Biphenyl derivatives useful as BFL-1 inhibitors

Abstract

The present invention is directed biphenyl derivatives, pharmaceutical compositions containing said compounds, and the use of said compounds in the treatment of leukemias, lymphomas and other cancers.

Description

[0001] BIPHENYL 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 / 714,896 filed November 1, 2024, the content of which is incorporated by reference in its entirety.

[0004] Field of the Invention

[0005] The present invention is directed biphenyl 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_1: 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.

[0008] 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).

[0009] 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.

[0010] However, R CHOP treatment fails in about 30% to 50% of patients with DLBCL (COIFFER B & SARKOZY C,. Hematology Am Soc Hematol Educ Program.

[0011] 2016;2016(1):366-378). Less than half of these patients can be cured with stem cell transplantation (GISSELBRECHT etal., 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 al., Hematological Oncology. 2017;35(S2):419-428 & Younes etal., Lancet Oncol.

[0012] 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.

[0013] Follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL) 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.

[0014] 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 liati vely, 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 et al., Health Qual Life Outcomes. 2018; 16: 193).

[0015] 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 co-morbidities, and newly diagnosed intermediate / high / very high risk MDS patients.

[0016] 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.

[0017] 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 etal., Cancers. 2022; 14 (14): 3456)

[0018] 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 etal., 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 etal., Oncogene. 2003; 22: 2457-2465).

[0019] 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 etal., Leukemia. 2020; 34: 63-74). 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 eta / ., 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 / n vivo (ESTEVE-ARENYS etal., 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 etal., 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.

[0020] ALI, F. E., in PCT Publication WO96 / 19223, published 27 June 1996 describe fibrinogen receptor antagonists effective for inhibiting platelet aggregation.

[0021] 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 and related cancers.

[0022] Summary of the Invention

[0023] The present invention is directed to compounds of formula (I)

[0024]

[0025] wherein

[0026] a is an integer from 0 to 4;

[0027] each R1is independently selected from the group consisting of halogen, -OH, -CN, -NO2, Ci-4alkyl, fluoro substituted Ci-4alkyl, hydroxy substituted Ci-4alkyl, C2- 4alkenyl, fluoro substituted C2-4alkenyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-4alkyl), -(Ci-4alkyl)-O-(Ci-4alkyl), -C(O)OH, -C(O)-(Ci-4alkyl), -C(O)O-(Ci-4alkyl), -C(O)-NRARB, -NRARB, -(Ci-4alkyl)-NRARB, -NHC(O)-(Ci-3alkyl)-NRARB, -NH-C(O)-(Ci-3alkyl)-NH-C(O)-(Ci-4alkyl), -CH(CN)-NRARB, and -CH(CN)-NH-C(O)-(Ci-4alkyl);

[0028] wherein RAis selected from the group consisting of hydrogen, and Ci-4alkyl; wherein RBis selected from the group consisting of hydrogen, C1-4alkyl, hydroxy substituted Ci-4alkyl, and -(Ci-4alkyl)-O-(Ci-4alkyl);

[0029] R2is selected from the group consisting of hydrogen, and Ci-4alkyl;

[0030] R3is selected from the group consisting of

[0031] (a) hydrogen;

[0032] (b) Ci-4alkyl;

[0033] (c) hydroxy substituted Ci-4alkyl;

[0034] — I— (L2)b— f A )

[0035] (d); wherein

[0036] b is an integer from 0 to 1;

[0037] L2is selected from the group consisting of — (Ci-4alkyl)-, -(Ci- 4alkyl)-(SO2)-, -(hydroxy substituted Ci-4alkyl)-, -(hydroxy substituted Ci-4alkyl)-(SO2)-, -(Ci-4alkyl)-C(O)-, and -(Ci-4alkyl)-O-; provided that L2is bound to the nitrogen atom through an alkyl carbon atom;

[0038] ( A j

[0039] v / is selected from the group consisting of C3-6cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 4 to 8 membered heterocycloalkyl; wherein the C3-6cycloalkyl, phenyl, 5 to 6 membered heteroaryl or 4 to 8 membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of -OH, oxo, Ci-4alkyl, hydroxy substituted Ci-4alkyl and - SO2-(Ci-4alkyl);

[0040]

[0041] wherein c is an integer from 1 to 2;

[0042]

[0043] phenyl or pyridyl;

[0044] R4is selected from the group consisting of hydrogen, Ci-4alkyl, - SO2-Ci-4alkyl, and SO2-NRGRH; wherein RGand RHare each independently selected from the group consisting of hydrogen and Ci- 4alkyl;

[0045] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0046] The present invention is further directed to compounds of formula (II)

[0047]

[0048] wherein

[0049] a is an integer from 0 to 3;

[0050] each R1is independently selected from the group consisting of halogen, -OH, -CN, -NO2, Ci-4alkyl, fluoro substituted Ci-4alkyl, hydroxy substituted Ci-4alkyl, C2-4alkenyl, fluoro substituted C2-4alkenyl, -O-(Ci-4alkyl), -O-(fluoro substituted C1-4alkyl), -(Ci-4alkyl)-O-(Ci-4alkyl), -C(O)OH, -C(O)-(Ci-4alkyl), -C(O)O-(Ci-4alkyl), -C(O)-NRARB, -NRARB, -(Ci-4alkyl)-NRARB, -NH-C(O)-(Ci-3alkyl)-NRARB, -NH-C(O)-(Ci-3alkyl)-NH-C(O)-(Ci-4alkyl), -CH(CN)-NRARB, and -CH(CN)-NH-C(O)-(Ci-4alkyl);

[0051] wherein RAis selected from the group consisting of hydrogen, and Ci-4alkyl; wherein RBis selected from the group consisting of hydrogen, C1-4alkyl, hydroxy substituted Ci-4alkyl, and -(Ci-4alkyl)-O-(Ci-4alkyl);

[0052] R5is a 4 to 16 membered, nitrogen bound heterocyclyl; provided that the 4 to 16 membered heterocyclyl is other than piperazinyl; wherein the 4 to 16 membered nitrogen bound heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, Ci-4alkyl, hydroxy substituted Ci-4alkyl, fluoro substituted Ci-4alkyl, -(Ci-2alkyl)-CN, -O-Ci-4alkyl, -O-(fluoro substituted C1-4 alkyl), -C(O)-(Ci-4alkyl), -(Ci-4alkyl)-O-(Ci-4alkyl), -(Ci-4alkyl)-O-(Ci-4alkyl)-C(O)-(Ci-4alkyl), -(SO2)-(Ci-4alkyl), -(Ci-2alkyl)-(SO2)-(Ci-4alkyl), -C(O)-NRJRL, -(Ci-4alkyl)-C(O)-NRJRL, -NRJRL, -(Ci-2alkyl)-NRJRL, -NRJ-C(O)-(Ci-4alkyl), -N(RJ)-SO2-(Ci-4alkyl), -N(RJ)-(Ci-4alkyl)-SO2-(Ci-4alkyl), -N(RJ)-C(O)-(Ci-4alkyl)-SO2-(Ci-4alkyl), -C(O)-ORJ, -SO2-NRJRK, and -S(O)(NH)-RJ;

[0053] wherein RJand RKare each independently selected from the group consisting of hydrogen, and Ci-4alkyl; and RLis selected from the group consisting of hydrogen, Ci-4alkyl, and hydroxy substituted Ci-4alkyl;

[0054] provided that when a is 2 and each R1is CH3, then R5is other than 6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl;

[0055] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0056] The present invention is further directed to compounds of formula (III)

[0057]

[0058] wherein

[0059] a is an integer from 0 to 4;

[0060] each R1is independently selected from the group consisting of halogen, -OH, -CN, -NO2, Ci-4alkyl, fluoro substituted Ci-4alkyl, hydroxy substituted Ci-4alkyl, C2-4alkenyl, fluoro substituted C2-4alkenyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-4alkyl), -(Ci-4alkyl)-O-(Ci-4alkyl), -C(O)OH, -C(O)-(Ci-4alkyl), -C(O)O-(Ci-4alkyl), - C(O)-NRARB, -NRARB, -(Ci-4alkyl)-NRARB, -NH-C(O)-(Ci-3alkyl)-NRARB, -NH-C(O)-(Ci-3alkyl)-NH-C(O)-(Ci-4alkyl), -CH(CN)-NRARB, and -CH(CN)-NH-C(O)-(Ci-4alkyl);

[0061] wherein RAis selected from the group consisting of hydrogen, and Ci-4alkyl; wherein RBis selected from the group consisting of hydrogen, C1-4alkyl, hydroxy substituted Ci-4alkyl, and -(Ci-4alkyl)-O-(Ci-4alkyl);

[0062] R6is a 4 to 11 membered, nitrogen bound heterocyclyl; provided that the 4 to 11 membered, nitrogen bound heterocyclyl is other than piperazinyl;

[0063] wherein the 4 to 11 membered, nitrogen bound heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, Ci-4alkyl, hydroxy substituted Ci-4alkyl, -O-(Ci-4alkyl), -(Ci-4alkyl)-O-(Ci-4alkyl), -(NRM)-C(O)-(Ci-4alkyl), and -C(O)-NRMRV; wherein RMand Rvare each independently selected from the group consisting of hydrogen, and Ci-2alkyl;

[0064] and wherein the 4 to 11 membered, nitrogen bound heterocyclyl is further

[0065] substituted

[0066]

[0067] wherein

[0068] g is an integer from 0 to 1;

[0069] L3is selected from the group consisting of -O-, -C(O)-, -(C 1 -4al ky I)-, - CF2-, -C(O)-(Ci-4alkyl)-, -(Ci-4alkyl)-C(O)-, -SO2-, -SO2-(Ci-4alkyl)-, -(C1-4alkyl)-SO2-, -(Ci-2alkyl)-O-, -O-(Ci-2alkyl)-, -C(O)-N(RN)-, -N(RN)-C(O)-, - C(O)-N(RN)-(Ci-2alkyl)-, -(Ci-2alkyl)-N(RN)-C(O)-, -NRN-, -N(Rp)-(Ci-2alkyl)-, and -(C1-2alkyl)-N(Rᴾ)-; wherein RNis selected from the group consisting of hydrogen and Ci-4alkyl; and Rpis selected from the group consisting of hydrogen, Ci-2alkyl and -C(O)-Ci-2alkyl;

[0070] ( D )

[0071] ' is selected from the group consisting of C3-5cycloalkyl, phenyl, and 5 to 10 membered heterocyclyl;

[0072] wherein the C3-5cycloalkyl, phenyl, or 5 to 10 membered heterocyclyl is optionally substituted with one or two substituents independently selected from the group consisting of halogen, -CN, -OH, oxo, C1-2alkyl, hydroxy substituted Ci-4alkyl, fluoro substituted Ci-4alkyl, -(Ci-2alkyl)-CN, -O-(Ci- 4alkyl), -O-(fluoro substituted C1-4 alkyl), -C(0)-(Ci-4alkyl), -SO2-(Ci-4alkyl), - NRQRS, -N(RQ)-SO2-(Ci-4alkyl), -SO2-NRQRT, and -S(O)(NH)-NRQ;

[0073] wherein each RQand RTare each independently selected from the group consisting of hydrogen and Ci-2alkyl; and each Rsis selected from the group consisting of hydrogen, Ci -2alky I, and -C(O)-Ci-2alkyl;

[0074] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0075] The present invention is further directed to processes for the preparation of the compounds of formula (I), compounds of formula (II) and compounds of formula (III). The present invention is further directed to a product prepared according to the process described herein.

[0076] Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product prepared according to any of the process(es) described herein. An illustration of the invention is a pharmaceutical composition made by mixing the product prepared according to any of the process(es) described herein and a pharmaceutically acceptable carrier. Illustrating the invention is 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.

[0077] 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.

[0078] 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 panniculitislike 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.

[0079] 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. In an embodiment, the present invention is directed to a compound of formula (III) for use as a medicament.

[0080] In another embodiment, the present invention is directed to a compound of formula (I), a compound of formula (II) or a compound of formula (III) 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)).

[0081] In another embodiment, the present invention is directed to a compound of formula (I), a compound of formula (II) or a compound of formula (III) 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).

[0082] In another embodiment, the present invention is directed to a composition comprising a compound of formula (I), a compound of formula (II) or a compound of formula (III) 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)).

[0083] In another embodiment, the present invention is directed to a composition comprising a compound of formula (I), a compound of formula (II) or a compound of formula (III) 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 panniculitislike 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).

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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, 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, in a subject in need thereof.

[0088] Detailed Description of the Invention

[0089] The present invention is directed to compounds of formula (I)

[0090]

[0091] wherein a, R1, R2and R3are 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, but not limited to, leukemias and lymphomas.

[0092] The present invention is further directed to compounds of formula (II)

[0093]

[0094] wherein a, R1, 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, but not limited to, leukemias and lymphomas.

[0095] The present invention is directed to compounds of formula (III)

[0096]

[0097] wherein a, R1, and R6are 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, but not limited to, leukemias and lymphomas.

[0098] One skilled in the art will recognize that some of the variables (e.g. a, R1, RA, RB, etc.) may appear in compounds of formula (I), compounds of formula (II) and I or compounds of formula (III). One skilled in the art will further recognize that wherein a particular substituent or group is selected for a given variable for a compound of formula (I), said selection is not intended to limit the scope of said variable for compounds of formula (II) or compounds of formula (III). Similarly, the selection of a particular substituent or group for a given variable for a compound of formula (II), is not intended to limit the scope of said variable for compounds of formula (I) or compounds of formula (III); and the selection of a particular substituent or group for a given variable for a compound of formula (III), is not intended to limit the scope of said variable for compounds of formula (I) or compounds of formula (II).

[0099] In some embodiments, the present invention is directed to compounds of formula (I) wherein

[0100] a is an integer from 0 to 3;

[0101] each R1is independently selected from the group consisting of halogen, -OH, -CN, Ci-4alkyl, fluoro substituted Ci-4alkyl, hydroxy substituted Ci-4alkyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-4alkyl), -(Ci-4alkyl)-O-(Ci-4alkyl), -C(O)OH, -C(O)-(C1-3alkyl), and -C(O)O-(C1-4alkyl);

[0102] R2is selected from the group consisting of hydrogen, and Ci-2alkyl;

[0103] R3is selected from the group consisting of

[0104] (a) hydrogen;

[0105] (b) Ci-2alkyl;

[0106] (c) hydroxy substituted Ci-4alkyl;

[0107]

[0108] ; wherein

[0109] b is an integer from 0 to 1;

[0110] L2is selected from the group consisting of — (Ci-2alkyl)-, -(hydroxy substituted Ci-2alkyl)-, and -(Ci-2alkyl)-O-; provided that L2is bound to the nitrogen atom through an alkyl carbon atom;

[0111]

[0112] is selected from the group consisting of C3-6cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 4 to 8 membered heterocycloalkyl; wherein the C3-6cycloalkyl, phenyl, 5 to 6 membered heteroaryl or 4 to 8 membered heterocycloalkyl is optionally substituted with one to two substituents independently selected from the group consisting of -OH, oxo, Ci-2alkyl, hydroxy substituted Ci-2alkyl and -SO2-(C1-2alkyl);

[0113]

[0114] wherein

[0115] c is an integer from 1-2;

[0116] ( B )

[0117] Y-Y is selected from the group consisting of phenyl and pyridyl; wherein R4is selected from the group consisting of hydrogen, Ci-4alkyl, - SO2Ci-2alkyl, and -SO2NRGRH; wherein RGand RHare each independently selected from the group consisting of hydrogen and C1-2alkyl;

[0118] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0119] In some embodiments, the present invention is directed to compounds of formula (I) wherein

[0120] a is an integer from 1 to 3;

[0121] each R1is independently selected from the group consisting of C1-2alkyl, -(C1-2alkyl)-OH and –(C1-2alkyl)-O-(C1-2alkyl);

[0122] R2is selected from the group consisting of hydrogen, and Ci-2alkyl; R3is selected from the group consisting of

[0123] (a) hydrogen;

[0124] (b) Ci-2alkyl;

[0125] (c) hydroxy substituted Ci-4alkyl;

[0126]

[0127] b is an integer from 0 to 1;

[0128] L2is selected from the group consisting of — (Ci-2alkyl)-, -(hydroxy substituted Ci-2alkyl)-, and -(Ci-2alkyl)-O-; provided that L2is bound to the nitrogen atom through an alkyl carbon atom;

[0129]

[0130] is selected from the group consisting of C3-5cycloalkyl, phenyl, 5 membered heteroaryl, and 4 to 8 membered heterocycloalkyl; wherein the C3-5cycloalkyl, phenyl, 5 membered heteroaryl, or 4 to 8 membered heterocycloalkyl is optionally substituted with one to two substituents independently selected from the group consisting of -OH, oxo, Ci-2alkyl, hydroxy substituted Ci-2alkyl and -SO2(CH3);

[0131]

[0132] c is an integer from 1 to 2;

[0133] ( B )

[0134] is selected from the group consisting of phenyl and pyridyl;

[0135] R4is selected from the group consisting of hydrogen, Ci-2alkyl, - SO2CH3, and -SO2NH2;

[0136] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0137] In some embodiments the present invention is directed to compounds of formula (I) wherein

[0138] a is an integer from 2 to 3; each R1is independently selected from the group consisting of CH3, -CH2OH, and -CH2-O-CH3;

[0139] R2is selected from the group consisting of H and CH3

[0140] R3is selected from the group consisting of

[0141]

[0142] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0143] In some embodiments the present invention is directed to compounds of formula (I) wherein

[0144] a is an integer from 2 to 3;

[0145] each R1is independently selected from the group consisting of -CH3, -CH2OH, and -CH2-O-CH3;

[0146] R2is selected from the group consisting of hydrogen and -CH3;

[0147] R3is selected from the group consisting of -CH3,

[0148]

[0149] ,

[0150]

[0151] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0152] In some embodiments the present invention is directed to compounds of formula (I) wherein

[0153] a is an integer from 2 to 3;

[0154] each R1is independently selected from the group consisting of -CH3,-CH2OH, -CH2-O-CH3;

[0155] R2is hydrogen;

[0156] R3is selected from the group consisting of CH3, and

[0157]

[0158] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0159] In some embodiments the present invention is directed to compounds of formula (I) wherein

[0160] a is an integer from 2 to 2;

[0161] R1is CH3;

[0162] R2is CH3;

[0163] R3is selected from the group consisting

[0164]

[0165] and

[0166]

[0167] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof. In some embodiments the present invention is directed to compounds of formula (II) wherein

[0168] a is an integer from 0 to 3;

[0169] each R1is independently selected from the group consisting of Ci-2alkyl, -(Ci-2alkyl)-OH, and — (Ci-2alkyl)-O-(Ci-2alkyl);

[0170] R5is a 4 to 16 membered, nitrogen bound heterocyclyl; provided that the 4 to 16 membered heterocyclyl is other than piperazinyl;

[0171] wherein the 4 to 16 membered, nitrogen bound heterocyclyl is optionally substituted with one to four substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, Ci-4alkyl, hydroxy substituted Ci-4alkyl, -(Ci-2alkyl)-CN, -O-Ci-4alkyl, -O-(fluoro substituted C1-4 alkyl), -(Ci-2alkyl)-O-(Ci-4alkyl), -C(O)-(Ci-4alkyl), -(SO2)-(Ci-2alkyl), -(Ci-2alkyl)-(SO2)-(Ci-2alkyl), -C(O)-NRJRL, -(Ci-3alkyl)-C(O)-NRJRL, -NRJRL, -(Ci-2alkyl)-NRJRL, -NRJ-C(O)-(Ci-4alkyl), -N(RJ)-SO2-(Ci-4alkyl), -N(RJ)-(Ci-4alkyl)-SO2-(Ci-4alkyl), -N(RJ)-C(O)-(Ci-4alkyl)-SO2-(Ci-4alkyl), -C(O)-ORJ, and -SO2-NRJRK;

[0172] wherein each RJand RKare each independently selected from the group consisting of hydrogen, and C1-2alkyl; and each RLis selected from the group consisting of hydrogen, Ci-4alkyl, and hydroxy substituted Ci-4alkyl;

[0173] provided that when a is 2 and each R1is CH3, then R5is other than 6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl;

[0174] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0175] In some embodiments, the present invention is directed to compounds of formula (II) wherein

[0176] a is an integer from 1 to 3;

[0177] each R1is independently selected from the group consisting of Ci-2alkyl, hydroxy substituted Ci-2alkyl and - (Ci-2alky l)-O-(Ci-2alkyl);

[0178] R5is a 4 to 16 membered, nitrogen bound heterocyclyl; provided that the 4 to 16 membered heterocyclyl is other than piperazinyl;

[0179] wherein the 4 to 16 membered, nitrogen bound heterocyclyl is optionally substituted with one to four substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, Ci-4alkyl, hydroxy substituted C1-3alkyl, -O-C1-4alkyl, -(Ci-2alkyl)-O-(Ci-4alkyl), -C(O)-(Ci-4alkyl), -(SO2)-(Ci-2alkyl), -(Ci-2alkyl)-(SO2)-(Ci-2alkyl), -C(O)-NRJRL, -(Ci-2alkyl)-C(O)-NRJRL, -NRJRL, -(Ci-2alkyl)-NRJRL, -NRJ-C(O)-(Ci-2alkyl), -N(RJ)-(Ci-4alkyl)-SO2-(Ci-4alkyl), -N(RJ)-C(O)-(Ci-4alkyl)-SO2-(Ci-4alkyl), -C(O)-ORJ, and -SO2-NRJRK;

[0180] wherein each RJand RKare each independently selected from the group consisting of hydrogen, and Ci-2alkyl; and each RLis selected from the group consisting of hydrogen, Ci-4alkyl and hydroxy substituted Ci-2alkyl;

[0181] provided that when a is 2 and each R1is CH3, then R5is other than 6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl;

[0182] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0183] In some embodiments the present invention is directed to compounds of formula (II) wherein

[0184] a is an integer from 2 to 3;

[0185] each R1is independently selected from the group consisting of -CH3, -CH2OH, and -CH2-O-CH3;

[0186] R5is selected from the group consisting of

[0187]

[0188]

[0189]

[0190] LO

[0191]

[0192]

[0193]

[0194]

[0195] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0196] In some embodiments the present invention is directed to compounds of formula (II) wherein a is an integer from 2 to 3;

[0197] each R1is independently selected from the group consisting of -CH3, -CH2OH, and -CH2-O-CH3;

[0198] R5is selected from the group consisting of

[0199]

[0200]

[0201] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0202] In some embodiments the present invention is directed to compounds of formula (II) wherein

[0203] a is an integer from 2 to 3;

[0204] each R1is independently selected from the group consisting of -CH3, - CH2OH, and -CH2-O-CH3;

[0205] R5is selected from the group consisting of

[0206]

[0207] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0208] In some embodiments the present invention is directed to compounds of formula (II) wherein

[0209] a is an integer from 2 to 3;

[0210] each R1is independently selected from the group consisting of -CH3, - CH2OH, and -CH2-O-CH3;

[0211] R5is selected from the group consisting of

[0212]

[0213] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof. In some embodiments the present invention is directed to compounds of formula (II) wherein

[0214] a is an integer from 2 to 3;

[0215] each R1is independently selected from the group consisting of -CH3, -CH2OH, and -CH2-O-CH3;

[0216]

[0217] wherein said R5is optionally substituted with one or more substituents independently selected from the group consisting of oxo, C1-3alkyl, hydroxy substituted Ci-2alkyl, -C(O)-( Ci-2alkyl), -N(Ci-2alkyl)(hydroxy substituted Ci-2alkyl), and -NH-C(O)-(Ci-2alkyl)-SO2-(Ci-2alkyl);

[0218] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0219] In some embodiments the present invention is directed to compounds of formula (III) wherein

[0220] a is an integer from 0 to 3;

[0221] each R1is independently selected from the group consisting of halogen, -OH, -CN, Ci-4alkyl, fluoro substituted Ci-4alkyl, hydroxy substituted Ci-4alkyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-4alkyl), -(Ci-4alkyl)-O-(Ci-4alkyl), -C(O)OH, -C(O)-(C1-3alkyl), and -C(O)O-(C1-4alkyl); R6is a 4 to 11 membered, nitrogen bound heterocyclyl; provided that the 4 to 11 membered heterocyclyl is other than piperazinyl;

[0222] wherein the 4 to 11 membered, nitrogen bound heterocyclyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, Ci-2alkyl, hydroxy substituted Ci-2alkyl, -O-(Ci-2alkyl), -(Ci-2alkyl)-O-(Ci-2alkyl), -(NRM)-C(O)-(Ci-2alkyl), and -C(O)-NRMRV; wherein RMand Rvare each independently selected from the group consisting of hydrogen, and Ci-2alkyl;

[0223] and wherein the 4 to 11 membered, nitrogen bound heterocyclyl is further

[0224] substituted

[0225]

[0226] wherein

[0227] g is an integer from 0 to 1;

[0228] L3is selected from the group consisting of -O-, -C(O)-, -(Ci-2alkyl)-,- CF2-, -C(O)-(Ci-4alkyl)-, -(Ci-4alkyl)-C(O)-, -(Ci-2alkyl)-O-, -O-(Ci-2alkyl)-, - C(O)-N(RN)-, -N(RN)-C(O)-, -C(O)-N(RN)-(Ci-2alkyl)-, -(Ci-2alkyl)-N(RN)-C(O)-, -NRN-, -N(Rp)-(Ci-2alkyl)-, and -(C1-2alkyl)-N(Rᴾ)-; wherein RNis selected from the group consisting of hydrogen and Ci-4alkyl; and Rpis selected from the group consisting of hydrogen, Ci-2alkyl and -C(O)-Ci-2alkyl;

[0229]

[0230] is selected from the group consisting of C3-5cycloalkyl, phenyl, and 5 to 10 membered heterocyclyl;

[0231] wherein the C3-5cycloalkyl, phenyl, or 5 to 10 membered heterocyclyl is optionally substituted with one or two substituents independently selected from the group consisting of halogen, -CN, -OH, oxo, Ci-4alkyl, hydroxy substituted Ci-2alkyl, fluoro substituted Ci-2alkyl, -(Ci-2alkyl)-CN, -O-(Ci-2alkyl), -O-(fluoro substituted C1-2 alkyl), -C(O)-(Ci-2alkyl), -SO2-(Ci-2alkyl), -NRQRS, -N(RQ)-SO2-(Ci-4alkyl), and -SO2-NRQRT; wherein RQand RTare each independently selected from the group consisting of hydrogen and Ci-2alkyl; and Rsis selected from the group consisting of hydrogen, Ci-2alkyl, and -C(O)-Ci-2alkyl;

[0232] and stereoisomers, isotopologues, or pharmaceutically acceptable salts thereof. In some embodiments, the present invention is directed to compounds of formula (III) wherein

[0233] a is an integer from 1 to 3;

[0234] each R1is independently selected from the group consisting of C1-2alkyl, -(C1-2alkyl)-OH and –(C1-2alkyl)-O-(C1-2alkyl);

[0235] R6is a 4 to 11 membered, nitrogen bound heterocyclyl; provided that the 4 to 11 membered, nitrogen bound heterocyclyl is other than piperazinyl;

[0236] wherein the 4 to 11 membered, nitrogen bound heterocyclyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, Ci-2alkyl, hydroxy substituted Ci-2alkyl, -O-(Ci-2alkyl), -(Ci-2alkyl)-O-(Ci-2alkyl), and -(NRM)-C(O)-(Ci-2alkyl), wherein RMis selected from the group consisting of hydrogen, and Ci-2alkyl;

[0237] and wherein the 4 to 11 membered, nitrogen bound heterocyclyl is further

[0238] substituted

[0239]

[0240] wherein

[0241] g is an integer from 0 to 1;

[0242] L3is selected from the group consisting of -O-, -C(O)-, -(C1-2alkyl)-, -CF2-, -(Ci-2alkyl)-O-, -O-(Ci-2alkyl)-, -C(O)-N(RN)-(Ci-2alkyl)-, -NRN-, -N(RP)-(C1-2alkyl)-, and -(C1-2alkyl)-N(Rp)-; wherein RNis selected from the group consisting of hydrogen and Ci-4alkyl; and Rpis selected from the group consisting of hydrogen, Ci-2alkyl and -C(O)-Ci-2alkyl;

[0243] provided that when L3is -C(O)-N(RN)-(Ci-2alkyl)-, then the Ci-2alkyl ( D )

[0244] portion is bound to;

[0245] ( D )

[0246] is selected from the group consisting of C4-5cycloalkyl, phenyl, and 5 to 10 membered heterocyclyl;

[0247] wherein the C4-5cycloalkyl, phenyl, or 5 to 10 membered heterocyclyl is optionally substituted with one or two substituents independently selected from the group consisting of halogen, -CN, -OH, oxo, C1-2alkyl, hydroxy substituted Ci-2alkyl, fluoro substituted Ci-2alkyl, -(Ci-2alkyl)-CN, -O-(Ci- 2alkyl), -O-(fluoro substituted C1-2 alkyl), -C(O)-(Ci-2alkyl), -SO2-(Ci-2alkyl), - NRQRS, -N(RQ)-SO2-(Ci-2alkyl), and -SO2-NRQRT; wherein each RQand RTare each independently selected from the group consisting of hydrogen and Ci-2alkyl; and Rsis selected from the group consisting of hydrogen, Ci-2alkyl, and -C(O)-Ci-2alkyl;

[0248] and stereoisomers, isotopologues, or pharmaceutically acceptable salts thereof.

[0249] In some embodiments, the present invention is directed to compounds of formula (III) wherein

[0250] a is an integer from 2 to 3;

[0251] each R1is independently selected from the group consisting of -CH3, -CH2OH, and -CH2-O-CH3;

[0252] R6is selected from the group consisting of

[0253]

[0254]

[0255] ze

[0256]

[0257]

[0258]

[0259]

[0260] and stereoisomers, isotopologues, or pharmaceutically acceptable salts thereof.

[0261] In some embodiments, the present invention is directed to compounds of formula (III) wherein

[0262] a is an integer from 2 to 3;

[0263] each R1is independently selected from the group consisting of -CH3, -CH2OH, and -CH2-O-CH3;

[0264] R6is selected from the group consisting of

[0265]

[0266]

[0267] and stereoisomers, isotopologues, or pharmaceutically acceptable salts thereof.

[0268] In some embodiments, the present invention is directed to compounds of formula (III) wherein

[0269] a is an integer from 2 to 3;

[0270] each R1is independently selected from the group consisting of -CH3, -CH2OH, and -CH2-O-CH3;

[0271] R6is selected from the group consisting of

[0272]

[0273] and stereoisomers, isotopologues, or pharmaceutically acceptable salts thereof.

[0274] In some embodiments, the present invention is directed to compounds of formula (III) wherein a is an integer from 2 to 3;

[0275] each R1is independently selected from the group consisting of -CH3, -CH2OH, and -CH2-O-CH3;

[0276] R6is selected from the group consisting of

[0277]

[0278] and stereoisomers, isotopologues, or pharmaceutically acceptable salts thereof.

[0279] In some embodiments, the present invention is directed to compounds of formula (III) wherein

[0280] a is an integer from 2 to 3; each R1is independently selected from the group consisting of -CH3, -CH2OH, and -CH2-O-CH3;

[0281] R6is selected from the group consisting of

[0282]

[0283] wherein said R6is optionally substituted with one to two substituents independently selected from the group consisting of fluoro, -OH, oxo, and -CH2OH;

[0284] and wherein said R6is further substituted with

[0285]

[0286] ; wherein g is an integer from 0 to 1;

[0287] L3is selected from the group consisting of -O-, -(CH2)-, -NH-, and - N(C(O)-CH3)-(CH2)-; provided that when L3is -N(C(O)-CH3)-(CH2)-, then the ( D )

[0288] -(CH2)- group is bound to;

[0289] a < Q O —7is selected from the group consisting of •~YVV,jvvvn', '~YVU'',

[0290] 0 0 0 0 V Q Q Q O?

[0291] ;

[0292] (D)

[0293] wherein is optionally substituted with one or two substituents independently selected from the group consisting of chloro, -OH, oxo, -CH3, - CH-(CH3)2, -CF3, -(CH2)-CN, -O-(CH3), -SO2-(CH3), and -SO2-NH2; and stereoisomers, isotopologues, or pharmaceutically acceptable salts thereof.

[0294] In some embodiments, the present invention is directed to compounds of formula (III) wherein

[0295] a is an integer from 2 to 3;

[0296] each R1is independently selected from the group consisting of -CH3, -CH2OH, and -CH2-O-CH3;

[0297] R6is selected from the group consisting of

[0298]

[0299] wherein said R6is optionally substituted with one to two substituents independently selected from the group consisting of fluoro, -OH, oxo and -CH2OH;

[0300] and wherein said R6is further substituted with

[0301]

[0302] wherein g is an integer from 0 to 1;

[0303] L3is selected from the group consisting of -O-, -(CH2)-, and -NH-;

[0304]

[0305] independently selected from the group consisting of -OH, oxo, -(CH2)-CN, - SO2-(CH3), and -SO2-NH2; and stereoisomers, isotopologues, or pharmaceutically acceptable salts thereof.

[0306] In some embodiments, the present invention is directed to compounds of formula (III) wherein

[0307] a is an integer from 2 to 3;

[0308] each R1is independently selected from the group consisting of -CH3, -CH2OH, and -CH2-O-CH3;

[0309] R6is selected from the group consisting of

[0310]

[0311] wherein R6is optionally substituted with one to two substituents independently selected from the group consisting of fluoro, -OH, and -CH2OH;

[0312] and wherein R6is further substituted with

[0313]

[0314] ; wherein

[0315] g is an integer from 0 to 1;

[0316] L3is selected from the group consisting of -O-, -(CH2)-, and -NH-;

[0317]

[0318] ( D )

[0319] wherein ' — / is optionally substituted with one or two substituents independently selected from the group consisting of OH, oxo, -(CH2)-CN, - SO2-(CH3), and -SO2-NH2; and stereoisomers, isotopologues, or pharmaceutically acceptable salts thereof.

[0320] In some embodiments of the present invention, a is 0. In some embodiments of the present invention, a is 1. In some embodiments of the present invention, a is 2. In some embodiments of the present invention, a is 3. In some embodiments of the present invention, a is an integer from 0 to 1. In some embodiments of the present invention, a is an integer from 0 to 2. In some embodiments of the present invention, a is an integer from 0 to 3. In some embodiments of the present invention, a is from 1 to 3. In some embodiments of the present invention, a is from 2 to 3.

[0321] In some embodiments of the present invention, each R1is independently selected from the group consisting of halogen, -OH, -CN, Ci-4alkyl, fluoro substituted Ci-4alkyl, hydroxy substituted Ci-4alkyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-4alkyl), -(Ci-4alkyl)-O-(Ci-4alkyl), -C(O)OH, -C(O)-(Ci-3alkyl), and -C(O)O-(Ci-4alkyl). In some embodiments of the present invention, R1is independently selected from the group consisting of Ci-2alkyl, -(Ci-2alkyl)-OH and — (Ci-2alkyl)-O-(Ci-2alky I).

[0322] In some embodiments of the present invention, R1is independently selected from the group consisting of -CH3, -CH2OH, and -CH2-O-CH3. In some embodiments of the present invention, R1is CH3.

[0323] In some embodiments of the present invention, R2is selected from the group consisting of hydrogen, and Ci-4alkyl. In some embodiments of the present invention, R2is selected from the group consisting of hydrogen, and Ci-2alkyl. In some embodiments of the present invention, R2is selected from the group consisting of H and -CH3. In some embodiments of the present invention, R2is hydrogen. In some embodiments of the present invention, R2is CH3.

[0324] In some embodiments of the present invention, R3is selected from the group consisting of (a) hydrogen; (b) Ci-2alkyl; (c) hydroxy substituted Ci-4alkyl; (d)

[0325]

[0326] wherein b is an integer from 0 to 1; L2is selected from the group consisting of — (Ci-2alkyl)-, -(hydroxy substituted Ci-2alkyl)-, and -(Ci-2alkyl-O)-;

[0327] provided that L2is bound to the nitrogen atom through an alkyl carbon atom;

[0328]

[0329] is selected from the group consisting of C3-6cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 4 to 8 membered heterocycloalkyl; wherein the C3-6cycloalkyl, phenyl, 5 to 6 membered heteroaryl or 4 to 8 membered heterocycloalkyl is optionally substituted with one to two substituents independently selected from the group consisting of -OH, oxo, Ci-2alkyl, hydroxy substituted Ci-2alkyl and -SO2(Ci-2alkyl);

[0330]

[0331] ; wherein c is an integer from 1 to 2;

[0332]

[0333] is selected from the group consisting of phenyl and pyridyl; wherein R4is selected from the group consisting of hydrogen, Ci-4alkyl, -SO2Ci-2alkyl, and -SO2NG H; wherein RGand RHare each independently selected from the group consisting of hydrogen and C1- 2alkyl.

[0334] In some embodiments of the present invention, R3is hydrogen. In some embodiments of the present invention, R3is Ci-2alkyl. In some embodiments of the present invention, R3is hydroxy substituted Ci-4alkyl. In some embodiments of the

[0335] present invention, R3is

[0336]

[0337] wherein b is an integer from 0 to 1; L2is selected from the group consisting of - (Ci-2alkyl)-, -(hydroxy substituted Ci-2alkyl)-, and -(Ci-2alkyl-O)-; provided that L2is bound to the nitrogen atom through an alkyl

[0338] carbon atom;

[0339]

[0340] is selected from the group consisting of Cs-ecycloalkyl, phenyl, 5 to 6 membered heteroaryl and 4 to 8 membered heterocycloalkyl; wherein the C3- ecycloalkyl, phenyl, 5 to 6 membered heteroaryl or 4 to 8 membered heterocycloalkyl is optionally substituted with one to two substituents independently selected from the group consisting of -OH, oxo, Ci-2alkyl, hydroxy substituted Ci-2alkyl and -SO2(Ci- 2alkyl).

[0341] In some embodiments of the present invention, L2is selected from the group consisting of — (Ci-2alkyl)-, -(hydroxy substituted Ci-2alkyl)-, and -(Ci-2alkyl-O)-; provided that L2is bound to the nitrogen atom through an alkyl carbon atom.

[0342] In some embodiments of the present invention, b is 0. In some embodiments of the present invention, b is 1.

[0343] In some embodiments of th

[0344]

[0345] e present invention, is selected from the group consisting of C3-6cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 4 to 8 membered heterocycloalkyl; wherein the C3-6cycloalkyl, phenyl, 5 to 6 membered heteroaryl or 4 to 8 membered heterocycloalkyl is optionally substituted with one to two substituents independently selected from the group consisting of -OH, oxo, Ci-2alkyl, hydroxy substituted Ci-2alkyl and -SO2(Ci-2alkyl).

[0346] kA)

[0347] In some embodiments of the present invention, ' is selected from the group consisting of C3-5cycloalkyl, phenyl, 5 membered heteroaryl, and 4 to 8 membered heterocycloalkyl; wherein the C3-5cycloalkyl, phenyl, 5 membered heteroaryl, or 4 to 8 membered heterocycloalkyl is optionally substituted with one to two substituents independently selected from the group consisting of -OH, oxo, Ci-2alkyl, hydroxy substituted Ci-2alkyl and -SO2(CH3).

[0348] In some embodiments of the present invention, R3is

[0349]

[0350] ;

[0351] wherein c is an integer fr

[0352]

[0353] om 1 to 2; and is selected from the group consisting of phenyl and pyridyl; wherein R4is selected from the group consisting of hydrogen, Ci-4alkyl, -SO2Ci-2alkyl, and -SO2NG H; wherein RGand RHare each independently selected from the group consisting of hydrogen and Ci -2alky I. In some embodiments of the present invention, c is 1. In some embodiments of the present invention, c is 2.

[0354] In some embodiments of the present invention,

[0355]

[0356] is optionally substituted phenyl; wherein the substituents are as herein described. In some embodiments of

[0357] the present invention,

[0358]

[0359] is optionally substituted pyridyl; wherein the substituents are as herein described.

[0360] In some embodiments of the present invention, R4is selected from the group consisting of hydrogen, Ci-4alkyl, -SO2Ci-2alkyl, and -SO2NRGRH; wherein RGand RHare each independently selected from the group consisting of hydrogen and Ci-2alkyl. In some embodiments of the present invention, R4is selected from the group consisting of hydrogen, Ci-2alkyl, -SO2CH3, and -SO2NH2.

[0361] In some embodiments of the present invention, R3is selected from the group

[0362]

[0363]

[0364] In some embodiments of the present invention, R3is selected from the group consisting of -

[0365]

[0366] embodiments of the present invention, R3is -CH3or

[0367]

[0368] . In some

[0369] embodiments of the present invention, R3

[0370]

[0371] , or

[0372]

[0373] In some embodiments of the present invention, R5is a 4 to 16 membered, nitrogen bound heterocyclyl; wherein the 4 to 16 membered nitrogen bound heterocyclyl is optionally substituted with one to four substituents independently selected from the group consisting of fluoro, chloro, -OH, -CN, oxo, Ci-4alkyl, hydroxy substituted Ci-4alkyl, -(Ci-2alkyl)-CN, -O-(Ci-4alkyl), -O-(fluoro substituted Ci- 4 alkyl), -C(O)-(Ci-4alkyl), -(SO2)-(Ci-2alkyl), -(Ci-2alkyl)-(SO2)-(Ci-2alkyl), -C(O)- NRJRL, -(Ci-3alkyl)-C(O)-NRJRL, -NRJRL, -N(RJ)-SO2-(Ci-4alkyl), -(Ci-2alkyl)-NRJRL, - C(O)-ORJ, and -SO2-NRJRK; wherein each RJand RKare each independently selected from the group consisting of hydrogen, and Ci-2alkyl; and each RLis selected from the group consisting of hydrogen, Ci-4alkyl, hydroxy substituted Ci-4alkyl, -C(O)-(Ci-4alkyl), -C(O)-(Ci-2alkyl)-SO2-(Ci-2alkyl) and -(Ci-4alkyl)-SO2-(Ci-2alkyl).

[0374] In some embodiments of the present invention, R5is selected from the group

[0375] consisting

[0376]

[0377]

[0378]

[0379] gg

[0380]

[0381] 95

[0382]

[0383]

[0384]

[0385] 5

[0386]

[0387] . in some embodiments of the present invention, R5is selected from the

[0388]

[0389]

[0390]

[0391] present invention, R5is selected from the group consisting

[0392]

[0393]

[0394] In some embodiments of the present invention, R6is 4 to 11 membered, nitrogen bound heterocyclyl; wherein the 4 to 11 membered, nitrogen bound heterocyclyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, Ci-2alkyl, hydroxy substituted Ci-2alkyl, -O-(Ci-2alkyl), -(Ci-2alkyl)-O-(Ci-2alkyl), -(NRM)-C(O)-(Ci-2alkyl), and -C(O)-(NRM)-(Ci-2alkyl); wherein RMis selected from the group consisting of hydrogen, and Ci-2alkyl; and wherein the 4 to 11 membered, nitrogen bound heterocyclyl is further

[0395] substituted

[0396]

[0397] wherein g is an integer from 0 to 1;

[0398] L3is selected from the group consisting of -O-, -C(O)-, -CF2-, -C(O)-(Ci-4alkyl)-, -(Ci-4alkyl)-C(O)-, -(Ci-2alkyl)-, -(Ci-2alkyl)-O-, -O-(Ci-2alkyl)-, -C(O)-N(RN)-, -N(RN)-C(O)-, -C(O)-N(RN)-(Ci-2alkyl)-, -(Ci-2alkyl)-N(RN)-C(O)-, -NRN-, -N(Rᴾ)-(C1-2alkyl)-, and -(C1-2alkyl)-N(Rᴾ)-; wherein RNis selected from the group consisting of hydrogen and Ci -4alky I; and Rpis selected from the group consisting of hydrogen, Ci-2alkyl and -C(O)-Ci-2alkyl;

[0399]

[0400] is selected from the group consisting of C3-5cycloalkyl, phenyl, and 5 to

[0401] 10 membered heterocyclyl; wherein

[0402]

[0403] is optionally substituted with one or two substituents independently selected from the group consisting of fluoro, chloro, bromo, -CN, OH, oxo, Ci-4alkyl, hydroxy substituted Ci-2alkyl, fluoro substituted Ci-2alkyl, -(Ci-2alkyl)-CN, -O-(Ci-2alkyl), -O-(fluoro substituted C1-2 alkyl), -C(O)-(Ci-2alkyl), -SO2-(Ci-2alkyl), -NRQRS, -N(RQ)-SO2-(Ci-4alkyl), -SO2-NRQRTand-S(O)(NH)NRQ; wherein each RQand RTare each independently selected from the group consisting of hydrogen and Ci-2alkyl; and wherein Rsis selected from the group consisting of hydrogen, Ci-2alkyl, and -C(O)-Ci-2alkyl.

[0404] In some embodiments of the present invention, R6is a 4 to 11 membered, nitrogen bound heterocyclyl; wherein the 4 to 11 membered, nitrogen bound heterocyclyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, Ci-2alkyl, hydroxy substituted Ci-2alkyl, -O-(Ci-2alkyl), -(Ci-2alkyl)-O-(Ci-2alkyl), and -(NRM)-C(O)-(Ci-2alky I), wherein RMis selected from the group consisting of hydrogen, and Ci-2alkyl; and wherein the 4 to 11 membered, nitrogen bound heterocyclyl is further

[0405] substituted

[0406]

[0407] wherein g is an integer from 0 to 1;

[0408] L3is selected from the group consisting of -O-, -C(O)-, -CF2-, -(Ci -2alkyl)-, - Ci-2alkyl)-, -C(O)-N(RN)-(Ci-2alkyl)-, -NRN-, -N(Rp)-(Ci-2alkyl)-, and wherein RNis selected from the group consisting of hydrogen and

[0409]

[0410] selected from the group consisting of hydrogen, Ci -2alkyl and -C(O)-Ci-2alkyl; provided that when L3is -C(O)-N(RN)-(Ci-2alkyl)-, then the Ci-2alkyl

[0411] portion is bound

[0412]

[0413]

[0414] is selected from the group consisting of C4-5cycloalkyl, phenyl, and 5 to

[0415] 10 membered heterocyclyl; wherein

[0416]

[0417] is optionally substituted with one or two substituents independently selected from the group consisting of fluoro, chloro, bromo, -CN, OH, oxo, Ci-4alkyl, hydroxy substituted Ci-2alkyl, fluoro substituted C1-2alkyl, -(Ci-2alkyl)-CN, -O-(Ci-2alkyl), -O-(fluoro substituted C1-2 alkyl), -C(O)-(Ci-2alkyl), -SO2-(Ci-2alkyl), -NRQRS, -N(RQ)-SO2-(Ci-2alkyl), and -SO2-NRQRT; wherein each RQand RTare each independently selected from the group consisting of hydrogen and Ci-2alkyl; and wherein Rsis selected from the group consisting of hydrogen, Ci-2alkyl, and -C(O)-Ci-2alkyl.

[0418] In some embodiments, the present invention is directed to compounds of

[0419] formula (II) wherein R6is selected from the group consisting

[0420]

[0421] 179

[0422]

[0423] 59

[0424]

[0425]

[0426] Z9

[0427]

[0428]

[0429] In some embodiments, the present invention is directed to compounds of formula (II) wherein R6is selected from the group consisting

[0430]

[0431]

[0432]

[0433]

[0434] . In some embodiments, the present invention is directed to compounds of formula (II) wherein R6is selected from the group consisting of 5

[0435]

[0436]

[0437] In some embodiments, the present invention is directed to compounds of formula (II) wherein R6is selected from the group consisting

[0438]

[0439]

[0440]

[0441] In some embodiments of the present invention, g is 0. In some embodiments of the present invention, g is 1.

[0442] In some embodiments of the present invention, L3is selected from the group consisting of -O-, -C(O)-, -CF2-, -C(O)-(Ci-4alkyl)-, -(Ci-4alkyl)-C(O)-, -(Ci-2alkyl)-, -(Ci-2alkyl)-O-, -O-(Ci-2alkyl)-, -C(O)-N(RN)-, -N(RN)-C(O)-, -C(O)-N(RN)-(Ci-2alkyl)-, -(Ci-2alkyl)-N(RN)-C(O)-, -NRN-, -N(Rp)-(Ci-2alkyl)-, and -(Ci-2alkyl)-N(Rp)-; wherein RNis selected from the group consisting of hydrogen and Ci-4alkyl; and Rpis selected from the group consisting of hydrogen, Ci-2alkyl and -C(O)-Ci-2alkyl.

[0443] In some embodiments of the present invention, L3is selected from the group consisting of -O-, -C(O)-, -CF2-, -(Ci-2alkyl)-, -(Ci-2alkyl)-O-, -O-(Ci-2alkyl)-, -C(O)-N(RN)-(Ci-2alkyl)-, -NRN-, -N(Rp)-(Ci-2alkyl)-, and -(Ci-2alkyl)-N(Rp)-; wherein RNis selected from the group consisting of hydrogen and C1-4alkyl; and Rpis selected from the group consisting of hydrogen, Ci-2alkyl and -C(O)-Ci-2alkyl provided that when L3is -C(O)-N(RN)-(Ci-2alkyl)-, then the Ci-2alkyl portion is bound to

[0444]

[0445] .

[0446] In some embodiments of the present invention, L3is selected from the group consisting of -O-, -(CH2)-, -NH-, and -N(C(O)-CH3)-(CH2)-. In some embodiments of the present invention, L3is selected from the group consisting of -O-, -(CH2)-, and -NH-.

[0447] In some embodiments of the present invention,

[0448]

[0449] is selected from the group consisting of C3-5cycloalkyl, phenyl, and 5 to 10 membered heterocyclyl; wherein

[0450]

[0451] is optionally substituted with one or two substituents independently selected from the group consisting of fluoro, chloro, bromo, -OH, -CN, oxo, Ci-4alkyl, hydroxy substituted Ci-2alkyl, fluoro substituted Ci-2alkyl, -(Ci-2alkyl)-CN, -O-(Ci-2alkyl), -O-(fluoro substituted C1-2 alkyl), -C(O)-(Ci-2alkyl), -SO2-(Ci-2alkyl), -NRQRS, -N(RQ)-SO2-(Ci-4alkyl), -SO2-NRQRTand-S(O)(NH)NRQ; wherein each RQand RTare each independently selected from the group consisting of hydrogen and Ci-2alkyl; and each Rsis selected from the group consisting of hydrogen, Ci-2alkyl, and -C(O)- Ci-2alkyl.

[0452] In some embodiments of the present invention,

[0453]

[0454] is selected from the group consisting of C4-5cycloalkyl, phenyl, and 5 to 10 membered heterocyclyl;

[0455] wherein

[0456]

[0457] is optionally substituted with one or two substituents independently selected from the group consisting of fluoro, chloro, bromo, -OH, -CN,, oxo, Ci-4alkyl, hydroxy substituted Ci-2alkyl, fluoro substituted Ci-2alkyl, -(Ci-2alkyl)-CN, -0-(Ci-2alkyl), -O-(fluoro substituted C1-2 alkyl), -C(O)-(Ci-2alkyl), -SO2-(Ci-2alkyl), -NRQRS, -N(RQ)-SO2-(Ci-2alkyl), and -SO2-NRQRT; wherein each RQand RTare each independently selected from the group consisting of hydrogen and Ci-2alkyl; and each Rsis selected from the group consisting of hydrogen, Ci-2alkyl, and -C(O)-Ci-2alkyl.

[0458] In some embodiments of the present invention R5is other than a 10 membered, nitrogen bound heterocyclyl; wherein the 10 membered, nitrogen bound heterocyclyl contains one ring nitrogen. In some embodiments of the present invention R5is other than a 10 membered, nitrogen bound heterocyclyl; wherein the 10 membered, nitrogen bound heterocyclyl contains one ring nitrogen, and wherein the 10 membered, nitrogen bound heterocyclyl is optionally substituted with one to two -OH groups. In some embodiments R5is other than 1,2,3,4-tetrahydroisoquinolin-2-yl, wherein the 1,2,3,4-tetrahydroisoquinolin-2-yl is optionally substituted with one to two hydroxy groups. In some embodiments of the present invention, R5is other than 6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl.

[0459] In some embodiments of the present invention, wherein the compound of formula (III), when the 4 to 11 membered, nitrogen bound heterocyclyl is piperidin-1-

[0460] yl, and g is 0, then

[0461]

[0462] is other than piperidin-4-yl or piperazin-4-yl; wherein the piperidin-4-yl or piperazin-4-yl is optionally substituted at the 1 -position with Ci-4alkyl. In some embodiments of the present invention, wherein the compound of formula (III), when a is an integer from 1 to 3, each R1is independently selected from the group consisting of halogen, Ci-4alkyl, trifluoroCi-4alky I, and -O-(Ci-4alkyl), the 4 to

[0463] 11 membered, nitrogen bound heterocyclyl is piperidin-1 -yl, and g is 0, then

[0464]

[0465] is other than piperidin-4-yl or piperazin-4-yl; wherein the piperidin-4-yl or piperazin-4-yl is optionally substituted at the 1 -position with Ci-4alkyl.

[0466] In some embodiments of the present invention, wherein the compound of

[0467]

[0468] formula (III), when a is an integer from 2 to 3, each R1 is -CH3, R6 is [piperidine structure], and g is 0, then

[0469]

[0470] is other than

[0471]

[0472] ; wherein the

[0473]

[0474] optionally substituted at the 1 -position with -CH3 or -CH-(CH3)2. In some embodiments of the present invention, wherein the compound of formula (III), when a is an integer from 2

[0475] to 3, each

[0476]

[0477] then

[0478]

[0479] other than

[0480]

[0481] In some embodiments of the present invention, wherein the compound of formula

[0482]

[0483] (III), when a is an integer from 2 to 3, each R1 is -CH3, R6 is [piperidine structure], and g is 0, then

[0484]

[0485] In some embodiments of the present invention, wherein the compound of formula (III), when the 4 to 11 membered, nitrogen bound heterocyclyl is piperidin-1 - ( D )

[0486] yl, and g is 0, then is other than pyrindin-4-yl; wherein the pyridin-4-yl is optionally substituted with Ci-4alkyl, amino, Ci-4alkylamino or di(Ci-4alkyl)amino.

[0487] In some embodiments of the present invention, wherein the compound of formula (III), when a is an integer from 1 to 3, each R1is independently selected from the group consisting of halogen, Ci-4alkyl, trifluoroCi-4alkyl, and -O-(Ci-4alkyl), the 4 to 11 membered, nitrogen bound heterocyclyl is piperidin-1 -yl, and g is 0, then

[0488]

[0489] is other than pyrindin-4-yl; wherein the pyridin-4-yl is optionally substituted with Ci-4alkyl, amino, Ci-4alkylamino or di(Ci-4alkyl)amino.

[0490] In some embodiments, the present invention is directed to compounds of

[0491] formula (III) wherein

[0492]

[0493] is other than piperidin-4-yl, wherein the piperidin-4-yl is optionally substituted at the 1 -position with Ci-4alkyl. In some embodiments, the

[0494] present invention is directed to compounds of formula (III) wherein

[0495]

[0496] is other than pyridin-4-y I, wherein the py ridin-4-yl is substituted with one substituent selected from the group consisting of amino, Ci-4alkylamino or di(Ci-4alkyl)amino. In some embodiments, the present invention is directed to compounds of formula (III)

[0497] wherein

[0498]

[0499] is other than (a) piperidin-4-yl, wherein the piperidin-4-yl is optionally substituted at the 1 -position with Ci-4alkyl; or (b) pyridin-4-yl, wherein the pyridin-4-yl is substituted with one substituent selected from the group consisting of amino, Ci-4alkylamino or di(Ci-4alkyl)amino.

[0500] 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, R5, and R6) are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein.

[0501] In additional embodiments, the present invention is directed to any single compound or subset of compounds independently selected from the representative compounds listed in Tables 1-3, below.

[0502] 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. 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 2, below. 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 3, below.

[0503] 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 Tables 1-3, below.

[0504] 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. 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 2, below. 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 3, below.

[0505] Representative compounds of formula (I), compounds of formula (II) and compounds of formula (III) of the present invention are as listed in Table 1 to 3, below. Unless otherwise noted, wherein a stereogenic center is present in the listed compound, the compound was prepared as a mixture of stereo-configurations.

[0506] Wherein the compound contains at least on stereocenter, and the compound was prepared in a stereogenic excess of any stereoisomer, the S*- and R*- designations are intended to indicate that the exact stereo-configuration at the noted center has not been determined. Wherein the compound contains at least on stereocenter, and the compound was prepared in a stereogenic excess of any stereoisomer, the S- and R- designations are intended to indicate the measured / determined stereoconfiguration at the noted center.

[0507] 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.

[0508] Table 1: Representative Compounds for Formula (I)

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515] thereof. In certain embodiments, the present invention is directed to one or more compounds of formula (II) independently selected from the group consisting of the compounds listed in Table 2, below.

[0516] Table 2: Representative Compounds for Formula (II)

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557] and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof.

[0558] In certain embodiments, the present invention is directed to one or more compounds of formula (III) independently selected from the group consisting of the compounds listed in Table 3, below.

[0559] Table 3: Representative Compounds for Formula (III)

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583] and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In certain embodiments, the present invention is directed to compounds of formula (I), compounds of formula (II) and compounds of formula (III) 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 25 nM, more preferably less than or equal to about 15 nM.

[0584] Abbreviations and Definitions

[0585] Abbreviations used in the specification, for example in the Schemes, Synthesis Examples and Biological Examples, are as listed in the Table A, below:

[0586] Table A: Abbreviations

[0587]

[0588]

[0589]

[0590]

[0591] As used herein, unless otherwise noted, “halogen” shall mean chloro, bromo, fluoro and iodo, preferably bromo, fluoro or chloro, more preferably fluoro or chloro.

[0592] 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 wherein the oxo group is bound to a ring nitrogen or a nitrogen substituted with two non-hydrogen substituent groups, the result will be a N-oxide bond (i.e. > N+-Oj.

[0593] 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-4alky I 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.

[0594] As used herein, unless otherwise noted, the term “fluoro substituted Cx-yalkyl” shall mean any Cx-Yalkyl group as defined above substituted with one or more fluoro groups, preferably one to three fluoro group. For example, “fluoro substituted Ci-4alkyl” includes -CH2F, CHF2, -CF3, -CH2-CF3, -CF2-CH3, -CH2-CH2-CH2F, -CH2-CH2-CF3, -C(CH3)2CF3, -C(CF3)3, and the like. Similarly, the term “trifluoroCx-valkyl” shall mean any CX-Y alkyl group as defined above substituted with three fluoro group. For example, “trifluoroCi-2alkyl” includes -CF3, -CH2-CF3, -CHF-CHF2, and the like.

[0595] As used herein, unless otherwise noted, the term “hydroxy substituted Cx-Yalkyl” shall mean any Cx-Yalkyl group as defined above substituted with one or more hydroxy (-OH) groups, preferably one to three, more preferably one to two hydroxy groups. For example, “hydroxy substituted Ci-4alkyl” includes -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH(OH)CH2OH, -CH2CH2CH2OH, -C(CH2OH)3, and the like.

[0596] As used herein, unless otherwise noted, the terms “Cx-Yalkenyl” 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, “C2-4alkenyl” includes -CH=CH2, -CH2CH=CH2, -CH2CH2CH=CH2, -CH=CHCH2CH3, -CH=CHCH=CH2and the like.

[0597] As used herein, unless otherwise noted, the term “fluoro substituted Cx-Yalkenyl” shall mean any Cx-Yalkenyl as defined above, substituted with one or more fluoro groups, preferably one to three fluoro groups. For example, “fluoro substituted C2-4alkenyl” includes -CH=CF2, -CF2CH=CH2, -CH2CH2CH=CF2, -CH=CHCH2CF3, -CH=CHCH=CF2and the like.

[0598] As used herein, unless otherwise noted, the term “Cx-Ycycloalkyl”, 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 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1 ]hept-2-yl, cyclooctyl, bicyclo[2.2.2]octan-2-yl, and the like. As used herein, unless otherwise noted, the term “4 to 8 membered heterocycloalkyl” shall denote any four to eight membered monocyclic or bicyclic, fused, bridged or spiro-cyclic saturated ring structure containing at least one heteroatom selected from the group consisting of 0, N, and S; optionally containing one to three (preferably one to two) additional heteroatoms independently selected from the group consisting of 0, N and S. The 4 to 8 membered heterocycloalkyl group may be attached at any carbon atom or heteroatom of the ring such that the result is a

[0599]

[0600] 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 0, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of 0, N and S. Unless otherwise noted, the 5 to 6 membered heteroaryl (regardless of the number and identity of ring heteroatoms, etc.) 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.

[0601] The term “5 membered heteroaryl” shall denote any five membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of 0, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of 0, N and S. The term “6 membered heteroaryl” shall denote any six membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of 0, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of 0, N and S. In certain embodiments of the present invention, the 5 to 6 membered heteroaryl is preferably a 5 membered heteroaryl. In certain embodiments of the present invention, the 5 to 6 membered heteroaryl is preferably a 6 membered heteroaryl.

[0602] As used herein, unless otherwise noted, the term “heterocyclyl” shall denote any 4 to 8 (preferably 4 to 6 membered) membered monocyclic saturated, partially unsaturated or aromatic ring structure containing at least one heteroatom selected from the group consisting of 0, N and S, optionally containing one to three additional heteroatoms (preferably one to two additional heteroatoms) independently selected from the group consisting of 0, N and S; or any 6 to 18 (preferably 6 to 16 membered) membered saturated, partially unsaturated, partially aromatic or aromatic, bicyclic, polycyclic, fused, bridged or spiro-cyclic ring system containing at least one heteroatom selected from the group consisting of 0, N and S, optionally containing one to five additional heteroatoms (preferably one to three additional heteroatoms, more preferably one to two) independently selected from the group consisting of 0, N and S. The heterocyclyl may be attached at any carbon atom or heteroatom of the rin g such that the result is a stable structure.

[0603]

[0604]

[0605]

[0606]

[0607] As used herein, unless otherwise noted, the term “5 to 10 membered heterocyclyl” shall denote any 5 to 10 membered monocyclic, saturated, partially unsaturated or aromatic ring structure containing at least one heteroatom selected from the group consisting of N, 0 and S; optionally containing one to two additional heteroatoms independently selected from the group consisting of 0, N and S; or any 9 to 10 membered saturated, partially unsaturated, partially aromatic or aromatic, bicyclic, fused, bridged or spiro-cyclic ring system. The 5 to 10 membered heterocyclyl group may be attached at any carbon atom or heteroatom of the ring such that the

[0608] result is a stable structure. Suitable examples include, but are not limited to,

[0609]

[0610]

[0611]

[0612] As used herein, unless otherwise noted, the term “4 to 16 membered, nitrogen bound heterocyclyl” shall denote any 4 to 8 membered monocyclic, saturated, partially unsaturated or aromatic ring structure containing at least one nitrogen atom, optionally containing one to two additional heteroatoms independently selected from the group consisting of 0, N and S; or any 6 to 16 membered saturated, partially unsaturated, partially aromatic or aromatic bicyclic, polycyclic, fused, bridged or spiro-cyclic ring system containing at least one nitrogen atom, optionally containing one to five additional heteroatoms independently selected from the group consisting of 0, N and S. The 4 to 16 membered nitrogen bound heterocyclyl may be bound through any ring nitrogen atom, provided that the result is a stable structure. Suitably examples include, but are not limited to, azetidinyl, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, trithianyl, azepanyl, 1,4-diazepanyl, 1,4-oxazepanyl, indolinyl, isoindolinyl, chromenyl, 3,4- methylenedioxyphenyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 2,3-dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.

[0613] The term a “4 to 11 membered, nitrogen bound heterocyclyl” shall denote any 4 to 6 membered monocyclic, saturated, partially unsaturated or aromatic ring structure containing at least one nitrogen atom, optionally containing one to two (preferably one) additional heteroatoms independently selected from the group consisting of 0, N and S; or any 6 to 11 membered saturated, partially unsaturated, partially aromatic or aromatic polycyclic, fused, bridged or spiro-cyclic ring system containing at least one nitrogen atom, optionally containing one to three additional heteroatoms independently selected from the group consisting of 0, N and S. The 4 to 11 membered nitrogen bound heterocyclyl may be bound through any nitrogen atom, provided that the result is a stable structure.

[0614] In certain embodiments of the present invention, the 4 to 16 membered nitrogen

[0615]

[0616]

[0617] the like. In certain embodiments of the present invention, the 4 to 16 membered

[0618]

[0619] When a particular group is "substituted" (e.g. Cx-yalkyl, heterocyclyl, heteroacycloalkyl, 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.

[0620] One skilled in the art will recognize that any of the compounds of formula (I), compounds of formula (II) and compounds of formula (III) 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. In some embodiments, the present invention is directed to pharmaceutically acceptable salts of the compounds of formula (I), compounds of formula (II) and I or compounds of formula (III).

[0621] 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.

[0622] 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.

[0623] 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, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic 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, α-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.

[0624] 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, 1H-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.

[0625] It is further intended that the present invention includes the compounds of formula (I), compounds of formula (II) and compounds of formula (III) described herein, including all isomers thereof (including, but not limited to stereoisomers, enantiomers, diastereomers, tautomers, isotopologues, isotopomers, and the like).

[0626] As used herein, the symbol or notation shall denote the presence of a stereogenic center.

[0627] 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 / 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.

[0628] 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%.

[0629] Throughout the specification and claims, wherein a compound or substituent group is drawn or named, the “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.

[0630] Wherein a compound or substituent group contains two stereo-centers which are drawn using

[0631]

[0632] “ 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(s) of said stereo-centers, although the exact stereo-configuration has not been determined.

[0633] In some embodiments, the present invention is directed to compounds of formula (I) 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. In some embodiments, the present invention is directed to compounds of formula (II) wherein the stereocenter denoted with a is present in the R- stereoorientation. In some embodiments, the present invention is directed to compounds of formula (II) wherein the stereocenter denoted with a is present in an S- stereoorientation. In some embodiments, the present invention is directed to compounds of formula (III) wherein the stereocenter denoted with a is present in the R- stereoorientation. In some embodiments, the present invention is directed to compounds of formula (III) wherein the stereocenter denoted with a is present in an S- stereoorientation.

[0634] 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 (d2O 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 d218O.

[0635] 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, CH3CHDCH3and CH3CH2CH2D are a pair of constitutional isotopomers of n-propane; whereas (R)-CH3CHDOH and (S)-CH3CHDOH or (Z)-CH3CH=CHD and (E)-CH3CH=CHD are examples of isotopic stereoisomers of ethanol and n-propene, respectively.

[0636] The present invention is further directed to compounds of formula (I), compound or formula (II) and compounds of formula (III) 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) may comprise one or more radioactive isotope(s) selected from the group of3H,11C,18F,122I,123I,125I,131I,75Br,76Br,77Br and82Br. Preferably, the radioactive isotope is selected from the group of3H,11C and18F.

[0637] 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-C6alkylene)-” substituent refers to a group of the formula

[0638]

[0639] 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 another embodiment of the present invention, the compound of formula (II) is present in an isolated form. In another embodiment of the present invention, the compound of formula (III) is present in an isolated form.

[0640] 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 another embodiment of the present invention, the compound of formula (II) is present as a substantially pure form. In another embodiment of the present invention, the compound of formula (III) is present as a substantially pure form.

[0641] 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 saltform(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 another embodiment of the present invention, the compound of formula (II) is present in a form which is substantially free of corresponding salt form(s). In another embodiment of the present invention, the compound of formula (III) is present in a form which is substantially free of corresponding salt form(s).

[0642] General Synthesis Schemes

[0643] Compounds of formula (I) may be prepared as described in Scheme 1, below.

[0644]

[0645]

[0646] Scheme 1

[0647] Accordingly, a suitably substituted compound of formula (V), wherein A1is Ci-4alky I, preferably methyl or ethyl, and wherein Hal1is a suitably selected halogen such as I, Br, or Cl, preferably Br, a known compound or compound prepared by known methods, is selectively protected by reacting with a suitably selected protecting reagent such as BOC anhydride, benzyl bromide, and the like; in the presence of suitably selected additive such as DMAP, and the like; in a suitably selected organic solvent such as THF, DMF, acetonitrile, and the like; at a temperature in the range of from about room temperature to about 50 °C, preferably at about 25 °C; to yield the corresponding compound of formula (VI) wherein A2is the corresponding oxygen protecting group. For example, wherein the protecting reagent is BOC anhydride, A2is t-butyl.

[0648] Preferably, the protecting reagent is selected such that A1and A2on the compound of formula (VI) are not the same and are chosen to allow for selective deprotection of the -C(O)OA1or -C(O)OA2ester at the desired step in the synthesis. For example, when A1is CH3 and A2is t-butyl, one skilled in the art will recognize that A1can be selectively deprotected in the presence of a suitably selected base such as NaOH, LiOH, and the like; whereas the A2can be selectively deprotected in the presence of a suitably selected acid such as H3PO4, TFA, and the like.

[0649] The compound of formula (VI) is reacted with a suitably selected boron source such as bis(pinacolato)diboron, B2(OH)4, and the like; in the presence of a suitably selected palladium catalyst such Pd(dppf)Cl2, PdCl2(PPhs)2, XPhos Pd G4, and the like; in the presence of a suitably selected base such a KOAc, TEA, K3PO4, NaOtBu, and the like; in a suitably selected solvent or mixture of solvents, such as 1,4-dioxane, DMSO, toluene, and the like; at a temperature greater than about 80 °C, preferably at about 100 °C; to yield the corresponding compound of formula (VII); wherein B(R)2 represents a boronic acid (where each R is OH), or a boronic ester (where both R groups are the same and are -O-Ci-4alky I), or a group where the two R groups are taken together with the boron atom to which they are bound to

[0650]

[0651] The compound of formula (VII) is reacted with a suitably substituted compound of formula (VIII), wherein Q1is a suitably selected leaving group such as I, Br, -OSO2CF3, and the like, a known compound or compound prepared by known methods; in the presence of a suitably selected palladium catalyst such Pd(dppf)Cl2, CataCXium A Pd G3, Pd(PPhs)4, XPhos Pd G3, and the like; in the presence of a suitably selected inorganic base such as K3PO4, CS2CO3, KOAc, CsF, and the like; in a suitably selected solvent or mixture of solvent and water such as 1,4-dioxane, toluene, DMSO, and the like; at a temperature in the range of from about room temperature to about 120 °C, preferably at about 90 °C; to yield the corresponding compound of formula (IX).

[0652] The compound of formula (IX) is selectively de-protected by reacting with a suitably selected acid such as HCI, TFA, and the like or a suitably selected base such as NaOH, LiOH, KOH and the like; in a suitably selected solvent or mixture of solvents such as 1,4-dioxane, DCM, water, EtOH, MeOH, THF, and the like; at a temperature in the range of from about 0 °C to about 50 °C, preferably at about 25 °C; to yield the corresponding compound of formula (X). One skilled in the art will recognize that the selection of a suitable reagent to yield the removal of the A1group will be directed by the identity (e.g. which Ci -4alky I) of said A1group.

[0653] The compound of formula (X) is reacted with 2-amino- / \ / -methyl-3-(4-(trifluoromethyl)phenyl)propanamide, a known compound or compound prepared by known methods; in the presence of a suitably selected amide coupling reagent such as HATU, T3P®, TCFH, EDC, and the like; in the presence of a suitably selected base such as TEA, DIPEA and the like; in a suitably selected solvent such as DMF, DCM, DMSO, THF, DMA, and the like; at a temperature in the range of from about 0 °C to about 70 °C °C, preferably at about 25 °C; to yield the corresponding compound of formula (XII).

[0654] The compound of formula (XII) is de-protected by reacting with a suitably selected acid such as HCI, TFA, and the like or with a suitably selected base such as NaOH, LiOH, KOH and the like; in a suitably selected solvent or mixture of solvents, such as 1,4-dioxane, DCM, water, EtOH, MeOH, THF, and the like; at a temperature in the range of from about 0 °C to about room temperature, preferably at about 25 °C; to yield the corresponding compound of formula (XIII). One skilled in the art will recognize that the selection of a suitable reagent to yield the removal of the A2group will be directed by the identity (e.g. which C1-2alkyl) of said A2group.

[0655] The compound of formula (XIII) is reacted with a suitably substituted compound of formula (XIV), a known compound or compound prepared by known methods; in the presence of a suitably selected amide coupling reagent such as HATU, T3P®, TCFH, EDC, and the like; in the presence of a suitably selected base such as TEA, DIPEA and the like; in a suitably selected solvent such as DMF, DCM, DMSO, THF, and the like; at a temperature in the range of from about 0 °C to about 70 °C, preferably at about 25 °C; to yield the corresponding compound of formula (I). Compounds of formula (II) may be similarly prepared as described in Scheme 1, by reacting a suitably substituted compound of formula (XIII) with a suitably substituted compound of formula (XV)

[0656] r5“H(XV)

[0657] (wherein R5is an optionally substituted 4 to 16 membered, nitrogen bound heterocyclyl as herein defined), a known compound or compound prepared by known methods; in the presence of a suitably selected amide coupling reagent such as HATU, T3P®, TCFH, EDC, and the like; in the presence of a suitably selected base such as TEA, DIPEA and the like; in a suitably selected solvent such as DMF, DCM, DMSO, THF, and the like; at a temperature in the range of from about 0 °C to about 70 °C, preferably at about 25 °C; to yield the corresponding compound of formula (II).

[0658] Compounds of formula (III) may be similarly prepared as described in Scheme 1, by reacting a suitably substituted compound of formula (XIII) with a suitably substituted compound of formula (XVI),

[0659] R6-H (XVI)

[0660] (wherein R6is a substituted 4 to 11 membered, nitrogen bound heterocyclyl as herein defined), a known compound or compound prepared by known methods; in the presence of a suitably selected amide coupling reagent such as HATU, T3P®, TCFH, EDC, and the like; in the presence of a suitably selected base such as TEA, DIPEA and the like; in a suitably selected solvent such as DMF, DCM, DMSO, THF, and the like; at a temperature in the range of from about 0 °C to about 70 °C, preferably at about 25 °C; to yield the corresponding compound of formula (III).

[0661] One skilled in the art will recognize that compounds of formula (I), compounds of formula (II) and compounds of formula (III) may alternatively be prepared by applying the reaction steps of Scheme 1 above, including coupling of

[0662] (a) a suitably substituted compound of formula (VIII),

[0663] (b) 2-amino- / V-methyl-3-(4-(trifluoromethyl)phenyl)propanamide, and (c) a suitably substituted compound of formula (XIV), compound of formula (XV) or compound of formula (XVI)

[0664] onto a suitably substituted compound of formula (V), compound of formula (VI), or compound of formula (VI I) (with the addition of one or more suitable protection and I or deprotection steps, as needed or desired), in any order which results in the desired product. (See for example, Synthesis Examples 3, 43, and 48 which follow hereinafter.)

[0665] For example, compounds of formula (I), compounds of formula (II) and compounds of formula (III) may be prepared by

[0666] (a) selectively deprotecting the -C(O)OA1ester on the compound of formula (VI) (to yield the corresponding -C(O)OH)); and then reacting the resulting intermediate with 2-amino- / V-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; to yield the corresponding compound of formula (XVII)

[0667]

[0668] (b) deprotecting the -C(O)OA2ester on the compound of formula (XVII) (to yield the corresponding -C(O)OH)); and then reacting the resulting intermediate with a suitably substituted compound of formula (XIV), compound of formula (XV) or compound of formula (XVI), as described herein; to yield the corresponding compound of formula

[0669]

[0670] wherein Q3is the corresponding -NR2R3, -R5or -R6substituent;

[0671] and (c) reacting the compound of formula (XVIII) with a suitably selected source of boron (to convert the Hal1group to a suitable -B(R)2 group); and then reacting the resulting intermediate with a suitably substituted compound of formula (VIII); to yield the corresponding compound of formula (I), formula (II) or formula (III).

[0672] Certain compounds of formula (II) and formula (III) may alternatively be prepared by reacting a suitably substituted compound of formula (XIX)

[0673]

[0674] prepared for example as described in Scheme 1 above (substituting piperidin-1-y|-4-one, a known compound, for the compound of formula (XIV)); with a suitably substituted amine, a known compound or compound prepared by known methods; under reductive amination conditions; in the presence of a reducing agent such as NaCNBH3, NaBH(OAc)3, and the like; in the presence of a suitably selected additive such as ZnCl2, acetic acid and the like; in a suitably selected solvent such as MeOH and the like; at a temperature in the range of from about 0 °C to about 80 °C, preferably at about 60 °C; to yield the corresponding compound of formula (II) or formula (III). (See for example, Synthesis Example 57 which follows herein.)

[0675] One skilled in the art will further recognize that wherein any of the compounds of formula (I), compounds of formula (II), compounds of formula (III), or any of the intermediates prepared in the synthesis of said compounds, contains a reactive group, said reactive group may be further functionalized according to known methods, at any appropriate step within the synthesis. For example, reactive group such as -CHO, -CH2OH, and the like, may be functionalized according to known methods, for example, as described in Synthesis Examples 47-56 which follow herein. Terminal amine group such as -NH₂, > NH, -NH(PG), and the like, wherein PG is a suitable nitrogen protecting group, may also be functionalized according to known methods, for example, as described in Synthesis Examples 22-23, and 41-42 which follow herein.

[0676] 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.

[0677] 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.

[0678] 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 / type (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.

[0679] 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.

[0680] 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.

[0681] 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.

[0682] 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.

[0683] 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.

[0684] 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.

[0685] 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 & PG. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

[0686] 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.

[0687] 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.

[0688] Where the processes for the preparation of the compounds according to the invention yield 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 (+)-di-p-toluoyl-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.

[0689] Additionally, chiral HPLC against a standard may be used to determine percent enantiomeric excess (%ee). The enantiomeric excess may be calculated as follows

[0690] [ (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:

[0691] ee = ([α-obs] / [α-max]) X 100.

[0692] Methods of Treatment / Disorders Mediated by BFL-1 Receptor

[0693] 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), a compound of formula (II) or a compound of formula (III).

[0694] 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).

[0695] 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.

[0696] 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).

[0697] 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).

[0698] 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.

[0699] 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.

[0700] 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.

[0701] Pharmaceutical Compositions

[0702] The present invention is further directed to pharmaceutical compositions comprising, consisting of, or consisting essentially of a compound of formula (I), a compound of formula (II) or a compound of formula (III) as described herein. The present invention is further directed to pharmaceutical compositions comprising, consisting of, or consisting essentially of a compound of formula (I), a compound of formula (II) or a compound of formula (III) as described herein and one or more pharmaceutically acceptable carriers or excipients.

[0703] 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.

[0704] 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. The present invention further comprises pharmaceutical compositions containing a compound of formula (I), compound of formula (II) or compound of formula (III) 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.

[0705] 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.

[0706] 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.

[0707] 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.

[0708] 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.

[0709] 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.

[0710] 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.

[0711] 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, com 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. The liquid forms may include suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methylcellulose 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.

[0712] To prepare a pharmaceutical composition of the present invention, a compound of formula (I), compound of formula (II) or compound of formula (III) 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 Pharmaceutical Excipients, 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 Dosage Forms: Tablets, Second Edition, Revised and Expanded, 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.

[0713] 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 required.

[0714] 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.

[0715] Examples

[0716] 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.

[0717] 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 MgSO4or 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.

[0718] 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.

[0719] 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% TFAwith 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.

[0720] 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®).

[0721] 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-d6, Chloroform-d, Methanol-d4, Deuterium Oxide, Acetic Acid-d4, Acetone-d6, Acetonitrile-d3, Benzene-d6, Cyclohexane-d12, N, N-Dimethyl-formamide-d7, 1,4-Dioxane-d8, Ethanol-d6, Methylene Chloride-d2, Pyridine-d5, 1,1, 2, 2-Tetrachloroethane-d2, Tetrahydrofuran-d8, Toluene-d8, Trifluoroacetic Acid-d, Trifluoroethanol-d3, 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. Intermediate Compound Synthesis Examples

[0722] Intermediate A: (R)-2-amino- / \ / -methyl-3-(4-(trifluoromethyl)phenyl)propanamide HCI.

[0723]

[0724] Step A. te / Y-Butyl (R)-(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 (3.039 g, 45 mmol) and triethylamine (20.85 mL, 150 mmol) in DMF (100 mL) at 0°C was added HATU (13.69 g, 36 mmol). The reaction mixture was stirred at room temperature for 16 h. 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 resulting 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+H-56]+.1H NMR (400 MHz, CDCI3) 6 7.56 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 7.8 Hz, 2H), 5.90 (brs, 1H), 5.00 (br s, 1H), 4.34 (brd, J = 7.5 Hz, 1H), 3.23-3.14 (m, 1H), 3.12-3.03 (m, 1H), 2.76 (d, J = 4.8 Hz, 3H), 1.39 (s, 9H).

[0725] Step B. (R)-2-amino- / V-methyl-3-(4-(trifluoromethyl)phenyl)propanamide HCI. To a solution of te / Y-butyl (R)-(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 mL, 112 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was filtered and the solid was dried under vacuum to yield the title compound. MS (ESI): mass calculated for C11H13F3N2O, 246.1; m / z measured, 247.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 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, 1H), 3.18-3.10 (m, 1H), 3.09-3.01 (m, 1H), 2.61 (d, J = 4.5 Hz, 3H).19F NMR (376 MHz, DMSO-d6) 6 -60.86 (s, 1F).

[0726] Intermediate B: (R)-2',5'-Dimethyl-5-((1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylic acid.

[0727]

[0728] Step A: Dimethyl 2',5'-dimethyl-[1,1'-biphenyl]-3,5-dicarboxylate. To a mixture of dimethyl 5-bromoisophthalate (5.0 g, 18 mmol), (2,5-dimethylphenyl)boronic acid (4.1 g, 27 mmol), and K2CO3 (7.6 g, 55 mmol) in 1,4-dioxane (50 mL) and water (12.5 mL) was added Pd(dppf)Cl2 (1.3 g, 1.8 mmol) under N2 (g). The reaction mixture was heated to 90 °C overnight. The reaction mixture was filtered, washing the filter cake with EtOAc (100 mL). The filtrate was concentrated under vacuum, then diluted with EtOAc (150 mL) and washed with water (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. Purification of the resulting residue by chromatography (FCC, silica gel, 0-10% EtOAc in petroleum ether) yielded the title compound.1H NMR (400 MHz, CDCI3) 68.67 (t, J = 1.7 Hz, 1H), 8.21 (d, J= 1.7 Hz, 2H), 7.22 - 7.17 (m, 1H), 7.15 - 7.10 (m, 1H), 7.06 (s, 1H), 3.97 (s, 6H), 2.37 (s, 3H), 2.22 (s, 3H).

[0729] Step B: 5-(Methoxycarbonyl)-2',5'-dimethyl-[1,1'-biphenyl]-3-carboxylic acid. To a mixture of dimethyl 2',5'-dimethyl-[1,1'-biphenyl]-3,5-dicarboxylate (5.0 g, 17 mmol) in 1:1 (v / v) THF / MeOH (200 mL) was added NaOH (1 M in water, 16.8 mL, 16.8 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and EtOAc (80 mL) and HCI (2 M in water, 60 mL) were added. The layers were separated, and the aqueous layer was extracted with EtOAc (2x 80 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. Purification of the resulting residue chromatography (FCC, silica gel, 0-40% EtOAc (containing 0.1% AcOH) in petroleum ether) yielded the title compound as a white solid.1H NMR (400 MHz, CDCh) 68.75 (s, 1 H), 8.30 -8.25 (m, 2H), 7.23 - 7.18 (m, 1H), 7.17 - 7.12 (m, 1H), 7.08 (s, 1H), 3.98 (s, 3H), 2.38 (s, 3H), 2.24 (s, 3H).

[0730] Step C: Methyl (R)-2',5'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1,1'-biphenyl]-3-carboxylate. To a mixture of 5-(methoxycarbonyl)-2',5'-dimethyl-[1, 1 '-biphenyl]-3-carboxylic acid (800 mg, 2.78 mmol), (R)-2-amino- / V-methyl-3-(4-(trifluoromethyl)phenyl)propanamide hydrochloride (943 mg, 3.34 mmol), and HATU (1.4 g, 3.6 mmol) in DMF (25 mL) was added DIPEA (2.16 g, 16.7 mmol). The reaction mixture was stirred at room temperature overnight. Water (20 mL) was added, and the resultant mixture was filtered. The filter cake was collected, and combined with another batch of methyl (R)-2',5'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1,1'-biphenyl]-3-carboxylate previously prepared as described in Steps A-C of this Example. The combined solids were suspended in 1: 1 (v / v) EtOAc / petroleum ether (40 mL), stirred for 15 min at room temperature, and filtered. The resulting filter cake was washed with 1:1 (v / v) EtOAc / petroleum ether (5 mL), collected, and dried under vacuum to yield the title compound as a white solid. MS (ESI): mass calculated for C28H27F3N2O4, 512.2; m / z measured, 513.1 [M+H]+.1H NMR (400 MHz, CDCI3) 68.33 (s, 1 H), 8.16 (s, 1 H), 7.93 (s, 1 H), 7.58 (d, J = 8.0 Hz, 2H), 7.40 (d, J= 8.1 Hz, 2H), 7.21 - 7.17 (m, 1H), 7.15 - 7.10 (m, 1H), 7.05 - 6.98 (m, 2H), 5.84 (br d, J = 4.1 Hz, 1 H), 4.88 - 4.79 (m, 1 H), 3.96 (s, 3H), 3.30 - 3.23 (m, 2H), 2.77 (d, J= 4.9 Hz, 3H), 2.36 (s, 3H), 2.20 (s, 3H).19F NMR (376 MHz, CDCI3) 5-62.52 (s, 1F).

[0731] Step D: (R)-2',5'-Dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylic acid. A mixture of methyl (R)-2',5'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylate (500 mg, 0.98 mmol) and LiOH*H2O (2 M in water, 5.0 mL, 10 mmol) in 6:3:3 (v / v / v) THF / MeOH / water (8 mL) was stirred at 25 °C for 16 h. The reaction mixture was poured into water (50 mL) and the aqueous phase was acidified to pH 6-7 with 1 M aqueous HCI. The resultant mixture was extracted with EtOAc (2x 100 ml_), and the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the title compound as a white solid. MS (ESI): mass calculated for C27H25F3N2O4, 498.2; m / z measured, 499.0 [M+H]+.

[0732] Intermediate C: 2-amino- / V-methyl-3-(4-(trifluoromethyl)phenyl)propanamide HCI.

[0733]

[0734] Intermediate C was prepared according to the procedure described for Intermediate A, substituting 2-((te / Y-butoxycarbonyl)amino)-3-(4-(trifluoromethyl)phenyl)propanoic acid for (R)-2-((terf-butoxycarbonyl)amino)-3-(4-(trifluoromethyl)phenyl)propanoic acid in Step A to yield the title compound as a white solid. MS (ESI): mass calculated for C11H13F3N2O, 246.1; m / z measured, 247.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) 68.42 (br d, J = 4.5 Hz, 1H), 8.23 (br s, 2H), 7.71 (d, J= 8.1 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 4.00 - 3.92 (m, 1H), 3.17 -3.02 (m, 2H), 2.61 (d, J = 4.5 Hz, 3H).19F NMR (376 MHz, DMSO-d6) 6 -60.88 (br s, 1F).

[0735] Intermediate D: 2',5'-Dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylic acid

[0736]

[0737] Step A: 3-(te / Y-Butyl) 5-methyl 2',5'-dimethyl-[1,1'-biphenyl]-3,5-dicarboxylate. A mixture of 5-(methoxycarbonyl)-2',5'-dimethyl-[1,1'-biphenyl]-3-carboxylic acid (90.0 g, 317 mmol), di-te / Y-butyl dicarbonate (145 mL, 633 mmol), and DMAP (58.0 g, 475 mmol) in THF (500 ml_) was degassed and purged with N2 (g) three times. The mixture was stirred at 25 °C for 12 h under N2 (g) atmosphere. The reaction mixture was diluted with H2O (500 m L) and extracted with EtOAc (2x 1.0 L). The combined organic layers were washed with 0.5 N HCI (2x 600 m L), dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the resulting residue by chromatography (FCC, SiO2, 100 / 0 to 50 / 1 petroleum ether / EtOAc) yielded the title compound as a white solid.1H NMR (400 MHz, CDCI3) 5 8.64 - 8.58 (m, 1H), 8.20 - 8.13 (m, 2H), 7.22 - 7.17 (m, 1H), 7.15 - 7.10 (m, 1H), 7.07 (s, 1H), 3.97 (s, 3H), 2.37 (s, 3H), 2.24 (s, 3H), 1.63 (s, 9H).

[0738] Step B: 5-(tert-Butoxycarbonyl)-2',5'-dimethyl-[1,1'-biphenyl]-3-carboxylic acid. To a solution of 3-(tert-butyl) 5-methyl 2',5'-dimethyl-[1,1'-biphenyl]-3,5-dicarboxylate (69.0 g, 202 mmol) in THF (300 mL) and MeOH (300 mL) was added a solution of LiOH*H2O (17.0 g, 405 mmol) in H2O (60 mL). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove THF / MeOH. The resulting residue was diluted with H2O (200 mL) and the pH was adjusted to pH 4 by the addition of 10% citric acid. The mixture was extracted with EtOAc (2x 500 mL). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound as a white solid.1H NMR (400 MHz, CDCI3) 6 8.70 (t, J= 1.4 Hz, 1H), 8.24 (td, J= 1.5, 15.1 Hz, 2H), 7.23 - 7.19 (m, 1H), 7.17 -7.12 (m, 1H), 7.09 (s, 1H), 2.38 (s, 3H), 2.25 (s, 3H), 1.65 (s, 9H).

[0739] Step C: te / Y-Butyl 2',5'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1,1'-biphenyl]-3-carboxylate. To a mixture of 2-amino- / V-methyl-3-(4-(trifluoromethyl)phenyl)propanamide hydrochloride (130 mg, 0.46 mmol), 5-(te / Y-butoxycarbonyl)-2',5'-dimethyl-[1, T-biphenyl]-3-carboxylic acid (180 mg, 0.55 mmol), and DIPEA (297 mg, 2.30 mmol) in DMF (4 mL) was added HATU (227 mg, 0.60 mmol). The reaction mixture was stirred at room temperature for 1 h and then combined with another batch of the same reaction mixture prepared according to Steps A-C of this Example. To the combined reaction mixtures was added sat. aq. NH4CI (10 mL) and the resulting mixture was extracted with EtOAc (3x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. Purification of the resulting residue by chromatography (FCC, silica gel, 0-60% EtOAc in petroleum ether) yielded the title compound as a white solid. MS (ESI): mass calculated for C31H33F3N2O4, 554.2; m / z measured, 555.3 [M+H]+.1H NMR (400 MHz, CDCI3) 6 8.29 (s, 1H), 8.10 (s, 1H), 7.87 (s, 1H), 7.56 (d, J= 8.0 Hz, 2H), 7.39 (br d, J= 8.0 Hz, 2H), 7.20 - 7.16 (m, 1H), 7.15 - 7.08 (m, 1H), 7.07 - 7.00 (m, 2H), 5.96 (brd, J = 4.0 Hz, 1 H), 4.86 (q, J = 7.3 Hz, 1 H), 3.25 (d, J = 7.0 Hz, 2H), 2.77 (d, J = 4.8 Hz, 3H), 2.36 (s, 3H), 2.20 (s, 3H), 1.61 (s, 9H).19F NMR (376 MHz, CDCI3) 6 -62.51 (s, 1F).

[0740] Step D: 2',5'-Dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid. To a mixture of te / Y-butyl 2',5'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylate (100 mg, 0.16 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to yield the title compound as a white solid. MS (ESI): mass calculated for C27H25F3N2O4, 498.2; m / z measured, 499.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 8.94 (d, J= 8.5 Hz, 1H), 8.39 (s, 1H), 8.13 - 8.07 (m, 1H), 7.99 (s, 1H), 7.95 (s, 1H), 7.63 - 7.59 (m, 2H), 7.55 - 7.51 (m, 2H), 7.23 (d, J = 7.7 Hz, 1 H), 7.15 (br d, J = 8.0 Hz, 1 H), 7.06 (s, 1 H), 4.81 - 4.69 (m, 1 H), 3.26 - 3.03 (m, 2H), 2.62 (d, J = 4.5 Hz, 3H), 2.32 (s, 3H), 2.15 (s, 3H).19F NMR (376 MHz, DMSO-de) 6 -75.10 (br s, 1F).

[0741] Intermediate E: (R)-2',3',6'-trimethyl-5-((1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylic acid

[0742]

[0743] Step A: 3-Bromo-5-(methoxycarbonyl)benzoic acid. Aqueous NaOH (1M, 95 mL) was added to a solution of dimethyl 5-bromoisophthalate (25 g, 91.5 mmol) in 1:1 THF: MeOH (1 L). The reaction mixture was stirred at room temperature for 4 h. The solvent was evaporated under vacuum and the resulting residue was resuspended in H2O (150 m L). The pH of the mixture was adjusted to pH 4 with 1 M aq. HCI, and the resulting mixture was then extracted with EtOAc (300 mL x3). The extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by silica gel flash column chromatography (0-50% EtOAc with 0.1% AcOH in petroleum ether) yieldd the title compound.1H NMR (400 MHz, DMSO-d6) 6= 13.71 (brs, 1H), 8.42 (d, J= 1.5 Hz, 1H), 8.29 (d, J= 1.3 Hz, 2H), 3.91 (s, 3H).

[0744] Step B: 1 -(tert-Butyl) 3-methyl 5-bromoisophthalate. A mixture of 3-bromo-5-(methoxycarbonyl)benzoic acid (50.0 g, 193 mmol), di-tert-butyl dicarbonate (53.2 mL, 231 mmol), and DMAP (9.43 g, 77.2 mmol) in THF (500 mL) was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure.

[0745] Purification of the resulting residue by chromatography (FCC, SiO2, petroleum ether / EtOAc 20 / 1 to 1 to 10 / 1) yielded the title compound as a white solid.1H NMR (400 MHz, CD3OD) <58.54 (t, J =1.5 Hz, 1H), 8.32 (t, J= 1.8 Hz, 1H), 8.28 (t, J= 1.8 Hz, 1 H), 3.96 - 3.92 (m, 3H), 1.61 (s, 9H).

[0746] Step C: 1 -(ferf-Butyl) 3-methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isophthalate. A mixture of 1 -(ferf-butyl) 3-methyl 5-bromoisophthalate (33.0 g, 104 mmol), bis(pinacolato)diboron (53.1 g, 209 mmol), Pd(dppf)Cl2 (3.83 g, 5.24 mmol), and KOAc (30.8 g, 314 mmol) in 1,4-dioxane (500 mL) was degassed and purged with N2 (g) three times, and the mixture was stirred at 100 °C for 12 h under N2 (g) atmosphere. The reaction mixture was diluted with H2O (500 mL) and then extracted with EtOAc (3x 600 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressue. Purification of the resulting residue by chromatography (FCC, SiO2, petroleum ether / EtOAc 1 / 0 to 2 / 1) yielded the title compound as a white solid.1H NMR (400 MHz, CD3OD) 68.69 (t, J = 1.7 Hz, 1H), 8.60 (s, 1H), 8.58 (s, 1H), 3.94 (s, 3H), 1.36 (s, 9H), 1.29 - 1.27 (m, 12H).

[0747] Step D: 3-(tert-Butyl) 5-methyl 2',3',6'-trimethyl-[1, 1 '-biphenyl]-3,5-dicarboxylate. A mixture of 1 -(tert-butyl) 3-methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isophthalate (26.4 g, 73.1 mmol), 2-iodo-1,3,4-trimethylbenzene (18.0 g, 73.1 mmol), Pd(P(t-Bu3))2(1.87 g, 3.66 mmol), and K3PO4 (46.5 g, 219 mmol) in 1,4-dioxane (500 mL) was degassed and purged with N2 (g) three times, and the mixture was stirred at 90 °C for 12 h under N2 (g) atmosphere. The reaction mixture was diluted with H2O (1000 mL) and then extracted with EtOAc (3x 1000 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the resulting residue by prep-TLC (SiO2, petroleum ether / EtOAc 10:1) yielded the title compound as a white solid. MS (ESI): mass calculated for C22H26O4, 354.2; m / z measured, 298.9 [M+H-56]+, [M+H-(t-butyl)].1H NMR (400 MHz, CD3OD) 58.63 (s, 1H), 7.99 (d, J= 11.4 Hz, 2H), 7.14 - 7.03 (m, 2H), 3.95 (s, 3H), 2.31 (s, 3H), 1.97 (s, 3H), 1.92 (s, 3H), 1.62 (s, 9H).

[0748] Step E: 5-(te / Y-Butoxycarbonyl)-2',3',6'-trimethyl-[1, 1 '-biphenyl]-3-carboxylic acid. To a solution of 3-(terf-butyl) 5-methyl 2',3',6'-trimethyl-[1, 1 '-biphenyl]-3,5-dicarboxylate (18.0 g, 50.7 mmol) in H2O (180 mL), THF (180 mL), and MeOH (90 mL) was added LiOH*H2O (4.26 g, 101 mmol). The mixture was stirred at 25 °C for 5 h. The reaction mixture was acidified by addition of 2 N HCI to pH = 6, then concentrated under reduced pressure to remove THF and MeOH, before extracting with EtOAc (3x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the resulting residue by chromatography (FCC, SiO2, petroleum ether / EtOAc 5 / 1 to 3 / 1) yielded the title compound as a white solid. MS (ESI): mass calculated for C21H24O4, 340.2; m / z measured, 339.1 [M-H]+.1H NMR (400 MHz, CD3OD) 68.70 (t, J = 1.6 Hz, 1 H), 8.06 (td, J= 1.6, 15.6 Hz, 2H), 7.17 - 7.00 (m, 2H), 2.31 (s, 3H), 1.98 (s, 3H), 1.93 (s, 3H), 1.63 (s, 9H).

[0749] Step F: terf-Butyl (R)-2',3',6'-trimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1,1'-biphenyl]-3-carboxylate. To a mixture of 5-(te / Y-butoxycarbonyl)-2',3',6'-trimethyl-[1,1'-biphenyl]-3-carboxylic acid (535 mg, 1.57 mmol) in DCM (7.9 mL) were sequentially added (R)-2-amino- / \ / -methyl-3-(4-(trifluoromethyl)phenyl)propanamide (426 mg, 1.73 mmol), DIPEA (0.81 mL, 4.71 mmol), and T3P® (50% in EtOAc, 1.35 mL, 3.14 mmol). The reaction mixture was stirred at room temperature for ~2.5 h. The reaction mixture was poured in a mixture of H2O (10 ml_), sat. sodium bicarbonate (10 ml_), and EtOAc (20 ml_). The layers were separated, and the aqueous layer was extracted with EtOAc (2x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous MgSO4, filtered, and concentrated. Purification of the resulting residue by chromatography (FCC, silica gel, 0-5% MeOH(+5%NH4OH) / EtOAc) yielded the title compound as an off-white foam. MS (ESI): mass calculated for C32H35F3N2O4, 568.3; m / z measured, 569.0 [M+H]+.1H NMR (400 MHz, CDCI3) 58.34 (s, 1H), 7.95 (s, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 7.8 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 7.1-7.2 (m, 1 H), 7.0-7.1 (m, 1 H), 6.94 (br d, J = 7.3 Hz, 1 H), 5.90 (br d, J = 1.0 Hz, 1 H), 4.8-4.9 (m, 1 H), 3.27 (br d, J = 7.8 Hz, 2H), 2.77 (d, J = 4.9 Hz, 3H), 2.32 (s, 3H), 1.96 (d, J = 2.9 Hz, 3H), 1.92 (d, J = 2.4 Hz, 3H), 1.63 (s, 9H).

[0750] Step G: (R)-2',3',6'-Trimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid. To a solution of te / Y-butyl (R)-2',3',6'-trimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylate (708 mg, 1.25 mmol) in toluene (1 mL) was added H3PO4 (0.43 mL, 6.23 mmol) dropwise over 1.5 min. The reaction was stirred at room temperature for 49 h. The reaction mixture was diluted with EtOAc (20 mL) and poured into H2O (20 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous MgSO4, filtered, and concentrated to yield the title compound as a light orange powder. MS (ESI): mass calculated for C28H27F3N2O4, 512.2; m / z measured, 511.1 [M-H]+.1H NMR (400 MHz, CDCI3) 59.60 (br d, J = 8.8 Hz, 1H), 9.20 (s, 1H), 8.1-8.2 (m, 2H), 7.58 (d, J = 7.8 Hz, 2H), 7.47 (d, J = 7.8 Hz, 2H), 7.1-7.2 (m, 1H), 7.0-7.1 (m, 1H), 6.5-6.7 (m, 1H), 5.1-5.2 (m, 1H), 3.48 (dd, J= 9.0, 13.5 Hz, 1H), 3.3-3.4 (m, 1H), 2.78 (d, J = 4.9 Hz, 3H), 2.32 (d, J = 6.8 Hz, 3H), 1.97 (dd, J= 17.6, 19.6 Hz, 6H).

[0751] Intermediate F: (R)-2'-(Methoxymethyl)-3',6'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylic acid

[0752]

[0753] Step A: 2-lodo-3,6-dimethylbenzoic acid. To a solution of 2,5-dimethylbenzoic acid (10 g, 66.59 mmol) and NIS (18 g, 79.9 mmol) in anhydrous DMF (100 ml_) was added Pd(OAc)2 (1.5 g, 6.66 mmol) under N2. The reaction mixture was heated to 100°C and stirred for 16 h. Upon completion, H2O (150 mL) was added, and the mixture was extracted with EtOAc (3x150 mL). The combined extracts were washed with brine (200 mL), dried over Na2SO4, and concentrated. The resultant residue was purified by flash column chromatography (silica, 0-70% EtOAc in petroleum ether) to yield the title compound as a solid.

[0754] Step B: (2-lodo-3,6-dimethylphenyl) methanol. To a solution of 2-iodo-3,6-dimethylbenzoic acid (20 g, 72.45 mmol) in anhydrous THF (200 mL) was added borane THF complex (1M, 217 mL, 217 mmol) dropwise at 0°C under N2. After addition, the solution was heated to 60°C and stirred for 16 h. Upon completion, MeOH (50 mL) was added dropwise, and the reaction was stirred at room temperature for 30 min. Next, H2O (300 mL) was added, and the mixture was extracted with EtOAc (500 mL x 2). The combined organic extracts were washed with brine (300 mL), dried over Na2SO4, and concentrated. The resulting residue was purified by flash column chromatography (silica, 0-30% EtOAc in petroleum ether) to yield the title compound as a solid.

[0755] Step C: 2-lodo-3-(methoxymethyl)-1,4-dimethylbenzene. To a solution of (2-iodo-3,6-dimethylphenyl) methanol (9 g, 34.34 mmol) in anhydrous THF (200 mL) was added NaH (60% w / w, 2.06 g, 51.51 mmol) in small portions at 0°C, and the resulting mixture was then stirred for 30 min before methyl iodide (4.5 mL, 72.11 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 16 h. Upon completion, sat. aq. NH4CI (150 mL) was added, and the mixture was extracted with EtOAc (200 mL x2). The combined organic extracts were washed with brine (150 ml_), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography (SiO2, 0-20% EtOAc in petroleum ether) to yield 2-iodo-3-(methoxymethyl)-1,4-dimethylbenzene as an oil.

[0756] Step D: te / Y-Butyl (R)-3-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

[0757]

[0758] A suspension of te / Y-butyl (R)-3-bromo-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)benzoate (2 g, 3.8mmol), bis(pinacolato)diboron (1.44 g, 5.67 mmol), KOAc (1.48 g, 15.1 mmol), and Pd(dppf)Cl2 (276 mg, 0.380 mmol) in 1,4-dioxane (30 mL) under N2 was heated to 90°C for 16 h. The reaction mixture was cooled to room temperature before H2O (30 mL) was added, and the resulting mixture was extracted with EtOAc (2x50 mL). The combined extracts were washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. The resultant residue was purified by flash column chromatography (silica, 0-100% EtOAc in petroleum ether) to yield the title compound as a solid. MS (ESI): mass calculated for C29H36BF3N2O6, 576.3; m / z found, 577.3 [M+H]+.

[0759] Step E: te / Y-butyl (R)-2'-(methoxymethyl)-3',6'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-bi pheny l]-3-carboxylate. A suspension of te / Y-butyl (R)-3-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.0 g, 1.74 mmol), 2-iodo-3-(methoxymethyl)-1,4-dimethylbenzene (574.8 mg, 2.08 mmol), Pd-118 (113.1 mg, 0.17 mmol), and Na2COs (551.6 mg, 5.21 mmol) in 4:1 1,4-dioxane: H2O (20 mL) was heated to 60°C and stirred under N2 for 16 h. The reaction mixture was cooled to room temperature before H2O (20 mL) and EtOAc (30 ml_) were added, and the mixture was filtered over Celite®. The layers were separated, and the aqueous layer was extracted with EtOAc (2x30 mL). The combined extracts were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The resultant residue was purified by flash column chromatography (silica gel, 0-100% EtOAc in petroleum ether) to yield the title compound as a solid. MS (ESI): mass calculated for C33H37-F3N2O5, 598.3; m / z measured, 621.1 [M+Na]+.

[0760] Step F: (R)-2'-(Methoxymethyl)-3',6'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid. To a solution of terf-butyl (R)-2'-(methoxymethyl)-3',6'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylate (630 mg, 1.052 mmol) in DCM (6 mL) was added TFA (6 mL). The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated under vacuum to yield the title compound as an oil. MS (ESI): mass calculated for C29H29-F3N2O5, 542.2; m / z measured, 543.4 [M+H]+.

[0761] Intermediate G: 2'-(Hydroxymethyl)-3',6'-dimethyl-5-((1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylic acid

[0762]

[0763] Step A: Dimethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isophthalate. A suspension of dimethyl 5-bromoisophthalate (2 g, 7.32 mmol), bis(pinacolato)diboron (2.79 g, 10.99 mmol), KOAc (2.88 g, 29.30 mmol), and Pd(dppf)Cl2 (535.9 mg, 0.73 mmol) in 1,4-dioxane (50 mL) under IX was heated to 100°C for 16 h. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10% ethyl acetate with 0.1% AcOH in petroleum ether) to yield the title compound as a solid. MS (ESI): mass calculated for C16H21BO6, 320.1; m / z measured, 238.9 [M+H-82]+, 321.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ = 8.78-8.74 (m, 1H), 8.64 (d, J= 1.7 Hz, 2H), 3.95 (s, 6H), 1.37 (s, 12H).

[0764] Step B: 2-Formyl-3,6-dimethylphenyl trifluoromethanesulfonate. To a solution of 2-hydroxy-3,6-dimethylbenzaldehyde (2.0 g, 13 mmol) and DMAP (168 mg, 1.38 mmol) in DCM (38 mL) was added Et3N (5.6 mL, 40 mmol) followed by slow addition of 1,1,1-trifluoro- / V-phenyl- / V-((trifluoromethyl)sulfonyl)methanesulfonamide (7.3 g, 20 mmol) over 1 minute. The reaction mixture was then stirred at room temperature overnight, poured into a mixture of DCM and sat. aq. NaHCOs. The aqueous layer was extracted twice with DCM and the combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated. The residue was purified by column chromatography (0-30% ethyl acetate in heptane) to yield the title compound as a yellow oil. MS (ESI): mass calculated for C10H9F3O4S, 282.0; m / z measured, 283.0 [M+H]+.1H NMR (400 MHz, CDCI3) 610.41 (s, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 2.60 (s, 3H), 2.42 (s, 3H).

[0765] Step C: Dimethyl 2'-formyl-3',6'-dimethyl-[1,1'-biphenyl]-3,5-dicarboxylate. A suspension of dimethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isophthalate (2.69 g, 7.56 mmol), 2-formyl-3,6-dimethylphenyl trifluoromethanesulfonate (2.72 g, 9.076 mmol), 1, T-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride (553.4 mg, 0.756 mmol), and Na2COs (2.41 g, 22.69 mmol) in 4:1 1,4-dioxane: H2O (50 mL) was heated to 70°C and stirred under N2for 16 h. The reaction mixture was cooled to room temperature before water was added. The mixture was extracted with EtOAc (30 mL x 3), and the combined organic extracts were dried over Na2SO4 and concentrated. The resultant residue was purified by flash column chromatography (silica gel, 0-20% ethyl acetate in petroleum ether) to yield the title compound as a solid. MS (ESI): mass calculated for C19H18O5, 326.1; m / z measured, 327.1 [M+H]+.

[0766] 1H NMR (400 MHz, CDCI3) 6= 9.81 (s, 1H), 8.74 (t, J= 1.6 Hz, 1H), 8.10 (d, J= 1.7 Hz, 2H), 7.38 (d, J = 7.9 Hz, 1 H), 7.24 (d, J = 7.7 Hz, 1 H), 3.96 (s, 6H), 2.63 (s, 3H), 2.03 (s, 3H).

[0767] Step D: Dimethyl 2'-(hydroxymethyl)-3',6'-dimethyl-[1,1'-biphenyl]-3,5-dicarboxylate. To a solution of dimethyl 2’-formyl-3’-6’-dimethyl-[1,1’-biphenyl]-3,5-dicarboxylate (200 mg, 0.60 mmol) in THF (3 mL) at 0°C was added sodium borohydride (30 mg, 0.79 mmol). After addition, the mixture was warmed to room temperature and stirred for 2 h. Upon completion, sat. aq. NaHCOs (15 mL) was added slowly at 0°C and the mixture was allowed to warm to room temperature and then stirred for 10 min. The aqueous phase was extracted with ethyl acetate (15 mL x 3) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 0-55% ethyl acetate in petroleum ether) to yield the title compound as a solid. MS (ESI): mass calculated for C19H20O5, 328.1; m / z measured, 311.0 [M+H-18]+.1H NMR (400 MHz, CDCI3) 6= 8.72 (t, J= 1.6 Hz, 1H), 8.10 (d, J= 1.7 Hz, 2H), 7.21-7.14 (m, 2H), 4.36 (s, 2H), 3.96 (s, 6H), 2.49 (s, 3H), 1.97 (s, 3H).

[0768] Step E: 2'-(Hydroxymethyl)-5-(methoxycarbonyl)-3',6'-dimethyl-[1, 1 '-biphenyl]-3-carboxylic acid. Aqueous NaOH (1M, 0.51 mL) was added to a solution of dimethyl 2'-(hydroxymethyl)-3',6'-dimethyl-[1,1'-biphenyl]-3,5-dicarboxylate (195 mg, 0.48 mmol) in 1:1 THF: MeOH (5.2 mL). The reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated under vacuum and the resulting residue was resuspended in H2O (15 mL). The pH of the mixture was adjusted to pH 4 with 1 M aq. HCI, then extracted with EtOAc (20 mL x3). The extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.

[0769] Purification of the resulting residue by flash column chromatography (0-50% EtOAc with 0.1% AcOH in petroleum ether) yielded the title compound as a solid. MS (ESI): mass calculated for CisHisOs, 314.1; m / z measured, 297.0 [M+H-18]+.1H NMR (400 MHz, CDCI3) <58.76 (s, 1H), 8.15 (d, J= 1.7 Hz, 2H), 7.21-7.14 (m, 2H), 4.37 (s, 2H), 3.97 (s, 3H), 2.49 (s, 3H), 1.98 (s, 3H).

[0770] Step F: Methyl (R)-2'-(hydroxymethyl)-3',6'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-bi pheny l]-3-carboxylate. To a solution of 2'-(hydroxymethyl)-5-(methoxycarbonyl)-3',6'-dimethyl-[1,1'-biphenyl]-3-carboxylic acid (130 mg, 0.41 mmol), (R)-2-amino- / \ / -methyl-3-(4-(trifluoromethyl)phenyl)propanamide (110 mg, 0.45 mmol) and DIPEA (0.41 mL, 2.4 mmol) in DMF (3 mL) was added HATU (235 mg, 0.62 mmol). The reaction mixture was stirred at room temperature for 16 h. Water (20 mL) was added to the reaction mixture, and the resulting mixture was extracted with EtOAc (20 mL x 3). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (0-70% EtOAc in petroleum ether) to yield the title compound as a solid. MS (ESI): mass calculated for C29H29F3N2O5, 542.2; m / z measured, 525.3 [M+H-18]+.1H NMR (400 MHz, CDCI3) 6= 8.42-8.28 (m, 1H), 8.06 (s, 1H), 7.89-7.79 (m, 1H), 7.60-7.51 (m, 2H), 7.45-7.31 (m, 3H), 7.22-7.12 (m, 2H), 5.98-5.74 (m, 1H), 4.78 (qd, J= 7.0, 13.7 Hz, 1H), 4.47-4.21 (m, 2H), 3.96-3.93 (m, 3H), 3.31-3.16 (m, 2H), 2.77-2.63 (m, 3H), 2.49 (d, J = 4.6 Hz, 3H), 1.96 (d, J = 13.6 Hz, 3H).

[0771] Step G: (R)-2'-(Hydroxymethyl)-3',6'-dimethyl-5-((1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylic acid. Aqueous NaOH (1.5 M, 0.9 mL) was added to a solution of methyl (R)-2'-(hydroxymethyl)-3',6'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1,1'-biphenyl]-3-carboxylate (120 mg, 0.18 mmol) in 1:1 THF: MeOH (2 mL). The reaction mixture was stirred at room temperature for 1 h. Volatiles were evaporated under vacuum and the pH of the resulting aqueous solution was adjusted to pH 2 with 2 M aq. HCI. The resulting mixture was then extracted with EtOAc (10 mL x3). The extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the title compound as a sticky solid. MS (ESI): mass calculated for C28H27F3N2O5, 528.2; m / z measured, 551.1 [M+Na]+.

[0772] Intermediate H: 2-(4-(Methylsulfonyl)phenyl)-2,6-diazaspiro[3.3]heptane.

[0773]

[0774] Step A: A mixture of 4-bromophenyl methyl sulfone (250 mg, 1.06 mmol), tertbutyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (374 mg, 1.60 mmol), sodium tert-butoxide (153 mg, 1.60 mmol) and Xphos Pd G2 (42 mg, 0.053 mmol) in toluene (1.67 mL) was heated at 120 °C 12 hours. The resulting mixture was filtered through a pad of Celite® and the filtrate was concentrated to yield the title compound as a residue. Intermediate I: 1-(Methylsulfonyl)-4-(piperidin-4-yl)piperazine.

[0775]

[0776] Step A: tert-Butyl 4-(4-(methylsulfonyl)piperazin-1-yl)piperidine-1 -carboxylate. To a solution of 1-(methylsulfonyl)piperazine (500 mg, 3.05 mmol) in CHCl3 (25 mL) was added tert-butyl 4-oxopiperidine-1 -carboxylate (728 mg, 3.65 mmol) and AcOH (35 pL, 0.609 mmol) The reaction mixture was stirred at room temperature for 1 hour. To the resulting mixture was added NaBH(OAc)3 (1.94 g, 9.13 mmol) and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (50 ml_) and 1M aq. NaOH (10 ml_) was added. The aqueous phase was extracted with ethyl acetate (50 mL). The organic layer was separated and dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Si O2, 24 g, gradient elution: 0 -10% MeOH in DCM ) to yield a white solid. The residue was further purified by RP-HPLC (Stationary phase: Xtimate C18, 5 pm, 150 x 40 mm; Mobile phase: H2O (0.05% NH3H2O) (A) - MeCN (B), gradient elution: 28 -58% B in A over 8 min, flow rate: 60 mL / min) to yield the title compound as a white powder. MS (ESI): mass calculated for C15H29N3O4S, 347.2; m / z measured, 348.2 [M+H]+.1H NMR (400MHz, CD3OD) δ4.11 (brd, J=13.1 Hz, 2H), 3.25 - 3.19 (m, 4H), 2.83 (s, 3H), 2.77 (br s, 2H), 2.72 - 2.66 (m, 4H), 2.51 (tt, J=3.4, 11.3 Hz, 1H), 2.17 - 2.17 (m, 1H), 1.86 (brd, J=12.0 Hz, 2H), 1.45 (s, 9H), 1.38 (br dd, J=4.1, 11.9 Hz, 2H).

[0777] Step B: 1-(Methylsulfonyl)-4-(piperidin-4-yl)piperazine. To a solution of tertbutyl 4-(4-(methylsulfonyl)piperazin-1-yl)piperidine-1 -carboxylate (100 mg, 0.288 mmol) was added a mixture of HCI / 1,4-dioxane (4M, 3.60 mL, 14.4 mmol). The reaction mixture was stirred at room temperature overnight. The resulting mixture was concentrated to dryness to yield the title compound as the HCI salt.1H NMR (400MHz, DMSO-d6) £ 11.72 (br s, 1 H), 9.05 (br s, 1 H), 8.82 (br s, 1 H), 3.71 (br d, J=11.5 Hz, 1H), 3.55 (brd, J=10.8 Hz, 6H), 3.46 - 3.31 (m, 2H), 3.14 (br s, 2H), 3.01 (s, 3H), 2.95 - 2.83 (m, 2H), 2.36 - 2.21 (m, 2H), 1.94 (br d, J=10.5 Hz, 2H). Compound Synthesis Examples

[0778] Example 1: (R)-2',5'-dimethyl- / V-(1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl) propan-2 -yl)-5-(4-(3-(methylsulfonyl)propanamido)piperidine- 1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamide

[0779]

[0780] Step A. te / Y-Butyl (R)-(1-(2',5'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carbonyl)piperidin-4-yl)carbamate. To a solution of (R)-2',5'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl) propan-2 -yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylic acid (Intermediate B, 250 mg, 502.mol), tert-butyl piperidin-4-ylcarbamate (121 mg, 604,mol) and DIEA (324 mg, 2.5 mmol) in DCM (10 ml_) was added HATU (248 mg, 652.mol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with sat. aq. NH4CI (15 ml_) and then extracted with ethyl acetate (10 mL x 3). The organic layer was separated, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 75% ethyl acetate in petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C37H43F3N4O5, 680.3; m / z measured, 581.3 [M+H-100]+.1H NMR (400MHz, CDCI3) <57.76 - 7.71 (m, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.44 (s, 1H), 7.37 (d, J=8.0 Hz, 2H), 7.31 (br d, J=5.2 Hz, 1 H), 7.19 - 7.14 (m, 1 H), 7.14 - 7.08 (m, 1H), 6.99 (s, 1 H), 6.16 (br s, 1 H), 4.82 (q, J=7.4 Hz, 1 H), 4.58 (br s, 2H), 3.71 (br s, 2H), 3.27 - 3.18 (m, 2H), 3.17 - 2.88 (m, 2H), 2.70 (d, J=4.8 Hz, 3H), 2.34 (s, 3H), 2.18 (s, 3H), 2.05 - 1.87 (m, 2H), 1.44 (s, 9H);19F NMR (376MHz, CDCI3) 6 -62.45 (br s, 1 F).

[0781] Step B. R)-5-(4-Aminopiperidine-1-carbonyl)-2',5'-dimethyl- / \ / -(1-(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-bi phe ny I ]-3- carboxamide. To a mixture of tert-butyl (R)-(1-(2',5'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-bi pheny l]-3-carbonyl)piperidin-4-yl)carbamate (80 mg, 113 pmol) in DCM (2 ml_) was added 4 M HCI / 1,4-dioxane (2 ml_) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was evaporated under vacuum to yield the title compound as an off-white solid. MS (ESI): mass calculated for C32H35F3N4O3, 580.3; m / z measured, 581.2 [M+H]+.1H NMR (400MHz, DMSO-d6) <58.87 (d, J=8.5 Hz, 1H), 8.11 (br d, J=4.6 Hz, 1H), 7.86 (s, 1H), 7.81 (s, 1H), 7.65 - 7.57 (m, 2H), 7.57 -7.49 (m, 2H), 7.40 (s, 1H), 7.25 - 7.19 (m, 1H), 7.17 - 7.10 (m, 1H), 7.06 (s, 1H), 4.78 - 4.69 (m, 1 H), 4.62 - 4.34 (m, 1 H), 3.34 - 3.26 (m, 3H), 3.20 (br d, J=4.1 Hz, 2H), 3.15 - 3.02 (m, 2H), 2.92 (br s, 1H), 2.61 (d, J=4.5 Hz, 3H), 2.32 (s, 3H), 2.17 (s, 3H), 2.08 - 1.80 (m, 2H), 1.50 (br d, J=6.6 Hz, 2H);19F NMR (376MHz, DMSO-d6) < -60.74 (s, 1F).

[0782] Step C. (R)-2',5'-Dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl) propan-2-yl)-5-(4-(3-(methylsulfonyl)propanamido)piperidine-1-carbonyl)-[1,1'-biphenyl]-3-carboxamide. To a mixture of (R)-5-(4-aminopiperidine-1 -carbony l)-2', 5'-di methy \-N-( 1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1,1'-biphenyl]-3-carboxamide (68 mg, 96 pmol), 3-(methylsulfonyl)propanoic acid (18 mg, 118 pmol), and DIEA (62 mg, 480 mol) in DMF (3 ml_) was added HATU (47 mg, 124 pmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with sat. aq. NH4CI (15 ml_) and then extracted with ethyl acetate (10 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative reverse phase HPLC (Stationary phase: Boston Prime C18, 5 pm, 150 x 30 mm; Mobile phase: (0.05% NH3H2O + 10 mM 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 white solid. MS (ESI): mass calculated for C36H41F3N4O6S, 714.3; m / z measured, 715.3 [M+H]+.1H NMR (400MHz, CDCI3) <57.90 (br s, 1H), 7.85 - 7.61 (m, 2H), 7.54 (d, J=8.1 Hz, 2H), 7.49 - 7.37 (m, 3H), 7.20 - 7.14 (m, 1H), 7.13 - 7.08 (m, 1H), 7.01 (s, 1H), 6.88 - 6.55 (m, 1 H), 6.53 - 6.19 (m, 1 H), 4.92 (brd, J=7.2 Hz, 1H), 4.57 - 4.33 (m, 1H), 3.98 (br s, 1H), 3.63 (br s, 1H), 3.56 - 3.44 (m, 1H), 3.43 - 3.33 (m, 1H), 3.25 (br s, 2H), 3.11 (br s, 2H), 2.97 (s, 3H), 2.84 (br s, 1H), 2.74 (br s, 4H), 2.34 (s, 3H), 2.18 (s, 3H), 2.00 (br d, J=14.2 Hz, 1H), 1.91 - 1.73 (m, 1H), 1.55 - 1.42 (m, 1H), 1.26 (brs, 1H);19F NMR (376MHz, CDCIs) 6 -62.42 (br s, 1F).

[0783] Example 2: (R)-5-(5-(Hydroxymethyl)-4-(4-(methylsulfonyl)phenyl)-1,2,3,6-tetrahydropyridine-1 -carbony l)-2', 5'-dimethy \-N-( 1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide.

[0784]

[0785] Step A. 1-ferf-Butyl 3-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine- 1,3(2 / - / )-dicarboxylate. To a solution of 1 -terf-butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate (5 g, 19 mmol) in THF (50 mL) was added NaH (60% in mineral oil, 1.55 g, 39 mmol) at 0 °C. After stirring at 0 °C for 30 minutes, PhNTf2 (10.41 g, 29 mmol) was added to the mixture at 0 °C. The reaction mixture was stirred at room temperature for 16h. The mixture was diluted with H2O (100 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic layer was 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. MS (ESI): mass calculated for C13H18F3NO7S, 389.1; m / z measured, 334.0 [M+H-56]+.1H NMR (400MHz, CDCI3) 6 4.28 (br s, 2H), 3.84 (s, 3H), 3.63 (t, J=5.6 Hz, 2H), 2.53 (td, J=2.8, 5.5 Hz, 2H), 1.49 (s, 9H);19F NMR (376MHz, CDCI3) 6 -74.61 (s, 1F).

[0786] Step B. 1 -ferf-Butyl 3-methyl 4-(4-(methylsulfonyl)phenyl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate. Pd(dppf)Cl2 (1.24 g, 1.7 mmol) was added to a mixture of 1-tert-buty I 3-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1,3(2 / - / )-dicarboxylate (7 g, 16.9 mmol), (4-(methylsulfonyl)phenyl)boronic acid (3.72 g, 18.6 mmol) and K2CO3 (7 g, 50.7 mmol) in 1,4-dioxane / H2O (v / v, 5 / 1, 90 ml_) under N2. The reaction mixture was heated at 75 °C for 16 h, then cooled to room temperature. The mixture was filtered, and the filter cake was rinsed with ethyl acetate (50 mL). The filtrate was concentrated to dryness under vacuum. The residue was diluted with ethyl acetate (100 mL) and washed with H2O (80 mL x 2). The organic layer was dried with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 55% ethyl acetate in petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C19H25NO6S, 395.1; m / z measured, 296.1 [M+H-100]+.1H NMR (400MHz, CDCI3) <57.93 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.3 Hz, 2H), 4.29 (brs, 2H), 3.63 (t, J=5.7 Hz, 2H), 3.53 (s, 3H), 3.09 (s, 3H), 2.48 (brs, 2H), 1.52 (s, 9H).

[0787] Step C. te / Y-Butyl 3-(hydroxymethyl)-4-(4-(methylsulfonyl)phenyl)-5,6-dihydropyridine- 1 (2H)-carboxylate. NaBH4 (8 mg, 211.mol) and CaCL (12 mg, 108.mol) were added to a mixture of 1 -tert-butyl 3-methyl 4-(4-(methylsulfonyl)phenyl)-5,6-dihydropyridine-1,3(2 / - / )- dicarboxylate (70 mg, 0.177 mmol) in EtOH (1 mL) at 0 °C under N2. The mixture was stirred at room temperature for 16 h. The mixture was filtered, diluted with sat. aq. NH4CI (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by prep-TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1) to yield the title compound as a white solid. MS (ESI): mass calculated for C18H25NO5S, 367.1; m / z measured, 312.1 [M+H-56]+.1H NMR (400MHz, CDCI3) 6 = 7.93 (d, J=8.2 Hz, 2H), 7.44 (br s, 1 H), 7.41 (d, J=8.2 Hz, 1 H), 4.20 - 4.11 (m, 2H), 4.01 (s, 2H), 3.63 (t, J=5.7 Hz, 2H), 3.12 - 3.07 (m, 3H), 2.43 (br s, 2H), 1.51 (s, 9H).

[0788] Step D. (4-(4-(Methylsulfonyl)phenyl)-1,2,5,6-tetrahydropyridin-3-yl)methanol HCI. 4 M HCI / 1,4-dioxane (0.5 mL) was added to a solution of tert-Buty I 3-(hydroxymethyl)-4-(4-(methylsulfonyl)phenyl)-5,6-dihydropyridine- 1 (2 / - / )-carboxylate (45 mg, 99.mol) in DCM (1 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 solid. Step E. R)-5-(5-(Hydroxymethyl)-4-(4-(methylsulfonyl)phenyl)-1,2,3,6-tetrahydropyridine-1 -carbony l)-2', 5'-dimethy l- / \ / -( 1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1,1'-biphenyl]-3-carboxamide. To a solution of (R)-2',5'-dimethyl-5-((1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl) propan-2-yl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid (Intermediate B, 30 mg, 60 pmol), (4-(4-(methylsulfonyl)phenyl)-1,2,5,6-tetrahydropyridin-3-yl)methanol HCI (22 mg) and EtsN (18 mg, 178 mol) in DMF (1 ml_) was added HATU (30 mg, 79 mol). The mixture was stirred at room temperature for 16h. The resulting mixture was then diluted with ethyl acetate (10 mL) and washed with H2O (10 mL x 3). The organic layer was washed with brine (10 mL x 3), dried with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative reversed phase HPLC (Stationary phase: Phenomenex Gemini-NX C18, 3 pm, 75 x 30 mm; Mobile phase: H2O (0.05% NH3H2O + 10 mM NH4HCO3) (A) - MeCN (B), gradient elution: 43 -73% B in A over 6 min, flow rate: 25 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C40H40F3N3O6S, 747.3; m / z measured, 748.5 [M+H]+.1H NMR (400MHz, DMSO-d6) 68.85 (br d, J=7.0 Hz, 1H), 8.08 (br d, J=4.3 Hz, 1 H), 7.91 (br d, J=7.6 Hz, 3H), 7.84 (br s, 1 H), 7.54 (br s, 7H), 7.26 - 7.10 (m, 2H), 7.07 (br s, 1H), 5.01 (br s, 1H), 4.73 (brs, 1H), 4.48 - 4.08 (m, 2H), 3.88 (br s, 2H), 3.76 - 3.46 (m, 2H), 3.30 (s, 2H), 3.23 (s, 3H), 3.20 - 3.02 (m, 2H), 2.61 (d, J=4.5 Hz, 3H), 2.32 (s, 3H), 2.18 (br s, 3H);19F NMR (376MHz, DMSO-d6) <5-60.76 (brs, 1F).

[0789] Example 3: (R)-2',5'-dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-morpholinopiperidine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamide

[0790]

[0791] To a solution of (R)-2',5'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4- (trifl uoromethy I ) phenyl ) propan-2 -yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylic acid (Intermediate B, 30 mg, 60 pmol), 4-(piperidin-4-yl)morpholine (12 mg, 72 pmol) and DIEA (24 mg, 186 pmol) in DMF (2 mL) was added HATU (30 mg, 79 pmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with sat. aq. NH4CI (5 mL) and then extracted with ethyl acetate (5 mL x 3). The organic layer was separated, washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative reverse phase HPLC (Stationary phase: Boston Prime C18, 5 pm, 150 x 30 mm; Mobile phase: (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 white solid. MS (ESI): mass calculated for C36H41F3N4O4, 650.3; m / z measured, 651.4 [M+H]+.1H NMR (400MHz, CDCI3) 67.76 (br s, 1 H), 7.74 (s, 1 H), 7.57 (d, J=8.0 Hz, 2H), 7.47 (s, 1H), 7.39 (d, J=7.9 Hz, 2H), 7.20 - 7.16 (m, 1H), 7.15 - 7.10 (m, 1 H), 7.05 (br d, J=8.0 Hz, 1 H), 7.02 (s, 1 H), 5.84 (br s, 1 H), 4.79 (q, J=7.3 Hz, 1 H), 4.71 (br s, 1 H), 3.87 - 3.76 (m, 1 H), 3.73 (br t, J=4.4 Hz, 4H), 3.24 (d, J=7.2 Hz, 2H), 3.07 (br s, 1 H), 2.87 (br s, 1 H), 2.75 (d, J=4.8 Hz, 3H), 2.56 (br s, 4H), 2.46 (br t, J=10.8 Hz, 1H), 2.36 (s, 3H), 2.20 (s, 3H), 1.98 (brs, 1H), 1.83 (br s, 1H), 1.59 -1.44 (m, 2H);19F NMR (376MHz, CDCI3) 6 -62.48 (s, 1F).

[0792] Example 4: 5-((3*R,4*S)-3-(hydroxymethyl)-4-(4-(methylsulfonyl)phenyl)piperidine-1-carbonyl)-2',5'-dimethyl- / \ / -((R)-1 -(methylamino)-1 -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide

[0793]

[0794] Step A: 1 -ferf-Butyl 3-methyl 4-(4-(methylsulfonyl)phenyl)piperidine-1,3-dicarboxylate. Pd / C (538 mg, 10%) was added to a solution of 1 -tert-butyl 3-methyl 4-(4-(methylsulfonyl)phenyl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (Example 2, Step B, 1 g, 2.5 mmol) in MeOH (80 mL). The mixture was degassed and purged with H2 three times. The mixture was stirred at room temperature under H2 (50 psi) overnight. The suspension was filtered through a pad of Celite® and the solid was washed with MeOH (50 m L_ x 2). The filtrate was concentrated to dryness under reduced pressure to yield the title compound as yellow solid. MS (ESI): mass calculated for C19H27NO6S, 397.2; m / z measured, 342.1 [M+H-56]+.

[0795] Step B: 1 -(te / Y-Butoxycarbonyl)-4-(4-(methylsulfonyl)phenyl)piperidine-3-carboxylic acid. 1 M aq. NaOH (3 ml_) was added to a solution of 1 -terf-butyl 3-methyl 4-(4-(methylsulfonyl)phenyl)piperidine-1,3-dicarboxylate (820 mg, 1.51 mmol) in THF / MeOH (v / v, 1 / 1, 10 mL). The mixture was stirred at room temperature for 16h. The solvent was removed in vacuo. The resulting residue was diluted with H2O (15 mL), then 1 M aq. HCI was added to adjust to pH 4, and the aqueous layer was extracted with ethyl acetate (20 mL x 3). The organic layer was dried with Na2SO4, filtered, and concentrated under vacuum to yield the title compound as a yellow solid. MS (ESI): mass calculated for C18H25NO6S, 383.1; m / z measured, 284.1 [M+H-100]+.

[0796] Step C: te / Y-Butyl 3-(hydroxymethyl)-4-(4-(methylsulfonyl)phenyl)piperidine-1-carboxylate. BH3 (1 M solution in THF, 10 mL, 10 mmol) was added to the mixture of 1 -(te / Y-butoxycarbonyl)-4-(4-(methylsulfonyl)phenyl)piperidine-3-carboxylic acid (900 mg) in THF (20 mL) at 0°C under N2. The resulting mixture was stirred at 60 °C for 2 hours and then cooled down to room temperature. The reaction was quenched with MeOH (15 mL). The resulting mixture was concentrated under vacuum to yield the title compound as a yellow solid. MS (ESI): mass calculated for C18H27NO5S, 369.2; m / z measured, 314.1 [M+H-56]+.

[0797] Step D. (4-(4-(Methylsulfonyl)phenyl)piperidin-3-yl)methanol HCI. To a mixture of tert-buty I 3-(hydroxymethyl)-4-(4-(methylsulfonyl)phenyl)piperidine-1 -carboxylate (200 mg) in DCM (5 mL) was added 4 M HCI / 1,4-dioxane (2.5 mL) at room temperature. The mixture was stirred at room temperature for 16h. The mixture was then concentrated under vacuum to yield the title compound as a yellow solid.

[0798] Step E: 5-((*trans)-3-(Hydroxymethyl)-4-(4-(methylsulfonyl)phenyl)piperidine-1 -carbonyl)- 2',5'-dimethyl- / \ / -((R)-1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1,1'-biphenyl]-3-carboxamide. To a solution of (R)-2',5'-dimethyl-5-((1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl) propan-2-yl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid (Intermediate B, 240 mg, 481 mol), (4-(4-(methylsulfonyl)phenyl)piperidin-3-yl)methanol HCI (170 mg, 556 pmol ) and Et3N (146 mg, 1.44 mmol) in DMF (10 mL) was added HATU (238 mg, 626 pmol). The mixture was stirred at room temperature overnight. The mixture was then diluted with ethyl acetate (40 mL) and washed with H2O (30 mL x 3). The organic layer was dried with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative reverse phase HPLC (Stationary phase: Xtimate C18, 5 pm, 150 x 40 mm; Mobile phase: H2O (0.05% NH3H2O) (A) - MeCN (B), gradient elution: 46 -76% B in A over 8 min, flow rate: 60 mL / min) to yield the title compound as the first eluting compound (retention time, 2.030 min) MS (ESI): mass calculated for C40H42F3N3O6S, 749.3; m / z measured, 750.2 [M+H]+.1H NMR (400MHz, DMSO-d6) 5 8.83 (br d, J=8.3 Hz, 1H), 8.10 (br s, 1H), 7.91 - 7.77 (m, 4H), 7.65 - 7.43 (m, 7H), 7.25 - 7.18 (m, 1 H), 7.17 - 7.09 (m, 1H), 7.06 (br s, 1H), 4.85 (brd, J=11.6 Hz, 1H), 4.77 - 4.69 (m, 1 H), 4.64 (br s, 1 H), 4.44 (br s, 1 H), 4.02 - 3.83 (m, 1 H), 3.22 (br s, 1H), 3.18 (s, 3H), 3.17 - 3.14 (m, 1H), 3.12 - 3.03 (m, 2H), 3.00 - 2.71 (m, 3H), 2.61 (d, J=4.3 Hz, 3H), 2.31 (s, 3H), 2.16 (s, 3H), 1.95 (br s, 1H);19F NMR (376MHz, DMSO-d6) 5-52.00 - -68.99 (m, 1F); and 5-((c / s)-3-(hydroxymethyl)-4-(4-(methylsulfonyl)phenyl) piperidi ne- 1 -carbonyl)-2',5'-dimethyl- / V-((R)-1 -(methylamino)-1-oxo-3-(4-(trifluoromethyl) phenyl)propan-2-yl)-[1,1'-biphenyl]-3-carboxamide as the second eluting compound.

[0799] Step F: 5-((3*R,4*S)-3-(Hydroxymethyl)-4-(4-(methylsulfonyl)phenyl)piperidine-1-carbonyl)-2',5'-dimethyl- / \ / -((R)-1 -(methylamino)-1 -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide. 5-((*trans)-3-(hydroxymethyl)-4-(4-(methylsulfonyl)phenyl)piperidine-1-carbonyl)-2',5'-dimethyl- / V-((R)-1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1,1'-biphenyl]-3-carboxamide (220 mg, 293.40 pmol) was separated by SFC:

[0800] (Column: DAICEL CHIRALPAK IC 250 x 30 mm, 10 pm; mobile phase: CO2 (A) -EtOH (0.1% NH3H2O) (B); isocratic: 55% B in A; flow rate: 80 mL / min; column temp.: 40 °C; ABPR: 100 bar.) to yield the title compound as the first eluting compound (retention time, 2.006 min). MS (ESI): mass calculated for C40H42F3N3O6S, 749.3; m / z measured, 750.3 [M+H]+.1H NMR (400MHz, CDCI3) 67.93 (br d, J=7.0 Hz, 2H), 7.85 - 7.69 (m, 2H), 7.55 (br d, J=7.9 Hz, 2H), 7.48 (br d, J=7.0 Hz, 2H), 7.36 (br s, 3H), 7.22 - 7.16 (m, 1H), 7.16 - 7.11 (m, 1H), 7.11 - 6.98 (m, 1H), 5.97 (br s, 1H), 4.84 (br s, 2H), 4.51 (br d, J=12.0 Hz, 1H), 3.50 (br s, 2H), 3.19 (br s, 4H), 3.09 (br s, 3H), 3.02 - 2.80 (m, 2H), 2.72 (br s, 3H), 2.36 (s, 3H), 2.24 (brs, 4H), 2.11 - 1.78 (m, 2H);19F NMR (376MHz, CDCI3) 6 -62.48 (br s, 1F); and 5-((3*S,4*R)-3-(hydroxymethyl)-4-(4-(methylsulfonyl)phenyl)piperidine-1-carbonyl)-2',5'-dimethyl- / \ / -((R)-1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl) propan-2-yl)-[1, 1 '-bi pheny I]-3-carboxamide (Example 5) as the second eluting compound (retention time, 3.350 min).

[0801] Example 5: 5-((3*S,4*R)-3-(hydroxymethyl)-4-(4-(methylsulfonyl)phenyl)piperidine-1-carbonyl)-2',5'-dimethyl- / \ / -((R)-1 -(methylamino)-1 -oxo-3-(4-(trifluoromethyl)phenyl) propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide

[0802]

[0803] The title compound was isolated from SFC purification of Example 4. MS (ESI): mass calculated for C40H42F3N3O6S, 749.3; m / z measured, 750.3 [M+H]+.1H NMR (400MHz, CDCI3) 68.07 - 7.83 (m, 2H), 7.83 - 7.65 (m, 3H), 7.57 (br s, 3H), 7.46 (br d, J=7.7 Hz, 2H), 7.37 (br d, J=6.9 Hz, 2H), 7.22 - 7.10 (m, 2H), 7.05 (br s, 1 H), 6.14 - 5.85 (m, 1 H), 5.05 - 4.73 (m, 2H), 4.53 (br s, 1 H), 3.47 (br s, 1 H), 3.20 (br d, J=6.8 Hz, 5H), 3.09 (br s, 3H), 2.95 (br d, J=11.4 Hz, 3H), 2.71 (br s, 3H), 2.35 (s, 3H), 2.23 (br s, 3H), 2.10 - 1.87 (m, 1H);19F NMR (376MHz, CDCI3) 6 -62.45 (br s, 1F).

[0804] Example 6: 5-((3*R,4*R)-3-(hydroxymethyl)-4-(4-(methylsulfonyl)phenyl)piperidine-1-carbonyl)-2',5'-dimethyl- / \ / -((R)-1 -(methylamino)-1 -oxo-3-(4-(trifluoromethyl)phenyl) propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide

[0805]

[0806] Step A: 5-((*c / s)-3-(Hydroxymethyl)-4-(4-(methylsulfonyl)phenyl)piperidine-1 -carbonyl)-2',5'-dimethyl- / V-((R)-1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide. 5-((*c / s)-3-(hydroxymethyl)-4-(4-(methylsulfonyl)phenyl)piperidine-1-carbonyl)-2',5'-dimethyl- / \ / -((R)-1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-bi pheny I]-3-carboxamide was isolated from the preparative reverse phase HPLC purification of Example 4, Step E and was further purified by preparative reverse phase HPLC (Stationary phase: Phenomenex Gemini-NX C18, 5 pm, 75 x 30 mm; Mobile phase: water (0.05% NH3H2O + 10 mM NH4HCO3) (A) - MeCN (B), gradient elution: 45 -75% B in A over 6 min, flow rate: 25 mL / min) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C40H42F3N3O6S, 749.3; m / z measured, 750.2 [M+H]+.1H NMR (400MHz, CDCI3) 68.43 - 8.03 (m, 1 H), 7.99 - 7.84 (m, 3H), 7.84 -7.64 (m, 2H), 7.60 - 7.42 (m, 3H), 7.41 - 7.27 (m, 3H), 7.22 - 6.98 (m, 3H), 6.73 -6.40 (m, 1H), 5.05 - 4.75 (m, 2H), 4.49 - 4.23 (m, 1H), 4.12 - 3.70 (m, 1H), 3.62 -3.15 (m, 4H), 3.11 (br s, 3H), 3.09 - 2.80 (m, 2H), 2.78 - 2.56 (m, 3H), 2.34 (br s, 3H), 2.29 - 2.16 (m, 3H), 2.15 - 1.90 (m, 3H);19F NMR (376MHz, CDCI3) 6 -62.36 (br d, J=76.3 Hz, 1F).

[0807] Step B: 5-((3*R,4*R)-3-(Hydroxymethyl)-4-(4-(methylsulfonyl)phenyl)piperidine-1-carbonyl)-2',5'-dimethyl- / \ / -((R)-1 -(methylamino)-1 -oxo-3-(4-(trifluoromethyl)phenyl) propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide. 5-((*c / s)-3-(hydroxymethyl)-4-(4-(methylsulfonyl)phenyl)piperidine-1-carbonyl)-2',5'-dimethyl- / V-((R)-1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1,1'-biphenyl]-3-carboxamide (35 mg, 46.7 mol) was separated by SFC: (Column: DAICEL CHIRALPAKAD 250 x 30 mm, 10 pm; mobile phase: CO2(A) - EtOH (0.1% NH3H2O) (B); isocratic: 40% B in A; flow rate: 60 mL / min; column temp.: 40 °C; ABPR: 100 bar.) to yield the title compound as the first eluting compound (retention time, 1.467 min). MS (ESI): mass calculated for C40H42F3N3O6S, 749.3; m / z measured, 750.3 [M+H]+.1H NMR (400MHz, CDCl3) δ 8.27 (br d, J=7.7 Hz, 1H), 8.04 - 7.83 (m, 3H), 7.69 (br s, 2H), 7.61 - 7.50 (m, 2H), 7.39 (br d, J=7.9 Hz, 2H), 7.29 (br s, 2H), 7.23 - 7.04 (m, 3H), 6.07 (br s, 1 H), 4.97 (br d, J=12.6 Hz, 2H), 4.32 (br d, J=13.0 Hz, 1H), 3.79 (br s, 1H), 3.68 - 3.37 (m, 1H), 3.17 (br d, J=19.8 Hz, 4H), 3.12 (s, 3H), 3.11 - 3.01 (m, 1H), 2.88 (brt, J=12.0 Hz, 1H), 2.82 - 2.64 (m, 3H), 2.35 (s, 3H), 2.25 (s, 3H), 2.16 - 1.91 (m, 2H);19F NMR (376MHz, CDCI3) 6 = -62.27 (s, 1F); and 5-((3*S,4*S)-3-(hydroxymethyl)-4-(4-(methylsulfonyl)phenyl)piperidine-1-carbonyl)-2',5'-dimethyl- / \ / -((R)-1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1,1'-biphenyl]-3-carboxamide (Example 7) as the second eluting compound (retention time, 2.475 min).

[0808] Example 7: 5-((3*S,4*S)-3-(hydroxymethyl)-4-(4-(methylsulfonyl)phenyl)piperidine-1-carbonyl)-2',5'-dimethyl- / \ / -((R)-1 -(methylamino)-1 -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide

[0809]

[0810] The title compound was isolated from the SFC purification of Example 6, Step B. MS (ESI): mass calculated for C40H42F3N3O6S, 749.3; m / z measured, 750.3 [M+H]+.1H NMR (400MHz, CDCl3) δ 8.09 - 7.87 (m, 3H), 7.83 (s, 1 H), 7.76 (s, 1 H), 7.53 (br d, J=8.1 Hz, 2H), 7.49 - 7.34 (m, 3H), 7.30 (br d, J=7.9 Hz, 2H), 7.23 - 7.04 (m, 3H), 5.79 (brs, 1H), 5.05 - 4.77 (m, 2H), 4.73 (br s, 1H), 4.46 (brd, J=13.8 Hz, 1H), 4.09 (brt, J=10.3 Hz, 1H), 3.67 - 3.16 (m, 4H), 3.13 (s, 3H), 3.08 - 2.84 (m, 2H), 2.80 - 2.58 (m, 3H), 2.36 (s, 3H), 2.26 (s, 3H), 2.18 - 1.89 (m, 2H);19F NMR (376MHz, CDCI3) 6 -62.49 (br s, 1 F).

[0811] Example 8: 5-((3*S,4*S)-3-Hydroxy-4-(4-(methylsulfonyl)phenyl)piperidine-1 -carbonyl)-2',5'-dimethyl- / \ / -((R)-1 -(methylamino)-l -oxo-3-(4- (trifl uoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide

[0812]

[0813] Step A: 4-(4-(Methylsulfonyl)phenyl)pyridin-3-ol. To a mixture of 4-bromopyridin-3-ol (3 g, 17 mmol) in 1,4-dioxane / H2O (v / v, 5 / 1, 60 ml_) was added (4-(methylsulfonyl)phenyl)boronic acid (4.14 g, 21 mmol) and K2CO3 (7.15 g, 52 mmol) at room temperature. The mixture was degassed with N2, then Pd(dppf)Cl2 (1.26 g, 1.72 mmol) added. The reaction mixture was stirred at 85 °C for 12 hours under N2. The mixture was diluted with H2O (30 ml_) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and evaporated 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 brown solid. MS (ESI): mass calculated for C12H11NO3S, 249.0; m / z measured, 249.9 [M+H]+.1H NMR (400MHz, DMSO-d6) 610.36 (br s, 1 H), 8.33 (s, 1 H), 8.15 (d, J=5.0 Hz, 1 H), 8.01 (d, J=8.5 Hz, 2H), 7.94 - 7.86 (m, 2H), 7.38 (d, J=4.8 Hz, 1 H), 3.27 (s, 3H).

[0814] Step B: 4-(4-(Methylsulfonyl)phenyl)piperidin-3-ol. Pd / C (2.78 g, 10% w / w) was added to a mixture of 4-(4-(methylsulfonyl)phenyl)pyridin-3-ol (1.3 g, 5.2 mmol) and acetic acid (63 mg, 1.1 mmol) in THF (50 mL). The mixture was stirred under H2 (50 psi) at 60 °C for 16h. The resulting mixture was filtered and the filtrate was concentrated in vacuo to yield the title compound as yellow solid.

[0815] Step C: 5-(3-Hydroxy-4-(4-(methylsulfonyl)phenyl)piperidine-1 -carbonyl)-2',5'-dimethyl- / V-((R)-1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3- carboxamide. To a solution of (R)-2',5'-dimethyl-5-((1-(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl) propan-2-yl)carbamoyl)-[1, 1 biphenyl]-3-carboxylic acid (Intermediate B, 75 mg, 150.mol), 4-(4-(methylsulfonyl)phenyl)piperidin-3-ol and HATU (74 mg, 195.mol) in DMF (10 mL) was added EtsN (91 mg, 899 pmol). The reaction mixture was stirred at room temperature for 16h. The mixture was diluted with H2O (30 ml_), and extracted with ethyl acetate (100 mL x 3). The combined organic layer was dried with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative reverse phase HPLC (Stationary phase: Xtimate C18, 5 pm, 150 x 40 mm; Mobile phase: H2O (0.05% NH3H2O) (A) - MeCN (B), gradient elution: 46 -76% B in A over 8 min, flow rate: 60 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C39H40F3N3O6S, 735.3; m / z measured, 736.2 [M+H]+.1H NMR (400MHz, CDCl3) δ 7.94 (d, J=8.0 Hz, 2H), 7.88 - 7.76 (m, 2H), 7.61 - 7.47 (m, 5H), 7.40 (br d, J=7.8 Hz, 2H), 7.32 - 7.29 (m, 1H), 7.23 - 7.13 (m, 2H), 7.05 (s, 1H), 5.92 (br d, J=4.0 Hz, 1 H), 5.10 - 4.73 (m, 2H), 4.16 - 3.70 (m, 2H), 3.25 (br d, J=6.5 Hz, 2H), 3.08 (s, 3H), 3.03 - 2.79 (m, 2H), 2.76 (d, J=4.8 Hz, 3H), 2.37 (s, 3H), 2.23 (s, 3H), 1.85 (brs, 1H), 1.40 - 1.13 (m, 2H);19F NMR (376MHz, CDCI3) 6 -62.46 (s, 1F).

[0816] Step D: 5-((3*S,4*S)-3-Hydroxy-4-(4-(methylsulfonyl)phenyl)piperidine-1 -carbonyl)- 2', 5'-di methy l-A / -((R)-1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)- [1,1 '-biphenyl]-3-carboxamide. 5-(3-hydroxy-4-(4-(methylsulfonyl)phenyl)piperidine-1-carbonyl)-2',5'-dimethyl- / \ / -((R)-1-(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-bi phe ny I ]-3-carboxamide (75 mg, 102 pmol) was separated by SFC (Column: DAICEL CHIRALPAKAD (250 mm x 30 mm, 10 pm)); Mobile phase: CO2 (A) - EtOH (0.1% NH3H2O) (B), gradient elution: 50% B in A at 80 mL / min) to yield the title compound as the first eluting compound (retention time, 3.167 min). MS (ESI): mass calculated for C39H40F3N3O6S, 735.3; m / z measured, 736.2 [M+H]+.1H NMR (400MHz, CDCI3) 6 8.00 - 7.72 (m, 4H), 7.50 (br d, J=7.8 Hz, 5H), 7.39 (br d, J=7.8 Hz, 2H), 7.22 -7.17 (m, 1H), 7.16 - 7.11 (m, 1H), 7.03 (br s, 1H), 6.14 (br s, 1H), 5.08 - 4.52 (m, 3H), 4.14 - 3.73 (m, 2H), 3.25 (br s, 3H), 3.07 (br s, 3H), 3.02 - 2.78 (m, 2H), 2.78 -2.62 (m, 4H), 2.36 (s, 3H), 2.21 (br s, 3H), 1.83 (br s, 1H);19F NMR (376MHz, CDCl3) δ -62.46 (br s, 1F).

[0817] Example 9: 5-((3*R,4*R)-3-Hydroxy-4-(4-(methylsulfonyl)phenyl)piperidine-1 -carbonyl)-2',5'-dimethyl- / \ / -((R)-1 -(methylamino)-l -oxo-3-(4- (trifl uoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide

[0818]

[0819] 5-(3-Hydroxy-4-(4-(methylsulfonyl)phenyl)piperidine-1-carbonyl)-2',5'-dimethyl- / \ / -((R)-1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1,1'-biphenyl]-3-carboxamide (75 mg, 102 pmol) was separated by SFC (Column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 pm)); Mobile phase: CO2(A) - EtOH (0.1% NH3H2O) (B), gradient elution: 50% B in A at 80 mL / min) to yield the title compound as the second eluting compound (retention time, 4.720 min). MS (ESI): mass calculated for C39H40F3N3O6S, 735.3; m / z measured, 736.3 [M+H]+.1H NMR (400MHz, CDCl3) δ 7.92 (br d, J=7.8 Hz, 2H), 7.84 (s, 1 H), 7.79 (br s, 1 H), 7.57 (br d, J=8.0 Hz, 2H), 7.50 (br d, J=8.0 Hz, 2H), 7.39 (br d, J=6.8 Hz, 2H), 7.21 - 7.17 (m, 1H), 7.16 - 7.11 (m, 1H), 7.03 (brs, 1H), 6.08 (br s, 1H), 5.10 - 4.70 (m, 2H), 4.14 -3.69 (m, 2H), 3.24 (br d, J=5.5 Hz, 3H), 3.07 (s, 3H), 2.95 - 2.79 (m, 2H), 2.74 (br d, J=4.3 Hz, 4H), 2.36 (s, 3H), 2.22 (s, 3H), 2.08 - 1.78 (m, 1H);19F NMR (376 MHz, CDCI3) <5 -62.44 (s, 1F).

[0820] Example 10: (R9-2',5'-Dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(3-(trifluoromethyl)-1 / - / -pyrazol-5-y I ) pi peri d i n e- 1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamide

[0821]

[0822] Step A: 4,4,4-Trifluoro-1-(pyridin-4-yl)butane-1,3-dione. To a solution of 1-(pyridin-4-yl)ethanone (2 g, 16.5 mmol) in DMF (20 mL) was added NaH (60% in mineral oil, 1.3 g, 32.5 mmol) in portions at 0 °C. After stirring at room temperature for 0.5 hour, a solution of ethyl 2,2,2-trifluoroacetate (2.82 g, 19.9 mmol) in DMF (5 ml_) was added slowly at 0 °C. The reaction mixture was stirred at room temperature for 5 hours. The mixture was quenched with sat. aq. NH4CI (15 ml_) and then extracted with ethyl acetate (30 mL x 2). The combined extracts 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 - 100% ethyl acetate in petroleum ether) to yield the title compound as a colorless oil. MS (ESI): mass calculated for C9H6F3NO2, 217.0; m / z measured, 217.7 [M+H]+.

[0823] 1H NMR (400MHz, DMSO-d6) 6 = 8.62 (brd, J=4.5 Hz, 2H), 7.63 (br s, 2H), 5.82 (br s, 1 H);19F NMR (376MHz, DMSO-d6) 6 = -74.56 (br s, 1 F).

[0824] Step B:4-(3-(Trifluoromethyl)-1 / - / -pyrazol-5-yl)pyridine. Hydrazine hydrate (570 mg, 11.2 mmol) was added slowly to a solution of 4,4,4-trifluoro-1-(pyridin-4-yl)butane-1,3-dione (500 mg, 2.3 mmol) in EtOH (10 mL) at 0 °C. The reaction mixture was stirred at 80 °C for 16 hours, then cooled to room temperature. The mixture was quenched with sat. aq. NH4CI (10 mL) and then extracted with ethyl acetate (30 mL x 3). The combined extracts were washed with brine (20 mL), dried with 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 colorless oil. MS (ESI): mass calculated for C9H6F3N3, 213.1; m / z measured, 213.8 [M+H]+.1H NMR (400MHz, DMSO-d6) 6= 14.46 (br s, 1H), 8.69 (br d, J=5.5 Hz, 2H), 7.82 (d, J=5.6 Hz, 2H), 7.49 (s, 1H);19F NMR (376MHz, DMSO-d6) 6 = -60.53 (s, 1F).

[0825] Step C. 4-(3-(Trifluoromethyl)-1 / - / -pyrazol-5-yl)piperidine. To a solution of 4-(3-(trifluoromethyl)-1 / - / -pyrazol-5-yl)pyridine (150 mg, 656.mol) in EtOH (4 mL) was added wet PtO2 (100 mg) and concentrated HCI (15 p. L) under N2. The reaction mixture was degassed in vacuo and purged with H2 several times and stirred under H2 (15 psi) at room temperature overnight. The mixture was filtered through a pad of Celite®, and the filter cake was rinsed with MeOH (20 mL x 2). The filtrate was concentrated to dryness in vacuo to yield the title compound as a colorless oil. MS (ESI): mass calculated for C9H12F3N3, 219.1; m / z measured 219.8 [M+H]+. Step D. (R)-2',5'-Dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan- 2-yl)-5-(4-(3-(trifluoromethyl)-1H-pyrazol-5-yl)piperidine-1-carbonyl)-[1,1'-biphenyl]-3- carboxamide. To a mixture of (R)-2',5'-dimethyl-5-((1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl) propan-2-yl)carbamoyl)-[1, T-biphenyl]-3-carboxylic acid (Intermediate B, 50 mg, 100 pmol), HATU (76 mg, 200 pmol) and DIEA (28 mg, 217 pmol) in DMF (3 mL) was added 4-(3-(trifluoromethyl)-1 / - / -pyrazol-5-yl)piperidine (50 mg). The mixture was stirred at room temperature for 2 hours, then quenched with H2O (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was purified by preparative reverse phase HPLC (Stationary phase: Welch Xtimate C18, 5 pm, 150 x 25 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 60 - 90% B inA over 7 min, flow rate: 25 mL / min) to yield the title compound as an off-white solid. MS (ESI): mass calculated for C36H35F6N5O3, 699.3; m / z measured, 700.2 [M+H]+.1H NMR (400MHz, DMSO-d6) 6 13.43 (br s, 1 H), 8.84 (br d, J=8.6 Hz, 1 H), 8.09 (br d, J=4.9 Hz, 1 H), 7.82 (d, J=1.4 Hz, 2H), 7.61 - 7.52 (m, 4H), 7.48 (s, 1H), 7.24 - 7.20 (m, 1H), 7.13 (d, J=8.0 Hz, 1 H), 7.06 (s, 1 H), 6.55 (s, 1 H), 4.78 - 4.70 (m, 1 H), 4.53 (br s, 1 H), 3.63 (br s, 1 H), 3.20 (br dd, J=4.0, 13.6 Hz, 2H), 3.05 (br d, J=13.2 Hz, 2H), 2.69 - 2.65 (m, 1H), 2.61 (d, J=4.5 Hz, 3H), 2.32 (s, 3H), 2.17 (s, 4H), 1.64 (brs, 2H);19F NMR (376MHz, DMSO-d6) 6 -60.23 (s, 1F), -60.78 (s, 1F).

[0826] Example 11: (R)-5-(4-(6-(Cyanomethyl)pyridin-3-yl)piperidine-1 -carbonyl)-2',5'-dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide

[0827]

[0828] Step A: te / Y-Butyl 4-(6-(cyanomethyl)pyridin-3-yl)piperidine-1 -carboxylate. To a mixture of 2-(5-bromopyridin-2-yl)acetonitrile (300 mg, 1.5 mmol), potassium (1-(tert-butoxycarbonyl)piperidin-4-yl)trifluoroborate (532 mg, 1.80 mmol), 2,6-lutidine (245 mg, 2.30 mmol), NiCl2*glyme (10 mg, 46 pmol ) and 4,4'-di-tert-butyl-2,2'-dipyridyl (12 mg, 45 pmol) in 1,4-dioxane (3 ml_) was added lr(df(CFs)ppy)2(dtbpy)PF6 (103 mg, 92.0 pmol) in the glovebox. The mixture was stirred at 25 °C overnight under LED (4x blue Kessil). The mixture was filtered through a pad of Celite®, and the filter cake was washed with ethyl acetate (30 mL). The filtrate was concentrated to dryness in vacuo. The residue was purified by preparative reverse phase 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 a yellow solid. MS (ESI): mass calculated for C17H23N3O2, 301.2; m / z measured, 245.8 [M+H-56]+.1H NMR (400MHz, CDCl3) δ 8.46 (d, J=2.0 Hz, 1H), 7.58 (dd, J=2.2, 8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 4.27 (s, 2H), 3.93 (s, 2H), 2.83 (t, J=11.6 Hz, 2H), 2.72 (tt, J=3.5, 12.2 Hz, 1H), 1.84 (d, J=13.4 Hz, 2H), 1.70 - 1.60 (m, 2H), 1.49 (s, 9H).

[0829] Step B: 2-(5-(Piperidin-4-yl)pyridin-2-yl)acetonitrile HCI. 4 M HCI / 1,4-dioxane (0.6 mL) was added to a solution of tert-butyl 4-(6-(cyanomethyl)pyridin-3-yl)piperidine-1 -carboxylate (70.0 mg, 222 pmol) in DCM (2 mL). The mixture was stirred at room temperature for 1 h then concentrated to dryness in vacuo to yield the title compound as a yellow solid.1H NMR (400 MHz, DMSO-d6) 69.36-9.13 (m, 2H), 8.52 (d, J= 1.7 Hz, 1H), 7.82 (dd, J = 8.1, 1.9 Hz, 1H), 7.52 (d, J= 8.1 Hz, 1H), 4.26 (s, 2H), 3.38-3.30 (m, 2H), 2.97 (br d, J = 6.1 Hz, 3H), 1.94 (br d, J= 5.7 Hz, 4H).

[0830] Step C. (R)-5-(4-(6-(cyanomethyl)pyridin-3-yl)piperidine-1 -carbonyl)-2',5'-dimethy I- / -( 1 - (methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3- carboxamide. To a solution of (R)-2',5'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl) propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylic acid (Intermediate B, 50.0 mg, 100 pmol), 2-(5-(piperidin-4-yl)pyridin-2-yl)acetonitrile HCI (39 mg, 0.164 mmol) and EtsN (60.0 mg, 593 pmol) in DMF (2.5 mL) was added HATU (50.0 mg, 132 pmol). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with brine (10 mL) and then extracted with ethyl acetate (15 mL x 2). The combined organic extracts were dried with anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was purified by preparative reverse phase HPLC (Stationary phase: Welch Xtimate C18, 5 pm, 150 x 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - ACN (B), gradient elution: 46-76% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound. MS (ESI): mass calculated for C39H38F3N5O3, 681.3; m / z measured, 682.3 [M+H]+.1H NMR (400MHz, CDCl3) δ 8.48 (d, J=2.1 Hz, 1H), 7.81 (s, 1H), 7.74 (t, J= 1.6 Hz, 1H), 7.63-7.55 (m, 3H), 7.53 (t, J= 1.4 Hz, 1H), 7.40 (t, J= 7.6 Hz, 3H), 7.21-7.17 (m, 1H), 7.15 - 7.11 (m, 1H), 7.04 (s, 1H), 6.95 (br d, J= 7.7 Hz, 1H), 5.74-5.62 (m, 1H), 5.04-4.84 (m, 1H), 4.83-4.74 (m, 1H), 3.94 (s, 3H), 3.33-3.13 (m, 3H), 2.97-2.82 (m, 2H), 2.76 (d, J= 4.9 Hz, 3H), 2.36 (s, 3H), 2.22 (s, 3H), 2.11-1.69 (m, 4H);19F NMR (376 MHz, CDCl3) δ -62.49 (s, 1F).

[0831] Example 12: (R)-2',5'-Dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(3-(methylsulfonyl)-1 / - / -pyrazol-5-y I ) pi peri d i n e- 1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamide

[0832]

[0833] Step A: 3,3-Bis(methylthio)-1-(pyridin-4-yl)prop-2-en-1-one. To a solution of NaH (60% in mineral oil, 3.3 g, 83 mmol) in THF (50 mL) was added 1-(pyridin-4-yl)ethanone (5.0 g, 41 mmol) dropwise at 0 °C under N2. The mixture was stirred for additional 30 minutes. CS2 (3.14 g, 41.3 mmol) was added dropwise with vigorous stirring followed by Mel (11.7 g, 82.6 mmol). The reaction mixture was stirred at room temperature for 16h. The reaction was quenched with ice-cold H2O (100 mL), then further stirred for 10 minutes, and filtered. The solids were washed with ice-cold EtOH (20 mL), dried in vacuo to yield the title compound as a yellow solid. MS (ESI): mass calculated for C10H11NOS2, 225.0; m / z measured, 226.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 5.9 Hz, 2H), 7.69 (d, J = 6.0 Hz, 2H), 6.68 (s, 1 H), 2.58 (s, 3H), 2.55 (s, 3H).

[0834] Step B: 4-(3-(Methylthio)-1 / - / -pyrazol-5-yl)pyridine. A solution of 3,3-bis(methylthio)-1-(pyridin-4-yl)prop-2-en-1-one (2.1 g, 9.2 mmol,), AcOH (606 mg, 10.1 mmol), and NH2NH2*H2O (85%, 810 mg, 13.8 mmol) in tBuOH (20 mL) was stirred at 100 °C for 2 hours under N2. The reaction mixture was cooled down to room temperature and then concentrated in vacuo. The residue was diluted with H2O (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined extracts were washed with brine (25 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 97% ethyl acetate in petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C9H9N3S, 191.1; m / z measured, 192.2 [M+H]+.1H NMR (400MHz, DMSO-d6) 613.77 - 13.31 (m, 1 H), 8.68 - 8.51 (m, 2H), 7.79 - 7.66 (m, 2H), 6.97 (s, 1 H), 2.51 (br s, 3H).

[0835] Step C: 4-(3-(Methylsulfonyl)-1 / - / -pyrazol-5-yl)pyridine. Oxone (1.46 g, 2.4 mmol) was added to a stirring solution of 4-(3-(methylthio)-1 / - / -pyrazol-5-yl)pyridine (350 mg, 1.6 mmol) in H2O (1.1 mL) and THF (5.5 mL). The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with MeOH (5 mL), stirred for 10 minutes and then filtered. The filter cake was rinsed with MeOH (5 mL). The filtrate was concentrated to dryness in vacuo to yield the title compound as a light-yellow oil. MS (ESI): mass calculated for C9H9N3O2S, 223.0; m / z measured, 223.9 [M+H]+.1H NMR (400MHz, DMSO-d6) 6 = 9.02 (d, J=6.8 Hz, 2H), 8.48 (d, J=6.8 Hz, 2H), 7.94 (s, 1H), 3.35 (s, 3H).

[0836] Step D: 4-(3-(Methylsulfonyl)-1 / - / -pyrazol-5-yl)piperidine HCI. A suspension of 4-(3-(methylsulfonyl)-1 / - / -pyrazol-5-yl)pyridine (232 mg, 1 mmol) in 4 M HCI / 1,4-dioxane was stirred at room temperature for 2 hours. The mixture was concentrated to dryness in vacuo to yield 4-(3-(methylsulfonyl)-1 / - / -pyrazol-5-yl)pyridine HCI.

[0837] PtO2 (49 mg, 216.mol) was added to a solution of 4-(3-(methylsulfonyl)-1H-pyrazol-5-yl)pyridine HCI (180 mg) in EtOH (6 mL) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (50 psi) at 60 °C for 48 hours. The reaction mixture was filtered, and the filtrate was concentrated to dryness in vacuo. The residue was diluted with water (20 mL) and washed with ethyl acetate (15 mL). The organic phase was extracted with water (10 mL x 2). The combined aqueous phase was concentrated to dryness in vacuo and lyophilized to yield the title compound as a yellow oil, which was used directly in the next step without further purification.

[0838] Step E: (R)-2',5'-Dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan- 2-yl)-5-(4-(3-(methylsulfonyl)-1 / - / -pyrazol-5-yl)piperidine-1-carbonyl)-[1,1'-biphenyl]-3- carboxamide. HATU (93 mg, 245 pmol) was added to a mixture of (R / 2',5'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl) carbamoyl)-[1, 1 '-biphenyl]-3-carboxylic acid (Intermediate B, 80 mg, 160 pmol), 4-(3-(methylsulfonyl)-1 / - / -pyrazol-5-yl)piperidine HCI (150 mg) and DIEA (83 mg, 642 pmol) in DMF (5 mL). The mixture was stirred at room temperature for 16 hours. The mixture was then diluted with DCM (25 mL) and 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 reverse phase HPLC (Stationary phase: Phenomenex C18, 3 pm, 80 x 40 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 50 - 80% B in A over 7 min, flow rate: 25 mL / min), followed by preparative reverse phase HPLC (Stationary phase: Boston Green ODS, 5 pm, 150 x 30 mm; Mobile phase: water (FA) (A) - MeCN (B), gradient elution: 45 - 75% B inA over 6 min, flow rate: 30 mL / min). The desired fractions were collected and further purified by SFC: (Column: DAICEL CHIRALCEL OD-H, 5 pm, 250 x 30 mm; mobile phase:

[0839] Supercritical CO2(A) - EtOH (0.1% NH3H2O) (B); isocratic elution: 40% 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 C36H38F3N5O5S, 709.3; m / z measured, 710.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 613.75-13.40 (m, 1H), 8.81 (d, J = 8.6 Hz, 1 H), 8.06 (br d, J = 4.6 Hz, 1 H), 7.82 (s, 2H), 7.64-7.55 (m, 2H), 7.55-7.50 (m, 2H), 7.48 (s, 1H), 7.24-7.19 (m, 1H), 7.16-7.11 (m, 1H), 7.06 (s, 1H), 6.64 (s, 1 H), 4.79-4.68 (m, 1 H), 4.66-4.42 (m, 1 H), 3.82-3.50 (m, 1 H), 3.21 (br dd, J = 4.2, 13.3 Hz, 2H), 3.17 (s, 3H), 3.11-3.02 (m, 2H), 3.01-2.85 (m, 1H), 2.61 (d, J = 4.5 Hz, 3H), 2.32 (s, 3H), 2.17 (s, 3H), 2.04-1.83 (m, 2H), 1.73-1.55 (m, 2H).19F NMR (376 MHz, DMSO-d6) <5-60.77 (s, 1F).

[0840] Example 13: (R)-5-(3-(cyclobutylmethyl)-2-oxo-1-oxa-3,8- diazaspiro[4.5]decane-8-carbonyl)-2',5'-dimethyl- / \ / -(1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide.

[0841]

[0842] To 3-(cyclobutylmethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one 2,2,2- trifluoroacetate (29.9 mg, 0.088 mmol) weighed into a 8 mL vial was added a solution of (R)-2',5'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylic acid (Intermediate B, 40 mg, 0.082 mmol ) in DMF (500 pL), a solution of HATU (39.3 mg, 0.100 mmol) in DMF (500 pL), and DIPEA (28 pL, 0.16 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with DMF (700 pL) and water (170 pL) and purified by RP-HPLC (Stationary phase: Waters XSelect CSH C18, 5 pm, 150 x 19 mm; Mobile phase: (0.1% TFA in H2O (A), 0.1% TFA in ACN (B)) (A) - MeCN (B), gradient elution: 45 - 80% B in A over 12 min, flow rate: 25 mL / min) to yield the title compound. MS (ESI): mass calculated for C39H43F3N4O5, 704.3; m / z measured, 705.3 [M+H]+.1H NMR (DMSO- cfe) 68.82 (d, J = 8.8 Hz, 1 H), 8.07 (d, J = 4.4 Hz, 1 H), 7.82 (t, J = 1.5 Hz, 2H), 7.61 (d, J= 8.3 Hz, 2H), 7.53 (d, J= 7.8 Hz, 2H), 7.48 (s, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 7.06 (s, 1H), 4.70-4.76 (m, 1H), 4.03 (br s, 1H), 3.28-3.43 (m, 5H), 3.16-3.24 (m, 3H), 3.03-3.11 (m, 1H), 2.62 (d, J = 4.9 Hz, 3H), 2.32 (s, 3H), 2.17 (s, 3H), 1.95-2.03 (m, 2H), 1.72-1.92 (m, 6H), 1.62-1.72 (m, 2H).

[0843] Example 14: (R)-5-(3-cyclopentyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carbony l)-2', 5'-di methy l-A / -( 1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide.

[0844]

[0845] To 3-cyclopentyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one 2,2,2-trifluoroacetate (30 mg, 0.088 mmol) weighed into a 8 mL vial was added a solution of (R)-2',5'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid (Intermediate B, 40 mg, 0.082 mmol) in DMF (500 pL), a solution of HATU (39.3 mg, 0.1 mmol) in DMF (500 pL), and DIPEA (28.0 pL, 0.16 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was then diluted with DMF (700 pL) and water (170 pL) and purified by RP-HPLC Stationary phase: Waters XSelect CSH C18, 5 pm, 150 x 19 mm; Mobile phase: (0.1% TFA in H2O (A), 0.1% TFA in ACN (B)) (A) - MeCN (B), gradient elution: 45 - 80% B in A over 10 min, flow rate: 25 mL / min) to yield the title compound. MS (ESI): mass calculated for C39H43F3N4O5, 704.3; m / z measured, 705.2 [M+H]+.1H NMR (DMSO-d6) <58.82 (d, J= 8.3 Hz, 1H), 8.08 (q, J = 4.4 Hz, 1 H), 7.82-7.84 (m, 2H), 7.61 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 7.8 Hz, 2H), 7.48 (t, J= 1.5 Hz, 1H), 7.22 (d, J= 7.6 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 7.06 (s, 1H), 4.70-4.76 (m, 1H), 3.95-4.13 (m, 2H), 3.29-3.34 (m, 3H), 3.21 (dd, J = 13.5, 4.2 Hz, 1H), 3.07 (dd, J= 13.7, 10.8 Hz, 1H), 2.62 (d, J = 4.4 Hz, 3H), 2.32 (s, 3H), 2.17 (s, 3H), 1.69-1.91 (m, 6H), 1.48-1.68 (m, 6H).

[0846] Example 15: (R)-2',5'-dimethyl- / V-(1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)-5-(2-oxo-3-propyl-1-oxa-3,8-diazaspiro[4.5]decane-8-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0847]

[0848] To 3-propyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one 2,2,2-trifluoroacetate (27.6 mg, 0.088 mmol) weighed into a 8 mL vial was added a solution of (R)-2',5'-dimethyl-5-((1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 biphenyl]-3-carboxylic acid (Intermediate B, 40 mg, 0.082 mmol) in DMF (500 pL), a solution of HATU (39.3 mg, 0.1 mmol) in DMF (500 pL), and DIPEA (28.0 pL, 0.16 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with DMF (700 pL) and water (170 pL), and then purified by RP-HPLC (Stationary phase: Waters XSelect CSH C18, 5 pm, 150 x 19 mm; Mobile phase: (0.1% TFA in H2O (A), 0.1% TFA in ACN (B)) (A) - MeCN (B), gradient elution: 40 - 75% B in A over 10 min, flow rate: 25 mL / min) to yield the title compound. MS (ESI): mass calculated for C37H41F3N4O5, 678.3; m / z measured, 679.2 [M+H]+.1H NMR (DMSO-d6) 68.82 (d, J= 8.8 Hz, 1H), 8.05-8.10 (m, 1H), 7.83 (d, J = 1.5 Hz, 2H), 7.59-7.62 (m, 2H), 7.48-7.55 (m, 3H), 7.22 (d, J = 7.8 Hz, 1H), 7.13 (d, J= 7.6 Hz, 1H), 7.06 (s, 1H), 4.70-4.76 (m, 1H), 4.04 (br s, 2H), 3.30-3.44 (m, 5H), 3.17-3.25 (m, 1H), 3.04-3.14 (m, 3H), 2.62 (d, J=4.4 Hz, 3H), 2.32 (s, 3H), 2.17 (s, 3H), 1.70-1.93 (m, 4H), 1.49 (sxt, J= 7.2 Hz, 2H), 0.83 (t, J= 7.3 Hz, 3H).

[0849] Example 16: 5-(3-(hydroxymethyl)-2-oxa-8-azaspiro[4.5]decane-8-carbonyl)-2',5'-dimethyl- / V-((R)-1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-y I )-[ 1, 1 '-biphenyl]-3-carboxamide.

[0850]

[0851] To (2-oxa-8-azaspiro[4.5]decan-3-yl)methanol (15.1 mg, 0.088 mmol) weighed into a 8 mL vial was added a solution of (R)-2',5'-dimethyl-5-((1-(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 biphenyl]-3-carboxylic acid (Intermediate B, 40 mg, 0.082 mmol) in DMF (500 pL), a solution of HATU (39.3 mg, 0.1 mmol) in DMF (500 pL), and DIPEA (28.0 pL, 0.16 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with DMF (700 pL) and water (170 pL), and then purified by RP-HPLC (Stationary phase: Waters XSelect CSH C18, 5 pm, 150 x 19 mm; Mobile phase: (0.1% TFA in H2O (A), 0.1% TFA in ACN (B)) (A) - MeCN (B), gradient elution: 35 - 70% B in A over 15 min, flow rate: 25 mL / min) to yield the title compound. MS (ESI): mass calculated for C36H40F3N3O5, 651.3; m / z measured, 652.2 [M+H]+.1H NMR (DMSO-d6) 68.82 (d, J= 8.3 Hz, 1H), 8.05-8.09 (m, 1H), 7.78-7.83 (m, 2H), 7.61 (d, J= 8.3 Hz, 2H), 7.53 (d, J= 8.3 Hz, 2H), 7.43 (s, 1H), 7.21 (d, J= 7.8 Hz, 1H), 7.13 (d, J= 7.6 Hz, 1H), 7.05 (s, 1H), 4.70-4.76 (m, 1H), 3.94 (br s, 3H), 3.51-3.54 (m, 4H), 3.34-3.40 (m, 4H), 3.21 (br dd, J = 13.5, 4.2 Hz, 3H), 3.04-3.11 (m, 1H), 2.62 (d, J = 4.9 Hz, 3H), 2.31-2.33 (m, 3H), 2.16 (s, 3H), 1.80-1.94 (m, 1H), 1.41-1.62 (m, 5H).

[0852] Example 17: (R)-2',5'-dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(2-oxa-8-azaspiro[4.5]decane-8-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0853]

[0854] To 2-oxa-8-azaspiro[4.5]decan-3-yl (12.5 mg, 0.088 mmol) weighed into a 8 ml_ vial was added a solution of (R)-2',5'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylic acid (Intermediate B, 40 mg, 0.082 mmol) in DMF (500 pL), a solution of HATU (39.3 mg, 0.1 mmol) in DMF (500 pL), and DIPEA (28.0 pL, 0.16 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with DMF (700 pL) and water (170 pL), and then purified by RP-HPLC (Stationary phase: Boston Prime C18, 5 pm, 150 x 30 mm; Mobile phase: (0.05% NH3H2O + 10 mM NH4HCO3) (A) - MeCN (B), gradient elution: 45 - 75% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound. MS (ESI): mass calculated for C35H38F3N3O4, 621.3; m / z measured, 622.2 [M+H]+.1H NMR (DMSO-d6) <58.82 (d, J= 8.3 Hz, 1H), 8.07 (d, J = 4.9 Hz, 1 H), 7.80 (dt, J = 8.7, 1.5 Hz, 2H), 7.61 (d, J=8.3 Hz, 2H), 7.53 (d, J=8.3 Hz, 2H), 7.43 (t, J=1.7 Hz, 1H), 7.21 (d, J=7.8 Hz, 1H), 7.14 (d, J= 7.7 Hz, 1H), 7.05 (s, 1H), 4.70-4.76 (m, 1H), 3.69-3.82 (m, 3H), 3.40-3.58 (m, 3H), 3.27-3.30 (m, 1H), 3.17-3.25 (m, 1H), 3.07 (dd, J= 13.7, 10.8 Hz, 1H), 2.62 (d, J = 4.4 Hz, 3H), 2.32 (s, 3H), 2.16 (s, 3H), 1.75 (brs, 2H), 1.41-1.63 (m, 4H).

[0855] Example 18: 2',5'-dimethyl- / V-((R)-1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-((R)-3-(morpholinomethyl)-2-oxa-8-azaspiro[4.5]decane-8-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide TFA.

[0856]

[0857] To (3R)-3-(morpholin-4-ylmethyl)-2-oxa-8-azaspiro[4.5]decane (21 mg, 0.088 mmol) weighed into a 8 mL vial was added a solution of (R)-2',5'-dimethyl-5-((1-(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 biphenyl]-3-carboxylic acid (Intermediate B, 40 mg, 0.082 mmol) in DMF (500 pL), a solution of HATU (39.3 mg, 0.1 mmol) in DMF (500 pL), and DIPEA (28.0 pL, 0.16 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with DMF (700 pL) and water (170 pL), and then purified by RP-HPLC (Stationary phase: Waters XSelect CSH C18, 5 pm, 150 x 19 mm; Mobile phase: (0.1% TFA in H2O (A), 0.1% TFA in ACN (B)) (A) - MeCN (B), gradient elution: 20 - 55% B in A over 15 min, flow rate: 25 mL / min) to yield the title compound as the trifluoroacetate salt. MS (ESI): mass calculated for C40H47F3N4O5, 720.4; m / z measured, 721.2 [M+H]+.1H NMR (DMSO-d6) <59.65-9.90 (m, 1H), 8.82 (d, J = 8.8 Hz, 1 H), 8.08 (d, J = 4.4 Hz, 1 H), 7.83 (t, J = 1.7 Hz, 1 H), 7.78 (d, J = 1.0 Hz, 1H), 7.59-7.63 (m, J= 8.3 Hz, 2H), 7.52-7.55 (m, J= 8.3 Hz, 2H), 7.43 (s, 1H), 7.22 (d, J= 7.8 Hz, 1H), 7.14 (d, J= 7.8 Hz, 1H), 7.06 (s, 1H), 4.70-4.76 (m, 1H), 4.38 (brs, 1H), 3.89-4.00 (m, 2H), 3.64-3.76 (m, 6H), 3.39-3.49 (m, 2H), 3.16-3.38 (m, 5H), 3.02-3.15 (m, 3H), 2.62 (d, J = 4.4 Hz, 3H), 2.32 (s, 3H), 2.17 (s, 3H), 2.07 (br s, 1 H), 1.62 (br s, 2H), 1.52 (br s, 2H), 1.35-1.49 (m, 1 H).

[0858] Example 19: 2',5'-dimethyl- / V-((R)-1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-((R)-3-(4-methylpiperazin-1-yl)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0859]

[0860] To (3R)-3-(4-methylpiperazin-1-yl)-1-oxa-8-azaspiro[4.5]decane hydrochloride (31 mg, 0.088 mmol) weighed into a 8 mL vial was added a solution of (R)-2',5'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid (Intermediate B, 40 mg, 0.082 mmol) in DMF (500 pL), a solution of HATU (39.3 mg, 0.1 mmol) in DMF (500 pL), and DIPEA (28.0 pL, 0.16 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with DMF (700 pL) and water (170 pL), and then purified by RP-HPLC (Stationary phase: Waters XSelect CSH C18, 5 pm, 150 x 19 mm; Mobile phase: (0.1% TFA in H2O (A), 0.1% TFA in ACN (B)) (A) - MeCN (B), gradient elution: 15 - 50% B in A over 8 min, flow rate: 25 mL / min) to yield the title compound as the ditrifluoroacetate salt. MS (ESI): mass calculated for C40H48F3N5O4, 719. 4; m / z measured, 720.3 [M+H]+.1H NMR (DMSO-d6) 58.82 (d, J = 8.3 Hz, 1 H), 8.08 (d, J = 4.9 Hz, 1 H), 7.82 (s, 1 H), 7.79 (s, 1 H), 7.59-7.63 (m, J= 7.8 Hz, 2H), 7.52-7.55 (m, J= 7.8 Hz, 2H), 7.45 (s, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.13 (d, J= 7.9 Hz, 1H), 7.05 (s, 1H), 4.69-4.76 (m, 1H), 3.89-3.98 (m, 4H), 3.57-3.65 (m, 1H), 3.27-3.45 (m, 5H), 3.17-3.24 (m, 1H), 2.84-3.16 (m, 6H), 2.76 (br s, 4H), 2.62 (d, J = 4.4 Hz, 3H), 2.32 (s, 5H), 2.16 (s, 3H), 2.04 (br s, 1 H), 1.49-1.77 (m, 5H).

[0861] Example 20: 5-((R)-3-(4-hydroxypiperidin-1 -yl)-1 -oxa-8-azaspiro[4.5]decane-8-carbonyl)-2',5'-dimethyl- / \ / -((R)-1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide.

[0862]

[0863] To 1-[(3R)-1-oxa-8-azaspiro[4.5]dec-3-yl]piperidin-4-ol hydrochloride (24 mg, 0.088 mmol) weighed into a 8 mL vial was added a solution of (R)-2',5'-dimethyl-5-((1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 biphenyl]-3-carboxylic acid (Intermediate B, 40 mg, 0.082 mmol) in DMF (500 pL), a solution of HATU (39.3 mg, 0.1 mmol) in DMF (500 pL), and DIPEA (28.0 pL, 0.16 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with DMF (700 pL) and water (170 pL), and then purified by RP-HPLC (Stationary phase: Waters XSelect CSH C18, 5 pm, 150 x 19 mm; Mobile phase: (0.1% TFA in H2O (A), 0.1% TFA in ACN (B)) (A) - MeCN (B), gradient elution: 20 - 55% B in A over 15 min, flow rate: 25 mL / min) to yield the title compound as the trifluoroacetate salt. MS (ESI): mass calculated for C40H47F3N4O5, 720.4; m / z measured, 721.3 [M+H]+.1H NMR (DMSO-d6) <59.29-9.45 (m, 1H), 8.82 (d, J= 8.8 Hz, 1H), 8.06-8.10 (m, 1H), 7.77-7.85 (m, 2H), 7.60-7.63 (m, J = 8.3 Hz, 2H), 7.51-7.55 (m, J= 8.3 Hz, 2H), 7.46 (s, 1H), 7.22 (d, J= 7.8 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 7.05 (s, 1H), 4.90-5.19 (m, 1H), 4.70-4.76 (m, 1H), 3.86-4.16 (m, 5H), 3.61-3.68 (m, 1H), 3.32-3.38 (m, 3H), 3.02-3.27 (m, 6H), 2.98 (br s, 1H), 2.62 (d, J = 4.4 Hz, 3H), 2.32 (s, 3H), 2.20-2.30 (m, 1H), 2.17 (s, 3H), 1.98 (br d, J= 12.7 Hz, 1H), 1.43-1.92 (m, 8H).

[0864] Example 21: 5-((R)-3-(ethyl(2-hydroxyethyl)amino)-2-oxa-8-azaspiro[4.5]decane-8-carbonyl)-2',5'-dimethyl- / \ / -((R)-1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide.

[0865]

[0866] To 2-{ethyl[(3R)-1-oxa-8-azaspiro[4.5]dec-3-yl]amino}ethanol hydrochloride (23 mg, 0.088 mmol) weighed into a 8 mL vial was added a solution of (R)-2',5'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid (Intermediate B, 40 mg, 0.082 mmol) in DMF (500 pL), a solution of HATU (39.3 mg, 0.1 mmol) in DMF (500 pL), and DIPEA (28.0 pL, 0.16 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with DMF (700 pL) and water (170 pL), and then purified by RP-HPLC (Stationary phase: Waters XSelect CSH C18, 5 pm, 150 x 19 mm; Mobile phase: (0.1% TFA in H2O (A), 0.1% TFA in ACN (B)) (A) - MeCN (B), gradient elution: 20 - 55% B in A over 12 min, flow rate: 25 mL / min) to yield the title compound as the trifluoroacetate salt. MS (ESI): mass calculated for C39H47F3N4O5, 708.4; m / z measured, 709.2 [M+H]+.1H NMR (DMSO-d6) 69.23-9.38 (m, 1H), 8.78-8.88 (m, 1H), 8.03-8.14 (m, 1H), 7.76-7.86 (m, 2H), 7.61 (d, J= 8.3 Hz, 2H), 7.53 (d, J= 8.3 Hz, 2H), 7.42-7.49 (m, 1H), 7.19-7.26 (m, 1H), 7.11-7.18 (m, 1H), 7.03-7.10 (m, 1H), 5.31-5.46 (m, 1H), 4.62-4.81 (m, 1H), 4.13-4.28 (m, 1H), 3.99 (br s, 3H), 3.67-3.74 (m, 3H), 3.31-3.39 (m, 2H), 3.15-3.25 (m, 4H), 3.04-3.12 (m, 2H), 2.62 (d, J = 4.4 Hz, 3H), 2.32 (s, 3H), 2.22-2.31 (m, 1H), 2.17 (s, 3H), 1.83-2.01 (m, 1H), 1.45-1.82 (m, 4H), 1.15-1.30 (m, 3H).

[0867] Example 22: (R)-2',5'-dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(3,9-diazaspiro[5.5]undecane-3-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0868]

[0869] To terf-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (86.2 mg, 0.339 mmol) weighed into a 8 mL vial was added a solution of (R)-2',5'-dimethyl-5-((1-(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 biphenyl]-3-carboxylic acid (Intermediate B, 84 mg, 0.17 mmol) in DMF (1000 pL), a solution of HATU (83.1 mg, 0.212 mmol) in DMF (1000 pL), and DIPEA (59.1 pL, 0.339 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was then concentrated to dryness and redissolved in DCE (2 mL). Trifluoroacetic acid (200 pL, 2.61 mmol) was added and the reaction mixture was stirred for 6 hours. The reaction mixture was concentrated to dryness and dissolved in 10% H2O:DMF (3.8 mL) and purified by RP-HPLC (Stationary phase: Waters XSelect CSH C18, 5 pm, 150 x 19 mm; Mobile phase: (0.1% TFA in H2O (A), 0.1% TFA in ACN (B)) (A) - MeCN (B), gradient elution: 20 - 55% B in A over 12 min, flow rate: 25 mL / min) to yield the title compound as the trifluoroacetate salt. MS (ESI): mass calculated for C36H41F3N4O3, 634.3; m / z measured, 635.3 [M+H]+. 1H NMR (DMSO-d6) <58.78-8.86 (m, 1H), 8.25-8.37 (m, 2H), 8.05-8.13 (m, 1H), 7.76-7.85 (m, 2H), 7.61 (d, J= 8.3 Hz, 2H), 7.53 (d, J= 8.3 Hz, 2H), 7.41-7.46 (m, 1H), 7.11-7.26 (m, 2H), 7.02-7.08 (m, 1H), 4.68-4.79 (m, 1H), 3.60-3.64 (m, 2H), 3.30 (brs, 2H), 3.17-3.25 (m, 1H), 3.01-3.11 (m, 5H), 2.62 (d, J = 4.4 Hz, 3H), 2.32 (s, 3H), 2.16 (s, 3H), 1.38-1.68 (m, 8H).

[0870] Example 23: (R)-5-(9-acetyl-3,9-diazaspiro[5.5]undecane-3-carbonyl)-2',5'-dimethy I- / -( 1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide.

[0871]

[0872] 3-(3,9-diazaspiro[5.5]undecane-9-carbonyl)-5-(2,5-dimethylphenyl)- / \ / -[(1R)-2-(methylamino)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]benzamide trifluoroacetate (40 mg, 0.051 mmol) was weighed into a 8 mL vial and dissolved in DMF (800 pL). DIPEA (44.6 pL, 0.256 mmol) and acetyl chloride (6.9 pL, 0.096 mmol) were added to the solution. The reaction mixture was diluted with water (80 pL) and DMF (800 pL) and purified by RP-HPLC (Stationary phase: Waters XBridge BEH C18, 5 pm, 150 x 19 mm; Mobile phase: (0.1% NH4OH in H2O (A), 0.1% NH4OH in ACN (B)) (A) - MeCN (B), gradient elution: 35 - 70% B in A over 10 min, flow rate: 25 mL / min) to yield the title compound. MS (ESI): mass calculated for C38H43F3N4O4, 676.3; m / z measured, 677.4 [M+H]+. 1H NMR (401 MHz, DMSO-d6) <58.85 (br d, J = 8.31 Hz, 1 H), 8.11 (br d, J = 4.40 Hz, 1 H), 7.83 (brd, J = 8.31 Hz, 2 H), 7.53-7.64 (m, 4 H), 7.45 (s, 1 H), 7.22 (d, J = 7.83 Hz, 1 H), 7.14 (br d, J = 7.82 Hz, 1 H), 7.06 (s, 1 H), 4.72 - 4.80 (m, 1 H), 3.17-3.29 (m, 1 H), 3.04-3.16 (m, 1 H), 2.64 (d, J = 4.40 Hz, 3 H), 2.33 (s, 3 H), 2.18 (s, 3 H), 1.98 (s, 3 H), 1.45-1.56 (m, 4 H), 1.41 (br s, 4 H) (Run with DMSO and H2O suppression).

[0873] Example 24: 2',5'-Dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperidine-1-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0874]

[0875] A solution of 2',5'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylic acid (Intermediate D, 66 mg, 0.132 mmol), HATU (75.5 mg, 0.20 mmol) and TEA (0.06 ml_, 0.4 mmol) in DMF (1 m L) was stirred for 30 min. 4-(4-(methylsulfonyl)phenyl)piperidine (48 mg, 0.199 mmol) was added and the reaction was continued at room temperature for 2 hours. The reaction mixture was diluted with EtOAc (3 mL) and water (10 mL) and the organic layer was extracted, dried over sodium sulfate and concentrated. The residue was purified by RP-HPLC (Stationary phase: Waters XBridge BEH C18, 5.m, 19x100 mm; Mobile phase: Modifier 0.16% NH4OH; Water(A)- MeCN (B), gradient elution: 40 - 75% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound. MS (ESI): mass calculated for C39H40F3N3O5S, 719.8; m / z measured, 720.1 [M+H]+.1H NMR (400 MHz, CD3OD) 61H NMR (400 MHz, CD3OD) 6 ppm 7.89 - 7.94 (m, 2 H) 7.78 - 7.83 (m, 2 H) 7.54 - 7.61 (m, 5 H) 7.45 - 7.52 (m, 2 H) 7.19 (s, 1 H) 7.15 (br d, J=1.5 Hz, 1 H) 7.08 (s, 1 H) 3.31 - 3.34 (m, 11 H) 3.11 (s, 3 H) 2.69 - 2.80 (m, 3 H) 2.36 (s, 3 H) 2.17 - 2.25 (m, 3 H).

[0876] Example 25: 5-(4-(4-Methoxyphenyl)piperidine-1 -carbonyl)-2',5'-dimethyl- / \ / -(1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-bi pheny l]-3-carboxamide.

[0877]

[0878] The title compound was prepared according to the procedure described in Example 24 substituting 4-(4-methoxyphenyl)piperidine for 4-(4-(methylsulfonyl)phenyl)piperidine. MS (ESI): mass calculated for C39H40F3N3O4, 671.8; m / z measured, 672.3 [M+H]+.1H NMR (400 MHz, CD3OD) 67.8-7.9 (m, 2H), 7.5-7.6 (m, 3H), 7.4-7.5 (m, 2H), 7.2-7.3 (m, 3H), 7.1-7.2 (m, 1H), 7.06 (s, 1H), 6.8-6.9 (m, 2H), 3.8-3.9 (m, 1 H), 3.77 (s, 3H), 3.35 (br s, 1 H), 3.28 (br s, 1 H), 3.14 (dd, J = 9.3, 13.7 Hz, 1H), 2.9-3.0 (m, 1H), 2.8-2.9 (m, 1H), 2.74 (s, 3H), 2.35 (s, 3H), 2.20 (s, 3H), 1.9-2.0 (m, 1H), 1.5-1.9 (m, 3H).

[0879] Example 26: 2',5'-Dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-sulfamoylphenyl)piperidine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0880]

[0881] The title compound was prepared according to the procedure described in Example 24 substituting 4-(piperidin-4-yl)benzenesulfonamide for4-(4-(methylsulfonyl)phenyl)piperidine. MS (ESI): mass calculated for C38H39F3N4O5S, 720.3; m / z measured, 721.2 [M+H]+.1H NMR (400 MHz, CD3OD) 58.14 (br d, J=4.9 Hz, 1 H) 7.78 - 7.86 (m, 4 H) 7.55 (br t, J=1.5 Hz, 3 H) 7.45 - 7.49 (m, 4 H) 7.19 (d, J=7.8 Hz, 1 H) 7.12 (d, J=7.6 Hz, 1 H) 7.06 (s, 1 H) 4.91 - 4.94 (m, 1 H) 4.79 - 4.89 (m, 1 H) 4.77 - 4.85 (m, 1 H) 3.86 (br d, J=10.8 Hz, 1 H) 3.33 - 3.38 (m, 1 H) 3.09 - 3.16 (m, 1 H) 2.92 - 3.03 (m, 2 H) 2.71 - 2.74 (m, 3 H) 2.34 (s, 3 H) 2.19 (s, 3 H) 1.65 - 2.07 (m, 4 H).

[0882] Example 27: 5-(4-(4-Chlorophenyl)piperidine-1-carbonyl)-2',5'-dimethyl- / \ / -(1-(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-bi phe ny I ]-3-carboxamide.

[0883]

[0884] The title compound was prepared according to the procedure described in Example 24 substituting 4-(4-chlorophenyl)piperidine for 4-(4-(methylsulfonyl)phenyl)piperidine. MS (ESI): mass calculated for C38H37CIF3N3O3, 675.3; m / z measured, 676.2 [M+H]+.1H NMR (400 MHz, CD3OD) 57.69 (d, J=5.1 Hz, 2 H) 7.40 - 7.48 (m, 3 H) 7.35 - 7.39 (m, 2 H) 7.13 - 7.20 (m, 4 H) 7.07 (d, J=7.8 Hz, 1 H) 7.01 (dd, J=7.8, 1.5 Hz, 1 H) 6.94 (s, 1 H) 4.67 - 4.80 (m, 2 H) 3.72 (br d, J=13.7 Hz, 1 H) 3.23 - 3.27 (m, 1 H) 3.11 - 3.19 (m, 1 H) 3.02 (dd, J=13.7, 9.3 Hz, 1 H) 2.72 - 2.91 (m, 2 H) 2.60 - 2.64 (m, 3 H) 2.23 (s, 3 H) 2.08 (s, 3 H) 1.81 - 1.90 (m, 1 H) 1.59 - 1.71 (m, 2 H) 1.51 - 1.59 (m, 1 H).

[0885] Example 28: 2',5'-Dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(6-(4-(methylsulfonyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0886]

[0887] The title compound was prepared according to the procedure described in Example 24 substituting 2-(4-(methylsulfonyl)phenyl)-2,6-diazaspiro[3.3]heptane (Intermediate H) for 4-(4-(methylsulfonyl)phenyl)piperidine. MS (ESI): mass calculated for C39H39F3N4O5S, 732.3; m / z measured, 733.2 [M+H]+.1H NMR (400 MHz, CD3OD) 58.63 (d, J=8.3 Hz, 1 H) 7.89 (t, J=1.7 Hz, 1 H) 7.73 (t, J=1.7 Hz, 1 H) 7.58 - 7.65 (m, 3 H) 7.47 (d, J=7.8 Hz, 2 H) 7.38 (d, J=8.3 Hz, 2 H) 7.09 (d, J=7.9 Hz, 1 H) 7.03 (d, J=7.6 Hz, 1 H) 6.94 (s, 1 H) 6.45 (d, J=8.1 Hz, 2 H) 4.74 - 4.79 (m, 1 H) 4.49 (s, 2 H) 4.30 (s, 2 H) 4.03 - 4.10 (m, 4 H) 3.22 - 3.27 (m, 1 H) 3.22 - 3.22 (m, 1 H) 3.03 (dd, J=13.9, 9.0 Hz, 1 H) 2.92 (s, 3 H) 2.62 (s, 3 H) 2.24 (s, 3 H) 2.09 (s, 3 H).

[0888] Example 29: 2',5'-Dimethyl- / \ / -(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-((1S,4S)-5-(4-(methylsulfonyl)phenyl)-2,5-diazabicyclo[2.2.1 ]heptane-2-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0889]

[0890] The title compound was prepared according to the procedure described in Example 24 substituting (1S,4S)-2-(4-(methylsulfonyl)phenyl)-2,5-diazabicyclo[2.2.1]heptane for 4-(4-(methylsulfonyl)phenyl)piperidine. MS (ESI): mass calculated for C39H39F3N4O5S, 732.3; m / z measured, 733.3 [M+H]+.

[0891] Example 30: 2',5'-Dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-((1R,4R)-5-(4-(methylsulfonyl)phenyl)-2,5-diazabicyclo[2.2.1 ]heptane-2-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0892]

[0893] The title compound was prepared according to the procedure described in Example 24 substituting (1R,4R)-2-(4-(methylsulfonyl)phenyl)-2,5-diazabicyclo[2.2.1]heptane for 4-(4-(methylsulfonyl)phenyl)piperidine. MS (ESI): mass calculated for C39H39F3N4O5S, 732.3; m / z measured, 733.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 ppm 8.86 (dd, J=19.8, 8.6 Hz, 1 H) 8.04 - 8.16 (m, 1 H) 7.90 - 7.94 (m, 1 H) 7.79 - 7.89 (m, 1 H) 7.67 (d, J=9.3 Hz, 1 H) 7.56 - 7.65 (m, 5 H) 7.53 (t, J=8.3 Hz, 1 H) 7.17 - 7.26 (m, 1 H) 6.97 - 7.16 (m, 2 H) 6.81 (brd, J=8.8 Hz, 1 H) 6.73 (br d, J=8.8 Hz, 1 H) 4.94 (s, 1 H) 4.67 - 4.81 (m, 1 H) 4.45 (s, 1 H) 4.43 - 4.97 (m, 1 H) 3.60 - 3.69 (m, 1 H) 3.56 (br d, J=7.8 Hz, 1 H) 3.78 (br d, J=8.3 Hz, 1 H) 3.37 - 3.44 (m, 1 H) 3.32 - 3.35 (m, 1 H) 3.16 - 3.26 (m, 1 H) 3.06 (br d, J=2.9 Hz, 1 H) 2.61 (br d, J=17.1 Hz, 1 H) 2.61 (br d, J=8.3 Hz, 2 H) 2.28 - 2.35 (m, 3 H) 2.21 (s, 1 H) 1.96 - 2.18 (m, 3 H).

[0894] Example 31: / \ / 3,2',5'-Trimethyl- / \ / 5-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)- / \ / 3-(1-(4-(methylsulfonyl)phenyl)piperidin-4-yl)-[1, 1 '-biphenyl]-3,5-dicarboxamide.

[0895]

[0896] The title compound was prepared according to the procedure described in Example 24 substituting N-methyl-1-(4-(methylsulfonyl)phenyl)piperidin-4-amine for 4-(4-(methylsulfonyl)phenyl)piperidine. MS (ESI): mass calculated for C40H43F3N4O5S, 748.3; m / z measured, 749.3 [M+H]+.1H NMR (400 MHz, CD3OD) 6 8.71 (brs, 1 H) 8.11 (br d, J=4.4 Hz, 1 H) 7.68 - 7.77 (m, 4 H) 7.54 (d, J=8.3 Hz, 2 H) 7.43 - 7.48 (m, 3 H) 7.16 (d, J=7.8 Hz, 1 H) 7.09 (br d, J=7.8 Hz, 2 H) 7.02 (s, 2 H) 4.67 (brs, 1 H) 4.12 (br d, J=12.7 Hz, 1 H) 3.98 (br d, J=11.7 Hz, 1 H) 3.30 - 3.35 (m, 1 H) 3.03 - 3.13 (m, 2 H) 3.01 (s, 3 H) 2.96 (br s, 1 H) 2.80 - 2.89 (m, 2 H) 2.70 (d, J=4.4 Hz, 3 H) 2.63 (brs, 1 H) 2.31 (s, 3 H) 2.16 (br s, 3 H) 1.90 - 2.02 (m, 2 H) 1.88 (br s, 2 H) 1.76 (br s, 1 H).

[0897] Example 32: 2',5'-Dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-((1 S,4S)-5-(4-sulfamoylphenyl)-2,5-diazabicyclo[2.2.1 ]heptane-2-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0898]

[0899] The title compound was prepared according to the procedure described in Example 24 substituting 4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2- yl)benzenesulfonamide for 4-(4-(methylsulfonyl)phenyl)piperidine. MS (ESI): mass calculated for C38H38F3N5O5S, 733.3; m / z measured, 734.1 [M+H]+.1H NMR (400 MHz, CD3OD) 67.76 (t, J=1.7 Hz, 1 H) 7.72 (dt, J=7.9, 1.7 Hz, 1 H) 7.60 - 7.64 (m, 1 H) 7.56 (d, J=9.3 Hz, 1 H) 7.43 - 7.51 (m, 3 H) 7.38 (d, J=8.3 Hz, 1 H) 7.33 (d, J=8.3 Hz, 1 H) 7.07 - 7.11 (m, 1 H) 6.95 - 7.06 (m, 1 H) 6.86 - 7.11 (m, 1 H) 6.88 (s, 1 H) 6.65 (d, J=9.3 Hz, 1 H) 6.55 (d, J=8.8 Hz, 1 H) 4.92 - 4.95 (m, 1 H) 4.64 - 4.79 (m, 2 H) 4.55 (s, 1 H) 4.47 (s, 1 H) 3.45 - 3.68 (m, 3 H) 3.22 - 3.34 (m, 2 H) 3.17 - 3.19 (m, 1 H) 2.91 - 3.10 (m, 1 H) 2.57 - 2.64 (m, 3 H) 2.19 - 2.26 (m, 3 H) 2.10 (s, 2 H) 1.95 - 2.08 (m, 3 H).

[0900] Example 33: / \ / 3,2',5'-Trimethyl- / \ / 5-(1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)- / \ / 3-(1 -(4-sulfamoylphenyl)pyrrolidin-3-yl)-[1, 1

[0901]

[0902] The title compound was prepared according to the procedure described in Example 24 substituting 4-(3-(methylamino)pyrrolidin-1-yl)benzenesulfonamide for 4-(4-(methylsulfonyl)phenyl)piperidine. MS (ESI): mass calculated for C38H40F3N5O5S, 735.3; m / z measured, 735.3 [M+H]+.1H NMR (400 MHz, CD3OD) 6 7.65 - 7.72 (m, 2 H) 7.60 (br d, J=8.8 Hz, 2 H) 7.42 - 7.48 (m, 3 H) 7.37 (d, J=8.3 Hz, 2 H) 7.07 (d, J=7.8 Hz, 1 H) 7.01 (dd, J=7.8, 1.5 Hz, 1 H) 6.94 (s, 1 H) 6.50 - 6.61 (m, 2 H) 4.74 - 4.79 (m, 2 H) 3.50 (br s, 2 H) 3.32 - 3.46 (m, 2 H) 3.22 - 3.27 (m, 2 H) 3.21 (s, 3 H) 2.88 - 3.06 (m, 1 H) 2.62 (s, 3 H) 2.23 (s, 3 H) 2.08 (s, 3 H) Example 34: 2',5'-Dimethyl- / \ / -(1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)piperazin-1-yl)piperidine- 1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0903]

[0904] The title compound was prepared according to the procedure described in Example 24 substituting 1-(methylsulfonyl)-4-(piperidin-4-yl)piperazine (Intermediate I) for 4-(4-(methylsulfonyl)phenyl)piperidine. MS (ESI): mass calculated for C37H44F3N5O5S, 727.3; m / z measured, 728.3 [M+H]+.1H NMR (400 MHz, CD3OD) 6 7.67 (d, J=5.3 Hz, 2 H) 7.45 - 7.48 (m, 2 H) 7.35 - 7.40 (m, 3 H) 7.08 (d, J=7.9 Hz, 1 H) 7.02 (d, J=7.6 Hz, 1 H) 6.94 (s, 1 H) 4.77 (dd, J=9.5, 6.1 Hz, 1 H) 4.57 (br d, J=11.2 Hz, 1 H) 3.67 (br d, J=12.2 Hz, 1 H) 3.23 - 3.27 (m, 1 H) 3.08 - 3.14 (m, 4 H) 2.98 - 3.08 (m, 2 H) 2.76 - 2.87 (m, 1 H) 2.73 (s, 3 H) 2.62 (s, 3 H) 2.52 - 2.62 (m, 5 H) 2.24 (s, 3 H) 2.08 (s, 3 H) 1.85 - 1.95 (m, 1 H) 1.69 - 1.81 (m, 1 H) 1.31 - 1.52 (m, 2 H).

[0905] Example 35: 2',5'-Dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0906]

[0907] The title compound was prepared as described in Scheme 1 (analogous to Example 3) substituting 1,2,3,4-tetrahydro-2,7-naphthyridine for 4-(piperidin-4-yl)morpholine. MS (ESI): mass calculated for C35H33F3N4O3, 614.3; m / z measured: 615.2 [M+H]+.1H NMR (400 MHz, CDCI3) 8.39 (s, 1H), 7.78 (d, J = 14.1 Hz, 2H), 7.52 (d, J = 7.6 Hz, 3H), 7.36 (d, J = 7.9 Hz, 2H), 7.16 (t, J = 8.1 Hz, 3H), 7.09 (d, J = 7.9 Hz, 1H), 7.00 (s, 1H), 5.96 (s, 1H), 4.91 (s, 1H), 4.79 (d, J = 7.6 Hz, 1H), 4.67 (s, 1H), 3.97 (s, 1H), 3.70 (d, J = 7.0 Hz, 1H), 3.21 (d, J = 7.1 Hz, 2H), 2.91 (s, 2H), 2.71 (d, J = 4.8 Hz, 3H), 2.32 (s, 3H), 2.18 (s, 3H), 1.28-1.06 (m, 1H).

[0908] Example 36: 2',5'-dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0909]

[0910] The title compound was prepared as described in Scheme 1 (analogous to Example 3) substituting 5,6,7,8-tetrahydro-1,6-naphthyridine for 4-(piperidin-4-yl)morpholine. MS (ESI): mass calculated for C35H33F3N4O3, 614.3; m / z measured: 615.2 [M+H]+.1H NMR (400 MHz, CDCI3) d 8.45 (s, 1H), 7.79 (d, J = 17.6 Hz, 2H), 7.61 (s, 1H), 7.52 (t, J = 4.3 Hz, 3H), 7.35 (d, J= 7.9 Hz, 2H), 7.24 (s, 2H), 7.21-7.06 (m, 3H), 7.00 (s, 1H), 5.92 (s, 1H), 4.91 (s, 1H), 4.78 (d, J= 7.4 Hz, 1H), 3.78 (s, 1H), 3.70 (q, J= 7.0 Hz, 1H), 3.21 (d, J = 7.1 Hz, 2H), 3.13 (s, 2H), 2.71 (d, J = 4.7 Hz, 3H), 2.32 (s, 3H), 2.19 (s, 3H).

[0911] Example 37: 2',5'-dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0912]

[0913] The title compound was prepared as described in Scheme 1 (analogous to Example 3) substituting 5,6,7,8-tetrahydropyrido[3,4-c / ]pyrimidine for 4-(piperidin-4-yl)morpholine. MS (ESI): mass calculated for C34H32F3N5O3, 615.2; m / z measured: 616.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) 8.89 (s, 1 H), 8.74 (d, J = 8.5 Hz, 1 H), 8.56 (s, 1H), 7.96 (d, J = 4.7 Hz, 1H), 7.93 (s, 2H), 7.53 (s, 3H), 7.48 (s, 2H), 7.15 (d, J = 8.0 Hz, 1H), 7.06 (s, 2H), 4.76 (s, 3H), 3.73 (s, 1H), 3.22-3.05 (m, 3H), 2.93 (s, 2H), 2.67 (d, J = 4.5 Hz, 3H), 2.35 (s, 3H), 2.24 (s, 3H).

[0914] Example 38: 2',5'-dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-6-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0915]

[0916] The title compound was prepared as described in Scheme 1 (analogous to Example 3) substituting 5,6,7,8-tetrahydropyrido[3,4-b]pyrazine for 4-(piperidin-4-yl)morpholine. MS (ESI): mass calculated for C34H32F3N5O3, 615.2; m / z measured: 616.4 [M+H]+.1H NMR (500 MHz, DMSO-d6) £8.73 (d, J = 8.4 Hz, 1H), 8.42 (s, 2H), 8.00 (s, 1H), 7.94 (dd, J = 8.6, 3.8 Hz, 2H), 7.51 (d, J = 19.7 Hz, 5H), 7.14 (d, J = 7.5 Hz, 1 H), 7.06 (d, J = 4.6 Hz, 2H), 5.04 - 4.54 (m, 3H), 3.98 (d, J = 166.8 Hz, 3H), 3.29 - 3.04 (m, 4H), 2.66 (d, J = 4.5 Hz, 3H), 2.35 (s, 3H), 2.24 (s, 3H). Example 39: 5-(3,3-difluoro-4-((1-(methylsulfonyl)piperidin-4-yl)amino)piperidine-1 -carbony l)-2', 3', 6'-tri methy l- / \ / -((R)-1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide.

[0917]

[0918] Step A: tert-Butyl 3,3-difluoro-4-((1-(methylsulfonyl)piperidin-4-yl)amino)piperidine-1 -carboxylate. To a mixture of terf-butyl 4-amino-3,3-difluoropiperidine-1 -carboxylate (149 mg, 0.63 mmol) in DCM (6.3 mL) at 0 °C was sequentially added AcOH (180 pL, 3.15 mmol), 1-methylsulfonylpiperidin-4-one (167 mg, 0.94 mmol), and NaBH(OAc)₃ (200 mg, 0.940 mmol). The reaction was warmed to room temperature and stirred for 19 h. The reaction was quenched by addition of sat. aq. NaHCOs (15 mL) and the mixture stirred until bubbles ceased forming. The layers were separated, and the aqueous layer was extracted with DCM (2x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous MgSO4, filtered, and concentrated. Purification of the resulting residue by chromatography (FCC, silica gel, 0-5% MeOH(+5% NH4OH) / EtOAc) yielded the title compound as a white solid. MS (ESI): mass calculated for C16H29F2N3O4S, 397.2; m / z measured, 398.0 [M+H]+.

[0919] Step B: 3,3-Difluoro- / \ / -(1-(methylsulfonyl)piperidin-4-yl)piperidin-4-amine. To a mixture of tert-butyl 3,3-difluoro-4-((1-(methylsulfonyl)piperidin-4-yl)amino)piperidine-1 -carboxylate (67.8 mg, 171 pmol) in DCM (0.5 mL) was added TFA (200 pL, 261 pmol) under Ar (g) atmosphere. The reaction mixture was placed into a pre-heated 35 °C metal heating block and stirred for 3 h. MeOH (1 mL) was then added, and the reaction mixture was concentrated. The residue was dissolved in water, then added to a mixture of water (5 ml_), sat. aq. NaHCOs (5 ml_), and EtOAc (5 ml_). The layers were separated, and the aqueous layer was extracted with EtOAc (2x 5 m L). The aqueous layer was then extracted with DCM (6x 2 m L). The combined organic layers were dried over MgSO4, filtered, and concentrated to yield the title compound as a white solid.

[0920] Step C: 5-(3,3-Difluoro-4-((1 -(methylsulfonyl)piperidin-4-yl)amino)piperidine-1 -carbonyl)-2',3',6'-trimethyl- / V-((R)-1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, T-biphenyl]-3-carboxamide. To a solution of (R)-2',3',6'-trimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid (Intermediate E, 35 mg, 68 pmol), 3,3-difluoro- / V-(1-(methylsulfonyl)piperidin-4-yl)piperidin-4-amine (22 mg, 73 pmol), and DIPEA (59.8 pL, 0.34 mmol) in DCM (1 mL) was added T3P® (50% solution in EtOAc, 58.8 pL, 0.14 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured into a mixture of water (2.5 mL), sat. aq. NaHCOs (2.5 mL), and EtOAc (5 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2x 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous MgSO4, filtered, and concentrated. Purification of the resulting residue by chromatography (FCC, silica gel, 0-5% MeOH(+5% NH4OH) / EtOAc) yielded the title compound as a white powder. MS (ESI): mass calculated for C39H46F5N5O5S, 791.3; m / z measured, 792.3 [M+H]+.1H NMR (500 MHz, DMSO-d6, 100 °C) 68.37-8.49 (m, 1H), 7.79 (br s, 1H), 7.65-7.71 (m, 1H), 7.63 (br s, 1H), 7.50-7.54 (m, 2H), 7.44-7.48 (m, 2H), 7.18 (s, 1H), 7.06-7.12 (m, 1H), 7.00-7.04 (m, 1H), 4.72-4.77 (m, 1H), 3.96-4.21 (m, 1H), 3.70-3.93 (m, 1 H), 3.56 (br d, J = 14.04 Hz, 1 H), 3.50 (br dd, J = 11.44, 5.34 Hz, 2H), 3.25-3.32 (m, 1H), 3.24 (br dd, J= 14.04, 5.04 Hz, 1H), 3.26 (br s, 2H), 3.09 (brdd, J= 13.73, 9.46 Hz, 2H), 2.79-2.81 (m, 2H), 2.78-2.85 (m, 3H), 2.80 (br s, 1 H), 2.62 (d, J = 4.58 Hz, 3H), 2.25 (s, 3H), 1.90 (br d, J = 12.36 Hz, 1 H), 1.87-1.92 (m, 4H), 1.86 (br d, J = 11.75 Hz, 1 H), 1.83-1.88 (m, 3H), 1.55 (br d, J = 9.61 Hz, 1 H), 1.33-1.42 (m, 2H).

[0921] Example 40: 5-(4-Hydroxy-3-(4-(methylsulfonyl)piperazin-1 -y I) piperidi ne-1 -carbonyl)-2',3',6'-trimethyl- / V-((R)-1-(methylamino)-1-oxo-3-(4- (trifl uoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide.

[0922]

[0923] Step A: tert-Butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate. A mixture of tert-butyl 3,6-dihydropyridine-1(2H)-carboxylate (15 g, 82 mmol), 3-chloroperoxybenzoic acid (27.5 g, 122 mmol) in DCM (273 mL) was stirred at room temperature. The resulting mixture was washed with saturated aqueous NaHCOs and brine. The organic phase was dried and concentrated under reduced pressure to yield the title compound.1H NMR (400 MHz, CDCIs) 63.8-4.0 (m, 1 H), 3.6-3.8 (m, 1H), 3.4-3.5 (m, 1H), 3.29 (br s, 1H), 3.21 (br s, 1H), 3.0-3.2 (m, 1H), 2.0-2.1 (m, 1H), 1.8-2.0 (m, 1H), 1.45 (s, 9H).

[0924] Step B: tert-Butyl 4-hydroxy-3-(4-(methylsulfonyl)piperazin-1-yl)piperidine-1-carboxylate. To a mixture of terf-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (1.28 g, 6.41 mmol) in EtOH (3 mL) was added Et₃N (1.69 mL, 12.2 mmol) and 1-(methylsulfonyl)piperazine (1.0 g, 6.1 mmol). The reaction mixture was then placed into a pre-heated 90 °C metal heating block and stirred for 19.5 h. The reaction mixture was cooled to room temperature and transferred into a mixture of water (25 mL), sat. aq. NaHCOs (25 mL), and EtOAc (25 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3x 25 mL). The solids remaining in the aqueous layer were collected by vacuum filtration, then washed first with water, and then EtOAc. The filter cake was collected and dried to yield the title compound as a white solid. MS (ESI): mass calculated for C15H29N3O5S, 363.2; m / z measured, 363.9 [M+H]+.

[0925] Step C: 3-(4-(Methylsulfonyl)piperazin-1-yl)piperidin-4-ol dihydrochloride. To te / Y-buty I 4-hydroxy-3-(4-(methylsulfonyl)piperazin-1 -y l)pi peridi ne-1 -carboxylate (52.5 mg, 144 pmol) was added HCI (5.5 M in / PrOH, 0.79 ml_, 4.33 mmol) under Ar (g) atmosphere. The reaction was stirred at room temperature for 4.5 h before heating to 55 °C for 1 h. The reaction mixture was concentrated to yield 3-(4-(methylsulfonyl)piperazin-1-yl)piperidin-4-ol dihydrochloride as a pale yellow powder.

[0926] 1H NMR (400 MHz, D2O) 54.11 (br d, J= 4.52 Hz, 1H), 3.71-3.83 (m, 1H), 3.48-3.55 (m, 3H), 3.44 (br dd, J= 13.69, 4.28 Hz, 2H), 3.37-3.44 (m, 1H), 3.44 (br s, 4H), 3.16-3.25 (m, 1 H), 2.95 (s, 4H), 2.26 (br s, 1 H), 2.24 (br s, 1 H), 1.65-1.84 (m, 1 H), 0.96-1.20 (m, 1H).

[0927] Step D: 5-(4-Hydroxy-3-(4-(methylsulfonyl)piperazin-1 -y I) piperidi ne-1 -carbonyl)-2',3',6'-trimethyl- / V-((R)-1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1,1'-biphenyl]-3-carboxamide. To a mixture of 3-(4-(methylsulfonyl)piperazin-1-yl)piperidin-4-ol dihydrochloride (48.5 mg, 144 pmol) in DMF (0.3 mL) was added Et₃N (0.04 mL, 273 pmol). The mixture was stirred for ~2 min before the addition of (R)-2',3',6'-trimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylic acid (Intermediate E, 20 mg, 39 pmol). The reaction mixture was heated to 50 °C for 5 min, then cooled to room temperature before the addition of HATU (22.3 mg, 58.5 pmol). The reaction mixture was then placed into a pre-heated 50 °C metal heating block and stirred for 19 h. The temperature was then increased to 70 °C and maintained for an additional 1.5 h. The reaction mixture was cooled to room temperature and then poured into a mixture containing water (3 mL), sat. aq.

[0928] NaHCOs (3 mL), and EtOAc (5 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3x 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous MgSO4, filtered, and then concentrated. Purification of the resulting residue by preparative reverse-phase HPLC (Stationary phase: Waters XBridge BEH C18, 5u, 19x100 mm; Mobile phase A: water + pH 10 NH4OH; Mobile Phase B: MeCN + pH 10 NH4OH; Gradient elution: 35 - 70% B in A over 10 min; Flow rate: 25 mL / min) yielded the title compound as a white solid. MS (ESI): mass calculated for C38H46F3N5O6S, 757.3; m / z measured, 757.8 [M+H]+.1H NMR (400 MHz, CDCI3) 57.84 (brs, 1H), 7.5-7.7 (m, 3H), 7.40 (br d, J= 7.8 Hz, 2H,), 7.32 (br s, 1 H), 7.1-7.2 (m, 1H), 7.05 (br d, J = 7.8 Hz, 2H,), 5.81 (br s, 1 H), 4.8-5.0 (m, 1 H), 4.7-4.8 (m, 1 H), 3.76 (br s, 2H), 3.3-3.6 (m, 4H), 3.2-3.3 (m, 4H), 3.0-3.1 (m, 2H), 2.83 (brs, 4H), 2.6-2.8 (m, 5H), 2.4-2.6 (m, 2H), 2.31 (s, 3H), 1.97 (br d, J = 5.4 Hz, 3H), 1.92 (br d, J = 5.4 Hz, 3H).

[0929] Example 41: (R)-2',3',6'-T ri methy \-N- 1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(piperidin-4-yloxy)piperidine-1-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0930]

[0931] Step A: tert-Butyl (R)-4-((1-(2',3',6'-trimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carbonyl)piperidin-4-yl)oxy)piperidine-1-carboxylate. To a solution of (R)-2',3',6'-trimethyl-5-((1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylic acid (Intermediate E, 67.9 mg, 132 pmol), 4-(piperidine-4-yloxy)-piperidine-1 -carboxylic acid tert-butyl ester (42.6 mg, 150 pmol ) and DIPEA (114 pL, 662 pmol) in DCM (1.3 mL) was added T3P® (50% solution in EtOAc, 118 pL, 397 pmol ). The reaction was stirred at room temperature for 22 h. The reaction mixture was then added to a mixture containing water (5 mL), sat. aq. NaHCOs (5 mL), and EtOAc (5 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2x 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous MgSO4, filtered, and then concentrated to yield the title compound as a white solid. MS (ESI): mass calculated for C43H53F3N4O6, 778.4; m / z measured, 679.3 [M+H-100]+.

[0932] Step B: (R)-2',3',6'-Trimethyl- / V-(1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)-5-(4-(piperidin-4-yloxy)piperidine-1 -carbonyl)-[1,1'-biphenyl]-3-carboxamide. To a solution of tert-butyl (R)-4-((1-(2',3',6'-trimethyl-5-((1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 biphenyl]-3-carbonyl)piperidin-4-yl)oxy)piperidine-1 -carboxylate (105 mg, 135 pmol ) in DCM (0.7 ml_) was added TFA (300 pL, 3.92 mmol) under Ar (g) atmosphere. The reaction mixture was stirred at room temperature for 40 minutes. The reaction mixture was concentrated and the resulting residue was purified by preparative reverse-phase HPLC (Stationary phase: Waters XSelect CSH C18, 5p, 19 x 150 mm; Mobile phase A: water + 0.16% TFA; Mobile Phase B: MeCN + 0.16% TFA; Gradient elution: 20 - 55% B in A over 12 min; Flow rate: 25 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C38H45F3N4O4, 678.3; m / z found, 679.2 [M+H]+. 1 H NMR (400 MHz, CD3OD) 67.78 (s, 1 H), 7.60 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H), 7.30 (s, 1H), 7.09 (d, J = 7.8 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 3.9-4.1 (m, 1H), 3.8-3.9 (m, 2H), 3.5-3.7 (m, 2H), 3.3-3.4 (m, 3H), 3.1-3.2 (m, 3H), 2.73 (s, 3H), 2.29 (s, 3H), 1.8-2.1 (m, 13H), 1.69 (brs, 1H), 1.55 (brs, 1H).

[0933] Example 42: (R)-2',3',6'-Trimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-((1-(methylsulfonyl)piperidin-4-yl)oxy)piperidine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0934]

[0935] To a solution of (R)-2',3',6'-trimethyl- / V-(1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)-5-(4-(piperidin-4-yloxy)piperidine-1 -carbonyl)- [1, 1 '-biphenyl]-3-carboxamide (Example 41, 60 mg, 80 pmol) in DCM (0.8 m L) was added Et₃N (34.3 pL, 247 pmol). The reaction mixture was stirred for 1 min before MsCI (6.8 pL, 88 pmol) was added. The reaction mixture was stirred at room temperature for 1.5 h and then poured into a mixture of water (2.5 mL), sat. aq. NaHCOs (2.5 mL), and EtOAc (5 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2x 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous MgSO4, filtered, and then concentrated. Purification of the resulting residue by chromatography (FCC, silica gel, 0-10% MeOH(+1% NH4OH) / EtOAc) yielded the title compound as a white solid. MS (ESI): mass calculated for C39H47F3N4O6S, 756.3; m / z measured, 757.3 [M+H]+.

[0936] 1H NMR (400 MHz, CDCI3) 67.80 (s, 1 H), 7.5-7.6 (m, 3H), 7.39 (d, J = 8.3 Hz, 2H), 7.30 (s, 2H), 7.1-7.2 (m, 1H), 7.0-7.1 (m, 1H), 6.90 (brd, J= 7.8 Hz, 1H), 5.69 (br d, J= 3.9 Hz, 1H), 4.7-4.9 (m, 1H), 3.9-4.1 (m, 1H), 3.5-3.8 (m, 4H), 3.3-3.4 (m, 2H), 3.1-3.3 (m, 5H), 2.79 (s, 3H), 2.76 (d, J = 4.4 Hz, 3H), 2.29 (s, 3H), 1.95 (d, J= 3.9 Hz, 3H), 1.90 (br d, J = 4.4 Hz, 6H), 1.7-1.8 (m, 4H).

[0937] Example 43: (R)-2',5'-Dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(3-oxo-4-(pyridin-2-ylmethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carbonyl)-[1,1'-biphenyl]-3-carboxamide.

[0938]

[0939] To a solution of (R)-2',5'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylic acid (Intermediate B, 55 mg, 0.11 mmol), 4-(pyridin-2-ylmethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one HCI (29 mg, 0.11 mmol) and Et₃N (74 pL, 0.53 mmol) in DMF (0.6 mL) was added HATU (49 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was filtered, and the filtrate was purified directly by RP-HPLC (Stationary phase: Phenomenex Gemini-NX C18, 3 pm, 75 x 30 mm; Mobile phase: (0.05% NH4OH in H2O (A) - MeCN (B), gradient elution: 43 - 73% B in A over 6 min, flow rate: 25 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C41H42F3N5O5, 741.3; m / z measured, 742.2 [M+H]+.1H NMR (400 MHz, CDCI3) 6 = 8.55 (d, J = 4.8 Hz, 1 H), 7.79-7.73 (m, 2H), 7.70 (dt, J= 7.7, 1.9 Hz, 1H), 7.59 (d, J= 8.0 Hz, 2H), 7.47 (s, 1H), 7.40 (d, J = 7.8 Hz, 2H), 7.35 (d, J= 7.8 Hz, 1H), 7.26-7.18 (m, 2H), 7.17-7.11 (m, 1H), 7.03 (s, 1 H), 6.96 (d, J = 7.5 Hz, 1 H), 5.70 (br s, 1 H), 4.88-4.72 (m, 2H), 4.64 (br s, 1 H), 4.42 (brs, 1H), 4.26 (brd, J = 4.3 Hz, 2H), 3.53 (brs, 1H), 3.38 (s, 3H), 3.31-3.16 (m, 3H), 2.77 (d, J = 4.8 Hz, 3H), 2.37 (s, 3H), 2.21 (s, 3H), 2.03 (br d, J = 15.8 Hz, 1H), 1.82 (brs, 1H), 1.46 (br s, 2H).

[0940] Example 44: 5-(6-(Hydroxymethyl)-1 -methyl-4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridine-5-carbonyl)-2',5'-dimethyl- / \ / -((R)-1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide.

[0941]

[0942] The title compound was prepared according to the procedure described in Example 43, substituting (1-methyl-4,5,6,7-tetrahydro-1 / - / -imidazo[4,5-c]pyridin-6-yl)methanol HCI for 4-(pyridin-2-ylmethyl)-1 -oxa-4,9-diazaspiro[5.5]undecan-3-one HCI, to yield the title compound as a white solid. MS (ESI): mass calculated for C35H36F3N5O4, 647.3; m / z measured, 648.3 [M+H]+.1H NMR (400 MHz, CDCI3) 6 8.06 (br s, 1 H), 7.99-7.72 (m, 2H), 7.52 (br d, J = 8.0 Hz, 3H), 7.46-7.32 (m, 3H), 7.20-7.06 (m, 2H), 7.04-6.92 (m, 1H), 6.47-6.11 (m, 1H), 5.53-5.17 (m, 1H), 4.81 (br s, 1H), 4.58-4.34 (m, 2H), 4.32-4.14 (m, 1H), 3.91-3.69 (m, 2H), 3.56 (br s, 3H), 3.46 (br s, 1 H), 3.25 (br d, J = 6.8 Hz, 2H), 2.96 (br s, 1 H), 2.75-2.60 (m, 3H), 2.33 (d, J = 11.3 Hz, 3H), 2.25-2.13 (m, 3H).

[0943] Example 45: (R)-5-(6-Benzyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-2',5'-dimethy \-N-( 1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '- biphenyl]-3-carboxamide.

[0944]

[0945] The title compound was prepared according to the procedure described in Example 43, substituting 2-benzyl-2,6-diazaspiro[3.3]heptane oxalate for 4-(pyridin-2-ylmethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one HCI, to yield the title compound as a white solid. MS (ESI): mass calculated for C39H39F3N4O3, 668.3; m / z measured, 669.5 [M+H]+.1H NMR (400 MHz, CD3OD) 67.98 (s, 1 H), 7.85 (br s, 1 H), 7.71 (s, 1H), 7.59 (br d, J= 7.4 Hz, 2H), 7.49 (br s, 7H), 7.18 (brd, J= 19.0 Hz, 2H), 7.05 (br s, 1H), 4.87-4.83 (m, 1H), 4.71-4.50 (m, 1H), 4.49-4.21 (m, 8H), 3.43-3.36 (m, 1H), 3.20-3.08 (m, 1 H), 2.74 (br s, 3H), 2.37 (br s, 3H), 2.20 (br s, 3H).

[0946] Example 46: (R)-5-(7-Benzyl-2,7-diazaspiro[3.5]nonane-2-carbonyl)-2',5'-dimethy I- / -( 1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide.

[0947]

[0948] The title compound was prepared according to the procedure described in Example 43, substituting 7-benzyl-2,7-diazaspiro[3.5]nonane dihydrochloride for 4-(pyridin-2-ylmethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one HCI, to yield the title compound as a white solid. MS (ESI): mass calculated for C41H43F3N4O3, 696.3; m / z measured, 697.3 [M+H]+.1H NMR (400 MHz, CDCI3) 6= 8.03 (s, 1H), 7.79 (s, 1H), 7.69 (s, 1 H), 7.54 (br d, J = 7.7 Hz, 2H), 7.37 (br d, J = 7.9 Hz, 2H), 7.35-7.27 (m, 5H), 7.26-7.07 (m, 3H), 7.01 (s, 1H), 6.12 (br s, 1H), 4.85 (brd, J = 6.6 Hz, 1H), 3.96 (s, 2H), 3.87 (s, 2H), 3.46 (s, 2H), 3.33-3.15 (m, 2H), 2.80-2.65 (m, 3H), 2.35 (s, 7H), 2.19 (s, 3H), 1.84 (br s, 2H), 1.79 (brs, 2H).

[0949] Example 47: (R)-2'-(Methoxymethyl)- / \ / 3,3',6'-tnmethyl- / \ / 5-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3,5-dicarboxamide.

[0950]

[0951] To a solution of (R)-2'-(methoxymethyl)-3',6'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylic acid (Intermediate F, 100 mg, 0.12 mmol), methylamine HCI (16.2 mg, 0.24 mmol) and Et₃N (100 pL, 0.72 mmol) in DMF (2 mL) was added HATU (59.2 mg, 0.16 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was purified directly by RP-HPLC (Stationary phase: Phenomenex Gemini-NX C18, 3 pm, 75 x 30 mm; Mobile phase: (0.05% NH3H2O + 10 mM NH4HCO3in water) (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 white solid. MS (ESI): mass calculated for C30H32F3N3O4, 555.2; m / z measured, 578.1 [M+Na]+.1H NMR (400 MHz, CDCI3) 6 8.24 (d, J = 8.0 Hz, 1 H), 7.83 (d, J = 1.3 Hz, 1 H), 7.77 (d, J = 6.5 Hz, 1 H), 7.56 (d, J = 8.0 Hz, 2H), 7.37-7.39 (m, 2H), 7.21-7.08 (m, 3H), 6.43-6.47 (m, 1H), 5.96-5.98 (m, 1H), 4.90-4.79 (m, 1H), 4.07-3.94 (m, 2H), 3.31-3.21 (m, 2H), 3.16 (d, J= 13.8 Hz, 3H), 3.03 (dd, J = 4.8, 2.3 Hz, 3H), 2.77 (dd, J = 4.8, 1.8 Hz, 3H), 2.44 (s, 3H), 1.99 (s, 3H).

[0952] Example 48: (R)-2'-(Hydroxymethyl)- / V3,3',6'-trimethyl- / V5-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3,5-dicarboxamide.

[0953]

[0954] To a solution of (R)-2'-(hydroxymethyl)-3',6'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylic acid (Intermediate G, 100 mg, 0.15 mmol), methylamine HCI (20.7 mg, 0.31 mmol) and Et3N (107 pL, 0.77 mmol) in DMF (2 mL) was added HATU (75.8 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was purified directly by RP-HPLC (Stationary phase: Phenomenex Gemini-NX C18, 3 pm, 75 x 30 mm; Mobile phase: (0.05% NH3H2O + 10 mM NH4HCO3in water) (A) - MeCN (B), gradient elution: 35 - 65% 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 C29H30F3N3O4, 541.2; m / z measured, 564.0 [M+Na]+.1H NMR (400 MHz, DMSO-d6) 6 8.78 (dd, J = 8.4, 3.6 Hz, 1 H), 8.51 (t, J = 4.4 Hz, 1 H), 8.30 (d, J = 8.0 Hz, 1 H), 8.16-8.06 (m, 1H), 7.83-7.73 (m, 2H), 7.64-7.56 (m, 2H), 7.55-7.49 (m, 2H), 7.15 (s, 2H), 4.80-4.67 (m, 1H), 4.59-4.48 (m, 1H), 4.21-4.03 (m, 2H), 3.23-3.13 (m, 1H), 3.12-3.02 (m, 1 H), 2.79 (d, J = 4.3 Hz, 3H), 2.61 (d, J = 4.5 Hz, 3H), 2.41 (d, J = 2.5 Hz, 3H), 1.90 (d, J= 18.6 Hz, 3H).

[0955] Example 49: (R)-2'-(Hydroxymethyl)-3',6'-dimethyl- / \ / -(1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(morpholine-4-carbonyl)-[1, 1 '-bi pheny l]-3-carboxamide.

[0956]

[0957] The title compound was prepared according to the procedure described in Example 48, substituting morpholine for methylamine HCI, to yield the title compound as a white solid. MS (ESI): mass calculated for C32H34F3N3O5, 597.2; m / z measured, 580.3 [M+H-H2O]+.1H NMR (400 MHz, DMSO-d6) 6 = 8.80 (dd, J= 8.4, 3.4 Hz, 1H), 8.14-8.04 (m, 1H), 7.86 (s, 1H), 7.71 (s, 1H), 7.60 (d, J= 7.2 Hz, 2H), 7.52 (d, J= 7.4 Hz, 2H), 7.36 (d, J= 7.9 Hz, 1H), 7.15 (d, J= 1.9 Hz, 2H), 4.80-4.67 (m, 1H), 4.63-4.52 (m, 1H), 4.27-4.12 (m, 1H), 4.05-3.97 (m, 1H), 3.70-3.54 (m, 6H), 3.18 (d, J= 11.6 Hz, 1H), 3.10-3.03 (m, 1H), 2.90 (d, J= 19.8 Hz, 1H), 2.61 (d, J = 4.5 Hz, 3H), 2.43-2.38 (m, 3H), 1.90 (d, J= 11.9 Hz, 3H).

[0958] Example 50: (R)-2'-(Hydroxymethyl)-3',6'-dimethyl- / \ / -(1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0959]

[0960] The title compound was prepared according to the procedure described in Example 48, substituting 5,6,7,8-tetrahydro-1,6-naphthyridine for methylamine HCI, to yield the title compound as a white solid. MS (ESI): mass calculated for C36H35F3N4O4, 644.3; m / z measured, 645.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 = 8.83 (d, J = 4.5 Hz, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 7.95 (s, 1H), 7.74 (s, 2H), 7.61 (s, 2H), 7.53-7.37 (m, 2H), 7.26 (s, 1H), 7.15 (d, J= 1.9 Hz, 2H), 4.92-4.58 (m, 4H), 4.27-3.99 (m, 2H), 3.69 (s, 1H), 3.19-3.16 (m, 1H), 3.14-2.88 (m, 4H), 2.61 (d, J = 4.4 Hz, 3H), 2.41 (d, J= 2.4 Hz, 3H), 1.92 (d, J= 9.7 Hz, 3H).

[0961] Example 51: (R)-5-(4-(1, 1 -Dioxidothiomorpholino)piperidine-1 -carbonyl)-2'-(hydroxymethyl)-3',6'-dimethyl- / \ / -(1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide.

[0962]

[0963] The title compound was prepared according to the procedure described in Example 48, substituting 4-(piperidin-4-yl)thiomorpholine 1,1 -dioxide dihydrochloride for methylamine HCI, to yield the title compound as a white solid. MS (ESI): mass calculated for C37H43F3N4O6S, 728.3; m / z measured, 729.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 68.79 (d, J = 5.6 Hz, 1 H), 8.11 (d, J = 4.4 Hz, 1 H), 7.85 (s, 1 H), 7.70 (s, 1H), 7.60 (d, J= 7.3 Hz, 2H), 7.55-7.49 (m, 2H), 7.40-7.31 (m, 1H), 7.15 (d, J= 1.4 Hz, 2H), 4.80-4.64 (m, 1H), 4.63-4.48 (m, 2H), 4.24-3.97 (m, 2H), 3.62 (s, 1H), 3.20-3.16 (m, 1H), 3.08-2.95 (m, 9H), 2.80-2.77 (m, J= 11.3 Hz, 2H), 2.61 (d, J = 4.5 Hz, 3H), 2.41 (d, J = 2.6 Hz, 3H), 1.90 (d, J = 12.5 Hz, 3H), 1.82-1.59 (m, 2H), 1.44-1.42 (m, 2H).

[0964] Example 52: / \ / 3-((S)-1 -hydroxypropan-2-yl)-2'-(methoxymethyl)-3',6'-dimethyl- / \ / 5-((R)-1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3,5-dicarboxamide.

[0965]

[0966] The title compound was prepared according to the procedure described in Example 47, substituting L-alaninol for methylamine HCI, to yield the title compound as a white solid. MS (ESI): mass calculated for C32H36F3N3O5, 599.3; m / z measured, 600.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 68.80 (dd, J= 8.4, 2.9 Hz, 1H), 8.32 (d, J= 5.3 Hz, 1H), 8.21 (dd, J = 7.8, 4.8 Hz, 1H), 8.10 (t, J = 4.3 Hz, 1H), 7.80 (d, J = 6.0 Hz, 1H), 7.74 (d, J= 15.8 Hz, 1H), 7.62-7.56 (m, 2H), 7.55-7.48 (m, 2H), 7.23- 7.15 (m, 2H), 4.81-4.70 (m, 2H), 4.04 (td, J= 13.4, 6.6 Hz, 1H), 3.99-3.89 (m, 2H), 3.46 (td, J= 10.9, 5.5 Hz, 1H), 3.37-3.36 (m, 1H), 3.23-3.14 (m, 1H), 3.13-3.03 (m, 1H), 3.00-2.90 (m, 3H), 2.62 (d, J = 4.5 Hz, 3H), 2.36 (s, 3H), 1.94 (d, J = 13.8 Hz, 3H), 1.13 (d, J= 6.8 Hz, 3H).

[0967] Example 53: (R)-2'-(Methoxymethyl)-3',6'-dimethyl- / \ / -(1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(morpholine-4-carbonyl)-[1, 1 '-bi pheny l]-3-carboxamide.

[0968]

[0969] The title compound was prepared according to the procedure described in Example 47, substituting morpholine for methylamine HCI, to yield the title compound as a white solid. MS (ESI): mass calculated for C33H36F3N3O5, 611.3; m / z measured, 612.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 68.81 (dd, J= 8.5, 3.3 Hz, 1H), 8.11-8.08 (m, 1H), 7.91-7.83 (m, 1H), 7.69 (d, J= 13.6 Hz, 1H), 7.63-7.57 (m, 2H), 7.55-7.49 (m, 2H), 7.28 (s, 1H), 7.22-7.14 (m, 2H), 4.80-4.68 (m, 1H), 4.07-3.97 (m, 1H), 3.92 (dd, J= 10.2, 1.9 Hz, 1H), 3.77-3.36 (m, 8H), 3.24-3.16 (m, 1H), 3.13-3.03 (m, 1H), 2.98 (d, J= 16.8 Hz, 3H), 2.62 (d, J = 4.3 Hz, 3H), 2.35 (s, 3H), 1.92 (d, J= 9.8 Hz, 3H).

[0970] Example 54: (R)-2'-(Methoxymethyl)-3',6'-dimethyl- / \ / -(1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0971]

[0972] The title compound was prepared according to the procedure described in Example 47, substituting 5,6,7,8-tetrahydro-1,6-naphthyridine for methylamine HCI, to yield the title compound as a white solid. MS (ESI): mass calculated for C37H37F3N4O4, 658.3; m / z measured, 659.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 = 8.89-8.76 (m, 1H), 8.40-8.41 (m, 1H), 8.12-8.09 (m, 1H), 7.95 (s, 1H), 7.72 (d, J = 12.0 Hz, 2H), 7.62-7.57 (m, 2H), 7.53-7.52 (m, 2H), 7.36 (s, 1H), 7.27 (s, 1H), 7.21-7.14 (m, 2H), 4.96-4.52 (m, 3H), 4.09-3.63 (m, 4H), 3.21-3.20 (m, 1H), 3.08 (brd, J = 11.3 Hz, 1 H), 3.00-2.99 (m, 5H), 2.62 (d, J = 4.5 Hz, 3H), 2.36 (d, J = 2.0 Hz, 3H), 1.95 (d, J = 6.8 Hz, 3H).

[0973] Example 55: (R)-5-(4-(1,1-Dioxidothiomorpholino)piperidine-1-carbonyl)-2'-(methoxymethyl)-3',6'-dimethyl- / \ / -(1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide.

[0974]

[0975] The title compound was prepared according to the procedure described in Example 47, substituting 4-(piperidin-4-yl)thiomorpholine 1,1 -dioxide dihydrochloride for methylamine HCI, to yield the title compound as a white solid. MS (ESI): mass calculated for C38H45F3N4O6S, 742.3; m / z measured, 743.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) <58.84-8.75 (m, 1H), 8.11-8.10 (m, 1H), 7.90-7.82 (m, 1H), 7.68 (d, J= 11.3 Hz, 1H), 7.62-7.56 (m, 2H), 7.56-7.48 (m, 2H), 7.27 (s, 1H), 7.22-7.14 (m, 2H), 4.76-4.71 (m, 1H), 4.56-4.53 (m, 1H), 4.10-3.98 (m, 1H), 3.97-3.89 (m, 1H), 3.61 (s, 1H), 3.24-3.15 (m, 1H), 3.11-2.91 (m, 13H), 2.81-2.79 (m, 2H), 2.62 (d, J = 4.5 Hz, 3H), 2.39-2.33 (m, 3H), 1.92 (d, J= 10.5 Hz, 3H), 1.79 (s, 1H), 1.64 (s, 1H), 1.44 (s, 2H).

[0976] Example 56: 2'-(Hydroxymethyl)- / \ / 3-((S)-1 -hydroxypropan-2-yl)-3',6'-dimethyl- / \ / 5-((R)-1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3,5-dicarboxamide.

[0977]

[0978] The title compound was prepared according to the procedure described in Example 48, substituting L-alaninol for methylamine HCI, to yield the title compound as a white solid. MS (ESI): mass calculated for C31H34F3N3O5, 585.2; m / z measured, 568.3 [M +H-H2O]+.1H NMR (400 MHz, DMSO-d6) 68.80-8.77 (m, 1 H), 8.29 (m, 1 H), 8.18 (d, J= 7.8 Hz, 1H), 8.15-8.07 (m, 1H), 7.81 (s, 1H), 7.76 (d, J= 9.5 Hz, 1H), 7.63-7.56 (m, 2H), 7.55-7.49 (m, 2H), 7.15 (s, 2H), 4.79-4.71 (m, 2H), 4.58-4.49 (m, 1H), 4.18-3.99 (m, 3H), 3.46 (td, J= 10.7, 5.5 Hz, 1H), 3.22-3.14 (m, 1H), 3.12-3.03 (m, 1H), 2.61 (d, J = 4.3 Hz, 3H), 2.42 (d, J = 2.3 Hz, 3H), 1.90 (d, J= 18.6 Hz, 3H), 1.13 (d, J= 6.8 Hz, 3H).

[0979] Example 57: (R)-5-(4-(1,1-Dioxidothiomorpholino)piperidine-1-carbony -2’,5'-dimethy I- / -( 1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[T, 1 '-biphenyl]-3-carboxamide.

[0980]

[0981] Step A. (R)-2',5'-Dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan- 2-yl)-5-(4-oxopiperidine-1 -carbonyl)-[1, 1 '-bi phenyl ]-3-carboxamide. To a solution of (R)-2',5'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl) phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylic acid (Intermediate B, 300 mg, 0.60 mmol), piperidin-4-one (90 mg, 0.91 mmol) and DIEA (0.62 mg, 3.6 mmol) in DMF (8 mL) was added HATU (297 mg, 0.78 mmol). The mixture was stirred at room temperature for 16 h. The mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (20 ml_ x 3). The combined organic extracts were washed with brine (50 mL x 3), dried over Na2SO4, filtered, and then concentrated under vacuum. The resulting residue was purified by column chromatography (SiO2, 0-100% ethyl acetate in petroleum ether) to yield the title compound as a brown solid. MS (ESI): mass calculated for C32H32F3N3O4, 579.2; m / z measured, 580.2 [M+H]+.1H NMR (400 MHz, CDCI3) 57.85 (t, J= 1.5 Hz, 1H), 7.77 (t, J= 1.7 Hz, 1H), 7.59-7.53 (m, 3H), 7.38 (d, J= 8.1 Hz, 2H), 7.21-7.16 (m, 1H), 7.13 (d, J= 7.7 Hz, 2H), 7.02 (s, 1H), 5.83 (d, J = 4.4 Hz, 1H), 4.80 (q, J= 7.5 Hz, 1H), 4.09-3.92 (m, 2H), 3.77 (s, 2H), 3.30-3.17 (m, 2H), 2.74 (d, J = 4.9 Hz, 3H), 2.67-2.41 (m, 4H), 2.36 (s, 3H), 2.21 (s, 3H).19F NMR (376 MHz, CDCI3) 6 -62.49 (s, 1F).

[0982] Step B. (R)-5-(4-(1,1-Dioxidothiomorpholino)piperidine-1-carbonyl)-2',5'-dimethy I- / -( 1 - (methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide. To a solution of (R)-2',5'-dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl) propan-2-yl)-5-(4-oxopiperidine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamide (200 mg, 0.33 mmol) and thiomorpholine 1,1 -dioxide (132 mg, 0.98 mmol) in MeOH (12 mL) was added ZnCL (67 mg, 0.49 mmol). The mixture was stirred at 60°C for 16 h. NaBHsCN (41 mg, 0.65 mmol) was then added and the resulting mixture was stirred at 60°C for 2 h then concentrated under vacuum. The residue was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic extracts were dried over Na2SO4, filtered, and then concentrated under vacuum. The resulting residue was purified by RP-HPLC ((Stationary phase: Boston Prime C185 pm 150 x 30 mm, Mobile phase: (0.05% aqueous NH4OH + 10 mM NH4HCO3) (A) - MeCN (B), gradient elution: 55 - 75% 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 C36H41F3N4O5S, 698.3; m / z measured, 699.4 [M+H]+.

[0983] 1H NMR (400 MHz, CDCI3) 67.78-7.70 (m, 2H), 7.58 (d, J= 8.1 Hz, 2H), 7.48 (s, 1H), 7.39 (d, J= 7.9 Hz, 2H), 7.22-7.17 (m, 1H), 7.16-7.10 (m, 1H), 7.03 (s, 1H), 6.98-6.91 (m, 1H), 6.95 (d, J= 5.7 Hz, 1H), 5.66 (s, 1H), 4.90-4.71 (m, 2H), 3.84 (s, 1H), 3.32-3.16 (m, 2H), 3.07 (d, J= 3.1 Hz, 9H), 2.76 (d, J = 4.9 Hz, 5H), 2.36 (s, 3H), 2.21 (s, 3H), 1.98-1.69 (m, 2H), 1.45 (s, 1H).19F NMR (376 MHz, CDCI3) 6- 62.47 (s, 1F).

[0984] Example 58: 5-(3-( / V-((5-isopropyloxazol-2-yl)methyl)acetamido)pyrrolidine-1 -carbonyl)-2',5'-dimethyl- / V-((R)-1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide.

[0985]

[0986] The title compound was prepared as described in Scheme 1 (analogous to Example 3) substituting / V-((5-isopropyloxazol-2-yl)methyl)- / \ / -(pyrrolidin-3-yl)acetamide for 4-(piperidin-4-yl)morpholine. MS (ESI): mass calculated for C40H44F3N5O5, 731.3; m / z measured: 732.4 [M+H]+.1H NMR (400 MHz, CDCI3) 6 7.87 (s, 1H), 7.77 (s, 1H), 7.54 (d, J = 9.4 Hz, 3H), 7.36 (dd, J = 18.3, 8.0 Hz, 3H), 7.22 - 7.06 (m, 2H), 7.00 (s, 1 H), 6.76 - 6.50 (m, 1 H), 6.21 (s, 1 H), 5.29 - 4.78 (m, 2H), 4.78 - 4.42 (m, 2H), 3.83 (s, 1 H), 3.63 (d, J = 41.4 Hz, 3H), 3.25 (s, 2H), 2.90 (s, 1H), 2.73 (d, J = 4.7 Hz, 3H), 2.35 (s, 3H), 2.19 (d, J = 6.1 Hz, 8H), 1.22 (d, J = 19.7 Hz, 6H).

[0987] Example 59: (R)-2',5'-dimethyl-5-(2-methyl-3-oxo-2,3,5,6,7,8-hexahydropyrido[4,3-c]pyridazine-6-carbonyl)- / \ / -(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide

[0988]

[0989] The title compound was prepared as described in Scheme 1 (analogous to Example 3) substituting 2-methyl-5,6,7,8-tetrahydropyrido[4,3-c]pyridazin-3(2 / - / )-one for 4-(piperidin-4-yl)morpholine. MS (ESI): mass calculated for C35H34F3N5O4, 645.3; m / z measured: 646.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 68.74 (d, J = 8.4 Hz, 1 H), 7.95 (d, J = 18.8 Hz, 3H), 7.69 - 7.33 (m, 5H), 7.15 (d, J = 7.9 Hz, 1H), 7.06 (d, J = 6.8 Hz, 2H), 6.81 (s, 1H), 4.76 (td, J = 9.3, 5.0 Hz, 3H), 3.72 (s, 2H), 3.64 (s, 3H), 3.21 - 3.12 (m, 2H), 2.82 (s, 2H), 2.66 (d, J = 4.6 Hz, 3H), 2.35 (s, 3H), 2.23 (d, J = 3.3 Hz, 3H).

[0990] Example 60: (R)-5-(4-([1,2, 4]triazolo[4, 3-a]py rim idin-3-y l)pi peridine-1 -carbony l)-2', 5'-di methy l-A / -( 1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide

[0991]

[0992] The title compound was prepared as described in Scheme 1 (analogous to Example 3) substituting 3-(piperidin-4-yl)-[1,2,4]triazolo[4,3-a]pyrimidine for 4-(piperidin-4-yl)morpholine. MS (ESI): mass calculated for C37H36F3N7O3, 683.3; m / z measured: 684.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) 69.21 (d, J = 6.7 Hz, 1 H), 8.86 - 8.67 (m, 2H), 8.02 - 7.75 (m, 3H), 7.52 (s, 4H), 7.40 (s, 1H), 7.24 (dd, J = 6.9, 4.4 Hz, 1H), 7.14 (d, J = 7.7 Hz, 1H), 7.05 (d, J = 7.0 Hz, 2H), 4.74 (d, J = 6.9 Hz, 1H), 4.52 (s, 1H), 3.81 (s, 1H), 3.27 (s, 2H), 3.13 (q, J = 10.6 Hz, 3H), 2.66 (d, J = 4.5 Hz, 3H), 2.35 (s, 3H), 2.23 (s, 3H), 2.00 (d, J = 56.2 Hz, 4H).

[0993] Example 61: (R)-2',5'-dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(9-oxo-4,8-diazaspiro[2.6]nonane-4-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide

[0994]

[0995] The title compound was prepared as described in Scheme 1 (analogous to Example 3) substituting 4,8-diazaspiro[2.6]nonan-9-one for 4-(piperidin-4- yl)morpholine. MS (ESI): mass calculated for C34H35F3N4O4, 620.3; m / z measured: 621.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) 68.87 (s, 1H), 8.75 (s, 1H), 8.08 (s, 1H), 7.88 (d, J = 51.8 Hz, 3H), 7.60 (d, J = 7.9 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.27 - 6.88 (m, 3H), 4.72 (s, 1H), 4.40 (s, 1H), 3.46 (s, 2H), 3.20 (d, J = 11.0 Hz, 2H), 3.15 - 2.95 (m, 2H), 2.61 (d, J = 4.5 Hz, 3H), 2.31 (d, J = 5.1 Hz, 3H), 2.11 (d, J = 32.2 Hz, 3H), 1.91 (s, 1 H), 1.54 - 0.77 (m, 3H), 0.60 (s, 1 H).

[0996] Additional representative compounds of the present invention, listed in Table 4 below, were similarly prepared according to the general synthesis schemes and example procedures described herein, selecting and substituting suitable starting materials, reagents and adjusting conditions, as would be readily recognized by those skilled in the art.

[0997] Table 4: Representative Compounds of the Present Invention

[0998]

[0999]

[1000]

[1001]

[1002]

[1003]

[1004]

[1005]

[1006]

[1007]

[1008]

[1009]

[1010]

[1011]

[1012]

[1013]

[1014]

[1015]

[1016]

[1017]

[1018]

[1019]

[1020]

[1021]

[1022]

[1023]

[1024]

[1025]

[1026]

[1027]

[1028]

[1029]

[1030]

[1031]

[1032]

[1033]

[1034]

[1035]

[1036]

[1037]

[1038]

[1039]

[1040]

[1041]

[1042]

[1043]

[1044]

[1045]

[1046]

[1047]

[1048]

[1049]

[1050]

[1051]

[1052]

[1053]

[1054]

[1055]

[1056]

[1057]

[1058]

[1059]

[1060]

[1061]

[1062]

[1063]

[1064]

[1065] Biological Example 1:

[1066] BFL-1 BIM (WIAQ peptide) homogeneous time-resolved fluorescence assay

[1067] 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.

[1068] 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

[1069] Table 5: Test Compound Serial Dilutions

[1070]

[1071]

[1072] 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, #61HI2TLB) 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 (ICso) were determined using Genedata Screener® software.

[1073] Biological Example 2:

[1074] BFL-1 BID BH3 homogeneous time-resolved fluorescence assay

[1075] 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.

[1076] 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, #61HI2TLB) 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 (ICso) were determined using Genedata Screener® software.

[1077] Calculation of Ki values for BID and BIM assays

[1078] The Percent-of-Control (Generic) Normalization Method in Genedata Screener® was used to calculate % inhibition for curve fitting:

[1079] Central Reference = Neutral Control (high control): 1%DMSO only Scale Reference = Blank Control (low control):

[1080] 1pM NH2-EDIIRNIARHLAQVGDSMDR-OH Scale Reference Control type = Stimulator

[1081] %controlinhibition(%Inh) = 100* [ (Lsample-Lneutral) / (LBlank-Lneutral) ]

[1082] The 4-points curve fit equation below was used to fit the dose response curves to determine ICso:

[1083] y= Sinf+ [ (S0-Sinf) / (1 +(x / S50)h) ]

[1084] where x=concentration, y = activity, So=activity at bottom plateau of curve, Sinf=acti vity at top plateau of curve, S5o=inflection point, halfway between So and Sinf and h is hill slope. Ki was calculated using the Cheng-Prusoff equation:

[1085] Ki = IC50 / (1 + ([L] / KD)),

[1086] 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, I C50 = 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.

[1087] 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.

[1088] Representative compounds of the present invention were tested according to the procedures 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.

[1089] Table BIO-1: BFL-1 Receptor Inhibition

[1090]

[1091]

[1092]

[1093]

[1094]

[1095]

[1096]

[1097]

[1098]

[1099]

[1100] aCompound exhibited low solubility, which precluded testing at higher concentrations.

[1101] Formulation Example 1:

[1102] Solid, Oral Dosage Form - Prophetic Example

[1103] As a specific embodiment of an oral composition, 100 mg of Compound ID No. 2, prepared as described in Example 2, is formulated with sufficient finely divided lactose to yield a total amount of 580 to 590 mg to fill a size O hard gel capsule. 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.

[1104] 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)whereina is an integer from 0 to 4;each R1is independently selected from the group consisting of halogen, -OH, -CN, -NO2, Ci-4alkyl, fluoro substituted Ci-4alkyl, hydroxy substituted Ci-4alkyl, C2-4alkenyl, fluoro substituted C2-4alkenyl, -O-(Ci-4alkyl), -O-(fluoro substituted C1-4alkyl), -(Ci-4alkyl)-O-(Ci-4alkyl), -C(O)OH, -C(O)-(Ci-4alkyl), -C(O)O-(Ci-4alkyl), -C(O)-NRARB, -NRARB, -(Ci-4alkyl)-NRARB, -NHC(O)-(Ci-3alkyl)-NRARB, -NH-C(O)-(Ci-3alkyl)-NH-C(O)-(Ci-4alkyl), -CH(CN)-NRARB, and -CH(CN)-NH-C(O)-(Ci-4alkyl);wherein RAis selected from the group consisting of hydrogen, and Ci-4alkyl; wherein RBis selected from the group consisting of hydrogen, C1-4alkyl, hydroxy substituted Ci-4alkyl, and -(Ci-4alkyl)-O-(Ci-4alkyl);R2is selected from the group consisting of hydrogen, and Ci-4alkyl;R3is selected from the group consisting of(a) hydrogen;(b) Ci-4alkyl;(c) hydroxy substituted Ci-4alkyl;whereinb is an integer from 0 to 1;L2is selected from the group consisting of — (Ci-4alkyl)-, -(Ci-4alkyl)-(SO2)-, -(hydroxy substituted Ci-4alkyl)-, -(hydroxy substituted Ci-4alkyl)-(SO2)-, -(Ci-4alkyl)-C(O)-, and -(Ci-4alkyl)-O-; provided that L2is bound to the nitrogen atom through analkyl carbon atom;( A jis selected from the group consisting of Cs-ecycloalkyl, phenyl, 5 to 6 membered heteroaryl and 4 to 8 membered heterocycloalkyl; wherein the C3-ecycloalkyl, phenyl, 5 to 6 membered heteroaryl or 4 to 8 membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of -OH, oxo, Ci-4alkyl, hydroxy substituted Ci-4alkyl and -SO2-(Ci-4alkyl);whereinc is an integer from 1 to 2;(B)— ' is phenyl or pyridyl;R4is selected from the group consisting of hydrogen, Ci-4alkyl, -SO2-Ci-4alkyl, and SO2-NRGRH; wherein RGand RHare each independently selected from the group consisting of hydrogen and C1-4alkyl;or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

2. A compound as in Claim 1, whereina is an integer from 0 to 3;each R1is independently selected from the group consisting of halogen, -OH, -CN, Ci-4alkyl, fluoro substituted Ci-4alkyl, hydroxy substituted Ci-4alkyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-4alkyl), -(Ci-4alkyl)-O-(Ci-4alkyl), -C(O)OH, -C(O)-(C1-3alkyl), and -C(O)O-(C1-4alkyl);R2is selected from the group consisting of hydrogen, and Ci-2alkyl;R3is selected from the group consisting of(a) hydrogen;(b) Ci-2alkyl;(c) hydroxy substituted Ci-4alkyl;; whereinb is an integer from 0 to 1;L2is selected from the group consisting of — (Ci-2alkyl)-, -(hydroxy substituted C1-2alkyl)-, and -(Ci-2alkyl)-O-; provided that L2is bound to the nitrogen atom through an alkyl carbon atom;( A )' is selected from the group consisting of C3-6cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 4 to 8 membered heterocycloalkyl; wherein the C3-6cycloalkyl, phenyl, 5 to 6 membered heteroaryl or 4 to 8 membered heterocycloalkyl is optionally substituted with one to two substituents independently selected from the group consisting of -OH, oxo, Ci-2alkyl, hydroxy substituted Ci-2alkyl and -SO2-(C1-2alkyl);'N TY"4(e) '; whereinc is an integer from 1-2;is selected from the group consisting of phenyl and pyridyl; wherein R4is selected from the group consisting of hydrogen, Ci-4alkyl, -SO2Ci-2alkyl, and -SO2NG H; wherein RGand RHare each independently selected from the group consisting of hydrogen and Ci-2alkyl;or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

3. A compound as in Claim 1, whereina is an integer from 1 to 3;each R1is independently selected from the group consisting of Ci-2alkyl, -(C1-2alkyl)-OH and — (Ci-2alky l)-O-(Ci-2alkyl);R2is selected from the group consisting of hydrogen, and Ci-2alkyl;R3is selected from the group consisting of(a) hydrogen;(b) Ci-2alkyl;(c) hydroxy substituted Ci-4alkyl;— (L2)b— b A )(d); whereinb is an integer from 0 to 1;L2is selected from the group consisting of — (Ci-2alkyl)-, -(hydroxy substituted C1-2alkyl)-, and -(Ci-2alkyl)-O-; provided that L2is bound to the nitrogen atom through an alkyl carbon atom;is selected from the group consisting of C3-5cycloalkyl, phenyl, 5 membered heteroaryl, and 4 to 8 membered heterocycloalkyl; wherein the C3-scycloalkyl, phenyl, 5 membered heteroaryl, or 4 to 8 membered heterocycloalkyl is optionally substituted with one to two substituents independently selected from the group consisting of -OH, oxo, Ci-2alkyl, hydroxy substituted Ci-2alkyl and -SO2(CH3);whereinc is an integer from 1 to 2;( B )— ' is selected from the group consisting of phenyl and pyridyl;R4is selected from the group consisting of hydrogen, C1-2alkyl, -SO2CH3, and -SO2NH2;or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

4. A compound as in Claim 1, whereina is an integer from 2 to 3;each R1is independently selected from the group consisting of CH3, -CH2OH, and -CH2-O-CH3;R2is selected from the group consisting of H and -CH3R3is selected from the group consisting ofor a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

5. A compound as in Claim 4, whereina is an integer from 2 to 3;each R1is independently selected from the group consisting of -CH3, -CH2OH, and -CH2-O-CH3;R2is selected from the group consisting of hydrogen and -CH3;R3is selected from the group consisting of -CH3,or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

6. A compound as in Claim 4, whereina is an integer from 2 to 3;each R1is independently selected from the group consisting of -CH3, -CH2OH, -CH2-0-CH3;R2is hydrogen;R3is selected from the group consisting of -CH3, andor a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

7. A compound as in Claim 4, whereina is 2;R1is -CH3;R2is -CH3;R3is selected from the group consisting ofandor a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

8. 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 any one of Claims 1 to 7.

9. The method of Claim 8, 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).

10. The method of Claim 8, wherein the leukemia is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

11. The method of Claim 8, 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 panniculitislike 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.

12. The method of Claim 8, wherein the lymphoma is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

13. The use of the compound of any one of Claims 1 to 7 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.

14. The use as in Claim 13, 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).

15. The use as in Claim 13, 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.

16. The compound of any one of Claims 1 to 7, 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.

17. The compound of any one of Claims 1 to 7, 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)18. The compound of any one of Claims 1 to 7, 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-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.

19. The compound of any one of Claims 1 to 7, for use as a medicament.

20. The compound of any one of Claims 1 to 7, 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.

21. The compound of any one of Claims 1 to 7, 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)22. The compound of any one of Claims 1 to 7, 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.

23. A composition comprising a compound of any one of Claims 1 to 7, 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.

24. A composition comprising a compound of any one of Claims 1 to 7, 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)25. A composition comprising a compound of any one of Claims 1 to 7, 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.

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

27. A compound of formula (II)whereina is an integer from 0 to 3;each R1is independently selected from the group consisting of halogen, -OH, -CN, -NO2, Ci-4alkyl, fluoro substituted Ci-4alkyl, hydroxy substituted Ci-4alkyl, C2-4alkenyl, fluoro substituted C2-4alkenyl, -O-(Ci-4alkyl), -O-(fluoro substituted C1-4alkyl), -(Ci-4alkyl)-O-(Ci-4alkyl), -C(O)OH, -C(O)-(Ci-4alkyl), -C(O)O-(Ci-4alkyl), -C(O)-NRARB, -NRARB, -(Ci-4alkyl)-NRARB, -NH-C(O)-(Ci-3alkyl)-NRARB, -NH-C(O)-(Ci-3alkyl)-NH-C(O)-(Ci-4alkyl), -CH(CN)-NRARB, and -CH(CN)-NH-C(O)-(Ci-4alkyl); wherein RAis selected from the group consisting of hydrogen, and Ci-4alkyl; wherein RBis selected from the group consisting of hydrogen, C1-4alkyl, hydroxy substituted Ci-4alkyl, and -(Ci-4alkyl)-O-(Ci-4alkyl);R5is a 4 to 16 membered, nitrogen bound heterocyclyl; provided that the 4 to 16 membered heterocyclyl is other than piperazinyl;wherein the 4 to 16 membered nitrogen bound heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, Ci-4alkyl, hydroxy substituted Ci-4alkyl, fluoro substituted Ci-4alkyl, -(Ci-2alkyl)-CN, -O-Ci-4alkyl, -O-(fluoro substituted C1-4 alkyl), -C(O)-(Ci-4alkyl), -(Ci-4alkyl)-O-(Ci-4alkyl), -(Ci-4alkyl)-O-(Ci-4alkyl)-C(O)-(Ci-4alkyl), -(SO2)-(Ci-4alkyl), -(Ci-2alkyl)-(SO2)-(Ci-4alkyl), -C(O)-NRJRL, -(Ci-4alkyl)-C(O)-NRJRL, -NRJRL, -(Ci-2alkyl)-NRJRL, -NRJ-C(O)-(Ci-4alkyl), -N(RJ)-SO2-(Ci-4alkyl), -N(RJ)-(Ci-4alkyl)-SO2-(Ci-4alkyl), -N(RJ)-C(O)-(Ci-4alkyl)-SO2-(Ci-4alkyl), -C(O)-ORJ, -SO2-NRJRK, and -S(O)(NH)-RJ;wherein RJand RKare each independently selected from the group consisting of hydrogen, and Ci-4alkyl; and RLis selected from the group consisting of hydrogen, Ci-4alkyl, and hydroxy substituted Ci-4alkyl;provided that when a is 2 and each R1is CH3, then R5is other than 6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl;or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

28. A compound as in Claim 27, whereina is an integer from 0 to 3;each R1is independently selected from the group consisting of Ci -2alky I, hydroxy substituted Ci-2alkyl, and — (Ci-2alkyl)-O-(Ci-2alkyl);R5is a 4 to 16 membered, nitrogen bound heterocyclyl; provided that the 4 to 16 membered heterocyclyl is other than piperazinyl;wherein the 4 to 16 membered, nitrogen bound heterocyclyl is optionally substituted with one to four substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, Ci-4alkyl, hydroxy substituted Ci-4alkyl, -(Ci-2alkyl)-CN, -O-Ci-4alkyl, -O-(fluoro substituted C1-4 alkyl), -(Ci-2alkyl)-O-(Ci-4alkyl), -C(O)-(Ci-4alkyl), -(SO2)-(Ci-2alkyl), -(Ci-2alkyl)-(SO2)-(Ci-2alkyl), -C(O)-NRJRL, -(Ci-3alkyl)-C(O)-NRJRL, -NRJRL, -(Ci-2alkyl)-NRJRL, -NRJ-C(O)-(Ci-4alkyl), -N(RJ)-SO2-(Ci-4alkyl), -N(RJ)-(Ci-4alkyl)-SO2-(Ci-4alkyl), -N(RJ)-C(O)-(Ci-4alkyl)-SO2-(Ci-4alkyl), -C(O)-ORJ, and -SO2-NRJRK;wherein each RJand RKare each independently selected from the group consisting of hydrogen, and C1-2alkyl; and each RLis selected from the group consisting of hydrogen, Ci-4alkyl, and hydroxy substituted Ci-4alkyl;provided that when a is 2 and each R1is CH3, then R5is other than 6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl;or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

29. A compound as in Claim 27, whereina is an integer from 1 to 3;each R1is independently selected from the group consisting of Ci-2alkyl, -(C1-2alkyl)-OH and - (C-i^alky l)-O-(Ci-2alkyl);R5is a 4 to 16 membered, nitrogen bound heterocyclyl; provided that the 4 to 16 membered heterocyclyl is other than piperazinyl;wherein the 4 to 16 membered, nitrogen bound heterocyclyl is optionally substituted with one to four substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, Ci-4alkyl, hydroxy substituted C1-3alkyl, -O-C1-4alkyl, -(Ci-2alkyl)-O-(Ci-4alkyl), -C(O)-(Ci-4alkyl), -(SO2)-(Ci-2alkyl), -(Ci-2alkyl)-(SO2)-(Ci-2alkyl), -C(O)-NRJRL, -(Ci-2alkyl)-C(O)-NRJRL, -NRJRL, -(Ci-2alkyl)-NRJRL, -NRJ-C(O)-(Ci-2alkyl), -N(RJ)-(Ci-4alkyl)-SO2-(Ci-4alkyl), -N(RJ)-C(O)-(Ci-4alkyl)-SO2-(Ci-4alkyl), -C(O)-ORJ, and -SO2-NRJRK;wherein each RJand RKare each independently selected from the group consisting of hydrogen, and C1-2alkyl; and each RLis selected from the group consisting of hydrogen, Ci-4alkyl and hydroxy substituted Ci-2alkyl;provided that when a is 2 and each R1is -CH3, then R5is other than 6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl;or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

30. A compound as in Claim 27, whereina is an integer from 2 to 3;each R1is independently selected from the group consisting of -CH3, -CH2OH, and -CH2-O-CH3;R5is selected from the group consisting ofor a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

31. A compound as in Claim 30, whereina is an integer from 2 to 3;each R1is independently selected from the group consisting of -CH3, - CH2OH, and -CH2-O-CH3;R5is selected from the group consisting ofL9£or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

32. A compound as in Claim 30, whereina is an integer from 2 to 3;each R1is independently selected from the group consisting of -CH3, - CH2OH, and -CH2-O-CH3;R5is selected from the group consisting ofor a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

33. A compound as in Claim 30, whereina is an integer from 2 to 3;each R1is independently selected from the group consisting of -CH3, -CH2OH, and -CH2-O-CH3;R5is selected from the group consisting ofor a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

34. 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 any one of Claims 27 to 33.

35. The method of Claim 34, 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).

36. The method of Claim 34, wherein the leukemia is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

37. The method of Claim 34, 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 panniculitislike 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.

38. The method of Claim 34, wherein the lymphoma is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

39. The use of the compound of any one of Claims 27 to 33 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.

40. The use as in Claim 39, 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).

41. The use as in Claim 39, 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.

42. The compound of any one of Claims 27 to 33, 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.

43. The compound of any one of Claims 27 to 33, 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)44. The compound of any one of Claims 27 to 33, 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-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.

45. The compound of any one of Claims 27 to 33, for use as a medicament.

46. The compound of any one of Claims 27 to 33, 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.

47. The compound of any one of Claims 27 to 33, for use in the treatment of a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1receptor 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)48. The compound of any one of Claims 27 to 33, 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.

49. A composition comprising a compound of any one of Claims 27 to 33, 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.

50. A composition comprising a compound of any one of Claims 27 to 33, 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)51. A composition comprising a compound of any one of Claims 27 to 33, 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.

52. A compound of formula (III)whereina is an integer from 0 to 4;each R1is independently selected from the group consisting of halogen, -OH, -CN, -NO2, Ci-4alkyl, fluoro substituted Ci-4alkyl, hydroxy substituted Ci-4alkyl, C2-4alkenyl, fluoro substituted C2-4alkenyl, -O-(Ci-4alkyl), -O-(fluoro substituted C1-4alkyl), -(Ci-4alkyl)-O-(Ci-4alkyl), -C(O)OH, -C(O)-(Ci-4alkyl), -C(O)O-(Ci-4alkyl), -C(O)-NRARB, -NRARB, -(Ci-4alkyl)-NRARB, -NH-C(O)-(Ci-3alkyl)-NRARB, -NH-C(O)-(Ci-3alkyl)-NH-C(O)-(Ci-4alkyl), -CH(CN)-NRARB, and -CH(CN)-NH-C(O)-(Ci-4alkyl);wherein RAis selected from the group consisting of hydrogen, and Ci-4alkyl; wherein RBis selected from the group consisting of hydrogen, C1-4alkyl, hydroxy substituted Ci-4alkyl, and -(Ci-4alkyl)-O-(Ci-4alkyl);R6is a 4 to 11 membered, nitrogen bound heterocyclyl; provided that the 4 to 11 membered, nitrogen bound heterocyclyl is other than piperazinyl;wherein the 4 to 11 membered, nitrogen bound heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, Ci-4alkyl, hydroxy substituted Ci-4alkyl, -O-(Ci-4alkyl), -(Ci-4alkyl)-O-(Ci-4alkyl), -(NRM)-C(O)-(Ci-4alkyl), and -C(O)-NRMRV; wherein RMand Rvare each independently selected from the group consisting of hydrogen,and Ci-2alkyl;and wherein the 4 to 11 membered, nitrogen bound heterocyclyl is furthersubstituted; whereing is an integer from 0 to 1;L3is selected from the group consisting of -O-, -C(O)-, -(Ci -4al ky I)-, -CF2-, -C(O)-(Ci-4alkyl)-, -(Ci-4alkyl)-C(O)-, -SO2-, -SO2-(Ci-4alkyl)-, -(Ci-4alkyl)-SO2-, -(C1-2alkyl)-O-, -O-(Ci-2alkyl)-, -C(O)-N(RN)-, -N(RN)-C(O)-, -C(O)-N(RN)-(Ci-2alkyl)-, -(C1-2alkyl)-N(RN)-C(O)-, -NRN-, -N(Rp)-(Ci-2alkyl)-, and -(Ci-2alkyl)-N(Rp)-; wherein RNis selected from the group consisting of hydrogen and C1-4alkyl; and Rpis selected from the group consisting of hydrogen, C1-2alkyl and -C(O)-Ci-2alkyl;(D)is selected from the group consisting of C3-5cycloalkyl, phenyl, and 5 to 10 membered heterocyclyl;wherein the C3-5cycloalkyl, phenyl, or 5 to 10 membered heterocyclyl is optionally substituted with one or two substituents independently selected from the group consisting of halogen, -CN, -OH, oxo, Ci-4alkyl, hydroxy substituted Ci-4alkyl, fluoro substituted Ci-4alkyl, -(Ci-2alkyl)-CN, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-4alkyl), -C(O)-(Ci-4alkyl), -SO2-(Ci-4alkyl), -NRQRS, -N(RQ)-SO2-(Ci-4alkyl), -SO2-NRQRT, and -S(O)(NH)-NRQ;wherein each RQand RTare each independently selected from the group consisting of hydrogen and Ci-2alkyl; and each Rsis selected from the group consisting of hydrogen, Ci-2alkyl, and -C(O)-Ci-2alkyl;or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

53. A compound as in Claim 52, whereina is an integer from 0 to 3;each R1is independently selected from the group consisting of halogen, -OH, -CN, Ci-4alkyl, fluoro substituted Ci-4alkyl, hydroxy substituted Ci-4alkyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-4alkyl), -(Ci-4alkyl)-O-(Ci-4alkyl), -C(O)OH, -C(0)-(Ci-3alkyl), and -C(O)O-(Ci-4alkyl);R6is a 4 to 11 membered, nitrogen bound heterocyclyl; provided that the 4 to 11 membered, nitrogen bound heterocyclyl is other than piperazinyl;wherein the 4 to 11 membered, nitrogen bound heterocyclyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, Ci-2alkyl, hydroxy substituted Ci-2alkyl, -O-(Ci-2alkyl), -(Ci-2alkyl)-O-(Ci-2alkyl), -(NRM)-C(O)-(Ci-2alkyl), and -C(O)-NRMRV; wherein RMand Rvare each independently selected from the group consisting of hydrogen, and Ci-2alkyl;and wherein the 4 to 11 membered, nitrogen bound heterocyclyl is furthersubstitutedwhereing is an integer from 0 to 1;L3is selected from the group consisting of -O-, -C(O)-, -(C1-2alkyl)-, -CF2-, -C(O)-(Ci-4alkyl)-, -(Ci-4alkyl)-C(O)-, -(Ci-2alkyl)-O-, -O-(Ci-2alkyl)-, -C(O)-N(RN)-, -N(RN)-C(O)-, -C(O)-N(RN)-(Ci-2alkyl)-, -(Ci-2alkyl)-N(RN)-C(O)-, -NRN-, -N(Rᴾ)-(C1-2alkyl)-, and -(C1-2alkyl)-N(Rᴾ)-; wherein RNis selected from the group consisting of hydrogen and Ci -4alky I; and Rpis selected from the group consisting of hydrogen, Ci-2alkyl and -C(O)-Ci-2alkyl;is selected from the group consisting of C3-5cycloalkyl, phenyl, and 5 to 10 membered heterocyclyl;wherein the C3-5cycloalkyl, phenyl, or 5 to 10 membered heterocyclyl is optionally substituted with one or two substituents independently selected from the group consisting of halogen, -CN, -OH, oxo, Ci-4alkyl, hydroxy substituted Ci-2alkyl, fluoro substituted Ci-2alkyl, -(Ci-2alkyl)-CN, -O-(Ci-2alkyl), -O-(fluoro substituted C1-2 alkyl), -C(O)-(Ci-2alkyl), -SO2-(Ci-2alkyl), -NRQRS, -N(RQ)-SO2-(Ci-4alkyl), and -SO2-NRQRT; wherein RQand RTare each independently selected from the groupconsisting of hydrogen and Ci-2alkyl; and Rsis selected from the group consisting of hydrogen, Ci-2alkyl, and -C(O)-Ci-2alkyl;or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

54. A compound as in Claim 52, whereina is an integer from 1 to 3;each R1is independently selected from the group consisting of C1-2alkyl, -(C1-2alkyl)-OH and –(C1-2alkyl)-O-(C1-2alkyl);R6is a 4 to 11 membered, nitrogen bound heterocyclyl; provided that the 4 to 11 membered, nitrogen bound heterocyclyl is other than piperazinyl;wherein the 4 to 11 membered, nitrogen bound heterocyclyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, -OH, -CN, oxo, Ci-2alkyl, hydroxy substituted Ci-2alkyl, -O-(Ci-2alkyl), -(Ci-2alkyl)-O-(Ci-2alkyl), and -(NRM)-C(O)-(Ci-2alkyl), wherein RMis selected from the group consisting of hydrogen, and Ci-2alkyl;and wherein the 4 to 11 membered, nitrogen bound heterocyclyl is furthersubstitutedwhereing is an integer from 0 to 1;L3is selected from the group consisting of -O-, -C(O)-, -(Ci-2alkyl)-, -CF2-, - Ci-2alkyl)-, -C(O)-N(RN)-(Ci-2alkyl)-, -NRN-, -N(Rp)-(Ci-2alkyl)-, and wherein RNis selected from the group consisting of hydrogen andselected from the group consisting of hydrogen, Ci-2alkyl and -C(O)-Ci-2alkyl;provided that when L3is -C(O)-N(RN)-(Ci-2alkyl)-, then the Ci-2alkyl portion isboundis selected from the group consisting of C4-5cycloalkyl, phenyl, and 5 to 10 membered heterocyclyl;wherein the C4-5cycloalkyl, phenyl, or 5 to 10 membered heterocyclyl is optionally substituted with one or two substituents independently selected from the group consisting of halogen, -CN, -OH, oxo, Ci-4alkyl, hydroxy substituted Ci-2alkyl, fluoro substituted Ci-2alkyl, -(Ci-2alkyl)-CN, -O-(Ci-2alkyl), -O-(fluoro substituted C1-2 alkyl), -C(O)-(Ci-2alkyl), -SO2-(Ci-2alkyl), -NRQRS, -N(RQ)-SO2-(Ci-2alkyl), and -SO2-NRQRT; wherein each RQand RTare each independently selected from the group consisting of hydrogen and Ci-2alkyl; and Rsis selected from the group consisting of hydrogen, Ci-2alkyl, and -C(O)-Ci-2alkyl;or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

55. A compound as in Claim 52, whereina is an integer from 2 to 3;each R1is independently selected from the group consisting of -CH3, -CH2OH, and -CH2-O-CH3;R6is selected from the group consisting ofizzeszezzeor a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

56. A compound as in Claim 55, whereina is an integer from 2 to 3;each R1is independently selected from the group consisting of -CH3, -CH2OH, and -CH2-O-CH3;R6is selected from the group consisting of62£or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

57. A compound as in Claim 55, whereina is an integer from 2 to 3;each R1is independently selected from the group consisting of -CH3, -CH2OH, and -CH2-O-CH3;R6is selected from the group consisting ofor a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

58. A compound as in Claim 55, whereina is an integer from 2 to 3;each R1is independently selected from the group consisting of -CH3, -CH2OH, and -CH2-O-CH3;R6is selected from the group consisting ofor a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

59. 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 any one of Claims 52 to 58.

60. The method of Claim 59, wherein the leukemia is selected from the groupconsisting 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).

61. The method of Claim 59, wherein the leukemia is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

62. The method of Claim 59, 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 panniculitislike 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.

63. The method of Claim 59, wherein the lymphoma is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

64. The use of the compound of any one of Claims 52 to 58 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.

65. The use as in Claim 64, 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).

66. The use as in Claim 64, 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.

67. The compound of any one of Claims 52 to 58, 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.

68. The compound of any one of Claims 52 to 58, 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)69. The compound of any one of Claims 52 to 58, 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-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.

70. The compound of any one of Claims 52 to 58, for use as a medicament.

71. The compound of any one of Claims 52 to 58, 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.

72. The compound of any one of Claims 52 to 58, 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)73. The compound of any one of Claims 52 to 58, 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.

74. A composition comprising a compound of any one of Claims 52 to 58, 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.

75. A composition comprising a compound of any one of Claims 52 to 58, 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)76. A composition comprising a compound of any one of Claims 52 to 58, for use in the treatment of a cancer mediated by the BFL-1 receptor, wherein the cancermediated 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.

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