.

[0315] Step A: (3-(2,5-Dimethylphenyl)-5-methoxy-2,6-naphthyridin-1 -yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone. To a solution of 3-(2,5- dimethylphenyl)-5-methoxy-2,6-naphthyridine-1 -carboxylic acid (Intermediate W, Step I, 80 mg) in DMF (2 mL) was added HATU (124 mg, 326 pmol) and EtaN (152 mg, 1.50 mmol), and the mixture was stirred at room temperature for 30 minutes. Then 1 -(4- (methylsulfonyl)phenyl)piperazine (72.4 mg, 301 pmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (20 mL), then washed with 3% aq. LiCI (5 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 100% ethyl acetate in petroleum ether) to yield the title compound as a light yellow gum. MS (ESI): mass calculated for C29H30N4O4S, 530.2; m / z measured, 531.1 [M+H]+.1H NMR (400 MHz, MeOD) 5 8.21 - 8.19 (m, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.42 (d, J=6.0 Hz, 1 H), 7.33 - 7.30 (m, 1 H), 7.25 - 7.21 (m, 1 H), 7.21 - 7.17 (m, 1 H), 7.10 (d, J=9.0 Hz, 2H), 4.19 (s, 3H), 4.10 - 4.05 (m, 2H), 3.66 - 3.61 (m, 2H), 3.51 - 3.45 (m, 2H), 3.40 - 3.35 (m, 2H), 3.04 (s, 3H), 2.38 (s, 3H), 2.35 (s, 3H).

[0316] Step B: (3-(2,5-Dimethylphenyl)-5-hydroxy-2,6-naphthyridin-1 -yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone. To a solution of (3-(2,5- dimethylphenyl)-5-methoxy-2,6-naphthyridin-1 -yl) (4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone (105 mg, 198 pmol) in MeCN (1.5 mL) were added chlorotrimethylsilane (27.9 mg, 257 gmol) and Nal (38.5 mg, 257 gmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with sat. aq. NaHCOs (2 mL), then extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over NaaSC , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiOa, gradient elution: 0 - 100% ethyl acetate in petroleum ether) to yield the title compound as a light brown solid. MS (ESI): mass calculated for C28H28N4O4S, 516.2; m / z measured, 517.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.80 (d, J=6.0 Hz, 1 H), 8.13 (s, 1 H), 7.69 (d, J=9.0 Hz, 2H), 7.35 (dd, J=5.9, 7.2 Hz, 1 H), 7.32 (s, 1 H), 7.24 - 7.21 (m, 1 H), 7.19 - 7.15 (m, 1 H), 7.09 (d, J=9.0 Hz, 2H), 6.52 (d, J=7.3 Hz, 1 H), 3.89 (br d, J=6.0 Hz, 2H), 3.55 (br s, 2H), 3.37 (br s, 4H), 3.09 (s, 3H), 2.34 (s, 3H), 2.33 (s, 3H).

[0317] Step C: (5-Chloro-3-(2,5-dimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone. (3-(2,5-Dimethylphenyl)-5-hydroxy- 2,6-naphthyridin-1 -yl)(4-(4-(methylsulfonyl)phenyl) piperazin-1 -yl)methanone (60.0 mg, 116 pmol) was added to POCI3 (2.34 g, 15.3 mmol). The mixture was stirred at 100 °C for 2 hours then cconcentrated under reduced pressure. To the residue was slowly added sat. aq. NaHCOs (2 mL), and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 100% ethyl acetate in petroleum ether) to yield the title compound as a light brown solid. MS (ESI): mass calculated for C28H27CIN4O3S, 534.1 ; m / z measured, 535.0 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.47 (d, J=5.8 Hz, 1 H), 8.27 (d, J=1 .0 Hz, 1 H), 7.91 (dd, J=1 .0, 5.8 Hz, 1 H), 7.81 (d, J=8.8 Hz, 2H), 7.33 (s, 1 H), 7.24 (s, 1 H), 7.23 - 7.20 (m, 1 H), 6.95 (d, J=9.0 Hz, 2H), 4.12 (t, J=5.3 Hz, 2H), 3.62 - 3.55 (m, 4H), 3.39 - 3.34 (m, 2H), 3.02 (s, 3H), 2.42 (s, 3H), 2.41 (s, 3H).

[0318] Intermediate Y: (5-Chloro-3-(2,4,5-trimethylthiophen-3-yl)-2,6-naphthyridin-1 - yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1 -yl)methanone.

[0319]

[0320] Step A: (5-Methoxy-3-(2,4,5-trimethylthiophen-3-yl)-2,6-naphthyridin-1 -yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone. To a mixture of (3-bromo-5-methoxy- 2,6-naphthyridin-1 -yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1 -yl)methanone (Intermediate C, Step A, 150 mg, 293 pmol) and 4,4,5,5-tetramethyl-2-(2,4,5- trimethylthiophen-3-yl)-1 ,3,2-dioxaborolane (96.0 mg, 381 pmol) in DMF / H2O (v / v, 9 / 1 , 10 mL) was added K3PO4 (187 mg, 880 pmol) at room temperature. The mixture was degassed with N2 for 1 minute, then CataCXium® A Pd G3 (21 .4 mg, 29.3 pmol) was added and the mixture was stirred at 80 °C for 12 hours. The mixture was diluted with ethyl acetate (50 mL) and washed with brine (20 mL x 3). The organic layer was dried with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 70% ethyl acetate in petroleum ether) to yield the title compound as a black solid. MS (ESI): mass calculated for C28H30N4O4S2, 550.2; m / z measured, 551.2 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.16 (d, J=6.1 Hz, 1 H), 8.04 (d, J=0.8 Hz, 1 H), 7.83 - 7.81 (m, 1 H), 7.80 - 7.78 (m, 1 H), 7.41 (dd, J=0.9, 6.0 Hz, 1 H), 6.98 - 6.95 (m, 1 H), 6.93 (s, 1 H), 4.17 (s, 3H), 4.11 - 4.08 (m, 2H), 3.58 - 3.52 (m, 4H), 3.35 - 3.32 (m, 2H), 3.02 (s, 3H), 2.37 (s, 3H), 2.36 (s, 3H), 2.04 (s, 3H).

[0321] Step B: (5-Hydroxy-3-(2,4,5-trimethylthiophen-3-yl)-2,6-naphthyridin-1 -yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone. To a mixture of Nal (114 mg, 763 pmol) in MeCN (15 mL) was added TMSCI (83.0 mg, 763 pmol) at room temperature. The mixture was stirred at room temperature for 5 minutes. (5-Methoxy-3-(2,4,5- trimethylthiophen-3-yl)-2,6-naphthyridin-1 -yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1 - yl)methanone (140 mg, 254 pmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with sat. aq. Na2SOs (15 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried with Na2SO4, filtered, and concentrated under vacuum. The residue was triturated with petroleum ether / ethyl acetate (v / v, 10 / 1 , 10 mL) at room temperature for 5 minutes. The mixture was filtered, and the filter cake was dried under vacuum to yield the title compound as a brown solid, which was used in the next step without further purification. MS (ESI): mass calculated for C27H28N4O4S2, 536.2; m / z measured, 537.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.80 (d, J=5.7 Hz, 1 H), 7.95 (s, 1 H), 7.69 (d, J=9.1 Hz, 2H), 7.38 - 7.31 (m, 1 H), 7.09 (d, J=9.1 Hz, 2H), 6.50 (d, J=7.2 Hz, 1 H), 3.91 - 3.86 (m, 2H), 3.55 (d, J=4.9 Hz, 2H), 3.32 - 3.27 (m, 4H), 3.09 (s, 3H), 2.33 (s, 3H), 2.31 (s, 3H), 1.99 (s, 3H).

[0322] Step C: (5-Chloro-3-(2,4,5-trimethylthiophen-3-yl)-2,6-naphthyridin-1 -yl) (4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone. To (5-hydroxy-3-(2,4,5- trimethylthiophen-3-yl)-2,6-naphthyridin-1 -yl)(4-(4-(methylsulfonyl) phenyl)piperazin-1 - yl)methanone (120 mg, 224 pmol) was added POCI3 (4.7 mL) at room temperature. The mixture was stirred at 100 °C for 1 hour. The reaction was quenched with sat. aq. NaHCOa (50 mL), then extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 20% ethyl acetate in dichloromethane) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C27H27CIN4O3S2, 554.1 ; m / z measured, 555.1 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.46 (d, J=5.7 Hz, 1 H), 8.12 (d, J=0.8 Hz, 1 H), 7.88 (dd, J=0.8, 5.7 Hz, 1 H), 7.81 (d, J=9.1 Hz, 2H), 6.96 (d, J=9.1 Hz, 2H), 4.14 - 4.07 (m, 2H), 3.57 (dd, J=3.8, 5.1 Hz, 4H), 3.40 - 3.32 (m, 2H), 3.03 (s, 3H), 2.42 (s, 3H), 2.38 (s, 3H), 2.08 (s, 3H).

[0323] Intermediate Z: (5-Chloro-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl) (2,2- dioxidohexahydropyrazino[2,1 -c][1 ,4]thiazin-8(1 H)-yl)methanone.

[0324] Step A: (3-Bromo-5-methoxy-2,6-naphthyridin-1 -yl) (2 ,2- dioxidohexahydropyrazino[2,1 -c][1 ,4]thiazin-8(1 H)-yl)methanone. HATU (3.5 g, 9.2 mmol) was added to a mixture of 3-bromo-5-methoxy-2,6-naphthyridine-1 -carboxylic acid (Intermediate A, 2.0 g, 7.07 mmol), octahydropyrazino[2,1 -c][1 ,4]thiazine 2,2- dioxide dihydrochloride (2.1 g, 8.0 mmol) and DIEA (2.8 g, 22 mmol) in DMF (30 mL). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with H2O (18 mL) and filtered. The filter cake was washed with H2O (20 mL), collected, and dried under vacuo to yield the title compound as a yellow solid. MS (ESI): mass calculated for CiyHigBrlShC S, 456.0; m / z measured, 456.7 [M+H]+.1H NMR (400 MHz, DMSO-ofe) 5 8.28 (s, 1 H), 8.26 (dd, J=1.4, 6.0 Hz, 1 H), 7.37 (dd, J=6.0, 13.9 Hz, 1 H), 4.56 - 4.39 (m, 1 H), 4.11 (d, J=3.2 Hz, 3H), 3.44 (d, J=15.7 Hz, 1 H), 3.25 - 2.83 (m, 8H), 2.73 - 2.62 (m, 2H), 2.43 - 2.32 (m, 1 H).

[0325] Step B: (2,2-Dioxidohexahydropyrazino[2,1 -c][1 ,4]thiazin-8(1 H)-yl)(5-methoxy-3- (2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)methanone. To a mixture of (3-bromo-5- methoxy-2,6-naphthyridin-1 -yl)(2,2-dioxidohexahydropyrazino [2,1 -c][1 ,4]thiazin-8(1 H)- yl)methanone (200 mg, 439 pmol) and (2,3,6-trimethylphenyl)boronic acid (86.0 mg, 524 pmol) in 1 ,4-dioxane / H2O (v / v, 9 / 1 , 12 mL) was added K3PO4 (280 mg, 1 .32 mmol) at room temperature. Then CataCXium® A Pd G3 (32 mg, 44 pmol) was added under N2, and the mixture was stirred at 80 °C for 2 days. The reaction mixture was filtered, and the filter cake was rinsed with ethyl acetate (20 mL). The filtrate was concentrated to dryness in vacuo to yield the title compound as a yellow solid, which was used in the next step without further purification. MS (ESI): mass calculated for C26H30N4O4S, 494.2; m / z measured, 495.1 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.19 (dd, J=2.0, 6.0 Hz, 1 H), 8.02 (d, J=8.0 Hz, 1 H), 7.42 (dd, J=3.4, 5.9 Hz, 1 H), 7.18 - 7.12 (m, 1 H), 7.10 - 7.03 (m, 1 H), 4.82 - 4.66 (m, 1 H), 4.15 (d, J=3.5 Hz, 3H), 3.48 - 3.26 (m, 2H), 3.26 - 3.11 (m, 2H), 3.10 - 2.76 (m, 6H), 2.75 - 2.67 (m, 1 H), 2.60 - 2.47 (m, 1 H), 2.30 (s, 3H), 2.02 (d, J=4.0 Hz, 3H), 1.93 (s, 3H).

[0326] Step C: (2,2-Dioxidohexahydropyrazino[2,1 -c][1 ,4]thiazin-8(1 H)-yl)(5-hydroxy-3- (2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)methanone. To a mixture of Nal (2.0 g, 13 mmol) in MeCN (20 mL) was added TMSCI (1.6 g, 15 mmol) at room temperature. The mixture was stirred for 15 minutes, then a solution of (2,2- dioxidohexahydropyrazino[2,1 -c][1 ,4]thiazin-8(1 / - / )-yl)(5-methoxy-3-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl)methanone (2.4 g, 4.9 mmol) in MeCN (80 mL) was added. The mixture was stirred at room temperature overnight. The reaction was quenched with sat. aq. Na2SOs (30 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was triturated with petroleum ether (10 mL) at room temperature for 2 hours. The mixture was filtered, the filter cake was collected and dried in vacuo to yield the title compound as a gray solid. MS (ESI): mass calculated for C25H28N4O4S, 480.2; m / z measured, 481.1 [M+H]+.1H NMR (400 MHz, CDCI3) 5 10.32 (s, 1 H), 8.19 (d, J=7.2 Hz, 1 H), 7.26 - 7.22 (m, 1 H), 7.17 - 7.13 (m, 1 H), 7.08 - 7.03 (m, 1 H), 6.80 - 6.73 (m, 1 H), 4.79 - 4.63 (m, 1 H), 3.56 - 3.31 (m, 2H), 3.29 - 3.18 (m, 1 H), 3.10 - 2.93 (m, 5H), 2.83 - 2.69 (m, 2H), 2.60 - 2.46 (m, 1 H), 2.37 (d, J=7.5 Hz, 1 H), 2.30 (s, 3H), 2.00 (s, 3H), 1.93 (s, 3H).

[0327] Step D: (5-Chloro-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl) (2,2- dioxidohexahydropyrazino[2,1 -c][1 ,4]thiazin-8(1 H)-yl)methanone. A mixture of (2,2- dioxidohexahydropyrazino[2,1 -c][1 ,4]thiazin-8(1 / - / )-yl)(5-hydroxy- 3-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl)methanone (500 mg, 920 pmol) in POCI3 (5 mL) was stirred at 100 °C for 2 hours, then cooled to room temperature. The mixture was concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate (40 mL) and then quenched with sat. aq. NaHCOs (60 mL), then extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to yield the title compound as a yellow solid. MS (ESI): mass calculated for C25H27CIN4O3S, 498.1 ; m / z measured, 499.1 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.51 (dd, J=1 .8, 5.8 Hz, 1 H), 8.15 - 8.09 (m, 1 H), 7.93 - 7.87 (m, 1 H), 7.23 - 7.17 (m, 1 H), 7.13 - 7.07 (m, 1 H), 4.88 - 4.70 (m, 1 H), 3.59 - 3.28 (m, 3H), 3.28 - 2.78 (m, 7H), 2.71 - 2.42 (m, 2H), 2.33 (s, 3H), 2.01 (s, 3H), 1.95 (s, 3H).

[0328] Compound Synthesis Examples

[0329] Example 1 : (R)- / V-(1 -Cyanocyclopropyl)-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)-2,6- naphthyridin-1 -yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide.

[0330]

[0331] A suspension of (5-chloro-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone (Intermediate C, 50 mg, 0.091 mml), (F?)-2-amino-N-(1 -cyanocyclopropyl)-3-(4-(trifluoromethyl)phenyl)propanamide (Intermediate I, 32 mg, 0.11 mmol), CS2CO3 (119 mg, 0.365 mmol), and rac-BINAP Pd G4 (13.7 mg, 0.0136 mmol) in 1 ,4-dioxane (0.48 mL) was sparged with Ar for 15 minutes and then the reaction mixture was heated at 90 °C with stirring overnight. The reaction was stopped and Si-Thiol Pd scavenger was added to the mixture and stirred for 2 hours. The solid was filtered and the filtrate was purified by RP-HPLC ((Stationary phase: Waters XSelect CSH C18, 5 pm, 19 x 150 mm; Mobile phase: water (0.16% TFA) (A) -MeCN (0.16% TFA) (B) 15 min run time, flow rate: 25 mL / min)) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C43H42F3N7O4S, 809.3; m / z measured, 810.3 [M+H]+.1H NMR (400 MHz, CDCI3) 5 9.35 (br s, 1 H), 9.02-8.84 (br s, 1 H), 8.32 (s, 1 H), 7.83-7.73 (m, 3H), 7.49 (d, J = 7.8 Hz, 2H), 7.40-7.30 (m, 3H), 7.22-7.01 (br m, 2H), 6.92 (d, J = 8.8 Hz, 2H), 5.54 (q, J= 7.5 Hz, 1 H), 4.13-3.96 (br m, 2H), 3.62-3.46 (m, 4H), 3.42-3.25 (m, 4H), 3.00 (s, 3H), 2.36-2.23 (m, 3H), 2.01 (s, 3H), 1 .94 (s, 3H), 1 .53-0.93 (br m, 4H).

[0332] Example 2: (F?)- / V-Methyl-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)amino)-3-(5- (trifluoromethyl)pyrimidin-2-yl)propanamide.

[0333] The title compound was prepared according to the procedure as described in Example 1 , substituting (F?)-2-amino-N-methyl-3-(5-(trifluoromethyl)pyrimidin-2- yl)propanamide (Intermediate J) for (F?)-2-amino-N-(1 -cyanocyclopropyl)-3-(4- (trifluoromethyl)phenyl)propanamide (Intermediate I) and toluene for 1 ,4-1 ,4-dioxane. MS (ESI): mass calculated for C38H39F3N8O4S, 760.3; m / z measured, 761.3 [M+H]+.1H NMR (400 MHz, DMSO-ofe) 6 9.15 (s, 2H), 8.20 (d, J=2.6 Hz, 1 H), 8.03 (d, J=6.0 Hz, 1 H), 7.98 - 7.88 (m, 2H), 7.69 (d, J=9.1 Hz, 2H), 7.16 (d, J=7.7 Hz, 1 H), 7.11 - 7.01 (m, 3H), 6.95 (d, J=6.2 Hz, 1 H), 5.53 - 5.36 (m, 1 H), 3.89 (br s, 2H), 3.68 - 3.60 (m, 1 H), 3.54 (br s, 2H), 3.52 - 3.46 (m, 1 H), 3.29 (s, 4H), 3.09 (s, 3H), 2.56 (d, J=4.6 Hz, 3H), 2.27 (br d, J=5.8 Hz, 3H), 2.02 - 1 .91 (m, 3H), 1.91 - 1 .81 (m, 3H).19F NMR (376 MHz, DMSO-cfe) 6 -60.78 (s, 1 F).

[0334] Example 3: (F?)- / V-Methyl-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)amino)-3-(2- (trifluoromethyl)pyrimidin-5-yl)propanamide.

[0335] To a mixture of (5-chloro-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone (Intermediate C, 70.0 mg, 121 pmol), (R)-2-amino- / V-methyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)propanamide (Intermediate K, 36.0 mg, 145 pmol) and CS2CO3 (154 mg, 473 pmol) in toluene (2.5 mL) was added BINAP (14.0 mg, 22.5 pmol) and Pd(OAc)2 (8.0 mg, 36 pmol) under N2. The mixture was stirred at 100 °C overnight, then cooled to room temperature. The reaction mixture was diluted with brine (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by prep-TLC (SiO2, DCM / MeOH = 10 / 1 ) and further purified by RP-HPLC (Stationary phase: Welch Xtimate C18, 5 pm, 150 x 25 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) -MeCN (B), gradient elution: 39 - 69% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as yellow powder. MS (ESI): mass calculated for C38H39F3N8O4S, 760.3; m / z measured, 761.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 8.97 (d, J=2.9 Hz, 2H), 8.29 (d, J=3.2 Hz, 1 H), 8.11 (d, J=4.1 Hz, 1 H), 8.01 - 7.91 (m, 2H), 7.68 (d, J=9.1 Hz, 2H), 7.23 - 7.15 (m, 1 H), 7.13 - 7.05 (m, 3H), 6.95 (d, J=6.1 Hz, 1 H), 5.01 (s, 1 H), 3.95 - 3.79 (m, 2H), 3.54 (s, 2H), 3.31 - 3.17 (m, 6H), 3.09 (s, 3H), 2.61 (d, J=4.4 Hz, 3H), 2.28 (d, J=2.6 Hz, 3H), 2.05 - 1.86 (m, 6H).19F NMR (376 MHz, DMSO-d6) 6 -68.84 (d, J=4.2 Hz, 1 F).

[0336] Example 4: ( / =?)- / -(( 1 s,3S)-3-Hydroxy-3-methylcyclobutyl)-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)-2,6- naphthyridin-1 -yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide.

[0337] The title compound was prepared according to the procedure as described in Example 3, substituting (R)-2-amino- / V-((1 s,3S)-3-hydroxy-3-methylcyclobutyl)-3-(4- (trifluoromethyl)phenyl)propanamide HCI (Intermediate D) for (R)-2-amino- / V-methyl-3- (2-(trifluoromethyl)pyrimidin-5-yl)propanamide (Intermediate K). MS (ESI): mass calculated for C44H47F3N6O5S, 828.3; m / z measured, 829.3 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 5 8.36 (d, J=7.2 Hz, 1 H), 8.31 (d, J=Q.Q Hz, 1 H), 7.96 (d, J=6.0 Hz, 1 H), 7.84 (d, J=8.3 Hz, 1 H), 7.67 (d, J=9.1 Hz, 2H), 7.58 (s, 4H), 7.20 - 7.15 (m, 1 H), 7.09 (d, J=7.9 Hz, 1 H), 7.06 (d, J=9.1 Hz, 2H), 6.90 (d, J=6.0 Hz, 1 H), 4.95 (s, 2H), 3.87 (d, J=4.3 Hz, 2H), 3.80 - 3.64 (m, 1 H), 3.53 (s, 2H), 3.26 (s, 4H), 3.15 (d, J=7.5 Hz, 2H), 3.08 (s, 3H), 2.29 (s, 3H), 2.25 - 2.17 (m, 2H), 2.02 - 1.86 (m, 8H), 1.21 (s, 3H).19F NMR (376 MHz, DMSO-d6) 5 -60.76 (s, 1 F).

[0338] Example 5: (F?)-(5-((3-Hydroxy-3-methyl-1 -(6-(trifluoromethyl)pyridin-3-yl)butan-2- yl)amino)-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone.

[0339]

[0340] To a vial were added (5-chloro-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)(4- (4-(methylsulfonyl)phenyl)piperazin-1 -yl)methanone (Intermediate C, 130 mg, 0.238 mmol), (F?)-3-amino-2-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)butan-2-ol HCI (Intermediate F, 65 mg, 0.26 mmol), rac-BINAP Pd G4 (24 mg, 0.024 mmol), potassium phosphate (152 mg, 0.714 mmol), BINAP (15 mg, 0.024 mmol) and THF (1 .6 mL). The vial was degassed with vacuum and backfilled with Ar three times, then the reaction mixture was heated at 100 °C for 8 hours. The volatiles were evaporated, and the residue was purified by silica gel flash chromatography (eluent 20% EtOAc / Heptane). The resulting residue was further purified by RP-HPLC (Phenomenex Gemini 5 pM C8 110A 150 x 30 mm column and eluted with a linear gradient of 40-100% B in A in 10 mins (A: 10 mM ammonium carbonate, 0.1 % ammonium hydroxide in water; B: 10 mM ammonium carbonate, 0.1% ammonium hydroxide in 90% acetonitrile 10% water)) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C40H43F3N6O4S, 760.3; m / z measured, 761.2 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.4- 8.6 (m, 1 H), 7.9-8.0 (m, 1 H), 7.7-7.8 (m, 2H), 7.6-7.7 (m, 1 H), 7.4-7.5 (m, 1 H), 7.3-7.4 (m, 1 H), 7.0-7.2 (m, 3H), 6.8-7.0 (m, 2H), 5.4-5.6 (m, 1 H), 4.4-4.5 (m, 1 H), 3.8-4.1 (m, 3H), 3.1 -3.6 (m, 8H), 3.0 (s, 3H), 2.2-2.3 (m, 3H), 1.9-2.0 (m, 6H), 1.3-1.5 (m, 6H).

[0341] Example 6: (F?)-(5-((3-Hydroxy-3-methyl-1 -(4-(trifluoromethyl)phenyl)butan-2- yl)amino)-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone. The title compound was prepared according to the procedure as described in Example 1 , substituting (F?)-3-amino-2-methyl-4-(4-(trifluoromethyl)phenyl)butan-2-ol HCI (Intermediate E) for (F?)-2-amino-N-(1 -cyanocyclopropyl)-3-(4- (trifluoromethyl)phenyl)propanamide (Intermediate I). MS (ESI): mass calculated for C41H44F3N5O4S, 759.3; m / z measured, 760.2 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.02 (d, J - 6.4 Hz, 1 H), 7.78 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 7.8 Hz, 2H), 7.22 (d, J= 7.8 Hz, 2H), 7.15 (d, J = 7.8 Hz, 1 H), 7.09 (d, J = 5.9 Hz, 1 H), 7.05 (d, J = 7.8 Hz, 1 H), 6.92 (d, J = 9.3 Hz, 2H), 5.42 (br d, J = 7.3 Hz, 1 H), 5.20-4.89 (m, 1 H), 4.40-4.23 (m, 1 H), 4.11 -3.99 (m, 2H), 3.58-3.39 (m, 4H), 3.36-3.20 (m, 3H), 3.12-3.01 (m, 1 H), 3.00 (s, 3H), 2.29 (s, 3H), 2.01 -1.81 (m, 6H), 1.39 (d, J= 4.9 Hz, 6H).

[0342] Example 7: (F?)- / V-Methyl-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)amino)-3-(2-nitro-4- (trifluoromethyl)phenyl)propanamide.

[0343] The title compound was prepared according to the procedure as described in Example 3, substituting (R)-2-amino- / V-methyl-3-(2-nitro-4- (trifluoromethyl)phenyl)propanamide (Intermediate H) for (R)-2-amino- / V-methyl-3-(2- (trifluoromethyl)pyrimidin-5-yl)propanamide (Intermediate K). MS (ESI): mass calculated for C40H40F3N7O6S, 803.3; m / z measured, 804.3 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.19 (s, 1 H), 7.92 (d, J=6.1 Hz, 1 H), 7.79 (d, J=8.9 Hz, 2H), 7.71 (br d, J=7.6 Hz, 1 H), 7.62 (br d, J=7.6 Hz, 2H), 7.20 - 7.10 (m, 2H), 7.08 (br d, J=5.5 Hz, 1 H), 6.92 (d, J=8.9 Hz, 2H), 6.74 - 6.34 (m, 2H), 5.46 - 5.25 (m, 1 H), 4.04 (br d, J=5.4 Hz, 2H), 3.75 (br dd, J=4.4, 13.5 Hz, 1 H), 3.52 (br t, J=5.0 Hz, 2H), 3.46 (br s, 3H), 3.30 (br d, J=4.9 Hz, 2H), 3.01 (s, 3H), 2.83 (d, J=4.8 Hz, 3H), 2.31 (br d, J=3.7 Hz, 3H), 2.00 (br s, 3H), 1 .93 (br d, J=9.1 Hz, 3H).19F NMR (376 MHz, CDCI3) 5 -62.93 (s, 1 F).

[0344] Example 8: (F?)-3-(2-Amino-4-(trifluoromethyl)phenyl)-N-methyl-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)-2,6- naphthyridin-1 -yl)amino)propanamide.

[0345] To a solution of (R)- / V-methyl-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)amino)-3-(2-nitro-4- (trifluoromethyl)phenyl)propanamide (Example 7, 150 mg, 135 pmol) in THF (15 mL) was added 10% wet. Pd / C (150 mg) under N2. The suspension was degassed in vacuo and purged with H2 several times, then stirred at room temperature under H2 (15 psi) overnight. The mixture was filtered through a pad of Celite®, and the filter cake was washed with THF / MeOH (v / v, 5 / 1 , 50 mL x 3). The filtrate was concentrated to dryness in vacuo and the residue was purified by RP-HPLC (Stationary phase: Welch Xtimate C18, 5 pm, 150 x 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 43 - 73% B in A over 9 min, flow rate: 35 mL / min) to yield the title compound (11 mg, 14.12 pmol, 31.36% yield, 99.34% purity) to yield the title compound as an off-white powder. MS (ESI): mass calculated for C40H42F3N7O4S, 773.3; m / z measured, 773.4 [M+H]+.1H NMR (400 MHz, DMSO-ofe) 6 8.32 (br d, J=6.8 Hz, 1 H), 8.11 (br d, J=4.8 Hz, 1 H), 7.99 (d, J=6.0 Hz, 1 H), 7.91 (br d, J=7.8 Hz, 1 H), 7.68 (d, J=8.8 Hz, 2H), 7.29 - 7.22 (m, 1 H), 7.20 - 7.14 (m, 1 H), 7.11 - 7.03 (m, 3H), 6.94 (d, J=6.0 Hz, 1 H), 6.89 (s, 1 H), 6.68 (br s, 1 H), 5.65 (s, 2H), 4.90 (br d, J=7.0 Hz, 1 H), 3.88 (br d, J=15.8 Hz, 2H), 3.55 (br s, 2H), 3.27 (br s, 4H), 3.09 (s, 3H), 3.02 (br d, J=6.8 Hz, 2H), 2.61 (d, J=4.5 Hz, 3H), 2.29 (br s, 3H), 2.06 - 1 .84 (m, 6H).19F NMR (376 MHz, DMSO-cfe) 6 -61.07 (br s, 1 F).

[0346] Example 9: (F?)-A / -(2-(3-(Methylamino)-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)-2,6- naphthyridin-1 -yl)amino)-3-oxopropyl)-5-(trifluoromethyl)phenyl)acrylamide.

[0347]

[0348] A solution of acryloyl chloride (5.7 mg, 63 pmol) in DCM (0.25 mL) was added dropwise to a solution of (F?)-3-(2-amino-4-(trifluoromethyl)phenyl)-N-methyl-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)-2,6- naphthyridin-1 -yl)amino)propanamide (Example 8, 40 mg, 47 pmol) and DIEA (64.0 mg, 495 pmol) in DCM (0.55 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 5 hours. The reaction was quenched with sat. aq. NaHCOa (5 mL), and the mixture extracted with DCM (5 mL x 3). The combined organic layers were concentrated to dryness in vacuo and the residue was purified by RP-HPLC (Stationary phase: Boston Prime C18, 5 pm, 150 x 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 55 - 85% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as an off-white powder. MS (ESI): mass calculated for C43H44F3N7O5S, 827.3; m / z measured, 828.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 9.87 (s, 1 H), 8.25 (d, J=5.3 Hz, 1 H), 8.14 - 8.03 (m, 2H), 8.00 (d, J=6.0 Hz, 1 H), 7.95 (br d, J=8.0 Hz, 1 H), 7.69 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.3 Hz, 1 H), 7.39 (br s, 1 H), 7.17 (d, J=7.8 Hz, 1 H), 7.08 (d, J=9.0 Hz, 3H), 6.95 (d, J=5.8 Hz, 1 H), 6.57 (br dd, J=11 .0, 15.3 Hz, 1 H), 6.25 (d, J=18.6 Hz, 1 H), 5.77 (br d, J=10.3 Hz, 1 H), 5.00 (br s, 1 H), 3.89 (br d, J=5.5 Hz, 2H), 3.55 (br s, 2H), 3.33 - 3.25 (m, 5H), 3.24 - 3.15 (m, 1 H), 3.09 (s, 3H), 2.60 (d, J=4.5 Hz, 3H), 2.28 (s, 3H), 2.04 - 1 .82 (m, 6H).19F NMR (376 MHz, DMSO-d6) 6 -61 .04 (s, 1 F).

[0349] Example 10: (F?)- / V-Methyl-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)amino)-3-(2-(2,2,2- trifluoroacetamido)-4-(trifluoromethyl)phenyl)propanamide.

[0350]

[0351] A solution of TFAA (28.0 mg, 133 pmol) in DCM (1 mL) was added to the mixture of (F?)-3-(2-amino-4-(trifluoromethyl)phenyl)-N-methyl-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)-2,6- naphthyridin-1 -yl)amino)propanamide (Example 8, 70 mg, 83 pmol) and EtaN (42.0 mg, 415 pmol) in DCM (1 .2 mL) at 0 °C under N2. The reaction mixture was stirred at 30 °C overnight. The mixture was diluted with DCM (10 mL), washed with sat. aq. NaHCOa (20 mL x 2), then dried over anhydrous NaaSC , filtered and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (Stationary phase: Welch Xtimate C18, 5 pm, 150 x 25 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 45 - 75% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as a yellow powder. MS (ESI): mass calculated for C42H41F6N7O5S, 869.3; m / z measured, 870.3 [M+H]+.1H NMR (400 MHz, MeCN-da) 5 11.66 - 11.01 (m, 1 H), 8.18 (d, J=6.1 Hz, 1 H), 8.01 (s, 1 H), 7.82 (d, J=1 .4 Hz, 1 H), 7.77 - 7.71 (m, 2H), 7.52 - 7.44 (m, 2H), 7.29 (br d, J=4.6 Hz, 1 H), 7.20 - 7.15 (m, 2H), 7.09 (br d, J=7.5 Hz, 1 H), 7.04 (d, J=9.1 Hz, 2H), 6.68 (br d, J=8.5 Hz, 1 H), 5.32 (dt, J=4.0, 8.1 Hz, 1 H), 4.05 - 3.92 (m, 2H), 3.57 (br s, 2H), 3.43 - 3.40 (m, 2H), 3.38 - 3.21 (m, 4H), 3.00 (s, 3H), 2.66 (d, J=4.9 Hz, 3H), 2.32 (s, 3H), 2.03 (s, 3H), 1 .98 (br s, 3H).19F NMR (376 MHz, MeCN-d3) 5 -63.13 (s, 1 F), -76.24 (s, 1 F).

[0352] Example 11 : (R)-3-(2-Acetamido-4-(trifluoromethyl)phenyl)- / V-methyl-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)-2,6- naphthyridin-1 -yl)amino)propanamide.

[0353]

[0354] A solution of AC2O (13.0 mg, 127 pmol) in DCM (0.5 mL) was added to a solution of (F?)-3-(2-amino-4-(trifluoromethyl)phenyl)-N-methyl-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)-2,6- naphthyridin-1 -yl)amino)propanamide (Example 8, 50 mg, 59 pmol) and EtsN (25.0 mg, 247 pmol) in DCM (0.5 mL). The reaction mixture was stirred at 30 °C overnight. The reaction mixture was concentrated to dryness in vacuo. The residue was purified by RP- HPLC (Stationary phase: Welch Xtimate C18, 5 pm, 150 x 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 43 - 73% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as a yellow powder. MS (ESI): mass calculated for C42H44F3N7O5S, 815.3; m / z measured, 816.3 [M+H]+.1H NMR (400 MHz, CDCI3) 5 9.49 - 9.27 (m, 1 H), 8.40 (br s, 1 H), 8.17 (d, J=6.0 Hz, 1 H), 7.80 (d, J=8.9 Hz, 2H), 7.66 (s, 1 H), 7.38 - 7.31 (m, 1 H), 7.28 - 7.22 (m, 2H), 7.18 (d, J=7.9 Hz, 1 H), 7.09 (br d, J=7.7 Hz, 1 H), 6.95 (d, J=8.9 Hz, 2H), 6.57 (br d, J=8.6 Hz, 1 H), 6.01 (br d, J=4.9 Hz, 1 H), 4.95 (dt, J=3.3, 6.4 Hz, 1 H), 4.13 - 4.05 (m, 2H), 3.63 - 3.48 (m, 5H), 3.39 - 3.30 (m, 2H), 3.06 - 2.95 (m, 4H), 2.74 (d, J=4.8 Hz, 3H), 2.38 (s, 3H), 2.32 (br s, 3H), 2.03 (br s, 3H), 1 .97 (br d, J=8.0 Hz, 3H).19F NMR (376 MHz, CDCI3) 5 -62.61 (s, 1 F).

[0355] Example 12: (R)- / V-Methyl-3-(2-(methylamino)-4-(trifluoromethyl)phenyl)-2-((5-(4- (4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)-2,6- naphthyridin-1 -yl)amino)propanamide.

[0356] The title compound was prepared according to the procedure as described in Example 3, substituting (R)-2-amino- / V-methyl-3-(2-(methylamino)-4- (trifluoromethyl)phenyl)propanamide (Intermediate L) for (R)-2-amino- / V-methyl-3-(2- (trifluoromethyl)pyrimidin-5-yl)propanamide (Intermediate K). MS (ESI): mass calculated for C41H44F3N7O4S, 787.3; m / z measured, 788.4 [M+H]+.1H NMR (400 MHz, MeCN-d3) 5 8.09 (d, J=6.0 Hz, 1 H), 7.77 (s, 1 H), 7.71 (d, J=9.0 Hz, 2H), 7.18 - 7.11 (m, 2H), 7.07 (d, J=6.3 Hz, 2H), 7.00 (d, J=9.0 Hz, 2H), 6.80 (d, J=7.3 Hz, 1 H), 6.78 - 6.71 (m, 2H), 6.59 (s, 1 H), 5.87 (s, 1 H), 4.77 (q, J=6.4 Hz, 1 H), 3.95 (s, 2H), 3.52 (s, 2H), 3.34 (d, J=5.0 Hz, 2H), 3.25 (d, J=5.3 Hz, 2H), 3.18 - 3.02 (m, 2H), 2.96 (s, 3H), 2.85 (d, J=4.8 Hz, 3H), 2.61 (d, J=4.8 Hz, 3H), 2.30 (s, 3H), 1.97 (d, J=11.0 Hz, 6H).19F NMR (376 MHz, MeCN-cfe) 5 -62.98 (s, 1 F).

[0357] Example 13: (R)-3-(2-(Dimethylamino)-4-(trifluoromethyl)phenyl)- / V-methyl-2-((5- (4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)-2,6- naphthyridin-1 -yl)amino)propanamide.

[0358] AcOH (40 pL) was added to a mixture of (F?)-3-(2-amino-4- (trifluoromethyl)phenyl)-N-methyl-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)amino)propanamide (Example 8, 40 mg, 50 pmol) and 37% aq. formaldehyde (20.0 mg, 246 pmol) in MeOH (4 mL). The mixture was stirred at room temperature for 1 hour, then NaBHsCN (13.0 mg, 207 pmol) was added. The reaction mixture was stirred at room temperature for another 2 hours. The reaction was quenched with sat. aq. NaHCOs (5 mL) and the mixture extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried with anhydrous NaaSC , filtered and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (Stationary phase: Boston Prime C18, 5 pm, 150 x 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 60 - 90% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as an off-white powder. MS (ESI): mass calculated for C42H46F3N7O4S, 801.3; m / z measured, 802.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.22 (d, J=4.3 Hz, 1 H), 7.97 (d, J=5.8 Hz, 1 H), 7.91 (br d, J=4.8 Hz, 1 H), 7.82 (br d, J=7.5 Hz, 1 H), 7.68 (d, J=9.0 Hz, 2H), 7.43 (br d, J=7.8 Hz, 1 H), 7.28 (s, 1 H), 7.20 - 7.13 (m, 2H), 7.07 (d, J=9.0 Hz, 3H), 6.90 (d, J=6.0 Hz, 1 H), 5.13 - 5.04 (m, 1 H), 3.88 (br s, 2H), 3.53 (br s, 2H), 3.40 (br d, J=11 .0 Hz, 1 H), 3.30 (br s, 1 H), 3.27 (s, 3H), 3.21 - 3.12 (m, 1 H), 3.08 (s, 3H), 2.64 (s, 6H), 2.57 (d, J=4.8 Hz, 3H), 2.27 (s, 3H), 2.02 - 1 .84 (m, 6H).19F NMR (376 MHz, DMSO-ofe) 5 -60.72 - -60.86 (m, 1 F).

[0359] Example 14: (R)-3-(2-(Difluoromethyl)-4-(trifluoromethyl)phenyl)- / V-methyl-2-((5- (4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)-2,6- naphthyridin-1 -yl)amino)propanamide.

[0360] To a mixture of (R)-2-amino-3-(2-(difluoromethyl)-4-(trifluoromethyl)phenyl)- / V- methylpropanamide (Intermediate M, 100 mg, 264 pmol), (5-chloro-3-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1 - yl)methanone (Intermediate C, 100 mg, 182 pmol), 4A molecular sieve (100 mg) and CS2CO3 (300 mg, 921 pmol) in 1 ,4-dioxane (4 mL) was added SPhos Pd G3 (20 mg, 26 pmol) at room temperature in the glovebox. The reaction mixture was stirred at 100 °C overnight, then cooled to room temperature. The mixture was filtered through a pad of Celite® and the filter cake was rinsed with ethyl acetate (10 mL). The filtrate was concentrated to dryness in vacuo. The residue was purified by RP-HPLC (Stationary phase: Boston Prime, 5 pm, 150 x 25 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 47-77% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as a yellow powder. MS (ESI): mass calculated for C41H41F5N6O4S, 808.3; m / z measured, 809.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.28 (d, J=3.3 Hz, 1 H), 8.07 (br d, J=2.3 Hz, 1 H), 7.97 - 7.92 (m, 2H), 7.77 (s, 1 H), 7.74 (br d, J=1.5 Hz, 2H), 7.67 (d, J=9.1 Hz, 2H), 7.62 - 7.31 (m, 1 H), 7.19 - 7.14 (m, 1 H), 7.11 - 7.03 (m, 3H), 6.92 (d, J=6.0 Hz, 1 H), 5.05 (br d, J=4.1 Hz, 1 H), 3.87 (br s, 2H), 3.52 (br s, 2H), 3.39 (br d, J=4.2 Hz, 2H), 3.26 (s, 4H), 3.07 (s, 3H), 2.58 (d, J=4.5 Hz, 3H), 2.28 (d, J=3.6 Hz, 3H), 2.01 - 1.93 (m, 3H), 1.90 (br d, J=15.0 Hz, 3H).19F NMR (376 MHz, DMSO-cfe) 6 -61 .21 (d, J=5.5 Hz, 1 F), -108.91 - -114.31 (m, 1 F).

[0361] Example 15: (R)-3-(4-Amino-6-(trifluoromethyl)pyridin-3-yl)- / V-methyl-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)-2,6- naphthyridin-1 -yl)amino)propanamide.

[0362] JosiPhos Pd G3 (64 mg, 69 pmol) was added to a mixture of (5-chloro-3-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1 - yl)methanone (Intermediate C, 200 mg, 364 pmol), (R)-2-amino- / V-methyl-3-(4-(2,2,2- trifluoroacetamido)-6-(trifluoromethyl)pyridin-3-yl)propanamide HCI (Intermediate N, 168 mg, 406 pmol), CS2CO3 (600 mg, 1 .84 mmol) and 4A molecular sieve (200 mg) in 1 ,4- dioxane (12 mL) in the glovebox. The mixture was stirred at 80 °C for 3.5 hours, then cooled to room temperature. The mixture was filtered through a pad of Celite® and the filter cake was rinsed with ethyl acetate (15 mL x 3). The combined filtrate was concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 3% MeOH in DCM) followed by prep-TLC (SiO2, DCM / MeOH = 15 / 1 ) and further purified by RP-HPLC (Stationary phase: Boston Prime C18, 5 pm, 150 x 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 45 - 75% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as a yellow powder. MS (ESI): mass calculated for C39H41F3N8O4S, 774.3; m / z measured, 775.3 [M+H]+.1H NMR (400 MHz, CDCI3) 6 8.09 (s, 1 H), 8.02 (d, J=6.1 Hz, 1 H), 7.79 (d, J=8.9 Hz, 2H), 7.69 (s, 1 H), 7.24 - 7.14 (m, 2H), 7.08 (br s, 1 H), 7.00 - 6.80 (m, 4H), 6.53 (br s, 2H), 5.36 - 5.25 (m, 1 H), 4.62 (br dd, J=5.1 , 9.4 Hz, 1 H), 4.14 - 3.98 (m, 2H), 3.61 - 3.48 (m, 4H), 3.42 (br d, J=14.1 Hz, 1 H), 3.39 - 3.27 (m, 2H), 3.01 (s, 3H), 2.83 (d, J=4.8 Hz, 3H), 2.82 - 2.75 (m, 1 H), 2.32 (br s, 3H), 2.07 - 1 .92 (m, 6H).19F NMR (376 MHz, CDCI3) 6 -68.30 (s, 1 F). Example 16: (R)- / V-Methyl-3-(3-(methylamino)-4-(trifluoromethyl)phenyl)-2-((5-(4- (4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)-2,6- naphthyridin-1 -yl)amino)propanamide.

[0363] To a mixture of (5-chloro-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone (Intermediate C, 180 mg, 328 pmol), (F?)-2-amino-N-methyl-3-(3-(methylamino)-4-(trifluoromethyl)phenyl)propanamide (Intermediate O, 102 mg, 343 pmol) and CS2CO3 (324 mg, 994 pmol) in 1 ,4-dioxane (6 mL) were added SPhos Pd G3 (30 mg, 38 pmol) and 4A molecular sieve (180 mg) at room temperature in the glovebox. The mixture was stirred at 100 °C overnight then cooled to room temperature. The mixture was filtered through a pad of Celite® and the filter cake was rinsed with ethyl acetate (10 mL). The filtrate was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness under vacuum. The residue was purified by column chromatography (SiO2, 0 - 100% ethyl acetate in petroleum ether), then further purified by RP-HPLC (Stationary phase: Boston Prime C18, 5 pm, 150 x 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 55 - 85% B in A over 7 min, flow rate: 255 mL / min) to yield the title compound as a yellow powder. MS (ESI): mass calculated for C41H44F3N7O4S, 787.3; m / z measured, 788.4 [M+H]+.1H NMR (400 MHz, DMSO-ofe) 5 8.33 (d, J=7.3 Hz, 1 H), 8.08 (d, J=4.8 Hz, 1 H), 7.96 (d, J=6.0 Hz, 1 H), 7.86 (d, J=7.3 Hz, 1 H), 7.67 (d, J=8.9 Hz, 2H), 7.25 - 7.14 (m, 2H), 7.12 - 7.03 (m, 3H), 6.90 (d, J=6.0 Hz, 1 H), 6.80 (s, 1 H), 6.66 (d, J=6.2 Hz, 1 H), 5.45 (dd, J=4.6, 8.8 Hz, 1 H), 4.89 - 4.80 (m, 1 H), 3.96 - 3.77 (m, 2H), 3.60 - 3.45 (m, 2H), 3.28 - 3.21 (m, 4H), 3.15 - 2.99 (m, 5H), 2.61 (d, J=4.3 Hz, 6H), 2.29 (d, J=5.1 Hz, 3H), 2.03 - 1.92 (m, 3H), 1.91 - 1.80 (m, 3H).19F NMR (376 MHz, DMSO-ofe) 5 -60.96 (s, 1 F).

[0364] Example 17: (R)- / V-Methyl- / V-(5-(3-(methylamino)-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)-2,6- naphthyridin-1 -yl)amino)-3-oxopropyl)-2-(trifluoromethyl)phenyl)acrylamide.

[0365] A solution of acryloyl chloride (11.0 mg, 122 pmol) in DCM (1 mL) was added dropwise to a solution of (R)- / V-methyl-3-(3-(methylamino)-4-(trifluoromethyl)phenyl)-2- ((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)-2,6- naphthyridin-1 -yl)amino)propanamide (Example 16, 60 mg, 61 pmol in sat. aq. NaHCOs (2.5 mL) and DCM (1 .5 mL) at 0 °C. After 1 hour interval, another batch of acryloyl chloride (11.0 mg, 122 pmol) was added, followed by a third batch of acryloyl chloride (22.0 mg, 243 pmol) was added. The reaction mixture was allowed to warm to room temperature and then stirred at room temperature for 6 hours. The reaction mixture was diluted with H2O (5 mL) and extracted with DCM (5 mL x 3). The combined organic layers were dried with anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (Stationary phase: Boston Prime C18, 5 pm, 150 x 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 50 - 80% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as an off-white powder. MS (ESI): mass calculated for C44H46F3N7O5S, 841.3; m / z measured, 842.4 [M+H]+.1H NMR (400 MHz, DMSO-ofe) 6 8.23 (d, J=13.6 Hz, 1 H), 7.94 (dd, J=3.8, 5.8 Hz, 1 H), 7.84 (d, J=4.5 Hz, 1 H), 7.73 - 7.63 (m, 4H), 7.61 - 7.53 (m, 1 H), 7.39 (d, J=9.4 Hz, 1 H), 7.19 - 7.13 (m, 1 H), 7.10 - 7.02 (m, 3H), 6.91 (d, J=6.0 Hz, 1 H), 6.08 - 5.85 (m, 1 H), 5.59 - 5.04 (m, 3H), 3.90 (d, J=5.4 Hz, 2H), 3.59 - 3.52 (m, 1 H), 3.55 (t, J=5.0 Hz, 1 H), 3.36 - 3.27 (m, 5H), 3.24 - 3.17 (m, 1 H), 3.06 (s, 3H), 3.05 - 2.95 (m, 3H), 2.63 (d, J=3.7 Hz, 3H), 2.29 (s, 3H), 2.03 - 1 .85 (m, 6H).19F NMR (376 MHz, DMSO-cfe) 6 -59.50 (d, J=13.9 Hz, 1 F).

[0366] Example 18: (F?)- / V-Methyl-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)amino)-3-(6- (trifluoromethyl)pyridin-3-yl)propanamide.

[0367]

[0368] The title compound was prepared according to the procedure as described in Example 3, substituting (R)-2-amino- / V-methyl-3-(6-(trifluoromethyl)pyridin-3- yl)propanamide (Intermediate P) for (R)-2-amino- / V-methyl-3-(2- (trifluoromethyl)pyrimidin-5-yl)propanamide (Intermediate K). MS (ESI): mass calculated for C39H40F3N7O4S, 759.3; m / z measured, 760.4 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.59 (s, 1 H), 8.12 (d, J=5.8 Hz, 1 H), 7.81 - 7.76 (m, 3H), 7.60 (d, J=8.0 Hz, 1 H), 7.52 (s, 1 H), 7.20 (d, J=6.0 Hz, 1 H), 7.16 (d, J=7.8 Hz, 1 H), 7.06 (d, J=5.8 Hz, 1 H), 6.94 (s, 1 H),

[0369] 6.92 (s, 1 H), 6.20 (d, J=4.8 Hz, 1 H), 6.01 (d, J=7.3 Hz, 1 H), 5.10 (q, J=7.2 Hz, 1 H), 4.13 - 4.00 (m, 2H), 3.57 - 3.51 (m, 2H), 3.49 (d, J=4.8 Hz, 2H), 3.43 (dd, J=7.3, 14.1 Hz,

[0370] 1 H), 3.35 - 3.25 (m, 3H), 3.01 (s, 3H), 2.80 (d, J=5.0 Hz, 3H), 2.30 (s, 3H), 1 .99 (s, 3H),

[0371] 1 .93 (s, 3H).19F NMR (376 MHz, CDCI3) 5 -67.81 (s, 1 F).

[0372] Example 19: (F?)- / V-Methyl-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide.

[0373] The title compound was prepared according to the procedure as described in Example 3, substituting (R)-2-amino- / V-methyl-3-(4-(trifluoromethyl)phenyl)propanamide HCI (Intermediate G) for (R)-2-amino- / V-methyl-3-(2-(trifluoromethyl)pyrimidin-5- yl)propanamide (Intermediate K). MS (ESI): mass calculated for C40H41F3N6O4S, 758.3; m / z measured, 759.4 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.13 (d, J=6.0 Hz, 1 H), 7.80 (s, 1 H), 7.78 (s, 1 H), 7.55 (s, 1 H), 7.53 (s, 2H), 7.40 (s, 1 H), 7.38 (s, 1 H), 7.21 - 7.14 (m, 2H), 7.07 (br d, J=7.8 Hz, 1 H), 6.94 (s, 1 H), 6.92 (s, 1 H), 6.07 (br s, 2H), 5.06 (br d, J=6.8 Hz, 1 H), 4.10 - 4.02 (m, 2H), 3.57 - 3.51 (m, 2H), 3.50 - 3.44 (m, 2H), 3.39 - 3.26 (m, 4H), 3.01 (s, 3H), 2.76 (d, J=4.8 Hz, 3H), 2.31 (s, 3H), 1 .99 (br s, 3H), 1 .93 (s, 3H).19F NMR (376 MHz, CDCI3) 6 -62.51 (s, 1 F).

[0374] Example 20: (3 ,3-Dif luoro-4-(6-(methylsu If onyl) pyridi n-3-y I) piperid in- 1 -yl) (5-( (( / =?)- 3-hydroxy-3-methyl-1 -(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-3-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl)methanone.

[0375] HATU (65.0 mg, 171 pmol) was added to a mixture of (F?)-5-((3-hydroxy-3- methyl-1 -(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-3-(2,3,6-trimethylphenyl)-2,6- naphthyridine-1 -carboxylic acid (Intermediate S, 60 mg), 5-(3,3-difluoropiperidin-4-yl)-2- (methylsulfonyl)pyridine TFA (Intermediate R, 80 mg) and DIEA (58.0 mg, 449 pmol) in DMF (5 mL). The mixture was stirred at room temperature overnight. The mixture was diluted with DCM (15 mL), then washed with H2O (20 mL). The organic phase was dried with anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was purified by preparative high-performance liquid chromatography (Stationary phase: Boston Prime C18, 5 pm, 150 x 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 55 - 85% B in A over 10 min, flow rate: 25 mL / min) and then further purified by preparative reverse phase HPLC (Stationary phase: Welch Xtimate C18, 5 pm, 150 x 30 mm; Mobile phase: water (FA) (A) - MeCN (B), gradient elution: 40 - 70% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as a yellow powder. MS (ESI): mass calculated for C41H42F5N5O4S, 795.3; m / z measured, 796.3 [M+H]+.1H NMR (400 MHz, DMSO-ofe) 6 8.72 (br d, J=9.9 Hz, 1 H), 8.45 - 8.31 (m, 1 H), 8.17 - 8.07 (m, 1 H), 8.07 - 8.02 (m, 1 H), 7.94 - 7.83 (m, 1 H), 7.46 (br d, J=4.3 Hz, 2H), 7.42 - 7.23 (m, 3H), 7.18 (t, J=7.2 Hz, 1 H), 7.14 - 7.04 (m, 1 H), 6.77 - 6.64 (m, 1 H), 5.06 - 4.60 (m, 3H), 3.89 - 3.68 (m, 1 H), 3.65 - 3.46 (m, 1 H), 3.30 (d, J=1 .5 Hz, 3H), 3.27 - 2.88 (m, 4H), 2.36 - 2.28 (m, 3H), 2.12 - 1.76 (m, 8H), 1.29 - 1.16 (m, 6H).19F NMR (376 MHz, DMSO-ofe) 6 -59.91 - -61 .73 (m, 1 F), -101.96 - -106.21 (m, 1 F), -111.99 - -115.29 (m, 1 F).

[0376] Example 21 : ((*S)-2,2-Dioxidohexahydropyrazino[2,1 -c][ 1 ,4]thiazin-8(1 H)-yl) (5- (((F?)-3-hydroxy-3-methyl-1 -(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-3-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl)methanone. and ((*F?)-2,2-Dioxidohexahydropyrazino[2,1 -c][1 ,4]thiazin-8(1 H)-yl)(5-(((F?)-3- hydroxy-3-methyl-1 -(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-3-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl)methanone.

[0377] To a mixture of (5-chloro-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1-yl) (2,2- dioxidohexahydropyrazino[2,1 -c][1 ,4]thiazin-8(1 / - / )-yl)methanone (Intermediate Z, 140 mg, 264 pmol), (F?)-3-amino-2-methyl-4-(4-(trifluoromethyl)phenyl)butan-2-ol HCI (Intermediate E, 78.0 mg, 315 pmol) and K3PO4 (239 mg, 1.13 mmol) in DMA (5.4 mL) was added RuPhos Pd G4 (23 mg, 28 pmol) and 4A molecular sieve (140 mg) at room temperature in the glovebox. The mixture was stirred at 80 °C overnight, then cooled to room temperature. The reaction mixture was filtered and the filter cake was rinsed with ethyl acetate (40 mL). The filtrate was concentrated to dryness in vacuo. The residue was purified by RP-HPLC (Stationary phase: Boston Prime C18, 5 pm, 150 x 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 55 - 85% B in A over 7 min, flow rate: 25 mL / min) to yield (2,2-dioxidohexahydropyrazino[2,1 - c][1 ,4]thiazi n-8( 1 H)-yl)(5-(((F?)-3-hydroxy-3-methyl-1 -(4-(trifluoromethyl)phenyl)butan-2- yl)amino)-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)methanone as a white solid. MS (ESI): mass calculated for C37H42F3N5O4S, 709.3; m / z measured, 710.3 [M+H]+.

[0378] (2,2-dioxidohexahydropyrazino[2,1 -c][1 ,4]thiazin-8(1 H)-yl)(5-(((F?)-3-hydroxy-3- methyl-1 -(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-3-(2,3,6-trimethylphenyl)-2,6- naphthyridin-1 -yl)methanone (40 mg, 56 pmol) was separated by SFC: (Column: DAICEL CHIRALPAKAD, 10 pm, 250 x 30 mm; mobile phase: Supercritical CO2 (A) - IPA (0.1% NH3H2O) (B); isocratic elution: 35% B in A; flow rate: 70 mL / min; column temp.: 40 °C; ABPR: 100 bar.) to yield:

[0379] ((*R)-2,2-Dioxidohexahydropyrazino[2,1 -c][ 1 ,4]thiazin-8( 1 H)-y I) (5-((( R)-3- hydroxy-3-methyl-1 -(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-3-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl)methanone as the first eluting compound (retention time 1 .498 min), as a white powder. MS (ESI): mass calculated for C37H42F3N5O4S, 709.3; m / z measured, 710.3 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.03 (s, 1 H), 7.46 - 7.37 (m, 2H), 7.16 (s, 4H), 7.08 (s, 2H), 5.39 (s, 1 H), 4.82 - 4.63 (m, 1 H), 4.33 (d, J=6.8 Hz, 1 H), 3.40 - 3.20 (m, 4H), 3.08 - 2.91 (m, 7H), 2.74 (d, J=10.7 Hz, 2H), 2.61 - 2.47 (m, 1 H), 2.30 (s, 4H), 1.97 - 1.83 (m, 6H), 1.39 (s, 6H).19F NMR (376 MHz, CDCI3) 5 -62.49 (d, J=20.8 Hz, 1 F). and ((*S)-2,2-Dioxidohexahydropyrazino[2,1 -c][ 1 ,4]thiazin-8( 1 H)-yl)(5-(((F?)-3- hydroxy-3-methyl-1 -(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-3-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl)methanone, as the second eluting compound (retention time 2.031 min), as a white powder. MS (ESI): mass calculated for C37H42F3N5O4S, 709.3; m / z measured, 710.3 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.04 (s, 1 H), 7.45 - 7.37 (m, 2H), 7.28 - 7.22 (m, 3H), 7.18 (d, J=7.3 Hz, 1 H), 7.09 (s, 2H), 5.44 (s, 1 H), 5.06 (s, 1 H), 4.82 - 4.64 (m, 1 H), 4.30 (s, 1 H), 3.39 - 3.20 (m, 3H), 3.16 - 2.91 (m, 7H), 2.81 - 2.70 (m, 2H), 2.56 (d, J=11 .9 Hz, 1 H), 2.31 (s, 4H), 1 .93 (s, 3H), 1 .88 (s, 3H), 1 .46 - 1 .37 (m, 6H).19F NMR (376 MHz, CDCI3) 5 -62.46 (d, J=17.3 Hz, 1 F).

[0380] Example 22: (F?)- / V-((1 s,3S)-3-Hydroxy-3-methylcyclobutyl)-2-((5-(4-(6- (methylsulfonyl)pyridin-3-yl)piperidine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)-2,6- naphthyridin-1 -yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide.

[0381] BINAP Pd G4 (20 mg, 19 pmol) was added to the mixture of (5-chloro-3-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(6-(methylsulfonyl)pyridin-3-yl)piperidin-1 - yl)methanone (Intermediate Q, 100 mg, 182 umol), (F?)-2-amino- A / -((1 s,3S)-3-hydroxy- 3-methylcyclobutyl)-3-(4-(trifluoromethyl)phenyl)propanamide HCI (Intermediate D, 80.0 mg, 225 pmol), and CS2CO3 (200 mg, 614 pmol) in DMA (4 mL) under N2. The mixture was stirred at 100 °C overnight, then cooled to room temperature. The mixture was filtered through a pad of Celite® and the filter cake was rinsed with ethyl acetate (15 mL). The filtrate was washed with 3% aq. LiCI (10 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by prep-TLC (SiO2, ethyl acetate) and further purified by RP-HPLC (Stationary phase: Welch Xtimate C18, 5 pm, 150 x 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 45 - 75% B in A over 8 min, flow rate: 30 mL / min) to yield the title compound as an off-white powder. MS (ESI): mass calculated for C44H47F3N6O5S, 828.3; m / z measured, 829.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.71 (s, 1 H), 8.37 (br d, J=6.9 Hz, 1 H), 8.28 (br d, J=3.8 Hz, 1 H), 8.07 - 8.01 (m, 1 H), 8.00 - 7.93 (m, 2H), 7.83 (br d, J=8.1 Hz, 1 H), 7.57 (s, 4H), 7.17 (br d, J=7.7 Hz, 1 H), 7.09 (br s, 1 H), 6.91 (br d, J=3.2 Hz, 1 H), 4.97 (br s, 2H), 4.78 (br d, J=11 .9 Hz, 1 H), 3.73 (br d, J=5.7 Hz, 1 H), 3.25 (s, 3H), 3.22 - 3.11 (m, 3H), 3.11 - 2.93 (m, 2H), 2.28 (br s, 3H), 2.20 (br s, 2H), 2.04 - 1 .85 (m, 9H), 1 .84 - 1 .67 (m, 2H), 1 .48 (br d, J=12.9 Hz, 1 H), 1 .20 (br s, 3H).19F NMR (376 MHz, DMSO-d6) 5 -60.76 (br d, J=5.5 Hz, 1 F).

[0382] Example 23: (F?)-(5-((3-Hydroxy-3-methyl-1 -(4-(trifluoromethyl)phenyl)butan-2- yl)amino)-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(6-(methylsulfonyl)pyridin-3- yl) pi peridi n- 1 -yl)methanone.

[0383] The title compound was prepared according to the procedure as described in Example 3, substituting (5-chloro-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(6- (methylsulfonyl)pyridin-3-yl)piperidin-1 -yl)methanone (Intermediate Q) for (5-chloro-3- (2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1 - yl)methanone (Intermediate C) and (F?)-3-amino-2-methyl-4-(4- (trifluoromethyl)phenyl)butan-2-ol HCI (Intermediate E) for (R)-2-amino- / V-methyl-3-(2- (trifluoromethyl)pyrimidin-5-yl)propanamide (Intermediate K). MS (ESI): mass calculated for C41H44F3N5O4S, 759.3; m / z measured, 760.3 [M+H]+.1H NMR (400 MHz, DMS0-d6) 5 8.71 (s, 1 H), 8.34 - 8.26 (m, 1 H), 8.08 - 8.01 (m, 1 H), 8.00 - 7.93 (m, 1 H), 7.86 (d, J=5.8 Hz, 1 H), 7.50 - 7.42 (m, 2H), 7.41 - 7.33 (m, 2H), 7.26 (br d, J=8.9 Hz, 1 H), 7.20 - 7.14 (m, 1 H), 7.13 - 7.04 (m, 1 H), 6.74 (d, J=5.8 Hz, 1 H), 4.91 - 4.58 (m, 3H), 3.30 - 3.21 (m, 5H), 3.08 - 2.88 (m, 3H), 2.28 (dd, J=6.0, 12.3 Hz, 3H), 2.11 - 1 .81 (m, 8H), 1.81 - 1.62 (m, 2H), 1.53 - 1.41 (m, 1 H), 1.22 (s, 3H), 1.19 (s, 3H).19F NMR (376 MHz, DMSO-cfe) 5 -60.77 (t, J=8.3 Hz, 1 F).

[0384] Example 24: (F?)-2-((5-((*S)-2,2-Dioxidooctahydropyrazino[2,1 -c] [ 1 ,4]thiazine-8- carbonyl)-7-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)amino)- / V-((1 s,3S)-3-hydroxy- 3-methylcyclobutyl)-3-(4-(trifluoromethyl)phenyl)propanamide. and (R)-2-((5-((*F?)-2,2-Dioxidooctahydropyrazino[2,1 -c][ 1 ,4]thiazine-8-carbonyl)-7- (2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)amino)- / V-((1 s,3S)-3-hydroxy-3- methylcyclobutyl)-3-(4-(trifluoromethyl)phenyl)propanamide.

[0385] BINAP Pd G3 (50 mg, 50 pmol) was added to a mixture of (5-chloro-3-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl)(2,2-dioxidohexahydropyrazino[2,1 -c][ 1 ,4]thiazin- 8(1 H)-yl)methanone (Intermediate Z, 250 mg, 472 pmol), (R)-2-amino- / V-((1 s,3S)-3- hydroxy-3-methylcyclobutyl)-3-(4-(trifluoromethyl)phenyl)propanamide HCI (Intermediate D, 200 mg, 562 pmol) and CS2CO3 (500 mg, 1.53 mmol) in DMA (10 mL). The mixture was stirred at 100 °C overnight, then cooled to room temperature. The reaction mixture was filtered through a pad of Celite® and the solid was rinsed with ethyl acetate (10 mL x 3). The filtrate was washed with 3% aq. LiCI (10 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by RP-HPLC (Stationary phase: Boston Prime C18, 5 pm, 150 x 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 51 - 81% B in A over 7 min, flow rate: 25 mL / min) to yield (2F?)-2-((5-(2,2-dioxidooctahydropyrazino[2,1 - c][1 ,4]thiazine-8-carbonyl)-7-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)amino)- / V- ((1 s,3S)-3-hydroxy-3-methylcyclobutyl)-3-(4-(trifluoromethyl)phenyl)propanamide as a pale yellow powder. MS (ESI): mass calculated for C40H45F3N6O5S, 778.3; m / z measured, 779.4 [M+H]+.

[0386] (2F?)-2-((5-(2,2-dioxidooctahydropyrazino[2, 1 -c] [ 1 ,4]thiazine-8-carbonyl)-7-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl)amino)- / V-((1 s,3S)-3-hydroxy-3-methylcyclobutyl)- 3-(4-(trifluoromethyl)phenyl)propanamide (150 mg, 189.82 pmol) was separated by SFC: (Column: DAICEL CHIRALPAKAD, 10 pm, 250 x 30 mm; mobile phase: Supercritical CO2 (A) -IPA (Neu) (B); isocratic elution: 30% B in A; flow rate: 150 mL / min; column temp.: 40 °C; ABPR: 100 bar.) to yield:

[0387] (F?)-2-((5-((*F?)-2,2-Dioxidooctahydropyrazino[2,1 -c][1 ,4]thiazine-8-carbonyl)-7- (2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)amino)- / V-((1 s,3S)-3-hydroxy-3- methylcyclobutyl)-3-(4-(trifluoromethyl)phenyl)propenamide, as the first eluting compound (retention time, 1.659 min), as a pale yellow powder. MS (ESI): mass calculated for C40H45F3N6O5S, 778.3; m / z measured, 779.3 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 5 8.23 (s, 1 H), 8.05 - 7.96 (m, 2H), 7.61 (d, J=8.2 Hz, 1 H), 7.56 - 7.49 (m, 4H), 7.19 - 7.14 (m, 1 H), 7.10 - 7.05 (m, 1 H), 6.88 (d, J=6.0 Hz, 1 H), 5.09 - 4.97 (m, 1 H), 4.66 (s, 1 H), 4.48 (br t, J=10.5 Hz, 1 H), 3.82 - 3.68 (m, 1 H), 3.38 - 3.10 (m, 6H), 3.06 - 2.82 (m, 3H), 2.82 - 2.70 (m, 2H), 2.69 - 2.64 (m, 1 H), 2.37 (br s, 1 H), 2.30 (s, 3H), 2.27 - 2.19 (m, 2H), 2.19 - 2.08 (m, 1 H), 2.00 - 1.85 (m, 8H), 1.22 (s, 3H).19F NMR (376 MHz, DMSO-cfe) 5 -60.74 (br d, J=6.9 Hz, 1 F). and (F?)-2-((5-((*S)-2,2-Dioxidooctahydropyrazino[2,1 -c] [1 ,4]thiazine-8-carbonyl)- 7-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)amino)- / V-((1 s,3S)-3-hydroxy-3- methylcyclobutyl)-3-(4-(trifluoromethyl)phenyl)propenamide, as the second eluting compound (retention time, 1.675 min), as a pale yellow powder. MS (ESI): mass calculated for C40H45F3N6O5S, 778.3; m / z measured, 779.3 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 5 8.38 (br t, J=6.1 Hz, 1 H), 8.30 (dd, J=4.2, 9.1 Hz, 1 H), 7.97 (dd, J=2.0, 5.9 Hz, 1 H), 7.83 (br d, J=8.5 Hz, 1 H), 7.59 (d, J=14.5 Hz, 4H), 7.17 (br d, J=7.6 Hz, 1 H), 7.09 (br d, J=7.6 Hz, 1 H), 6.85 (t, J=5.5 Hz, 1 H), 5.03 - 4.85 (m, 2H), 4.49 (br t, J=10.7 Hz, 1 H), 3.79 - 3.67 (m, 1 H), 3.41 (br d, J=16.1 Hz, 1 H), 3.28 - 2.95 (m, 8H), 2.93 - 2.83 (m, 1 H), 2.82 - 2.71 (m, 1 H), 2.66 - 2.56 (m, 2H), 2.30 - 2.25 (m, 3H), 2.19 (br d, J=7.4 Hz, 2H), 2.13 - 1.81 (m, 9H), 1.20 (s, 3H).19F NMR (376 MHz, DMSO-d6) 5 -60.76 (br d, J=6.9 Hz, 1 F).

[0388] Example 25: (F?)-(5-((3-Hydroxy-3-methyl-1 -(6-(trifluoromethyl)pyridin-3-yl)butan- 2-yl)amino)-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)(morpholino)methanone.

[0389] To a mixture of (5-chloro-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1-yl) (morpholino)methanone (Intermediate T, 100 mg, 253 pmol), (F?)-3-amino-2-methyl-4-(6- (trifluoromethyl)pyridin-3-yl)butan-2-ol HCI (Intermediate F, 75.0 mg, 285 pmol) and CS2CO3 (239 mg, 734 pmol) in 1 ,4-dioxane (3.8 mL) was added SPhos Pd G4 (20 mg, 26 p mol) and 4A molecular sieve (100 mg) at room temperature in the glovebox. The mixture was stirred at 100 °C overnight, then cooled to room temperature. The reaction mixture was filtered through a pad of Celite® and filter cake was washed with ethyl acetate (5 mL x 3). The filtrate was concentrated to dryness in vacuo. The residue was purified by prep-TLC (SiO2, petroleum ether / ethyl acetate = 1 / 2) and then further purified by RP-HPLC (Stationary phase: Boston Prime C18, 3 pm, 80 x 40 mm; Mobile phase: water (NH3H2O) (A) - MeCN (B), gradient elution: 50 - 80% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as a yellow powder. MS (ESI): mass calculated for C33H36F3N5O3, 607.3; m / z measured, 608.3 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 5 8.61 (s, 1 H), 8.21 (s, 1 H), 7.94 - 7.78 (m, 2H), 7.51 (d, J=8.0 Hz, 1 H), 7.22 - 7.04 (m, 3H), 6.76 (d, J=6.0 Hz, 1 H), 4.84 - 4.73 (m, 1 H), 4.59 (s, 1 H), 3.80 - 3.68 (m, 4H), 3.47 (t, J=4.4 Hz, 2H), 3.30 (dd, J=2.7, 13.9 Hz, 1 H), 3.11 (d, J=4.5 Hz, 2H), 3.02 (dd, J=11.5, 13.8 Hz, 1 H), 2.31 (s, 3H), 1.96 (s, 3H), 1.91 (s, 3H), 1.28 (s, 3H), 1.24 (s, 3H).19F NMR (376 MHz, DMSO-d6) 5 -66.27 (s, 1 F).

[0390] Example 26: (F?)-2-((7-(2-Methoxy-3,6-dimethylphenyl)-5-(4-(4- (methylsulfonyl)phenyl)piperazine-1 -carbonyl)-2,6-naphthyridin-1 -yl)amino)- / V-methyl-3-

[0391] (4-(trifluoromethyl)phenyl)propanamide.

[0392] To a mixture of (5-chloro-3-(2-methoxy-3,6-dimethylphenyl)-2,6-naphthyridin-1 - yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1 -yl)methanone (Intermediate V, 18.0 mg, 26.4 pmol) in toluene (1 .5 mL) were added CS2CO3 (34.0 mg, 105 pmol) and (F?)-2-amino- / V- methyl-3-(4-(trifluoromethyl)phenyl)propanamide HCI (Intermediate G, 20 mg, 79 pmol) at room temperature. The mixture was degassed with N2 for 1 minute, then Pd(OAc)2 (1 mg, 4 pmol) and BINAP (3.3 mg, 5.3 pmol) were added. The mixture was then stirred at 100 °C for 16 hours under N2. The reaction mixture was concentrated under vacuum. The residue was purified by RP-HPLC (Stationary phase: Phenomenex Gemini-NX C18, 3 pm, 75 x 30 mm; Mobile phase: water (0.05% NH3H2O + 10 mM NH4HCO3) (A) - MeCN (B), gradient elution: 50 - 80% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as a yellow powder. MS (ESI): mass calculated for C40H41F3N6O5S, 774.3; m / z measured, 775.3 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.14 (d, J=6.0 Hz, 1 H), 7.81 (s, 1 H), 7.78 (s, 1 H), 7.66 (s, 1 H), 7.57 (s, 1 H), 7.55 (s, 1 H), 7.42 (s, 1 H), 7.40 (s, 1 H), 7.21 - 7.15 (m, 2H), 7.00 (d, J=7.9 Hz, 1 H), 6.95 (s, 1 H), 6.92 (s, 1 H), 6.03 (d, J=4.9 Hz, 1 H), 5.98 (d, J=7.3 Hz, 1 H), 5.04 (q, J=7.2 Hz, 1 H), 4.11 - 4.05 (m, 2H), 3.57 - 3.52 (m, 2H), 3.51 - 3.47 (m, 2H), 3.39 - 3.34 (m, 1 H), 3.34 (s, 3H), 3.33 - 3.26 (m, 3H), 3.02 (s, 3H), 2.76 (d, J=4.9 Hz, 3H), 2.34 (s, 3H), 2.10 (s, 3H).19F NMR (376 MHz, CDCI3) 5 -62.48 (s, 1 F).

[0393] Example 27: (F?)-2-((7-(2,5-Dimethylphenyl)-5-(4-(4- (methylsulfonyl)phenyl)piperidine-1 -carbonyl)-2,6-naphthyridin-1 -yl)amino)- / V-methyl-3- (4-(trifluoromethyl)phenyl)propanamide.

[0394]

[0395] BINAP (14 mg, 22 pmol) and Pd(OAc)2 (2.5 mg, 11 pmol) were added to a mixture of (5-chloro-3-(2,5-dimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(4- (methylsulfonyl)phenyl) piperazin-1 -yl)methanone (Intermediate W, 60.0 mg, 112 pmol), (R)-2-amino- / V-methyl-3-(4-(trifluoromethyl)phenyl)propanamide HCI (Intermediate G, 38.0 mg, 135 pmol) and CS2CO3 (110 mg, 336 pmol) in toluene (1.5 mL) under N2. The mixture was stirred at 80 °C overnight. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by RP-HPLC (Stationary phase: Boston Prime, 5 pm, 150 x 30 mm; Mobile phase: (0.05% NH3H2O + 10 mM NH4HCO3) (A) - MeCN (B), gradient elution: 55 - 85% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as a beige powder. MS (ESI): mass calculated for C39H39F3N6O4S, 744.3; m / z measured, 745.2 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.11 (d, J=6.0 Hz, 1 H), 7.79 (d, J=8.8 Hz, 2H), 7.66 (s, 1 H), 7.57 (d, J=8.3 Hz, 2H), 7.42 (d, J=7.8 Hz, 2H), 7.22 (d, J=7.3 Hz, 2H), 7.19 - 7.14 (m, 2H), 6.94 (d, J=9.0 Hz, 2H), 6.10 (d, J=7.3 Hz, 1 H), 6.00 (br d, J=4.8 Hz, 1 H), 5.06 (q, J=7.3 Hz, 1 H), 4.12 - 4.05 (m, 2H), 3.55 (br t, J=5.1 Hz, 2H), 3.53 - 3.49 (m, 2H), 3.40 - 3.26 (m, 4H), 3.02 (s, 3H), 2.76 (d, J=4.8 Hz, 3H), 2.41 (s, 3H), 2.33 (s, 3H).19F NMR (376 MHz, CDCI3) 5 -62.46 (s, 1 F).

[0396] Example 28: (F?)-2-((7-(2,5-Dimethylphenyl)-5-(4-(4- (methylsulfonyl)phenyl)piperazine-1 -carbonyl)-2,6-naphthyridin-1 -yl)amino)- / V-methyl-3- (4-(trifluoromethyl)phenyl)propanamide.

[0397] BINAP (14 mg, 22 pmol) and Pd(OAc)2 (2.5 mg, 11 pmol) were added to a mixture of (5-chloro-3-(2,5-dimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(4- (methylsulfonyl)phenyl) piperazin-1 -yl)methanone (Intermediate X, 60 mg, 112 pmol), (F?)-2-amino-A / -methyl-3- (4-(trifluoromethyl)phenyl)propanamide HCI (38.0 mg, 134 pmol) and CS2CO3 (110 mg, 336 pmol) in toluene (1.5 mL) under N2. The mixture was stirred at 80 °C overnight. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by RP-HPLC (Stationary phase: Boston Prime, 5 pm, 150 x 30 mm; Mobile phase: (0.05% NH3H2O + 10 mM NH4HCO3) (A) - MeCN (B), gradient elution: 55 - 85% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as a beige powder. MS (ESI): mass calculated for C39H39F3N6O4S, 744.3; m / z measured, 745.2 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.11 (d, J=6.0 Hz, 1 H), 7.79 (d, J=8.8 Hz, 2H), 7.66 (s, 1 H), 7.57 (d, J=8.3 Hz, 2H), 7.42 (d, J=7.8 Hz, 2H), 7.22 (d, J=7.3 Hz, 2H), 7.19 - 7.14 (m, 2H), 6.94 (d, J=9.0 Hz, 2H), 6.10 (d, J=7.3 Hz, 1 H), 6.00 (br d, J=4.8 Hz, 1 H), 5.06 (q, J=7.3 Hz, 1 H), 4.12 - 4.05 (m, 2H), 3.55 (br t, J=5.1 Hz, 2H), 3.53 - 3.49 (m, 2H), 3.40 - 3.26 (m, 4H), 3.02 (s, 3H), 2.76 (d, J=4.8 Hz, 3H), 2.41 (s, 3H), 2.33 (s, 3H).19F NMR (376 MHz, CDCI3) 5 -62.46 (s, 1 F).

[0398] Example 29: (F?)- / V-Methyl-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 - carbonyl)-7-(2,4,5-trimethylthiophen-3-yl)-2,6-naphthyridin-1 -yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide.

[0399] The title compound was prepared according to the procedure as described in Example 3, substituting (5-chloro-3-(2,4,5-trimethylthiophen-3-yl)-2,6-naphthyridin-1 - yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1 -yl)methanone (Intermediate Y) for (5-chloro- 3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1 - yl)methanone (Intermediate C) and (R)-2-amino- / V-methyl-3-(4- (trifluoromethyl)phenyl)propanamide HCI (Intermediate G) for (R)-2-amino- / V-methyl-3- (2-(trifluoromethyl)pyrimidin-5-yl)propanamide (Intermediate K). MS (ESI): mass calculated for C38H39F3N6O4S2, 764.2; m / z measured, 765.2 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.12 (d, J=6.0 Hz, 1 H), 7.81 (s, 1 H), 7.79 (s, 1 H), 7.56 (d, J=8.0 Hz, 2H), 7.51 (s, 1 H), 7.41 (d, J=8.0 Hz, 2H), 7.15 (d, J=6.0 Hz, 1 H), 6.95 (s, 1 H), 6.93 (s, 1 H), 6.07 - 5.99 (m, 2H), 5.05 (q, J=7.0 Hz, 1 H), 4.12 - 4.04 (m, 2H), 3.55 (t, J=5.1 Hz, 2H), 3.52 - 3.47 (m, 2H), 3.39 - 3.27 (m, 4H), 3.02 (s, 3H), 2.77 (d, J=4.8 Hz, 3H), 2.35 (s, 3H), 2.33

[0400] (s, 3H), 1 .99 (s, 3H).19F NMR (376 MHz, CDCI3) 5 -62.49 (s, 1 F).

[0401] Biological Example 1 :

[0402] BFL-1 BIM (WIAQ peptide) homogeneous time-resolved fluorescence assay Effect of a test compound on BFL-1 and a-helical Bcl-2 homology-3 (BH3) domains of pro-apoptotic proteins was determined using the homogeneous time- resolved fluorescence (HTRF) binding assay. The assay used the BIM BH3 peptide (H2N-(C / Cy5Mal) WIAQELRRIGDEFN-OH (New England Peptide, order #P612077) as the binding partner for BFL-1 . Test compounds that interacted with BFL-1 (6His.Tev.Avi.Bfl1 .1 -153, Proteros, ClonelD#: PROT_Bfl1_01 ) were identified through displacement of the BIM BH3 peptide (H2N-(C / Cy5Mal) WIAQELRRIGDEFN-OH.

[0403] The assay reaction buffer contained 10 mM Tris, pH 7.5 (Teknova, #T1075), 150 mM NaCI (VWR, #E529), 0.1 mM TCEP (Thermo Fisher, # 77720), 0.0025% Tween-20 (Thermo Fisher, #85113), and 0.1 mg / mL BSA (Sigma, #A7030). Test compounds were serially diluted at concentration including one or more of the 10-point or 11 -point dilution series A through E listed in Table 5, below

[0404] Table 5: Test Compound Serial Dilutions and were spotted into white 384-well Proxiplates (Perkin Elmer, #6008289). An 8 nM BFL-1 solution prepared in the reaction buffer was dispensed into the assay wells for a final concentration of 4 nM. The assay plate was incubated for 30 mins at room temperature. Detection reagents containing Cy5-BIM peptide and Mab Anti-6HIS Tb cryptate Gold (Tb-anti-His) (Perkin Elmer, #61 HI2TLB) were prepared in the reaction buffer (0.5nM Tb-anti-His and 120nM BIM peptide in 1X reaction buffer; 1X reaction buffer = 10 mM Tris, pH 7.5, 150 mM NaCI, 0.1 mM TCEP, 0.0025% Tween-20, and 0.1 mg / mL BSA) and dispensed into the assay wells for a final concentration of 60 nM Cy5- BIM peptide and 0.25 nM Tb-Anti-His. The assay plate was incubated for 60 mins at room temperature. The HTRF signal of the assay was read on a PHERAstar FSX microplate reader (BMG LabTech) using an HTRF optic module, and concentrations that achieved half-maximal inhibition relative to DMSO control (IC50) were determined using Genedata Screener® software.

[0405] Biological Example 2:

[0406] BFL-1 BID BH3 homogeneous time-resolved fluorescence assay

[0407] Effect of a test compound on BFL-1 and a-helical Bcl-2 homology-3 (BH3) domains of pro-apoptotic proteins was determined using the homogeneous time- resolved fluorescence (HTRF) binding assay. The assay used the BID BH3 peptide (H2N-(C / Cy5Mal) EDIIRNIARHLAQVGDSMDR-OH (New England Peptide, order #P612077) as the binding partner for BFL-1 . Test compounds that interacted with BFL- 1 (6His.Tev.Avi.Bfl1.1 -153, Proteros, ClonelD#: PROT_Bfl1_01 ) were identified through displacement of the BID BH3 peptide (H2N-(C / Cy5Mal) EDIIRNIARHLAQVGDSMDR- OH.

[0408] The assay reaction buffer contained 10 mM Tris, pH 7.5 (Teknova, #T1075), 150 mM NaCI (VWR, #E529), 0.1 mM TCEP (Thermo Fisher, #77720), 0.0025% Tween-20 (Thermo Fisher, #85113), and 0.1 mg / mL BSA (Sigma, #A7030). Serial diluted test compounds (at concentrations of 5 pM, 1 .67 pM, 556 nM, 185 nM, 62 nM, 21 nM, 6.9 nM, 2.3 nM, 0.8 nM, and 0.3 nM) were spotted into white 384-well Proxiplate (Perkin Elmer, #6008289). A 2 nM BFL-1 solution prepared in the reaction buffer was dispensed into the assay wells for a final concentration of 1 nM. The assay plate was incubated for 30 mins at room temperature. Detection reagents containing Cy5-BID peptide and Mab Anti-6HIS Tb cryptate Gold (Tb-anti-His) (Perkin Elmer, #61 HI2TLB) were prepared in the reaction buffer (0.5nM Tb-anti-His and 20nM BID peptide in 1X reaction buffer; with 1X reaction buffer = 10 mM Tris, pH 7.5, 150 mM NaCI, 0.1 mM TCEP, 0.0025% Tween-20, and 0.1 mg / mL BSA) and dispensed into the assay wells for a final concentration of 10 nM Cy5-Bid peptide and 0.25 nM Tb-anti-His. The assay plate was incubated for 60 mins at room temperature. The HTRF signal of the assay was read on a PHERAstar FSX microplate reader (BMG LabTech) using an HTRF optic module, and concentrations that achieved half-maximal inhibition relative to DMSO control (IC50) were determined using Genedata Screener® software.

[0409] Calculation of Ki values for BID and BIM assays

[0410] The Percent-of-Control (Generic) Normalization Method in Genedata Screener® was used to calculate % inhibition for curve fitting:

[0411] Central Reference = Neutral Control (high control): 1 %DMSO only

[0412] Scale Reference = Blank Control (low control) :

[0413] 1 iM NH2-EDIIRNIARHLAQVGDSMDR-OH

[0414] Scale Reference Control type = Stimulator

[0415] %COntrolinhibition (%lnh) — 100* [ (Lsample-Lneutral) / (LBIank-Lneutral) 1

[0416] The 4-points curve fit equation below was used to fit the dose response curves to determine IC50: y= Sinf + [ (So-Sinf) I (1 +(x / Sso)h) ] where x=concentration, y = activity, So=activity at bottom plateau of curve, Sinf=activity at top plateau of curve, S5o=inflection point, halfway between So and Sinf and h is hill slope.

[0417] Ki was calculated using the Cheng-Prusoff equation:

[0418] Ki = IC50 / (1 + ([L] / KD)), where [L] = the concentration of labeled ligand, Ki = the inhibition constant, defined as the equilibrium concentration of competitive inhibitor that would occupy 50% of receptor sites if no competing labeled ligand was present, IC50 = the concentration of competitive inhibitor that displaces 50% of the specifically bound labeled ligand, and KD = the affinity constant, defined as the equilibrium concentration of labeled ligand that occupies 50% of receptor sites in the absence of competition.

[0419] For the BIM assay of Biological Example 1 , it was experimentally determined [L] = 60 nM and KD = 61 nM, thus Ki = IC50 / 2. For the BID assay of Biological Example 2, it was experimentally determined that [L] = 10 nM and KD = 0.3 nM, thus Ki = IC50 / 34.3.

[0420] Representative compounds of the present invention were tested according to the procedure as described in Biological Example 1 and Biological Example 2 above, with results as listed in Table BIO-1 , below. Ki values > 2 nM were calculated based on measurements from the BIM assay described in Biological Example 1 . Ki values < 2 nM were calculated based on measurements from the BID assay described in Biological Example 2. Where a compound was tested more than once, the Ki value listed below represents the average of the individual measurements.

[0421] Table BIO-1 : BFL1 Inhibition

[0422] Formulation Example 1 :

[0423] Solid, Oral Dosage Form - Prophetic Example

[0424] As a specific embodiment of an oral composition, 100 mg of any of Compound ID No. 21 , prepared as described in Example 9, is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.

[0425] While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and / or modifications as come within the scope of the following claims and their equivalents.

[0426] Throughout this application, various publications are cited. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains. Where a conflict exists between the instant application and a reference provided herein, the instant application will be used.

Claims

What is claimed:

1. A compound of formula (I)whereinR1is hydrogen;R2is selected from the group consisting of hydroxy substituted Ci-4alkyl, -C(O)- NRARB, -C(O)-NRA-(C3-6cycloalkyl) and 4 to 8 membered heterocycloalkyl; wherein the 4 to 8 membered heterocycloalkyl or Ca ecycloalkyl, whether alone or as part of a substituent group is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, Ci-4alkyl, fluorinated Ci-2alkyl, and cyano; and wherein RAand RBare each independently selected from the group consisting of hydrogen and Ci-4alkyl;R3is selected from the group consisting of phenyl, 5 to 6 membered heteroaryl and 4-(trifluoromethyl)-bicyclo[2.2.2]octan-1 -yl; wherein the phenyl or 5 to 6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-4alkyl, fluorinated Ci-4alkyl, nitro, -NRCRD, -NRc-C(O)-(Ci-4alkyl), -NRc-C(O)-(fluorinated Ci- 4alkyl), and -NRc-C(O)-(C2-4alkenyl); and wherein Rcand RDare each independently selected form the group consisting of hydrogen and Ci-4alkyl;R4is phenyl; wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci-4alkyl, fluorinated Ci-4alkyl, hydroxy substituted Ci 4alkyl, Ci-4alkoxy, -NRERF, and -C(O)- NRERF; and wherein REand RFare each independently selected from the group consisting of hydrogen, and Ci-4alkyl;R5is selected from the group consisting of nitrogen bound, 5 to 6 memberedheterocycloalkyl and nitrogen bound, 9 to 10 membered bicyclic heterocycloalkyl; wherein the nitrogen bound, 5 to 6 membered heterocycloalkyl is optionally substituted with one or more halogen; wherein the nitrogen bound 5 to 6 membered heterocycloalkyl is further optionally substituted with phenyl or 5 to 6 membered heterocyclyl; wherein the phenyl or 5 to 6 membered heterocyclyl is further optionally substituted with halogen, hydroxy, oxo, Ci-4alkyl, fluorinated Ci-2alkyl, Ci-4alkoxy, fluorinated Ci-2alkoxy,-SO2-(Ci-2alkyl), - SO2-(fluorinated Ci-2alkyl), -SO2-NRGRH, and -SO(NH2)-CH3; wherein RGand RHare each independently selected from the group consisting of hydrogen and Ci-4alkyl; and wherein the nitrogen bound, 9 to 10 membered bicyclic heterocycloalkyl contains at least one ring S, said ring S is optionally substituted with one to two oxo groups; or a stereoisomer or pharmaceutically acceptable salt thereof.

2. A compound as in Claim 1 , whereinR1is hydrogen;R2is selected from the group consisting of hydroxy substituted Ci-4alkyl, -C(O)- NRARB, and -C(O)-NRA-(C3-4cycloalkyl); wherein RAand RBare each independently selected from the group consisting of hydrogen and Ci-2alkyl; and wherein the C3- 4cycloalkyl is optionally substituted with one to two substituents independently selected from the group consisting of hydroxy, Ci-2alkyl, and cyano;R3is selected from the group consisting of phenyl and 6 membered heteroaryl; wherein the phenyl or 6 membered heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of fluorinated Ci-2alkyl, nitro, -NRCRD, -NRc-C(O)-(Ci-2alkyl), -NRc-C(O)-(fluorinated Ci-2alkyl) and -NRc-C(O)- (C2-4alkenyl); wherein Rcand RDare each independently selected form the group consisting of hydrogen and Ci-2alkyl;R4is phenyl; wherein the phenyl is optionally substituted with one to three substituents independently selected from the group consisting of chloro, fluoro, C1- 2alkyl, fluorinated Ci-2alkyl, hydroxy substituted Ci-4alkyl, and Ci-2alkoxy;R5is selected from the group consisting of nitrogen bound, 6 memberedheterocycloalkyl and nitrogen bound, 10 membered bicyclic heterocycloalkyl; wherein the nitrogen bound 6 membered heterocycloalkyl is optionally substituted with one to two halogen; wherein the nitrogen bound, 6 membered heterocycloalkyl is further optionally substituted with phenyl or 6 membered heteroaryl; wherein the phenyl or 6 membered heteroaryl is optionally substituted with -SO2-Ci-2alkyl; and wherein the nitrogen bound, 10 membered bicyclic heterocycloalkyl contains at least one ring S, said ring S is optionally substituted with one to two oxo groups; or a stereoisomer or pharmaceutically acceptable salt thereof.

3. A compound as in Claim 2, whereinR1is hydrogen;R2is selected from the group consisting of R-(1 -hydroxy-isopropyl), R-(methyl- amino-carbonyl), R-(1 -cyano-cycloprop-1 -yl-amino-carbonyl), and R-(3-hydroxy-3- methyl-cyclobutyl-amino-carbonyl);R3is selected from the group consisting of 4-(trifluoro-methyl)-phenyl, 2-(difluoro- methyl)-4-(trifluoro-methyl)-phenyl, 2-nitro-4-(trifluoro-methyl)-phenyl, 2-amino-4- (trifluoro-methyl)-phenyl, 3-(methyl-amino)-4-(trifluoro-methyl)-phenyl, 2-(dimethyl- amino)-4-(trifluoro-methyl)-phenyl, 2-(methyl-carbonyl-amino)-4-(trifluoro-methyl)- phenyl, 2-(vinyl-carbonyl-amino)-4-(trifluoro-methyl)-phenyl, 3-(vinyl-carbonyl-(methyl- amino))-4-(trifluoro-methyl)-phenyl, 2-(trifluoro-methyl-carbonyl-amino)-4-(trifluoro- methyl)-phenyl, 5-(trifluoro-methyl)-pyrimidin-2-yl, 2-(trifluoro-methyl)-pyrimidin-5-yl, 6- (trifluoro-methyl)-pyridin-3-yl, and 4-amino-6-(trifluoro-methyl)-pyridin-3-yl;R4is selected from the group consisting of 2,5-dimethyl-phenyl, 2,3,6-trimethyl- phenyl, and 2-methoxy-3,6-dimethyl-phenyl;R5is selected from the group consisting of 4-(4-methyl-sulfonyl)-phenyl)- piperidi n-1 -yl, 4-(6-methyl-su If onyl)-py rid in-3-yl)-pi peridin- 1 -yl, 4-(6-(methyl-sulfonyl)- pyridin-3-y l)-3 ,3-dif luoro-pi peridin- 1 -yl, 4-(4-methyl-sulfonyl)-phenyl)-piperazin-1 -yl, 4-(6- methyl-sulfonyl)-pyridin-3-yl)-piperazin-1 -yl, morpholin-4-yl, (S*)-8- octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2-dioxide, and (R*)-8-octahydropyrazino[2,1 - c][1 ,4]thiazin-8-yl 2,2-dioxide; or a stereoisomer or pharmaceutically acceptable salt thereof.

4. A compound as in Claim 3, whereinR1is hydrogen;R2is selected from the group consisting of R-(1 -hydroxy-isopropyl), R-(methyl- amino-carbonyl), R-(1 -cyano-cycloprop-1 -yl-amino-carbonyl), and R-(3-hydroxy-3- methyl-cyclobutyl-amino-carbonyl);R3is selected from the group consisting of 4-(trifluoro-methyl)-phenyl, 2-(difluoro- methyl)-4-(trifluoro-methyl)-phenyl, 2-nitro-4-(trifluoro-methyl)-phenyl, 2-amino-4- (trifluoro-methyl)-phenyl, 3-(methyl-amino)-4-(trifluoro-methyl)-phenyl, 2-(dimethyl- amino)-4-(trifluoro-methyl)-phenyl, 2-(methyl-carbonyl-amino)-4-(trifluoro-methyl)- phenyl, 2-(vinyl-carbonyl-amino)-4-(trifluoro-methyl)-phenyl, 3-(vinyl-carbonyl-(methyl- amino))-4-(trifluoro-methyl)-phenyl, 2-(trifluoro-methyl-carbonyl-amino)-4-(trifluoro- methyl)-phenyl, 2-(trifluoro-methyl)-pyrimidin-5-yl, 6-(trifluoro-methyl)-pyridin-3-yl, and 4- amino-6-(trifluoro-methyl)-pyridin-3-yl;R4is selected from the group consisting of 2,5-dimethyl-phenyl, 2,3,6-trimethyl- phenyl, and 2-methoxy-3,6-dimethyl-phenyl;R5is selected from the group consisting of 4-(6-(methyl-sulfonyl)-pyridin-3-yl)- piperidi n-1 -yl, 4-(6-(methyl-su If ony l)-py ridin-3-y l)-3 ,3-difl uoro-pi peridin-1 -yl, 4-(4-(methyl- sulfonyl)-phenyl)-piperazin-1 -yl, and (S*)-8-octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2- dioxide; or a stereoisomer or pharmaceutically acceptable salt thereof.

5. A compound as in Claim 3, whereinR1is hydrogen;R2is R-(methyl-amino-carbonyl), R-(1 -cyano-cycloprop-1 -yl-amino-carbonyl) or R-(3-hydroxy-3-methyl-cyclobutyl-amino-carbonyl);R3is selected from the group consisting of 4-(trifluoro-methyl)-phenyl, 2-amino-4- (trifluoro-methyl)-phenyl, 2-(vinyl-carbonyl-amino)-4-(trifluoro-methyl)-phenyl, 2- (trifluoro-methyl)-pyrimidin-5-yl, 6-(trifluoro-methyl)-pyridin-3-yl, and 4-amino-6-(trifluoro- methyl)-pyridin-3-yl ;R4is 2,3,6-trimethyl-phenyl;R5is selected from the group consisting of 4-(6-(methyl-sulfonyl)-pyridin-3-yl)- 3 ,3-difl uoro-piperid in-1 -yl , and 4-(4-(methyl-sulfonyl)-phenyl)-piperazin-1 -yl; or a stereoisomer or pharmaceutically acceptable salt thereof.

6. A compound as in Claim 1 , selected from the group consisting of (2R)-N-(1 -cyanocyclopropyl)-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 - carbonyl]-7-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl]amino]-3-[4- (trifluoromethyl)phenyl]propanamide;[(4RS)-3,3-difluoro-4-(6-methylsulfonyl-3-pyridyl)-1 -piperidyl]-[5-[[(1 R)-2-hydroxy- 2-methyl-1 -[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]-3-(2,3,6-trimethylphenyl)- 2,6-naphthyridin-1 -yl]methanone;((*S)-2,2-Dioxidohexahydropyrazino[2,1 -c][1 ,4]thiazin-8(1 H)-yl) (5-(((R)-3- hydroxy-3-methyl-1 -(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-3-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl)methanone;((*R)-2,2-Dioxidohexahydropyrazino[2,1 -c][1 ,4]thiazin-8( 1 H)-y I) (5-((( R)-3- hydroxy-3-methyl-1 -(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-3-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl)methanone(2R)-N-(3-hydroxy-3-methyl-cyclobutyl)-2-[[5-[4-(6-methylsulfonyl-3- pyridyl)piperidine-1 -carbonyl]-7-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl]amino]-3- [4-(trifluoromethyl)phenyl]propanamide;[5-[[(1 R)-2-hydroxy-2-methyl-1 -[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]-3- (2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl]-[4-(6-methylsulfonyl-3-pyridyl)-1 - piperidyl]methanone;(R)-2-((5-((*S)-2,2-Dioxidooctahydropyrazino[2, 1 -c] [ 1 ,4]thiazine-8-carbonyl)-7- (2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)amino)- / V-((1 s,3S)-3-hydroxy-3- methylcyclobutyl)-3-(4-(trifluoromethyl)phenyl)propanamide;(R)-2-((5-((*R)-2,2-Dioxidooctahydropyrazino[2,1 -c][1 ,4]thiazine-8-carbonyl)-7- (2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl)amino)- / V-((1 s,3S)-3-hydroxy-3- methylcyclobutyl)-3-(4-(trifluoromethyl)phenyl)propanamide;(2R)-N-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl]amino]-3-[5-(trifluoromethyl)pyrimidin-2-yl]propanamide;(2R)-N-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl]amino]-3-[2-(trifluoromethyl)pyrimidin-5- yl]propanamide;(2R)-N-(3-hydroxy-3-methyl-cyclobutyl)-2-[[5-[4-(4- methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6-trimethylphenyl)-2,6-naphthyridin- 1 -yl]amino]-3-[4-(trifluoromethyl)phenyl]propanamide;[5-[[(1 R)-2-hydroxy-2-methyl-1 -[[6-(trifluoromethyl)-3- pyridyl]methyl]propyl]amino]-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl]-[4-(4- methylsulfonylphenyl)piperazin-1 -yl]methanone;[5-[[(1 R)-2-hydroxy-2-methyl-1 -[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]-3- (2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl]-[4-(4-methylsulfonylphenyl)piperazin-1 - yl]methanone;(2R)-N-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl]amino]-3-[2-[(2!2,2-trifluoroacetyl)amino]-4- (trifluoromethyl)phenyl]propanamide;(2R)-3-[2-acetamido-4-(trifluoromethyl)phenyl]-N-methyl-2-[[5-[4-(4- methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6-trimethylphenyl)-2,6-naphthyridin- 1 -yl]amino]propanamide;(2R)-N-methyl-3-[2-(methylamino)-4-(trifluoromethyl)phenyl]-2-[[5-[4-(4- methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6-trimethylphenyl)-2,6-naphthyridin- 1 -yl]amino]propanamide;(2R)-N-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl]amino]-3-[2-nitro-4- (trifluoromethyl)phenyl]propanamide;(2R)-3-[2-(dimethylamino)-4-(trifluoromethyl)phenyl]-N-methyl-2-[[5-[4-(4- methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6-trimethylphenyl)-2,6-naphthyridin- 1 -yl]amino]propanamide;(2R)-3-[2-(difluoromethyl)-4-(trifluoromethyl)phenyl]-N-methyl-2-[[5-[4-(4- methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6-trimethylphenyl)-2,6-naphthyridin- 1 -yl]amino]propanamide;(2R)-N-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl]amino]-3-[2-(prop-2-enoylamino)-4- (trifluoromethyl)phenyl]propanamide;[5-[[(1 R)-2-hydroxy-2-methyl-1 -[[6-(trifluoromethyl)-3- pyridyl]methyl]propyl]amino]-3-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl]-morpholino- methanone;(2R)-3-[2-amino-4-(trifluoromethyl)phenyl]-N-methyl-2-[[5-[4-(4- methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6-trimethylphenyl)-2,6-naphthyridin- 1 -yl]amino]propanamide;(2R)-3-[4-amino-6-(trifluoromethyl)-3-pyridyl]-N-methyl-2-[[5-[4-(4- methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6-trimethylphenyl)-2,6-naphthyridin- 1 -yl]amino]propanamide;(2R)-N-methyl-3-[3-[methyl(prop-2-enoyl)amino]-4-(trifluoromethyl)phenyl]-2-[[5- [4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6-trimethylphenyl)-2,6- naphthyridin-1 -yl]amino]propanamide;(2R)-N-methyl-3-[3-(methylamino)-4-(trifluoromethyl)phenyl]-2-[[5-[4-(4- methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6-trimethylphenyl)-2,6-naphthyridin- 1 -yl]amino]propanamide;(2R)-N-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl]amino]-3-[6-(trifluoromethyl)-3- pyridyl]propanamide;(2R)-2-[[7-(2-methoxy-3,6-dimethyl-phenyl)-5-[4-(4- methylsulfonylphenyl)piperazine-1 -carbonyl]-2,6-naphthyridin-1 -yl]amino]-N-methyl-3-[4- (trifluoromethyl)phenyl]propanamide;(2R)-N-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl]amino]-3-[4-(trifluoromethyl)phenyl]propanamide;(2R)-N-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl]amino]-3-[4-(trifluoromethyl)phenyl]propanamide;(2R)-N-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl]amino]-3-[4-(trifluoromethyl)phenyl]propanamide;(2R)-N-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6-trimethylphenyl)-2,6-naphthyridin-1 -yl]amino]-3-[4-(trifluoromethyl)phenyl]propanamide; (2R)-2-[[7-(2,5-dimethylphenyl)-5-[4-(4-methylsulfonylphenyl)piperidine-1 - carbonyl]-2,6-naphthyridin-1 -yl]amino]-N-methyl-3-[4- (trifluoromethyl)phenyl]propanamide;(2R)-2-[[7-(2,5-dimethylphenyl)-5-[4-(4-methylsulfonylphenyl)piperazine-1 - carbonyl]-2,6-naphthyridin-1 -yl]amino]-N-methyl-3-[4- (trifluoromethyl)phenyl]propanamide; and stereoisomers and pharmaceutically acceptable salt thereof.

7. A compound as in Claim 1 , selected from the group consisting of (2R)-N-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl]amino]-3-[2-(prop-2-enoylamino)-4- (trifluoromethyl)phenyl]propanamide;(2R)-N-methyl-3-[3-[methyl(prop-2-enoyl)amino]-4-(trifluoromethyl)phenyl]-2-[[5- [4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6-trimethylphenyl)-2,6- naphthyridin-1 -yl]amino]propanamide;(2R)-N-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl]amino]-3-[4-(trifluoromethyl)phenyl]propanamide;(2R)-N-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl]amino]-3-[6-(trifluoromethyl)-3- pyridyl]propanamide;(2R)-N-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6- trimethylphenyl)-2,6-naphthyridin-1 -yl]amino]-3-[4-(trifluoromethyl)phenyl]propanamide; and stereoisomers and pharmaceutically acceptable salt thereof.

8. A compound selected from the group consisting of (2R)-N-methyl-2-[[5-[4-(4- methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,4,5-trimethyl-3-thienyl)-2,6- naphthyridin-1 -yl]amino]-3-[4-(trifluoromethyl)phenyl]propenamide; and stereoisomers and pharmaceutically acceptable salt thereof.

9. A method of treating a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is a leukemia or a lymphoma, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of Claim 1 .

10. The method of Claim 9, wherein the leukemia is selected from the group consisting of lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), (acute) T- cell leukemia, acute monocytic leukemia, acute promyelocytic leukemia (APL), bisphenotypic B myelomonocytic leukemia, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia, and myelodysplastic syndrome (MDS).11 . The method of Claim 9, wherein the leukemia is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

12. The method of Claim 9, wherein the lymphoma is selected from the group consisting of AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell DLBCL, double-hit lymphoma, double- expressor lymphoma, anaplastic large cell lymphoma, marginal B cell lymphoma, primary mediastinal B-cell lymphoma, immunoblastic large cell lymphoma, Burkitt lymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoplasmatic lymphoma, precursor B -lymphoblastic lymphoma, lymphoma of the central nervous system, small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia (CLL), precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), angioimmunoblastic T- cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma, sarcoma of the soft tissue, gliosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma, breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma,lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma.

13. The method of Claim 9, wherein the lymphoma is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

14. The use of the compound of Claim 1 for the preparation of a medicament for the treatment a cancer mediated by the BFL-1 receptor, wherein the cancer mediate by the BFL-1 receptor is (a) a leukemia, or (b) a lymphoma, in a subject in need thereof.

15. The use as in Claim 14, wherein the leukemia is (a) acute lymphoblastic leukemia (ALL), (b) acute myeloid leukemia (AML), (c) (acute) T-cell leukemia, (d) acute monocytic leukemia, (e) acute promyelocytic leukemia (APL), (f) bisphenotypic B myelomonocytic leukemia, (g) chronic myeloid leukemia (CML), (h) chronic myelomonocytic leukemia (CMML), (i) large granular lymphocytic leukemia, (j) plasma cell leukemia, or (k) myelodysplastic syndrome (MDS).

16. The use as in Claim 14, wherein the lymphoma is (a) AIDS-related lymphoma, (b) Hodgkin lymphoma, (c) non-Hodgkin's lymphoma (NHL), (d) T-non-Hodgkin lymphoma (T-NHL), (e) Diffuse Large Cell Lymphoma (DLBCL), (f) activated B-cell DLBCL, (g) germinal center B-cell DLBCL, (h) double-hit lymphoma, (i) double- expressor lymphoma, (j) anaplastic large cell lymphoma, (k) marginal B cell lymphoma, (I) primary mediastinal B-cell lymphoma, (m) immunoblastic large cell lymphoma, (n) Burkitt lymphoma, (o) follicular lymphoma, (p) hairy cell leukemia, (q) Hodgkin's disease, (r) mantle cell lymphoma (MCL), (s) lymphoplasmatic lymphoma, (t) precursor B -lymphoblastic lymphoma, (u) lymphoma of the central nervous system, (v) small lymphocytic lymphoma (SLL), (w) chronic lymphocytic leukemia (CLL), (x) precursor T- lymphoblastic lymphoma / leukemia, (y) peripheral T-cell lymphoma (PTCL), (z) cutaneous T-cell lymphoma (CTCL), (aa) angioimmunoblastic T-cell lymphoma, (ab) extranodal natural killer T-cell lymphoma, (ac) enteropathy type T-cell lymphoma, (ad) subcutaneous panniculitis-like T-cell lymphoma, (ae) anaplastic large cell lymphoma,(af) sarcoma of the soft tissue, (ag) gliosarcoma, (ah) osteosarcoma, (ai) malignant fibrous histiocytoma, (aj) lymphosarcoma, (ak) rhabdomyosarcoma, (al) breast cancer, (am) colorectal carcinoma, (an) gastric cancer, (ao) gliosarcoma, (ap) head & neck cancer, (aq) hepatocellular carcinoma, (ar) lung cancer, (as) multiple myeloma, (at) neuroblastoma, (au) ovarian cancer, (av) pancreatic cancer, (aw) prostate cancer, or (ax) renal cell carcinoma.

17. The compound of Claim 1 , for use in a method for the treatment of a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is (a) a leukemia or (b) a lymphoma, in a subject in need thereof.

18. The compound of Claim 1 , for use in a method for the treatment of a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is (a) acute lymphoblastic leukemia (ALL), (b) acute myeloid leukemia (AML), (c) (acute) T-cell leukemia, (d) acute monocytic leukemia, (e) acute promyelocytic leukemia (APL), (f) bisphenotypic B myelomonocytic leukemia, (g) chronic myeloid leukemia (CML), (h) chronic myelomonocytic leukemia (CMML), (i) large granular lymphocytic leukemia, (j) plasma cell leukemia, or (k) myelodysplastic syndrome (MDS)19. The compound of Claim 1 , for use in a method for the treatment of a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is (a) AIDS-related lymphoma, (b) Hodgkin lymphoma, (c) non-Hodgkin's lymphoma (NHL), (d) T-non-Hodgkin lymphoma (T-NHL), (e) Diffuse Large Cell Lymphoma (DLBCL), (f) activated B-cell DLBCL, (g) germinal center B-cell DLBCL, (h) double-hit lymphoma, (i) double-expressor lymphoma, (j) anaplastic large cell lymphoma, (k) marginal B cell lymphoma, (I) primary mediastinal B-cell lymphoma, (m) immunoblastic large cell lymphoma, (n) Burkitt lymphoma, (o) follicular lymphoma, (p) hairy cell leukemia, (q) Hodgkin's disease, (r) mantle cell lymphoma (MCL), (s) lymphoplasmatic lymphoma, (t) precursor B -lymphoblastic lymphoma, (u) lymphoma of the central nervous system, (v) small lymphocytic lymphoma (SLL), (w) chronic lymphocytic leukemia (CLL), (x) precursor T-lymphoblastic lymphoma / leukemia, (y) peripheral T-celllymphoma (PTCL), (z) cutaneous T-cell lymphoma (CTCL), (aa) angioimmunoblastic T- cell lymphoma, (ab) extranodal natural killer T-cell lymphoma, (ac) enteropathy type T- cell lymphoma, (ad) subcutaneous panniculitis-like T-cell lymphoma, (ae) anaplastic large cell lymphoma, (at) sarcoma of the soft tissue, (ag) gliosarcoma, (ah) osteosarcoma, (ai) malignant fibrous histiocytoma, (aj) lymphosarcoma, (ak) rhabdomyosarcoma, (al) breast cancer, (am) colorectal carcinoma, (an) gastric cancer, (ao) gliosarcoma, (ap) head & neck cancer, (aq) hepatocellular carcinoma, (ar) lung cancer, (as) multiple myeloma, (at) neuroblastoma, (au) ovarian cancer, (av) pancreatic cancer, (aw) prostate cancer, or (ax) renal cell carcinoma.

20. The compound of Claim 1 , for use as a medicament.21 . The compound of Claim 1 , for use in the treatment of a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is (a) a leukemia or (b) a lymphoma, in a subject in need thereof.

22. The compound of Claim 1 , for use in the treatment of a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is (a) acute lymphoblastic leukemia (ALL), (b) acute myeloid leukemia (AML), (c) (acute) T-cell leukemia, (d) acute monocytic leukemia, (e) acute promyelocytic leukemia (APL), (f) bisphenotypic B myelomonocytic leukemia, (g) chronic myeloid leukemia (CML), (h) chronic myelomonocytic leukemia (CMML), (i) large granular lymphocytic leukemia, (j) plasma cell leukemia, or (k) myelodysplastic syndrome (MDS)23. The compound of Claim 1 , for use in the treatment of a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is (a) AIDS-related lymphoma, (b) Hodgkin lymphoma, (c) non-Hodgkin's lymphoma (NHL), (d) T-non- Hodgkin lymphoma (T-NHL), (e) Diffuse Large Cell Lymphoma (DLBCL), (f) activated B- cell DLBCL, (g) germinal center B-cell DLBCL, (h) double-hit lymphoma, (i) double- expressor lymphoma, (j) anaplastic large cell lymphoma, (k) marginal B cell lymphoma, (I) primary mediastinal B-cell lymphoma, (m) immunoblastic large cell lymphoma, (n)Burkitt lymphoma, (o) follicular lymphoma, (p) hairy cell leukemia, (q) Hodgkin's disease, (r) mantle cell lymphoma (MCL), (s) lymphoplasmatic lymphoma, (t) precursor B -lymphoblastic lymphoma, (u) lymphoma of the central nervous system, (v) small lymphocytic lymphoma (SLL), (w) chronic lymphocytic leukemia (CLL), (x) precursor T- lymphoblastic lymphoma / leukemia, (y) peripheral T-cell lymphoma (PTCL), (z) cutaneous T-cell lymphoma (CTCL), (aa) angioimmunoblastic T-cell lymphoma, (ab) extranodal natural killer T-cell lymphoma, (ac) enteropathy type T-cell lymphoma, (ad) subcutaneous panniculitis-like T-cell lymphoma, (ae) anaplastic large cell lymphoma, (af) sarcoma of the soft tissue, (ag) gliosarcoma, (ah) osteosarcoma, (ai) malignant fibrous histiocytoma, (aj) lymphosarcoma, (ak) rhabdomyosarcoma, (al) breast cancer, (am) colorectal carcinoma, (an) gastric cancer, (ao) gliosarcoma, (ap) head & neck cancer, (aq) hepatocellular carcinoma, (ar) lung cancer, (as) multiple myeloma, (at) neuroblastoma, (au) ovarian cancer, (av) pancreatic cancer, (aw) prostate cancer, or (ax) renal cell carcinoma.

24. A composition comprising a compound of Claim 1 , for use in the treatment of a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is (a) a leukemia or (b) a lymphoma.

25. A composition comprising a compound of Claim 1 , for use in the treatment of a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is (a) acute lymphoblastic leukemia (ALL), (b) acute myeloid leukemia (AML), (c) (acute) T-cell leukemia, (d) acute monocytic leukemia, (e) acute promyelocytic leukemia (APL), (f) bisphenotypic B myelomonocytic leukemia, (g) chronic myeloid leukemia (CML), (h) chronic myelomonocytic leukemia (CMML), (i) large granular lymphocytic leukemia, (j) plasma cell leukemia, or (k) myelodysplastic syndrome (MDS)26. A composition comprising a compound of Claim 1 , for use in the treatment of a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is (a) AIDS-related lymphoma, (b) Hodgkin lymphoma, (c) non-Hodgkin's lymphoma (NHL), (d) T-non-Hodgkin lymphoma (T-NHL), (e) Diffuse Large CellLymphoma (DLBCL), (f) activated B-cell DLBCL, (g) germinal center B-cell DLBCL, (h) double-hit lymphoma, (i) double-expressor lymphoma, (j) anaplastic large cell lymphoma, (k) marginal B cell lymphoma, (I) primary mediastinal B-cell lymphoma, (m) immunoblastic large cell lymphoma, (n) Burkitt lymphoma, (o) follicular lymphoma, (p) hairy cell leukemia, (q) Hodgkin's disease, (r) mantle cell lymphoma (MCL), (s) lymphoplasmatic lymphoma, (t) precursor B -lymphoblastic lymphoma, (u) lymphoma of the central nervous system, (v) small lymphocytic lymphoma (SLL), (w) chronic lymphocytic leukemia (CLL), (x) precursor T-lymphoblastic lymphoma / leukemia, (y) peripheral T-cell lymphoma (PTCL), (z) cutaneous T-cell lymphoma (CTCL), (aa) angioimmunoblastic T-cell lymphoma, (ab) extranodal natural killer T-cell lymphoma, (ac) enteropathy type T-cell lymphoma, (ad) subcutaneous panniculitis-like T-cell lymphoma, (ae) anaplastic large cell lymphoma, (af) sarcoma of the soft tissue, (ag) gliosarcoma, (ah) osteosarcoma, (ai) malignant fibrous histiocytoma, (aj) lymphosarcoma, (ak) rhabdomyosarcoma, (al) breast cancer, (am) colorectal carcinoma, (an) gastric cancer, (ao) gliosarcoma, (ap) head & neck cancer, (aq) hepatocellular carcinoma, (ar) lung cancer, (as) multiple myeloma, (at) neuroblastoma, (au) ovarian cancer, (av) pancreatic cancer, (aw) prostate cancer, or (ax) renal cell carcinoma.

27. A compound, composition, method of treatment or method of preparation as herein described.

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