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 / 714,902 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. 2015;125(1):22-32). DLBCL typically presents as an aggressive lymphoma, evolving over months and resulting in symptomatic disease that is fatal without treatment (Ibid).

[0008] Outcomes in DLBCL have improved dramatically over the last decade with the addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (R CHOP). This regimen remains the current standard of care. However, R CHOP treatment fails in about 30% to 50% of patients with DLBCL (COIFFiER B & Sarkozy C,. Hematology Am Soc Hematol Educ Program. 2016;2016(1):366-378). Less than half of these patients can be cured with stem cell transplantation (GISSELBRECHT et al., J Clin Oncol. 2010; 28(27): 4184-4190), and those who are not cured will typically die from their disease (CRUMP eta / ., 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. 2014; 15(9): 1019-1026). Thus, optimization of front-line therapy, as well as the development of more effective salvage strategies, remains an important objective.

[0009] Follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (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.

[0010] Acute myelogenous leukemia (AML) is a clonal disease of the blood and bone marrow resulting from mutations that occur in normal hematopoietic stem cells. AML is a heterogenous disease in that it presents with a range of cytogenetic, morphological and immunophenotypic features, and is characterized by an accumulation of clonal, abnormal myeloid progenitor cells, known as myeloblasts. These cells demonstrate disruption of normal myeloid differentiation and excessive proliferation, resulting in the decreased formation of hematopoietic cells. Disease remission can be achieved with standard induction chemotherapy, but refractory and relapsed disease remains a challenge due to persistence of leukemic stem cells. Patients refractory to salvage therapy are treated palliatively, as current treatment options are extremely limited.

[0011] These patients have a median survival of 2 months. Therefore, AML represents an unmet medical need with >20,000 new cases per year in the US with 5-year overall survival below 30% (STEIN ET etal., Health Qual Life Outcomes. 2018; 16: 193).

[0012] In addition, patients with newly diagnosed intermediate or higher-risk myelodysplastic syndrome (MDS) and those who relapse after standard care have a poor prognosis and high risk of progression to AML. Therefore, there is an urgent need for new treatment modalities for relapsed / refractory (R / R) AML and MDS patients, newly diagnosed AML patients ineligible for induction chemotherapy based on age and comorbidities, and newly diagnosed intermediate / high / very high risk MDS patients.

[0013] Intrinsic apoptosis (programmed cell death) is regulated by the B Cell lymphoma 2 (BCL-2) protein family. Anti-apoptotic family members sequester their pro-apoptotic counterparts through a highly conserved BH3 binding groove. Disruption of this balance will lead to mitochondrial pore formation and subsequent cell death. To evade apoptosis, tumors often upregulate the expression of one or more anti-apoptotic family members. As such anti-apoptotic family members have become attractive targets for anti-cancer drug development. The most advanced small molecule inhibitor targeting the anti-apoptotic protein BCL-2, Venetoclax, effectively improves clinical outcomes in newly diagnosed, relapsed and refractory acute myeloid leukemia (AML) patients, with complete response rates (with and without complete blood count recovery) ranging between 34-90% and 21-33%, respectively. (GRIFFIOEN etal., Cancers. 2022; 14 (14): 3456)

[0014] BFL-1 (‘Bcl-2 related gene expressed in fetal liver’ (Choi etal., Oncogene. 1995; 11: 1693-1698), gene name BCL2A 1 (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 et al., Oncogene. 2003; 22: 2457-2465).

[0015] 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.

[0016] 2020; 1: 826-839 & BISAILLON etal., Leukemia. 2020; 34: 63-74).

[0017] 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 oi BFL-1 was shown to be upregulated in MYC / BCL2 double hit lymphoma cell lines treated with Venetoclax / n vivo (ESTEVE-ARENYS eta / ., 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.

[0018] ALI, F. E., in PCT Publication WO96 / 19223, published 27 June 1996 describe fibrinogen receptor antagonists effective for inhibiting platelet aggregation.

[0019] 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.

[0020] Summary of the Invention

[0021] The present invention is directed to compounds of formula (I)

[0022]

[0023] wherein

[0024] R1is selected from the group consisting of

[0025] (a) phenyl; wherein the phenyl is optionally substituted with one or more substituent independently selected from the group consisting of halogen, hydroxy, -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)-(Ci-4alkyl), -C(O)OH, -C(O)O-(Ci-4alkyl), -C(O)-NRARB, -NRARB, -(Ci-4alkyl)-NRARB, -NRA-C(O)-(Ci-3alkyl), -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; and RBis selected from the group consisting of hydrogen, Ci-4alkyl, hydroxy substituted Ci-4alkyl, and -(Ci-4alkyl)-O-(Ci-4alkyl);

[0026] (b)

[0027]

[0028] wherein

[0029] b is an integer from 0 to 1;

[0030] L1is selected from the group consisting of -(Ci-4alkyl)-, -(Ci-4alkyl)-O-, -O-(Ci-4alkyl)-, -(Ci-4alkyl)-O-(Ci-4alkyl)-, -C(O)O-(Ci-4alkyl)-, -C(O)-NRD-, -C(O)-NH-(Ci-

[0031]

[0032] 4alkyl)-NRD-SO2-; wherein RDis selected from the group consisting of hydrogen, and Ci-2alkyl;

[0033] provided that when L1is -C(O)O-(Ci-4alkyl)-, -C(O)-NH-(Ci-4alkyl)-, -C(O)-NH

[0034]

[0035] , then the -C(O)- portion of L1is bound directly to the phenyl;

[0036] provided further that when L1is -NRD-C(O)-(Ci-4alkyl)-, then the -NRD- portion of L1is bound directly to the phenyl;

[0037] provided further that when L1is -(Ci-4alkyl)-NRD-SO2-, then the -(Ci-4alkyl)-portion of L1is bound directly to the phenyl;

[0038] R3is selected from the group consisting of C3-6cycloalkyl, aryl, and 4 to 10 membered heterocyclyl;

[0039] wherein the C3-6cycloalkyl, aryl, or 4 to 10 membered heterocyclyl is optionally substituted with one or more substituent independently selected from the group consisting of halogen, hydroxy, oxo, Ci-4alkyl, fluoro substituted Ci-4alkyl, hydroxy substituted Ci-4alkyl, -O-(Ci-4alkyl), -(Ci-4alkyl)-O-(Ci-4alkyl) and -NRERF; wherein RE and RFare each independently selected from the group consisting of hydrogen and Ci-4alkyl;

[0040] c is an integer from 0 to 3;

[0041] each R4is independently selected from the group consisting of halogen, hydroxy, -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)-(Ci-4alkyl), -C(O)OH, -C(O)O-(Ci-4alkyl), -C(O)-NRGRH, -NRGRH, and -(Ci-4alkyl)-NRGRH;

[0042] wherein RGis selected from the group consisting of hydrogen, and Ci-4alkyl; and RHis selected from the group consisting of hydrogen, Ci-4alkyl, hydroxy substituted Ci-4alkyl, and -(Ci-4alkyl)-O-(Ci-4alkyl);

[0043] and (c) 9 to 11 membered benzo-fused carbocyclyl or 9 to 11 membered benzofused heterocyclyl; wherein the 9 to 11 membered benzo-fused carbocyclyl or 9 to 11 membered benzo-fused heterocyclyl is bound through the benzo-fused portion;

[0044] wherein the 9 to 11 membered benzo-fused carbocyclyl, or 9 to 11 membered benzo-fused heterocyclyl is optionally substituted with one or more substituent independently selected from the group consisting of halogen, hydroxy, oxo, -CN, Ci-4alkyl, fluoro substituted Ci-4alkyl, hydroxy substituted Ci-4alkyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-4alkyl), -(Ci-4alkyl)-O-(Ci-4alkyl), -(Ci-4alkyl)-C(O)OH, -(Ci-4alkyl)-C(O)O-(Ci-4alkyl), and -NRJRK;

[0045] wherein RJand RKare each independently selected from the group consisting of hydrogen, and Ci-4alkyl;

[0046] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0047] The present invention is further directed to compounds of formula (II)

[0048]

[0049] wherein

[0050] e is an integer from 0 to 3;

[0051] each R6is independently selected from the group consisting of halogen, hydroxy, -CN, -NO2, Ci-4alkyl, hydroxy substituted Ci-4alkyl, fluoro substituted Ci-4alkyl, C2-4alkenyl, fluoro substituted C2-4alkenyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-4alkyl), -(C1-4alkyl)-O-(C1-4alkyl), -C(O)OH, -C(O)-(C1-4alkyl), -C(O)O-(C1-4alkyl), -C(O)-NRMRN, -NRMRN, -(C1-4alkyl)-NRMRN, -NH-C(O)-(C1-3alkyl)-NRMRN, -NH-C(O)-(C1-3alkyl)-NH-C(O)-(C1-4alkyl), -CH(CN)-NRMRN, and -CH(CN)-NH-C(O)-(C1-4alkyl);

[0052] wherein RMis selected from the group consisting of hydrogen, and C1-4alkyl; and RNis selected from the group consisting of hydrogen, C1-4alkyl, hydroxy substituted C1-4alkyl, and -(C1-4alkyl)-O-(C1-4alkyl);

[0053] R7is selected from the group consisting of C1-4alkyl, hydroxy substituted C1-4alkyl, fluoro substituted C1-4alkyl, -O-(C1-4alkyl), -(C1-4alkyl)-O-(C1-4alkyl), -(C1-4alkyl)-NRCRP, -SO2-(C1-2alkyl), C3-5cycloalkyl, 4 to 6 membered heterocycloalkyl, and -(C1-4alkyl)-(4 to 6 membered heterocycloalkyl);

[0054] wherein RCand RPare each independently selected from the group consisting of hydrogen, and Ci-4alkyl;

[0055] and wherein the C3-5cycloalkyl or 4 to 6 membered heterocycloalkyl, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, -CN, C1-4alkyl, and fluorinated substituted C1-4alkyl;

[0056]

[0057] wherein

[0058] f is an integer from 0 to 1;

[0059] L2is selected from the group consisting of -(C1-4alkyl)-, -(fluorinated C1-4alkyl)-, -(C1-4alkyl)-NH- and -(C1-4alkyl)-O-; provided that when L2is -(Ci-4alkyl)-NH- or-(Ci-4alkyl)-O-, then the -NH- and -0-

[0060] portion of L2is bound directly to

[0061]

[0062] ( B )

[0063] wherein ' — ' is selected from the group consisting of Ce-scycloalkyl, aryl, and 5 to 7 membered heterocyclyl; wherein the C6-8cycloalkyl, aryl, or 5 to 7 membered heterocyclyl or is optionally substituted with one or more substituent independently selected from the group consisting of halogen, hydroxy, oxo, Ci-4alkyl, fluoro substituted Ci-4alkyl, -(Ci-4alkyl)-CN, -0-(Ci-4alkyl), -O-(fluoro substituted Ci-4alkyl), -C(0)-(Ci-

[0064]

[0065] s-scycloalkyl;

[0066] wherein each RQand RRis independently selected from the group consisting of hydrogen, and C1-4alkyl;

[0067] and wherein R10is selected from the group consisting of Ci-4alkyl, halogen substituted Ci-2alkyl, C2-4alkenyl, C2-4alkynyl, and -CH=CH-CH2-NRSRT; wherein RSand RTare each independently selected from the group consisting of hydrogen, and Ci-2alkyl; alternatively, Rsand RTare taken together with the nitrogen atom to which they are bound to form pyrrolidin-1 -yl, piperidin-1 -yl, piperazin-1 -yl or morpholin-4-yl;

[0068] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0069] The present invention is further directed to compounds of formula (III)

[0070]

[0071] wherein

[0072] e is and integer from 0 to 3;

[0073] each R6is independently selected from the group consisting of halogen, hydroxy, -CN, -N02, Ci-4alkyl, hydroxy substituted Ci-4alkyl, fluoro substituted Ci-4alkyl, C2. 4alkenyl, fluoro substituted C2-4alkenyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-4alkyl), -(C1-4alkyl)-O-(C1-4alkyl), -C(O)OH, -C(O)-(C1-4alkyl), -C(O)O-(C1-4alkyl), -C(O)-NRMRN, -NRMRN, -(C1-4alkyl)-NRMRN, -NH-C(O)-(C1-3alkyl)-NRMRN, -NH-C(O)-(C1-3alkyl)-NH-C(O)-(C1-4alkyl), -CH(CN)-NRMRN, and -CH(CN)-NH-C(O)-(C1-4alkyl);

[0074] wherein RMis selected from the group consisting of hydrogen, and Ci-4alkyl; and RNis selected from the group consisting of hydrogen, Ci-4alkyl, hydroxy substituted Ci-4alkyl, and -(Ci-4alkyl)-O-(Ci-4alkyl);

[0075] R12is selected from the group consisting of phenyl, C4-8cycloalkyl, and 4 to 10 membered heterocyclyl; wherein the phenyl, C4-8cycloalkyl, or 4 to 10 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, -CN, -NO2, Ci-4alkyl, hydroxy substituted Ci-4alkyl, fluoro substituted Ci-4alkyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-4alkyl), -C(O)-(Ci-4alkyl), -C(O)-(fluoro substituted Ci-4alkyl), -NRWRX, -(Ci-4alkyl)-NRwRx, -C(O)-NRWRX, -NRw-SO2-(Ci-4alkyl), -SO2-(Ci-4alkyl), -SO2-(fluoro substituted Ci-4alkyl), -SO2-NRWRX, -S(O)(NH)(Ci-4alkyl), -SO2-(5 to 6 membered heterocycloalkyl) and P(O)(CH3)2;

[0076] wherein Rwand Rxare each independently selected from the group consisting of hydrogen, and Ci-4alkyl;

[0077] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] Exemplifying the invention are methods of treating a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is a lymphoma (selected from the group consisting of AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell DLBCL, double-hit lymphoma, double-expressor lymphoma, anaplastic large cell lymphoma, marginal B cell lymphoma, primary mediastinal B-cell lymphoma, immunoblastic large cell lymphoma, Burkitt lymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoplasmatic lymphoma, precursor B -lymphoblastic lymphoma, lymphoma of the central nervous system, small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia (CLL), precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma, sarcoma of the soft tissue, gliosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma, breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma) comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.

[0082] 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.

[0083] 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)).

[0084] 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).

[0085] In another embodiment, the present invention is directed to a composition comprising a compound of formula (I), a compound of formula (II) ora 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)).

[0086] In another embodiment, the present invention is directed to a composition comprising a compound of formula (I), a compound of formula (II) ora 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 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).

[0087] 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.

[0088] 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.

[0089] 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.

[0090] In another example, the present invention is directed to a compound as described herein for use in a method for treating a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is a lymphoma selected from the group consisting of AIDS-related lymphoma, Hodgkin lymphoma, nonHodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), subtypes of NHL such as Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell DLBCL, double-hit lymphoma and double-expressor lymphoma; anaplastic large cell lymphoma, marginal B cell lymphoma and primary mediastinal B-cell lymphoma, immunoblastic large cell lymphoma, Burkitt lymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoplasmatic lymphoma, precursor B -lymphoblastic lymphoma, lymphoma of the central nervous system, small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL); T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma; sarcomas including but not limited to sarcoma of the soft tissue, gliosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma; and other cancers, such as solid tumors, including but not limited to breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma, in a subject in need thereof.

[0091] Detailed Description of the Invention

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

[0093]

[0094] wherein R1is 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 further directed to compounds of formula (II)

[0096]

[0097] wherein e, R6, R7and R8are 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] The present invention is directed to compounds of formula (III)

[0099]

[0100] wherein e, R6, and R12are 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.

[0101] 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).

[0102] In some embodiments, the present invention is directed to compounds of formula (I) wherein

[0103] R1is selected from the group consisting of

[0104] (a) phenyl; wherein the phenyl is optionally substituted with one to four substituent independently selected from the group consisting of halogen, hydroxy, -CN, -NO2, Ci-salkyl, fluoro substituted Ci-2alkyl, hydroxy substituted Ci-salkyl, C2-salkenyl, fluoro substituted C2-3alkenyl, -O-(Ci-salkyl), -O-(fluoro substituted Ci-2alkyl), -(Ci-2alkyl)- O-(Ci-2alkyl), -C(O)-(Ci-2alkyl), -C(O)OH, -C(O)O-(Ci-2alkyl), -C(O)-NRARB, -NRARB, -(Ci-2alkyl)-NRARB, -NRAC(O)-(Ci-2alkyl), -NH-C(O)-(Ci-2alkyl)-NRARB, -NH-C(O)-(Ci-2alkyl)-NH-C(O)-(Ci-2alkyl), -CH(CN)-NRARB, and -CH(CN)-NH-C(O)-(Ci-2alkyl);

[0105] wherein RAis selected from the group consisting of hydrogen, and Ci-2alkyl; and RBis selected from the group consisting of hydrogen, Ci-2alkyl, hydroxy substituted Ci- (Ci-2alkyl);

[0106]

[0107] ; wherein

[0108] b is an integer from 0 to 1;

[0109] L1is selected from the group consisting of -(Ci-3alkyl)-, -(Ci-2alkyl)-O-, -O-(Ci-2alkyl)-, -(Ci-2alkyl)-O-(Ci-3alkyl)-, -C(O)O-(Ci-2alkyl)-, -C(O)-NRD-, -C(O)-NH-(Ci-3alkyl)-

[0110]

[0111] SO2-; wherein RDis selected from the group consisting of hydrogen, and Ci-2alkyl;

[0112] provided that when L1is -C(O)O-(Ci-2alkyl), -C(O)-NH-(Ci-3alkyl)-, -C(O)-NH [structure], -C(O)-NH [structure], or -C(O)-NH [structure], then the -C(O)- portion of L1is bound directly to the phenyl;

[0113] provided further that when L1is -NRD-C(O)-(Ci-2alkyl)-, then the -NRD- portion of L1is bound directly to the phenyl;

[0114] provided further that when L1is -(Ci-2alkyl)-NRD-SO2-, then the -(Ci-2alkyl)-portion of L1is bound directly to the phenyl;

[0115] R3is selected from the group consisting of C3-5cycloalkyl, aryl, and 4 to 9 membered heterocyclyl; wherein the C3-5cycloalkyl aryl, or 4 to 9 membered heterocyclyl is optionally substituted with one or three substituent independently selected from the group consisting of halogen, hydroxy, oxo, Ci-2alkyl, fluoro substituted Ci-2alkyl, hydroxy substituted Ci-2alkyl, -O-(Ci-2alkyl), -(Ci-2alkyl)-O-(Ci-2alkyl) and -NRERF; wherein REand RFare each independently selected from the group consisting of hydrogen and Ci-2alkyl;

[0116] c is an integer from 0 to 3;

[0117] each R4is independently selected from the group consisting of halogen, hydroxy, -CN, Ci-2alkyl, fluoro substituted Ci-2alkyl, hydroxy substituted Ci-2alkyl, -O-(Ci-2alkyl), -O-(fluoro substituted Ci-2alkyl), and -(C1-2alkyl)-O-(Ci-2alkyl);

[0118] and (c) 9 to 11 membered benzo-fused carbocyclyl or 9 to 11 membered benzofused heterocyclyl; wherein the 9 to 11 membered benzo-fused carbocyclyl, or 9 to 11 membered benzo-fused heterocyclyl is bound through the benzo-fused portion;

[0119] wherein the 9 to 11 membered benzo-fused carbocyclyl or 9 to 11 membered benzo-fused heterocyclyl is optionally substituted with one or four substituent independently selected from the group consisting of halogen, hydroxy, oxo, -CN, Ci-2alkyl, fluoro substituted Ci-2alkyl, hydroxy substituted Ci-2alkyl, -O-(Ci-2alkyl), -O-(fluoro substituted Ci-2alkyl), -(Ci-2alkyl)-O-(Ci-4alkyl), -(Ci-3alkyl)-C(O)OH, -(Ci-3alkyl)-C(O)O-(Ci-4alkyl), and -NRJRK;

[0120] wherein RJand RKare each independently selected from the group consisting of hydrogen, and Ci-2alkyl;

[0121] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0122] In some embodiments, the present invention is directed to compounds of formula (I) wherein

[0123] R1is selected from the group consisting of

[0124] (a) phenyl; wherein the phenyl is optionally substituted with one to four substituent independently selected from the group consisting of halogen, hydroxy, -CN, -NO2, Ci-3alkyl, fluoro substituted Ci-2alkyl, hydroxy substituted Ci-3alkyl, fluoro substituted C2-3alkenyl, -O-(Ci-3alkyl), -O-(fluoro substituted Ci-2alkyl), -(Ci-2alkyl)-OCH3, -C(O)-(Ci-2alkyl), -C(O)OH, -C(O)O-(Ci-2alkyl), -C(O)-NRARB, -NRARB, -(Ci-2alkyl)-NRARB, -NRA-C(O)-(Ci-2alkyl), -NHC(O)-(Ci-2alkyl)-NRARB, -NH-C(O)-(CH2)-NH-C(O)-(Ci-2alkyl), -CH(CN)-NRARB, and -CH(CN)-NH-C(O)-(Ci-2alkyl); wherein RAis selected from the group consisting of hydrogen, and Ci-2alkyl; and RBis selected from the group consisting of hydrogen, Ci-2alkyl, hydroxy substituted Ci- 2alkyl);

[0125]

[0126] ; wherein

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

[0128] L1is selected from the group consisting of -(Ci-3alkyl)-, -(C1-2alkyl)-O-, -O-(Ci-2alkyl)-, -(Ci-2alkyl)-O-(Ci-2alkyl)-, -C(O)O-(Ci-2alkyl)-, -C(O)-NRD-, -C(O)-NH-(Ci-3alkyl)-

[0129]

[0130] SO2-; wherein RDis selected from the group consisting of hydrogen, and Ci-2alkyl;

[0131] provided that when L1is -C(O)O-(Ci-2alkyl)-, -C(O)-NH-(Ci-3alkyl)-, -C(O)-NH

[0132]

[0133] , then the -C(O)- portion of L1is bound directly to the phenyl;

[0134] provided further that when L1is -NRD-C(O)-(Ci-2alkyl)-, then the -NRD- portion of L1is bound directly to the phenyl;

[0135] provided that when L1is -(Ci-2alkyl)-NRD-SO2-, then the -(Ci-2alkyl)- portion of L1is bound directly to the phenyl;

[0136] R3is selected from the group consisting of C3-4cycloalkyl, aryl, and 4 to 9 membered heterocyclyl; wherein the C3-4cycloalkyl, aryl, or 4-9 membered heterocyclyl is optionally substituted with one or two substituent independently selected from the group consisting of halogen, hydroxy, oxo, Ci-2alkyl, fluoro substituted Ci-2alkyl, hydroxy substituted Ci-2alkyl, -O-(Ci-2alkyl), -(C1-2alkyl)-O-(Ci-2alkyl) and -NRERF;

[0137] wherein REand RFare each independently selected from the group consisting of hydrogen and Ci-2alkyl;

[0138] c is an integer from 0 to 2; each R4is independently selected from the group consisting of halogen, Ci-2alkyl, and hydroxy substituted Ci-2alkyl;

[0139] and (c) 9 to 11 membered benzo-fused carbocyclyl or 9 to 11 membered benzofused heterocyclyl; wherein the 9 to 11 membered benzo-fused carbocyclyl, or 9 to 11 membered benzo-fused heterocyclyl is bound through the benzo-fused portion;

[0140] wherein the 9 to 11 membered benzo-fused carbocyclyl and 9 to 11 membered benzo-fused heterocyclyl is optionally substituted with one or four substituent independently selected from the group consisting of halogen, hydroxy, oxo, -CN, Ci-2alkyl, -O-(Ci-2alkyl), -(C1-2alkyl)-O-(Ci-2alkyl), -(Ci-2alkyl)-C(O)OH, and -NRJRK;

[0141] wherein RJand RKare each independently selected from the group consisting of hydrogen, and Ci-2alkyl;

[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]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0153] In some embodiments, the present invention is directed to compounds of formula (I) wherein

[0154]

[0155]

[0156]

[0157]

[0158]

[0159] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0160] In some embodiments, the present invention is directed to compounds of formula (I) wherein

[0161]

[0162]

[0163]

[0164]

[0165] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0166] In some embodiments, the present invention is directed to compounds of formula (I) wherein

[0167] R1is selected from the group consisting of

[0168]

[0169]

[0170]

[0171]

[0172] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0173] In some embodiments, the present invention is directed to compounds of formula (I) wherein

[0174] R1is selected from the group consisting of

[0175] (a) phenyl; wherein the phenyl is substituted with two or three substituents independently selected from the group consisting of chloro, fluoro, bromo, hydroxy, - CH3, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2-O-CH3, -CF2H, -CF3, -CHCF2, -OCH3, -C(O)CH3, -C(O)-NH2, -NH2, -NH-CH3, -NH-C(O)-CH2-NH-C(O)-CH3, -CH(CN)NH2, and

[0176]

[0177] provided that when L1is -CH2-NH-SO2-, -CH2-NH-, or -CH2CH2-NH- then the -CH2- portion of L1is bound directly to the phenyl;

[0178] provided further that when L1is -NH-CH2CH2-, or -NH-C(0)-CH2-, then the -NH-portion of L1is bound directly to the phenyl;

[0179] provided further that when L1is -C(O)O-CH2-, -C(O)-NH-CH2-, -C(O)-NH- ZO

[0180]

[0181] or-C(O)-NH^ then the -C(O)- portion of L1is bound directly to the phenyl;

[0182] provided further that when L1is -O-CH2CH2-, then the -0- portion of L1is bound to directly the phenyl;

[0183] R3is a selected from the group consisting of cyclopropyl, cyclobutyl, phenyl, azetidin-3-yl, oxetan-2-yl, pyrrolidin-2-yl, piperidin-2-yl, tetrahydro-2H-pyran-2-yl, 1,4-dioxan-2-yl, 3,4-dihydro-2H-pyran-2-yl, 1,2-dihydropyridin-4-yl, furan-2-yl, furan-3-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, 1 / - / -imidazol-5-yl, 1 / - / -imidazol-4-yl, 1-imidazol-2-yl, 1H-imidazol-1-yl, 1H-pyrazol-5-yl, 1 H-1,2,3-triazol-5-yl, 1H-1,2,4-triazol-3-yl, 4H-1,2,4-triazol-3-yl, 2H-tetrazol-5-yl, thiazol-2-yl, oxazol-2-yl, isoxazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrimidin-4-yl, pyridazin-3-yl, benzofuran-2-yl, 1 H-indol-2-yl, benzo[c / ][1,3]dioxol-2-yl, 1 / - / -benzo[d]imidazol-2-yl, and benzo[d]oxazol-2-yl; wherein said R3is optionally substituted with one or two substituents independently selected from the group consisting of chloro, fluoro, hydroxy, oxo, -CH3, -CH2-O-CH3, -OCH3, and -NH2;

[0184] c is 2; and each R4is independently selected from the group consisting of methyl, and -CH2OH;

[0185] and (c) indolin-7-yl, 1H-indazol-7-yl, 1,2,3,4-tetrahydroisoquinolin-8-yl, or 1, 2,3,4-tetrahydronaphthalen-5-yl; wherein the indolin-7-yl, 1H-indazol-7-yl, 1, 2,3,4-tetrahydroisoquinolin-8-yl, or 1,2,3,4-tetrahydronaphthalen-5-yl is optionally substituted with one or two substituents independently selected from the group consisting of methyl, hydroxy, and -CH2CH2-C(O)OH;

[0186] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof. In some embodiments, the present invention is directed to compounds of formula (I) wherein

[0187] R1is selected form the group consisting of

[0188] (a) phenyl; wherein the phenyl is substituted with three substituents independently selected from the group consisting of methyl, bromo, hydroxy, -CH2OH, - )NH2;

[0189]

[0190] ; wherein

[0191] b is an integer from 0 to 1;

[0192] L1is selected from the group consisting of -CH2-NH-, -C(O)-NH-, -C(O)-NH-CH2-,

[0193]

[0194] provided that when L1is -CH2-NH-, then the -CH2- portion of L1is bound directly to the phenyl;

[0195] provided further that when L1is -C(O)-NH-, -C(O)-NH-CH2-, -C(O)-NH-CH(CH3)2-

[0196]

[0197] then the -C(O)- portion of L1is bound directly to the phenyl;

[0198] R3is selected from the group consisting of azetidin-3-yl, oxetan-2-yl, piperidin-2-yl, tetrahydro-2H-pyran-2-yl, 1,4-dioxan-2-yl, 3,4-dihydro-2H-pyran-2-yl, 1,2-dihydropyridin-4-yl, furan-2-yl, furan-3-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, 1H-imidazol-4-yl, 1H-imidazol-2-yl, 1H-pyrazol-5-yl, 1 H-1,2,3-triazol-5-yl, 1 H-1,2,4-triazol-3-yl, 4H-1,2,4-triazol-3-yl, 2H-tetrazol-5-yl, thiazol-2-yl, oxazol-2-yl, isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrimidin-4-yl, pyridazin-3-yl, benzofuran-2-yl, 1 H-indol-2-yl, 1H-benzo[d]imidazole-2-yl, and benzo[d]oxazol-2-yl; wherein said R3is optionally substituted with one substituent selected from the group consisting of oxo, chloro, fluoro, -CH3, -CH2OCH3, -OCH3, and -NH2; c is 2; and each R4is methyl;

[0199] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0200] In some embodiments, the present invention is directed to compounds of formula (I) wherein

[0201]

[0202] wherein

[0203] b is an integer from 0 to 1;

[0204] L1is selected from the group consisting of -C(O)-NH-, -C(O)-NH-CH2-, -C(O)-NH- Z\ <3.

[0205] ,.

[0206] CH(CH3)2-, -C(O)-NH' i^, -C(O)-NH-, and -C(O)-NH^;

[0207] provided that when L1is -C(O)-NH-, -C(O)-NH-CH2-, -C(O)-NH-CH(CH3)2-, -

[0208]

[0209] then the -C(O)- portion of L1is bound directly to the phenyl;

[0210] R3is selected from the group consisting of piperidin-2-yl, 1-imidazol-2-yl, 1H-pyrazol-5-yl, 1 H-1,2,3-triazol-5-yl, 1 / - / -1,2,4-triazol-3-yl, 2H-tetrazol-5-yl, oxazol-2-yl, isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrimidin-4-yl, pyridazin-3-yl, 1-benzo[]imidazole-2-yl, and benzo[d]oxazol-2-yl; wherein said R3is optionally substituted with one substituent selected from the group consisting of chloro, -CH3, -CH2OCH3, and -OCH3;

[0211] c is 2; and each R4is methyl;

[0212] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0213] In some embodiments, the present invention is directed to compounds of formula (I) wherein

[0214]

[0215]

[0216] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0217] In some embodiments, the present invention is directed to compounds of formula (II) wherein

[0218] e is an integer from 0 to 3;

[0219] each R6is independently selected from the group consisting of halogen, hydroxy, -CN, Ci-2alkyl, hydroxy substituted Ci-2alkyl, fluoro substituted Ci-2alkyl, -O-(Ci-2alkyl), -O-(fluoro substituted Ci-2alkyl), and -(C1-2alkyl)-O-(Ci-2alkyl);

[0220] R7is selected from the group consisting of Ci-2alkyl, hydroxy substituted Ci-2alkyl, fluoro substituted Ci-2alkyl, -(C1-2alkyl)-O-(Ci-2alkyl), -O-(Ci-2alkyl), -(Ci-2alkyl)-NRCRP, -SO2-(Ci-2alkyl), C3-5cycloalkyl, 4 to 6 membered heterocycloalkyl, and -(C1-2alkyl)-(4 to 6 membered heterocycloalkyl); wherein RCand RPare each independently selected from the group consisting of hydrogen, and C1-2alkyl;

[0221] wherein the C3-5cycloalkyl or 4 to 6 membered heterocycloalkyl, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, Ci-2alkyl, and fluorinated substituted Ci-2alkyl;

[0222]

[0223] wherein

[0224] f is an integer from 0 to 1;

[0225] L2is selected from the group consisting of -(Ci-2alkyl)-, -(fluorinated Ci-2alkyl)-, -(Ci-2alkyl)-N- and -(C1-2alkyl)-O-; provided that when L2is -(Ci-2alkyl)-N- or -(C1-2alkyl)-O-, then the -N- and -O-

[0226] portion of L2is bound directly to

[0227]

[0228] wherein

[0229]

[0230] is selected from the group consisting of C6-8cycloalkyl, phenyl, and 5 to 7 membered heterocyclyl; wherein the C6-8cycloalkyl, phenyl, or 5 to 7 membered heterocyclyl is optionally substituted with one or three substituent independently selected from the group consisting of halogen, hydroxy, oxo, C1-3alkyl, fluoro substituted C1-3alkyl, -(C1-3alkyl)-CN, -O-(C1-3alkyl), -O-(fluoro substituted C1-3alkyl), -NRQRR, -C(O)-

[0231]

[0232] wherein each RQand RRis independently selected from the group consisting of hydrogen, and C1-3alkyl;

[0233] wherein R10is selected from the group consisting of halogen substituted C1-2alkyl, C2-3alkenyl, C2-3alkynyl, and -CH=CH-CH2-NRSRT; wherein RSand RTare each independently selected from the group consisting of hydrogen, and C1-2alkyl; alternatively, Rsand RTare taken together with the nitrogen atom to which they are bound to form pyrrolidin-1 -yl, piperidin-1 -yl, piperazin-1 -yl or morpholin-4-yl;

[0234] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0235] In some embodiments, the present invention is directed to compounds of formula (II) wherein

[0236] e is an integer from 0 to 3;

[0237] each R6is independently selected from the group consisting of halogen, hydroxy, Ci-2alkyl, hydroxy substituted Ci-2alkyl, and fluoro substituted Ci-2alkyl;

[0238] R7is selected from the group consisting of Ci-2alkyl, hydroxy substituted Ci-2alkyl, fluoro substituted Ci-2alkyl, -(C1-2alkyl)-O-(Ci-2alkyl), -O-(Ci-2alkyl), -(Ci-2alkyl)-NRCRP, -SO2-(Ci-2alkyl), C3-4cycloalkyl, 4 to 6 membered heterocycloalkyl, and -(Ci-2alkyl)-(6 membered heterocycloalkyl);

[0239] wherein RCand RPare each independently selected from the group consisting of hydrogen, and Ci-2alkyl; wherein the C3-4cycloalkyl or 4 to 6 membered heterocycloalkyl, whether alone or as part of a substituent group, is optionally substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy, Ci-2alkyl, and fluorinated substituted Ci-2alkyl;

[0240]

[0241] wherein

[0242] f is an integer from 0 to 1;

[0243] L2is selected from the group consisting of -(Ci-2alkyl)-, and -(C1-2alkyl)-O-; provided that when L2is -(C1-2alkyl)-O-, then the -0- portion of L2is bound

[0244] directly

[0245]

[0246] wherein

[0247]

[0248] is selected from the group consisting of C6-8cycloalkyl, phenyl, and 5 to 7 membered heterocyclyl; wherein the C6-8cycloalkyl, phenyl, or 5 to 7 membered heterocyclyl is optionally substituted with one or three substituent independently selected from the group consisting of halogen, hydroxy, oxo, C1-3alkyl, fluoro substituted C1-2alkyl, -(C1-2alkyl)-CN, -O-(C1-2alkyl), -O-(fluoro substituted C1-2alkyl), -NRQRR, -C(O)-(C1-2alkyl), -C(O)CH=CH2, -C(=CH2)CN, and -NRQC(O)-R10and cyclopropyl;

[0249] wherein each RQand RRis independently selected from the group consisting of hydrogen, and C1-3alkyl;

[0250] wherein R10is selected from the group consisting of halogen substituted C1-2alkyl, C2-3alkenyl, C2-3alkynyl, and -CH=CH-CH2-NRSRT; wherein RSand RTare each independently selected from the group consisting of hydrogen, and C1-2alkyl;

[0251] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0252] In some embodiments, the present invention is directed to compounds of formula (II) wherein

[0253] e is an integer from 2 to 3;

[0254] each R6is independently selected from the group consisting of -CH3, -CH2OH, and -CF3; R7is selected from the group consisting of -CH3, -CH2CH3, -CH2CH2OH, -

[0255]

[0256]

[0257]

[0258] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0259] In some embodiments, the present invention is directed to compounds of formula (II) wherein

[0260] e is an integer from 2 to 3;

[0261] each R6is independently selected from the group consisting of -CH3, -CH2OH, and -CF3;

[0262] R7is selected from the group consisting of -CH3, -CH2CH3, -CH2CH2OH, -

[0263]

[0264]

[0265]

[0266] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0267] In some embodiments, the present invention is directed to compounds of formula (II) wherein

[0268] e is an integer from 2 or 3;

[0269] each R6is independently selected from the group consisting of -CH3, -CH2OH, and -CF3;

[0270] R7is selected from the group consisting of -CH3, -CH2CH2OH, -CH2CH2-N(CH3)2,

[0271]

[0272]

[0273]

[0274] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0275] In some embodiments, the present invention is directed to compounds of formula (II) wherein

[0276] e is 2;

[0277] each R6is methyl;

[0278] R7is methyl;

[0279]

[0280]

[0281] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0282] In some embodiments, the present invention is directed to compounds of formula (II) wherein

[0283] e is 2; each R6is methyl;

[0284] R7is selected from the group consisting of -CH3, -CH2CH2-N(CH3)2, 1-methyl-azetidin-3-yl, and oxetan-3-yl;

[0285]

[0286] ; wherein

[0287] f is 1; L2is -CH2-;

[0288] ( B )

[0289] — ' is phenyl; wherein the phenyl is substituted with one, two or three substituents independently selected from the group consisting of -CFs, -OCH3, -OCF3, -NH2, -NH-C(O)-CH2CI, -NH-C(O-)CH=CH2, -NH-C(O)-CH=CHCH3, -NH-C(O)-CH=C=CH2, -NH-C(O)-CH=CHCH2-N(CH3)2, -NH-C(O)-C≡C-CH3, and -C(=CH2)CN; and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof. In some embodiments, the present invention is directed to compounds of formula (II) wherein

[0290] e is 2; each R6is methyl;

[0291] R7is methyl;

[0292] wherein

[0293]

[0294] ( B )

[0295] ' is phenyl; wherein the phenyl is substituted with two or three substituents independently selected from the group consisting of -CF3, -OCH3, -OCF3, -NH-C(O)-CH2Cl, -NH-C(O)-CH=CH2, -NH-C(O)-CH=CHCH3, -NH-C(O)-CH=CHCH2-N(CH3)2, -NH-C(O)-C≡C-CH3, and -C(=CH2)CN;

[0296] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0297] In some embodiments, the present invention is directed to compounds of formula (III) wherein

[0298] e is and integer from 2 to 3;

[0299] each R6is independently selected from the group consisting of halogen, hydroxy, Ci-2alkyl, hydroxy substituted Ci-2alkyl, fluoro substituted Ci-2alkyl, -O-(Ci-2alkyl), and -O-(fluoro substituted Ci-2alkyl);

[0300] R12is selected from the group consisting of C4-7cycloalkyl, phenyl, and 4 to 10 membered heterocyclyl; wherein the C4-7cycloalkyl, phenyl, or 4 to 10 membered heterocyclyl is optionally substituted with one to four substituents independently selected from the group consisting of halogen, hydroxy, oxo, -CN, -NO2, Ci-4alkyl, hydroxy substituted Ci-3alkyl, fluoro substituted Ci-3alkyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-3alkyl), -C(O)-(Ci-3alkyl), -C(O)-(fluoro substituted Ci-3alkyl), -NRWRX, -(Ci-3alkyl)-NRwRx, -C(O)-NRWRX, -NRw-SO2-(Ci-3alkyl), -SO2-(Ci-3alkyl), -SO2-(fluoro substituted Ci-salkyl), -SO2-NRWRX, -S(O)(NH)(Ci-salkyl), -SO2-(6 membered saturated heterocycloalkyl) and P(O)(CHs)2; wherein Rwand Rxare each independently selected from the group consisting of hydrogen, and Ci-3alkyl;

[0301] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0302] In some embodiments, the present invention is directed to compounds of formula (III) wherein

[0303] e is and integer from 2 to 3;

[0304] each R6is independently selected from the group consisting of hydrogen, and methyl;

[0305] R12is selected from the group consisting of C4-6cycloalkyl, phenyl, and 4 to 10 membered heterocyclyl; wherein the C4-6cycloalkyl, phenyl, or 4 to 10 membered heterocyclyl is optionally substituted with one to four substituents independently selected from the group consisting of halogen, hydroxy, oxo, -CN, -NO2, Ci-4alkyl, hydroxy substituted Ci-2alkyl, fluoro substituted Ci-2alkyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-2alkyl), -C(O)-(Ci-2alkyl), -C(O)-(fluoro substituted Ci-2alkyl), -N(CH3)2, -(Ci-2alkyl)-NH2, -C(O)-NH2, -C(O)-N(CH3)2, -NH-SO2-(Ci-2alkyl), -SO2-(Ci-3alkyl), -SO2-(fluoro substituted Ci-2alkyl), -SO2-NRWRX, -S(O)(NH)(Ci-2alkyl), -SO2-(6 membered saturated heterocycloalkyl), and P(O)(CH3)2;

[0306] wherein Rwand Rxare each independently selected from the group consisting of hydrogen, and Ci-3alkyl;

[0307] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0308] In some embodiments, the present invention is directed to compounds of formula (III) where

[0309] e is 2 or 3; each R6is methyl; R12is selected from the group consisting

[0310]

[0311]

[0312]

[0313] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0314] In some embodiments, the present invention is directed to compounds of formula (III) wherein

[0315] e is 2 or 3; each R6is methyl;

[0316] R12is selected from the group consisting

[0317]

[0318]

[0319]

[0320] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0321] In some embodiments, the present invention is directed to compounds of formula (III) wherein

[0322] e is 2 or 3; each R6is methyl;

[0323]

[0324]

[0325] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0326] In some embodiments, the present invention is directed to compounds of formula (III) wherein

[0327] e is 2 or 3; each R6is methyl;

[0328]

[0329] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0330] In some embodiments, the present invention is directed to compounds of formula (Ill) wherein e is and integer from 2 to 3; each R6is methyl;

[0331] R12is selected from the group consisting of phenyl, thiochroman-6-yl, and pyridin-3-yl; wherein phenyl, thiochroman-6-yl, or pyridin-3-yl is substituted with one, two or three substituents independently selected from the group consisting of hydroxy,

[0332] oxo,

[0333]

[0334] 0 / — \

[0335] - -S-N O

[0336] II \ _ / P(O)(CH3)2; provided that no more than one of the substituents iss o;

[0337] and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0338] In some embodiments of the present invention, R1is (a) phenyl; wherein the phenyl is optionally substituted with one to four substituent independently selected from the group consisting of halogen, hydroxy, -CN, -NO2, Ci-salkyl, fluoro substituted C1-2alkyl, hydroxy substituted Ci-salkyl, C2-3alkenyl, fluoro substituted C2-3alkenyl, -O-(C1-3alkyl), -O-(fluoro substituted Ci-2alkyl), -(C1-2alkyl)-O-(Ci-2alkyl), -C(O)OH, -C(O)-(Ci-2alkyl), -C(O)O-(Ci-2alkyl), -C(0)-NRARB, -NRARB, -(Ci-2alkyl)-NRARB, -NRAC(O)-(Ci-2alkyl), -NHC(O)-(Ci-2alkyl)-NRARB, -NHC(O)-(Ci-2alkyl)-NHC(O)-(Ci-2alkyl), -CH(CN)NRARB, and -CH(CN)NHC(O)-(Ci-2alkyl); wherein RAis selected from the group consisting of hydrogen, and Ci-2alkyl; and wherein RBis selected from the group consisting of hydrogen, Ci-2alkyl, hydroxy substituted Ci-2alkyl, and -(Ci-2alkyl)-0-(Ci-2alkyl).

[0339] In some embodiments of the present invention, R1is (a) phenyl; wherein the phenyl is optionally substituted with one to four substituent independently selected from the group consisting of halogen, hydroxy, -CN, -NO2, Ci-salkyl, fluoro substituted C1-2alkyl, hydroxy substituted Ci-salkyl, fluoro substituted C2-salkenyl, -O-(Ci-salkyl), -0-(fluoro substituted Ci-2alkyl), -(Ci-2alkyl)-OCH3, -C(0)0H, -C(O)-(Ci-2alkyl), -C(0)0-(Ci-2alkyl), -C(0)-NRARB, -NRARB, -(Ci-2alkyl)-NRARB, -NRA-C(O)-(Ci-2akyl), -NH-C(0)-(Ci-2alkyl)-NRARB, -NH-C(O)-(CH2)-NH-C(O)-(Ci-2alkyl), -CH(CN)-NRARB, and -CH(CN)- NH-C(O)-(Ci-2alkyl); wherein RAis selected from the group consisting of hydrogen, and Ci-2alkyl; and RBis selected from the group consisting of hydrogen, Ci-2alkyl, hydroxy substituted Ci-2alkyl, and -(C1-2alkyl)-O-(Ci-2alkyl).

[0340] In some embodiments of the present invention, R1is (a) phenyl; wherein the phenyl is substituted with two or three substituents independently selected from the group consisting of halogen, hydroxy, -CH3, -CH2OH, -CH2CH2OH, -CH2OCH3, - CH2CH2OCH3, -CF2H, -CF3, -CHCF2, -OCH3, -C(O)CH3, -C(O)NH2, -NH2, -NHCH3, -NH- C(O)-CH2-NH-C(O)-CH3, -CH(CN)-NH2Iand -CH(CN)-NH-C(O)-CH3. In some embodiments of the present invention, R1is (a) phenyl; wherein the phenyl is substituted with three substituents independently selected from the group consisting of bromo, hydroxy, -CH3, -CH2OH, -C(O)-NH2, -NH2, and -CH(CN)NH2.

[0341] In some embodiments of the present invention, R1is selected from the group

[0342]

[0343]

[0344]

[0345]

[0346]

[0347] In some embodiments of the present invention, R1is selected from the group

[0348]

[0349] In some embodiments of the present invention, R1is selected from the group

[0350]

[0351] In some embodiments of the present invention,

[0352]

[0353] wherein

[0354] b is an integer from 0 to 1;

[0355] L1is selected from the group consisting of -(Ci-3alkyl)-, -(C1-2alkyl)-O-, -O-(C1-2alkyl)-

[0356]

[0357] SO2-; wherein RDis selected from the group consisting of hydrogen, and Ci-2alkyl;

[0358] provided that when L1is -C(O)O-(Ci-2alkyl), -C(O)-NH-(Ci-3alkyl)-, -C(O)-NH

[0359]

[0360] then the -C(O)- portion of L1is bound directly to the phenyl;

[0361] provided further that when L1is -NRD-C(O)-(Ci-2alkyl)-, then the -NRD- portion of L1is bound directly to the phenyl;

[0362] provided further that when L1is -(Ci-2alkyl)-NRD-SO2-, then the -(Ci-2alkyl)- portion of L1is bound directly to the phenyl;

[0363] R3is selected from the group consisting of C3-5cycloalkyl, aryl, and 4 to 9 membered heterocyclyl; wherein the C3-5cycloalkyl, aryl, or 4 to 9 membered heterocyclyl is optionally substituted with one or three substituent independently selected from the group consisting of halogen, hydroxy, oxo, Ci-2alkyl, fluoro substituted Ci-2alkyl, hydroxy substituted Ci-2alkyl, -O-(Ci-2alkyl), -(Ci-2alkyl)-O-(Ci-2alkyl) and -NRERF; wherein REand RFare each independently selected from the group consisting of hydrogen and Ci-2alkyl;

[0364] c is an integer from 0 to 3; and each R4is independently selected from the group consisting of halogen, hydroxy, -CN, Ci-2alkyl, fluoro substituted Ci-2alkyl, hydroxy substituted Ci-2alkyl, -O-(Ci-2alkyl), -O-(fluoro substituted Ci-2alkyl), and -(Ci-2alkyl)-O-(Ci-2alkyl).

[0365] In some embodiments of the present invention,

[0366]

[0367] wherein

[0368] b is an integer from 0 to 1;

[0369] L1is selected from the group consisting of -(Ci-3alkyl)-, -(Ci-2alkyl)-O-, -O-(Ci-2alkyl)-, -(Ci-2alkyl)-O-(Ci-3alkyl)-, -C(O)O-(Ci-2alkyl)-, -C(O)-NRD-, -C(O)-NH-(Ci-3alkyl)-

[0370]

[0371] (Ci-2alkyl)-NRD-, - NRD-(Ci-2alkyl)-, -(Ci-2alkyl)-NRD-(Ci-3alkyl)-, and -(Ci-2alkyl)-NRD-SO2-; wherein RDis selected from the group consisting of hydrogen, and Ci-2alkyl;

[0372] provided that when L1is -C(O)O-(Ci-2alkyl)-, -C(O)-NH-(Ci-3alkyl)-, -C(O)-NH

[0373]

[0374] then the -C(O)- portion of L1is bound directly to the phenyl;

[0375] provided further that when L1is -NRD-C(O)-(Ci-2alkyl)-, then the -NRD- portion of L1is bound directly to the phenyl;

[0376] provided further that when L1is -(Ci-2alkyl)-NRD-SO2-, then the -(Ci-2alkyl)-portion of L1is bound directly to the phenyl;

[0377] R3is selected from the group consisting of C3-5cycloalkyl, aryl, and 4 to 9 membered heterocyclyl; wherein the C3-5cycloalkyl, aryl, or 4 to 9 membered heterocyclyl is optionally substituted with one or three substituent independently selected from the group consisting of halogen, hydroxy, oxo, Ci-2alkyl, fluoro substituted Ci-2alkyl, hydroxy substituted Ci-2alkyl, -O-(Ci-2alkyl), -(C1-2alkyl)-O-(Ci-2alkyl) and -NRERF; wherein REand RFare each independently selected from the group consisting of hydrogen and Ci-2alkyl;

[0378] R3is selected from the group consisting of C3-4cycloalkyl, aryl, and 4 to 9 membered heterocyclyl; wherein the C3-4cycloalkyl, aryl, or 4 to 9 membered heterocyclyl is optionally substituted with one or two substituent independently selected from the group consisting of halogen, hydroxy, oxo, Ci-2alkyl, fluoro substituted C1-2alkyl, hydroxy substituted Ci-2alkyl, -O-(Ci-2alkyl), -(C1-2alkyl)-O-(Ci-2alkyl) and -NRERF; wherein REand RFare each independently selected from the group consisting of hydrogen and Ci-2alkyl;

[0379] c is an integer from 0 to 2; and each R4is independently selected from the group consisting of halogen, Ci-2alkyl, and hydroxy substituted

[0380] In some embodiments of the present invention, R1

[0381]

[0382] wherein

[0383] b is an integer from 0 to 1;

[0384] L1is selected from the group consisting of -CH2CH2CH2-, -CH2OCH2-, -CH2-NH-

[0385]

[0386] provided that when L1is -CH2-NH-SO2-, -CH2-NH-, or -CH2CH2-NH- then the -CH2- portion of L1is bound directly to the phenyl;

[0387] provided further that when L1is -NH-CH2CH2-, -NH-C(O)-CH2-, then the -NH- portion of L1is bound directly to the phenyl;

[0388] provided further that when L1is -C(O)O-CH2-, -C(O)-NH-CH2-, -C(O)-NH- < / \ o

[0389] CH(CH3)2-, -C(O)-NH^ -C(O)-NH^ or-C(O)-NH^, then the -C(O)- portion of L1is bound directly to the phenyl; provided further that when L1is -O-CH2CH2-, then the -O- portion of L1is bound directly to the phenyl;

[0390] R3is a selected from the group consisting of cyclopropyl, cyclobutyl, phenyl, azetidin-3-yl, oxetan-2-yl, pyrrolidin-2-yl, piperidin-2-yl, tetrahydro-2H-pyran-2-yl, 1,4-dioxan-2-yl, 3,4-dihydro-2H-pyran-2-yl, 1,2-dihydropyridin-4-yl, furan-2-yl, furan-3-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, 1H-imidazol-5-yl, 1H-imidazol-4-yl, 1H-imidazol-2-yl, 1H-imidazol-1-yl, 1H-pyrazol-5-yl, 1 H-1,2,3-triazol-5-yl, 1H-1,2,4-triazol-3-yl, 4H-1,2,4-triazol-3-yl, 2H-tetrazol-5-yl, thiazol-2-yl, oxazol-2-yl, isoxazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrimidin-4-yl, pyridazin-3-yl, benzofuran-2-yl, 1 H-indol-2-yl, benzo[d][1,3]dioxol-2-yl, 1H-benzo[d]imidazol-2-yl, and benzo[d]oxazol-2-yl; wherein said R3is optionally substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy, oxo, -CH3, -CF2OCH3, -0CH3, and -NH2;

[0391] c is 2; and each R4is independently selected from the group consisting of -CH3, and -CH2OH.

[0392] In some embodiments of the present invention,

[0393]

[0394] wherein

[0395] b is an integer from 0 to 1;

[0396] L1is selected from the group consisting of -CH2-NH-, -C(O)-NH-, -C(O)-NH-CH2-,

[0397]

[0398] provided that when L1is -CH2-NH-, then the -CH2- portion of L1is bound directly to the phenyl;

[0399] provided further that when L1is -C(O)-NH-, -C(O)-NH-CH2-, -C(O)-NH-CH(CH3)2-

[0400]

[0401] then the -C(O)- portion of L1is bound directly to the phenyl; R3is selected from the group consisting of azetidin-3-yl, oxetan-2-yl, piperidin-2-yl, tetrahydro-2H-pyran-2-yl, 1,4-dioxan-2-yl, 3,4-dihydro-2H-pyran-2-yl, 1,2-dihydropyridin-4-yl, furan-2-yl, furan-3-yl, 1 H-pyrrol-2-yl, 1 H-pyrrol-3-yl, 1H-imidazol-4-yl, 1H-imidazol-2-yl, 1H-pyrazol-5-yl, 1 H-1,2,3-triazol-5-yl, 1 H-1,2,4-triazol-3-yl, 4H-1,2,4-triazol-3-yl, 2H-tetrazol-5-yl, thiazol-2-yl, oxazol-2-yl, isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrimidin-4-yl, pyridazin-3-yl, benzofuran-2-yl, 1 H-indol-2-yl, 1H-benzo[d]imidazole-2-yl, and benzo[d]oxazol-2-yl; wherein said R3is optionally substituted with one substituent selected from the group consisting of halogen, oxo, -CH3, -CH2OCH3, -OCH3, and -NH2;

[0402] c is 2; and each R4is methyl.

[0403] In some embodiments of the present invention,

[0404]

[0405] wherein

[0406] b is an integer from 0 to 1;

[0407] L1is selected from the group consisting of -C(O)-NH-, -C(O)-NH-CH2-, -C(O)-NH-

[0408]

[0409] provided that when L1is -C(O)-NH-, -C(O)-NH-CH2-, -C(O)-NH-CH(CH3)2-, - z°\

[0410] C(O)-NH^ii>, -C(O)-NH^^, or-C(O)-NH^, then the -C(O)- portion of L1is bound directly to the phenyl;

[0411] R3is selected from the group consisting of piperidin-2-yl, 1-imidazol-2-yl, 1H-pyrazol-5-yl, 1 H-1,2,3-triazol-5-yl, 1H-1,2,4-triazol-3-yl, 2H-tetrazol-5-yl, oxazol-2-yl, isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrimidin-4-yl, pyridazin-3-yl, 1H-benzo[d]imidazole-2-yl, and benzo[d]oxazol-2-yl; wherein said R3is optionally substituted with one substituent selected from the group consisting of chloro, -CH3, -CH2OCH3, and -OCH3;

[0412] c is 2; and each R4is methyl. In some embodiments of the present invention, R1is selected from the group

[0413]

[0414]

[0415]

[0416]

[0417] In some embodiments of the present invention, R1is selected from the group

[0418]

[0419]

[0420]

[0421] In some embodiments of the present invention, R1is selected from the group

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428] In some embodiments of the present invention, R1is (c) 9 to 11 membered benzo-fused carbocyclyl or 9 to 11 membered benzo-fused heterocyclyl; wherein the 9 to 11 membered benzo-fused carbocyclyl, or 9 to 11 membered benzo-fused heterocyclyl is bound through the benzo-fused portion; wherein the 9 to 11 membered benzo-fused carbocyclyl or 9 to 11 membered benzo-fused heterocyclyl is optionally substituted with one or four substituent independently selected from the group consisting of halogen, hydroxy, oxo, -CN, Ci-2alkyl, fluoro substituted Ci-2alkyl, hydroxy substituted Ci-2alkyl, -O-(Ci-2alkyl), O-(fluoro substituted C1 -2alkyl), -(C1-2alkyl)-O-(Ci-3alkyl), -(Ci-3alkyl)-C(O)OH, -(Ci-3alkyl)-C(O)O-(Ci-4alkyl) and -NRJRK; wherein RJand RKare each independently selected from the group consisting of hydrogen, and Ci-2alkyl.

[0429] In some embodiments of the present invention, R1is (c) 9 to 11 membered benzo-fused carbocyclyl or 9 to 11 membered benzo-fused heterocyclyl; wherein the 9 to 11 membered benzo-fused carbocyclyl, or 9 to 11 membered benzo-fused heterocyclyl is bound through the benzo-fused portion; wherein the 9 to 11 membered benzo-fused carbocyclyl or 9 to11 membered benzo-fused heterocyclyl is optionally substituted with one or four substituent independently selected from the group consisting of halogen, hydroxy, oxo, -CN, Ci-2alkyl, -O-(Ci-2alkyl), -(C1-2alkyl)-O-(Ci-2alkyl), -(Ci-2alkyl)-C(O)OH, and -NRJRK; wherein RJand RKare each independently selected from the group consisting of hydrogen, and Ci-2al ky I. In some embodiments of the present invention, R1is selected from the group consisting of indolin-7-yl, 1 H-indazol-7-yl, 1,2,3,4-tetrahydroisoquinolin-8-yl, and 1,2,3,4- tetrahydronaphthalen-5-yl; wherein the indolin-7-yl, 1H-indazol-7-yl, 1, 2,3,4- tetrahydroisoquinolin-8-yl, or 1,2,3,4-tetrahydronaphthalen-5-yl is optionally substituted with one or two substituents independently selected from the group consisting of methyl, hydroxy, and -CH2CH2-C(O)OH.

[0430] In some embodiments of the present invention, R1is selected from the group

[0431]

[0432]

[0433] In some embodiments of the present invention, R1is selected from the group

[0434]

[0435] In some embodiments of the present invention, R1is selected from the group

[0436]

[0437] In some embodiments of the present invention, b is an integer from 0 to 1. In some embodiments of the present invention, b is 0. In some embodiments of the present invention, b is 1.

[0438] In some embodiments of the present invention, L1is selected from the group consisting of -(Ci-3alkyl)-, -(C1-2alkyl)-O-, -O-(Ci-2alkyl)-, -(C1-2alkyl)-O-(Ci-2alkyl)-, -

[0439]

[0440]

[0441] group consisting of hydrogen, and Ci-2alkyl.

[0442] In some embodiments of the present invention, L1is selected from the group

[0443]

[0444] In some embodiments of the present invention, L1is selected from the group

[0445]

[0446] In some embodiments of the present invention, L1is selected from the group

[0447]

[0448] In some embodiments of the present invention, R3is selected from the group consisting of C3-5cycloalkyl, aryl, and 4 to 9 membered heterocyclyl; wherein the C3-5cycloalkyl, aryl, or 4 to 9 membered heterocyclyl is optionally substituted with one or three substituent independently selected from the group consisting of halogen, hydroxy, oxo, Ci-2alkyl, fluoro substituted Ci-2alkyl, hydroxy substituted Ci-2alkyl, -O-(Ci-2alkyl), -(C1-2alkyl)-O-(Ci-2alkyl) and -NRERF; wherein REand RFare each independently selected from the group consisting of hydrogen and C1-2alkyl.

[0449] In some embodiments of the present invention, R3is selected from the group consisting of C3-5cycloalkyl, aryl, and 4 to 9 membered heterocyclyl; wherein the C3-5cycloalkyl, aryl, or 4 to 9 membered heterocyclyl is optionally substituted with one or two substituent independently selected from the group consisting of halogen, hydroxy, oxo, Ci-2alkyl, fluoro substituted Ci-2alkyl, hydroxy substituted Ci-2alkyl, -O-(Ci-2alkyl), -(C1-2alkyl)-O-(Ci-2alkyl) and -NRERF; wherein REand RFare each independently selected from the group consisting of hydrogen and C1-2alkyl.

[0450] In some embodiments of the present invention, R3is a selected from the group consisting of cyclopropyl, cyclobutyl, phenyl, azetidin-3-yl, oxetan-2-yl, pyrrolidin-2-yl, piperidin-2-yl, tetrahydro-2H-pyran-2-yl, 1,4-dioxan-2-yl, 3,4-dihydro-2H-pyran-2-yl, 1,2-dihydropyridin-4-yl, furan-2-yl, furan-3-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, 1H-imidazol-5-yl, 1H-imidazol-4-yl, 1H-imidazol-2-yl, 1H-imidazol-1-yl, 1H-pyrazol-5-yl, 1-1,2,3-triazol-5-yl, 1-1,2,4-triazol-3-yl, 4-1,2,4-triazol-3-yl, 2H-tetrazol-5-yl, thiazol-2-yl, oxazol-2-yl, isoxazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrimidin-4-yl, pyridazin-3-yl, benzofuran-2-yl, 1 H-indol-2-yl, benzo[d][1,3]dioxol-2-yl, 1H-benzo[d]imidazol-2-yl, and benzo[d]oxazol-2-yl; wherein said R3is optionally substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy, oxo, -CH3, -CH2OCH3, -OCH3, and -NH2.

[0451] In some embodiments of the present invention, R3is selected from the group consisting of azetidin-3-yl, oxetan-2-yl, piperidin-2-yl, tetrahydro-2H-pyran-2-yl, 1,4-dioxan-2-yl, 3,4-dihydro-2H-pyran-2-yl, 1,2-dihydropyridin-4-yl, furan-2-yl, furan-3-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, 1H-imidazol-4-yl, 1H-imidazol-2-yl, 1H-pyrazol-5-yl, 1H- 1.2.3-triazol-5-yl, 1 H-1,2,4-triazol-3-yl, 4H-1,2,4-triazol-3-yl, 2H-tetrazol-5-yl, thiazol-2-yl, oxazol-2-yl, isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrimidin-4-yl, pyridazin-3-yl, benzofuran-2-yl, 1H-indol-2-yl, 1H-benzo[d]imidazole-2-yl, and benzo[d]oxazol-2-yl; wherein said R3is optionally substituted with one substituent selected from the group consisting of halogen, oxo, -CH3, -CH2OCH3, -OCH3, and -NH2.

[0452] In some embodiments of the present invention, R3is selected from the group consisting of piperidin-2-yl, 1H-imidazol-2-yl, 1H-pyrazol-5-yl, 1 H-1,2,3-triazol-5-yl, 1H- 1.2.4-triazol-3-yl, 2H-tetrazol-5-yl, oxazol-2-yl, isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrimidin-4-yl, pyridazin-3-yl, 1-benzo[]imidazole-2-yl, and benzo[d]oxazol-2-yl; wherein said R3is optionally substituted with one substituent selected from the group consisting of chloro, methyl, -CH2OCH3, and -OCH3.

[0453] In some embodiments of the present invention, c is an integer from 1 to 3. In some embodiments of the present invention, c is an integer from 0 to 2. In some embodiments of the present invention, c is an integer from 1 to 2. In some embodiments of the present invention, c is an integer from 2 to 3. In some embodiments of the present invention, c is 0. In some embodiments of the present invention, c is 1. In some embodiments of the present invention, c is 2. In some embodiments of the present invention, c is 3. In some embodiments of the present invention, each R4is independently selected from the group consisting of halogen, hydroxy, -CN, Ci-2alkyl, fluoro substituted Ci-2alkyl, hydroxy substituted Ci-2alkyl, -O-(Ci-2alkyl), -O-(fluoro substituted Ci-2alkyl), and -(C1-2alkyl)-O-(Ci-2alkyl). In some embodiments of the present invention, each R4is independently selected from the group consisting of halogen, Ci-2alkyl, and hydroxy substituted Ci-2alkyl. In some embodiments of the present invention, each R4is independently selected from the group consisting of -CH3, and -CH2OH. In some embodiments of the present invention, each R4is methyl.

[0454] In some embodiments of the present invention, e is an integer from 1 to 3. In some embodiments of the present invention, e is 0 or 2. In some embodiments of the present invention, e is 1 or 2. In some embodiments of the present invention, e is an integer from 2 to 3. In some embodiments of the present invention, e is 0. In some embodiments of the present invention, e is 1. In some embodiments of the present invention, e is 2. In some embodiments of the present invention, e is 3.

[0455] In some embodiments of the present invention, each R6is independently selected from the group consisting of halogen, hydroxy, -CN, Ci-2alkyl, hydroxy substituted Ci-2alkyl, fluoro substituted Ci-2alkyl, -O-(Ci-2alkyl), -O-(fluoro substituted C1-2alkyl), and -(C1-2alkyl)-O-(Ci-2alkyl). In some embodiments of the present invention, each R6is independently selected from the group consisting of halogen, hydroxy, C1-2alkyl, hydroxy substituted Ci-2alkyl, fluoro substituted Ci-2alkyl, -O-(Ci-2alkyl), and -0-(fluoro substituted Ci-2alkyl). In some embodiments of the present invention, each R6is independently selected from the group consisting of halogen, hydroxy, Ci-2alkyl, hydroxy substituted Ci-2alkyl, and fluoro substituted Ci-2alkyl. In some embodiments of the present invention, each R6is independently selected from the group consisting of -CH3, -CH2OH, and -CF3. In some embodiments of the present invention, each R6is independently selected from the group consisting of hydrogen, and -CH3. In some embodiments of the present invention, each R6is independently -CH3. In some embodiments of the present invention, R7is selected from the group consisting of Ci-2alkyl, hydroxy substituted Ci-2alkyl, fluoro substituted Ci-2alkyl, -(Ci-2alkyl)-O-(Ci-2alkyl), -O-(Ci-2alkyl), -(Ci-2alkyl)-NRCRP, -SO2-(Ci-2alkyl), C3-5cycloalkyl, 4 to 6 membered heterocycloalkyl, and -(Ci-2alkyl)-(4 to 6 membered heterocycloalkyl); wherein RCand RPare each independently selected from the group consisting of hydrogen, and Ci-2alkyl; wherein the C3-5cycloalkyl or 4 to 6 membered heterocycloalkyl, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, Ci-2alkyl, and fluorinated substituted Ci-2alkyl.

[0456] In some embodiments of the present invention, R7is selected from the group consisting of Ci-2alkyl, hydroxy substituted Ci-2alkyl, fluoro substituted Ci-2alkyl, -(Ci-2alkyl)-O-(Ci-2alkyl), -O-(Ci-2alkyl), -(Ci-2alkyl)-NRCRP, -SO2-(Ci-2alkyl), C3-4cycloalkyl, 4 to 6 membered heterocycloalkyl, and -(Ci-2alkyl)-(6 membered heterocycloalkyl); wherein RCand RPare each independently selected from the group consisting of hydrogen, and Ci-2alkyl; wherein the C3-4cycloalkyl or 4 to 6 membered heterocycloalkyl, whether alone or as part of a substituent group, is optionally substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy, Ci-2alkyl, and fluorinated substituted Ci-2alkyl.

[0457] In some embodiments of the present invention, R7is selected from the group consisting of -CH3, -CH2CH3, -CH2CH2OH, -CH2CH2OCH3, -CH2CF2H, -CH2CF3, -

[0458]

[0459] . In some embodiments of the present invention, R7is selected from the group consisting of -CH3, -CH2CH3, -CH2CH2OH, -CH2CH2OCH3, -CH2CF2H, -CH2CF3, -

[0460]

[0461] In some embodiments of the present invention, R7is selected from the group consisting of -CH3,

[0462]

[0463] In some embodiments of the present invention, R7is selected from the group consisting of -CH3, -CH2CH2-N(CH3)2, 1-methyl-azetidin-3-yl, and oxetan-3-yl. In some embodiments of the present invention, R7is -CH3.

[0464] In some embodiments of the present invention, R8is

[0465]

[0466] wherein f is an integer from 0 to 1; L2is selected from the group consisting of -(Ci-2alky I)-, -(fluorinated Ci-2alkyl)-, -(Ci-2alkyl)-N- and -(Ci-2alkyl)-O-; provided that when L2is -(C1-2alkyl)-N- or -(Ci-2alkyl)-O-, then the -N- and -0- portion of L2is bound to ' — ';

[0467] is selected from the group consisting of C6-8cycloalkyl, phenyl, and 5 to 7 membered heterocyclyl; wherein the C6-8cycloalkyl, phenyl, or 5 to 7 membered heterocyclyl is optionally substituted with one or three substituent independently selected from the group consisting of halogen, hydroxy, oxo, C1-3alkyl, fluoro substituted C1-3alkyl, -(C1-3alkyl)-CN, -O-(C1-3alkyl), -O-(fluoro substituted C1-3alkyl), -NRQRR, C3-4cycloalkyl, -C(O)-(Ci-3alkyl), -C(O)CH=CH2, -C(=CH2)CN, and -NRQ-C(O)-R10; wherein each RQand RRis independently selected from the group consisting of hydrogen, and Ci-3alkyl;

[0468] wherein R10is selected from the group consisting of halogen substituted C1-2alkyl, C2-3alkenyl, C2-3alkynyl, and -CH=CH-CH2-NRSRT; wherein RSand RTare each independently selected from the group consisting of hydrogen, and C1-2alkyl; alternatively, Rsand RTare taken together with the nitrogen atom to which they are bound to form pyrrolidin-1 -yl, piperidin-1 -yl, piperazin-1 -yl or morpholin-4-yl.

[0469] In some embodiments of the present invention, R8is

[0470]

[0471] wherein f is an integer from 0 to 1; wherein L2is selected from the group consisting of - (Ci-2al ky I)-, - and -(C1-2alkyl)-O-; provided that when L2is -(C1-2alkyl)-O-, then the -0-

[0472] portion of L2is bound to

[0473]

[0474]

[0475] is Ce-scycloalkyl, phenyl, 5 to 7 membered heterocyclyl; wherein the Ce- scycloalkyl, phenyl, or 5 to 7 membered heterocyclyl is optionally substituted with one or three substituent independently selected from the group consisting of halogen, hydroxy, oxo, Ci-salkyl, fluoro substituted Ci-2alkyl, -(Ci-2alkyl)-CN, -0-(Ci-2alkyl), -O-(fluoro substituted Ci-2alkyl), -NQ R, cyclopropyl, -C(0)-(Ci-2alkyl), -C(0)CH=CH2, - C(=CH2)CN, and -NRQ-C(O)-R10; wherein each RQand RRis independently selected from the group consisting of hydrogen, and C1-3alkyl;

[0476] wherein R10is selected from the group consisting of halogen substituted Ci- 2alkyl, C2-salkenyl, C2-salkynyl, and -CH=CH-CH2-NRSRT; wherein RSand RTare each independently selected from the group consisting of hydrogen, and C1-2alkyl.

[0477] In some embodiments of the present invention, R8is

[0478]

[0479] wherein

[0480] f is 1; wherein L2is -CH2-; and

[0481]

[0482] is phenyl; wherein the phenyl is substituted with one, two or three substituents independently selected from the group consisting of - CF3, -OCH3, -OCF3, -NH2, -NH-C(O)-CH2CI, -NH-C(O)-CH=CH2I-NH-C(O)-CH=CHCH3, -NH-C(O)-CH=C=CH2, -NH-C(O)-CH=CHCH2-N(CH3)2, -NH-C(O)-C=C-CH3Iand - C(=CH2)CN.

[0483] In some embodiments of the present invention, R8is

[0484]

[0485]

[0486] is phenyl; wherein the phenyl is substituted with two or three substituents independently selected from the group consisting of -CFs, -OCH3, -OCF3, - NH-C(O)-CH2CI, -NH-C(O)-CH=CH2I-NH-C(O)-CH=CHCH3I-NH-C(O)-CH=CHCH2-N(CH3)2, -NH-C(O)-C≡C-CH3, and -C(=CH2)CN.

[0487] In some embodiments of the present invention, R8is selected from the group

[0488]

[0489]

[0490]

[0491]

[0492] In some embodiments of the present invention, R8is selected from the group

[0493]

[0494] In some embodiments of the present invention, R8is selected from the group

[0495]

[0496] In some embodiments of the present invention, f is 0. In some embodiments of the present invention, f is 1.

[0497] In some embodiments of the present invention, L2is selected from the group consisting of -(Ci-2alkyl)-, -(fluorinated Ci-2alkyl)-, -(Ci-2alkyl)-N- and -(C1-2alkyl)-O-. In some embodiments of the present invention, L2is selected from the group consisting of -(Ci-2alkyl)-, and -(Ci-2alkyl)-0-. In some embodiments of the present invention, L2is -CH2-.

[0498] ( B )

[0499] In some embodiments of the present invention, is selected from the group consisting of Ce-scycloalkyl, phenyl, 5 to 7 membered heterocyclyl; wherein the C6-8cycloalkyl, phenyl, or 5 to 7 membered heterocyclyl is optionally substituted with one or three substituent independently selected from the group consisting of halogen, hydroxy, oxo, Ci-salkyl, fluoro substituted Ci-salkyl, -(Ci-3alkyl)-CN, -O-(Ci-salkyl), -O-(fluoro substituted Ci-3alkyl), -NRQRR, C3-4cycloalkyl, -C(O)-(Ci-3alkyl), -C(O)CH=CH2, -C(=CH2)CN, and -NRQC(O)-R10; wherein each RQand RRis independently selected from the group consisting of hydrogen, and C1-3alkyl;

[0500] wherein R10is selected from the group consisting of halogen substituted Ci-2alkyl, C2-salkenyl, C2-salkynyl, and -CH=CH-CH2-NRSRT; wherein RSand RTare each independently selected from the group consisting of hydrogen, and C1-2alkyl; alternatively, Rsand RTare taken together with the nitrogen atom to which they are bound to form pyrrolidin-1 -yl, piperidin-1 -yl, piperazin-1 -yl or morpholin-4-yl.

[0501] In some embodiments of the present invention,

[0502]

[0503] is selected from the group consisting of Ce-scycloalkyl, phenyl, and 5 to 7 membered heterocyclyl; wherein the C6-8cycloalkyl, phenyl, or 5 to 7 membered heterocyclyl is optionally substituted with one or three substituent independently selected from the group consisting of halogen, hydroxy, oxo, Ci-salkyl, fluoro substituted Ci-2alkyl, -(Ci-2alkyl)-CN, -0-(Ci-2alkyl), -O-(fluoro substituted Ci-2alkyl), -NRQRR, cyclopropyl, -C(0)-(Ci-2alkyl), -C(0)CH=CH2, -C(=CH2)CN, and -NRQ-C(O)-R10; wherein each RQand RRis independently selected from the group consisting of hydrogen, and C1-3alkyl;

[0504] wherein R10is selected from the group consisting of halogen substituted Ci-2alkyl, C2-salkenyl, C2-salkynyl, and -CH=CH-CH2-NRSRT; wherein RSand RTare each independently selected from the group consisting of hydrogen, and Ci-2alkyl. In some embodiments of the present invention,

[0505]

[0506] is phenyl; wherein the phenyl is substituted with one, two or three substituents independently selected from the group consisting of -CF3, -OCH3, -OCF3, -NH2, -NH-C(O)-CH2CI, -NH-C(O)-CH=CH2, -NH-C(O)-CH=CHCH3, -NH-C(O)-CH=C=CH2I-NH-C(O)-CH=CHCH2-N(CH3)2, -NH-C(O)-C=C-CH3, and -C(=CH2)CN. In some embodiments of the present invention, ( B )

[0507] is phenyl; wherein the phenyl is substituted with two or three substituents independently selected from the group consisting of -CF3, -OCH3, -OCF3, -NH-C(O)-CH2Cl, -NH-C(O)-CH=CH2, -NH-C(O)-CH=CHCH3, -NH-C(O)-CH=CHCH2-N(CH3)2, -NH-C(O)-C≡C-CH3, and -C(=CH2)CN.

[0508] In some embodiments of the present invention, R10is selected from the group consisting of halogen substituted Ci-2alkyl, C2-3alkenyl, C2-3alkynyl, and -CH=CH-CH2-NRSRT; wherein RSand RTare each independently selected from the group consisting of hydrogen, and Ci-2alkyl; alternatively, Rsand RTare taken together with the nitrogen atom to which they are bound to form pyrrolidin-1 -yl, piperidin-1 -yl, piperazin-1 -yl or morpholin-4-yl. In some embodiments of the present invention, R10is selected from the group consisting of halogen substituted Ci-2alkyl, C2-3alkenyl, C2-3alkynyl, and -CH=CH-CH2-NRSRT; wherein RSand RTare each independently selected from the group consisting of hydrogen, and Ci-2alkyl.

[0509] In some embodiments of the present invention, R12is selected from the group consisting of C4-7cycloalkyl, phenyl, and 4 to 10 membered heterocyclyl; wherein the C4-7cycloalkyl, phenyl, or 4 to 10 membered heterocyclyl is optionally substituted with one to four substituents independently selected from the group consisting of halogen, hydroxy, oxo, -CN, -NO2, Ci-4alkyl, hydroxy substituted C1-3alkyl, fluoro substituted C1-3alkyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-3alkyl), -C(O)-(Ci-3alkyl), -C(O)-(fluoro substituted Ci-3alkyl), -NRWRX, -(Ci-3alkyl)-NRwRx, -C(O)-NRWRX, -NRw-SO2-(Ci-3alkyl), -SO2-(Ci-3alkyl), -SO2-(fluoro substituted Ci-3alkyl), -SO2-NRWRX, -S(O)(NH)(Ci-3alkyl), -SO2-(6 membered saturated heterocycloalkyl) and P(O)(CH3)2; wherein each Rwand Rxis independently selected from the group consisting of hydrogen, and Ci-3alkyl. In some embodiments of the present invention, R12is selected from the group consisting of C4-6cycloalkyl, phenyl, and 4 to 10 membered heterocyclyl; wherein the C4-6cycloalkyl, phenyl, or 4 to 10 membered heterocyclyl is optionally substituted with one to four substituents independently selected from the group consisting of halogen, hydroxy, oxo, -CN, -NO2, Ci-4alkyl, hydroxy substituted C1-2alkyl, fluoro substituted C1-2alkyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-2alkyl), -C(O)-(Ci-2alkyl), -C(O)-(fluoro substituted Ci-2alkyl), -N(CH3)2, -(Ci-2alkyl)-NH2, -C(O)NH2, -C(O)N(CH3)2, -NH-SO2-(C1-2alkyl), -SO2-(Ci-3alkyl), -SO2-(fluoro substituted Ci-2alkyl), -SO2-NRWRX, -S(O)(NH)(CH3), -SO2-(6 membered saturated heterocycloalkyl) and P(O)(CH3)2; wherein each Rwand Rxis independently selected from the group consisting of hydrogen, and Ci-3alkyl.

[0510] In some embodiments of the present invention, when R12is substituted with -SO2-(5 to 6 membered heterocycloalkyl), then the 5 to 6 membered heterocycloalkyl preferably contains 1 to 2 ring heteroatoms.

[0511] In some embodiments of the present invention, R12is selected from the group consisting of phenyl, thiochroman-6-yl, and pyridin-3-yl; wherein phenyl, thiochroman-6-yl, or pyridine-3-yl is substituted with one, two or three substituents independently selected from the group consisting of oxo, hydroxy, -OCH3, -SO2CH3, -SO2NH2, -

[0512] SO2NHCH3, -S(O)(NH)(CH3), P(O)(CH3)2, and

[0513]

[0514] ; provided that no more than

[0515] one of the substituents is

[0516]

[0517] In some embodiments of the present invention, R12is selected from the group

[0518] consisting

[0519]

[0520] KH

[0521]

[0522] 20

[0523]

[0524] In some embodiments of the present invention, R12is selected from the group

[0525]

[0526]

[0527] In some embodiments of the present invention, R12is selected from the group

[0528]

[0529] In some embodiments of the present invention, R12is selected from the group

[0530]

[0531] In some embodiments of the present invention, wherein the compound of formula (III), when e is an integer from 0 to 3, and each R6is independently selected from the group consisting of halogen, hydroxy, Ci-4alkyl, trifluoroCi-4alkyl, and -O-(Ci-4alkyl), then R12is other than piperidin-4-yl, wherein the piperidin-4-y I is optionally substituted at the 1 -position with Ci-4alkyl; or pyridin-4-yl, wherein the pyridin-4-yl is optionally substituted with amino, Ci-4alkylamino or di(Ci-4alkyl)amino. In some embodiments of the present invention, wherein the compound of formula (III), when e is an integer from 2 to 3, each R6is independently selected from the group consisting of halogen, hydroxy, C1-2alkyl, trifluoroCi-2alkyl, and -O-(Ci-2alkyl), then R12is other than piperidin-4-yl, wherein the piperidin-4-yl is optionally substituted at the 1 -position with C1-3alkyl; or pyridin-4-yl, wherein the pyridin-4-yl is optionally substituted with amino, C1-3alkylamino or di(C1-4alkyl)amino. In some embodiments of the present invention, wherein the compound of formula (III), when e is an integer from 2 to 3, each R6is -CH3, then R12is other than piperidin-4-yl, wherein the piperidin-4-yl is optionally substituted at the 1 -position with C1-3alkyl; or pyridin-4-yl, wherein the pyridin-4-yl is optionally substituted with amino, C1-3alkylamino or di(Ci-4alkyl)amino.

[0532] In some embodiments, the present invention is directed to compounds of formula (III) wherein R12is other than piperidin-4-yl, wherein the piperidin-4-yl is optionally substituted at the 1 -position with Ci-4alkyl. In some embodiments, the present invention is directed to compounds of formula (III) wherein R12is other than pyridin-4-yl, wherein the pyridin-4-yl is substituted with one substituent selected from the group consisting of -NH2, -NH(Ci-4alkyl) and -N(Ci-4alkyl)2. In some embodiments, the present invention is directed to compounds of formula (III) wherein R12is 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 -NH2, -NH(Ci-4alkyl) and -N(Ci-4alkyl)2.

[0533] 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.

[0534] 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.

[0535] 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.

[0536] 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.

[0537] 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.

[0538] 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. Wherein the compound contains at least on stereo-center, stereochemistry at the stereo-center(s) is as noted in the name. Unless otherwise noted, wherein a stereogenic center is present in the listed compound (e.g. as denoted by the symbol in the structure at the head of the table), the compound was prepared as a mixture of stereo-configurations (for example, as a racemate). The “S*”- and “R*-“ or “*S-“ and “*R-“ designations in the name are intended to indicate that the compound was prepared in an enantiomeric excess of one stereo-isomer, although the exact stereoconfiguration was not determined; whereas the “S-“ and “R-“ designations in the name are intended to indicate that the compound was prepared in an enantiomeric excess of the corresponding S- or R- stereo-isomer.

[0539] 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.

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574] and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof.

[0575] 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.

[0576] Table 2: Representative Compounds for Formula (II)

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597] and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof.

[0598] 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.

[0599] Table 3: Representative Compounds for Formula (III)

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613] and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof.

[0614] 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 μM, 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, more preferably less than or equal to about 5 nM, more preferably less than or equal to about 1 nM, more preferably less than or equal to about 0.5 nM, more preferably less than or equal to about 0.1 nM.

[0615] Abbreviations and Definitions

[0616] Abbreviations used in the specification, for example in the Schemes, Synthesis Examples and Biological Examples, are as listed in the Table A, below:

[0617] Table A: Abbreviations

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624] Definitions

[0625] As used herein, unless otherwise noted, “halogen” shall mean chloro, bromo, fluoro and iodo, preferably bromo, fluoro or chloro, more preferably fluoro or chloro.

[0626] As used herein, unless otherwise noted, the term “oxo" shall mean a functional group of the structure =0 (i.e. a substituent oxygen atom connected to another atom by a double bond). One skilled in the art will recognize that when the oxo substituent is bound to a carbon atom, the oxygen atom is bound to the carbon atom through a double bond. One skilled in the art will recognize that wherein the oxo group is bound to a ring nitrogen or a nitrogen substituted with two non-hydrogen substituent groups, the result will be a N-oxide bond (i.e. > N+-O-).

[0627] 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, C1-4alkyl include straight and branched chains of between 1 and 4 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl.

[0628] As used herein, unless otherwise noted, the term “halogen substituted Cx.Yal ky I” shall mean any Cx-yalkyl group as defined above substituted with one or more halogen groups, preferably one to three, more preferably one to two halogen groups. Preferably the halogen is chloro or fluoro. Suitable examples include, but are not limited to, -CH2CI, -CH2F, -CHCI2, -CHF2, -CCI3, -CF3, -CH2CHF2, -CH2CF3, -CH2CH2CI, -CH2CH2F, -CH(CI)CH3, -CH(F)CH3, -CH2CH(CI)CH3, -CH2CH(F)CH3, -CH2CH2CH2CI, -CH2CH2CH2F, and the like. 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. Suitable examples include, but are not limited to, -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CH3, -CH-CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CH2F, -CH2CH2CF3, -C(CH3)2CF3, -C(CF3)3and the like.

[0629] Similarly, the term “trifluoroCx-yalkyl” shall mean any CX-Y alkyl group as defined above substituted with three fluoro group. For example, “trifluoro-Ci-2alkyl” includes -CF3, -CH2-CF3, -CHF-CHF2, and the like.

[0630] As used herein, unless otherwise noted, the term “hydroxy substituted Cx.Yal ky I” 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. Suitable examples include, but are not limited to, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH(OH)CH3, -CH(OH)CH2OH, -CH2CH2CH2OH, -C(CH2OH)3, -CH2C(OH)(CH3)2, -CH(CH3)CH2OH and the like.

[0631] 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, a C2-4alkenyl shall include -CH=CH2, -CHCCH2, -CH2CH=CH2, -CH2CH2CH=CH2, -CH=CHCH2CH3, -CH=CHCH=CH2and the like.

[0632] As used herein, unless otherwise noted, the term “fluoro substituted Cx.

[0633] Yalkenyl” shall mean any Cx-yalkenyl as defined above, substituted with one or more fluoro groups, preferably one to three fluoro groups. Suitable examples include, but are not limited to, -CH=CF2, -CF2CH=CH2, -CH2CH2CH=CF2, -CH=CHCH2CF3, -CH=CHCH=CF2and the like.

[0634] As used herein, unless otherwise noted, the terms “CX-yalkynyl” 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 triple bond. For example, a C2-4alkynyl shall include -CCH, -CH2CCH, -CCCH3, -CH2CH2CCH, -CCCH2CH3, -CH2CCCH3and the like. 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 structure. Preferably, the Cx-vcycloalkyl is a monocyclic, bicyclic or bridged saturated ring structure. For example, suitable

[0635]

[0636] cycloalkyl group is bound through any ring carbon atom). Suitably C3-5cycloalkyl groups

[0637] include

[0638]

[0639] Suitable C4-8cycloalkyl groups

[0640] include

[0641]

[0642]

[0643] , and the like. Suitably C6-8cycloalkyl include

[0644]

[0645]

[0646] the like.

[0647] As used herein, unless otherwise noted, the term “aryl” shall refer to any monocyclic or bicyclic aromatic ring structure containing 6 to 10 carbon atoms in the ring portion. Suitable examples include phenyl and naphthyl (preferably phenyl).

[0648] As used herein, the term “heterocycloalkyl” shall denote any five to eight membered monocyclic, saturated or partially unsaturated 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; or a nine to twelve membered saturated, partially unsaturated or partially aromatic bicyclic ring system containing at least one heteroatom selected from the group consisting of 0, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of 0, N and S. The heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.

[0649] As used herein, unless otherwise noted, the term “4 to 6 membered heterocycloalkyl” shall denote any 4 to 6 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 6 membered heterocycloalkyl group may be attached at any carbon atom or heteroatom of the ring such that the result is a stable structure. Suitable examples

[0650]

[0651] Similarly, the term “5 to 6 membered heterocycloalkyl” shall denote any 5 to 6 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 5 to 6 membered heterocycloalkyl group may be attached at any carbon atom or heteroatom of the ring such

[0652] that the result is a stable structure. Suitable examples include, but are not limited to ' — / ,

[0653]

[0654] As used herein, unless otherwise noted, the term “heterocyclyl” shall denote any 4 to 8 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 independently selected from the group consisting of 0, N and S; or any 7 to 12 membered saturated, partially unsaturated, partially aromatic or aromatic bicyclic, 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 four additional heteroatoms independently selected from the group consisting of 0, N and S. The “heterocyclyl” may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure. Suitable examples

[0655]

[0656]

[0657]

[0658] As used herein, unless otherwise noted, the term “5 to 7 membered heterocyclyl” shall denote any 5 to 7 membered monocyclic or spiro-cyclic, saturated, partially unsaturated, or aromatic ring system containing at least one heteroatom selected from the group consisting of 0, N and S (preferably 0 or N); optionally containing one to two additional heteroatoms independently selected from the group consisting of 0, N and S (preferably 0 or N). The “5-7 membered heterocyclyl” may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure. In certain embodiments of the present invention, the “5-7 membered heterocyclyl” is selected from

[0659] the group consisting

[0660]

[0661] As used herein, unless otherwise noted, the term “4 to 10 membered heterocyclyl” shall denote any 4 to 10 membered saturated, partially unsaturated, partially aromatic or aromatic, monocyclic, bicyclic, 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 four additional heteroatoms independently selected from the group consisting of 0, N and S. The “4-10 membered heterocyclyl” may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure. In certain embodiments of the present invention, the “4-10 membered heterocyclyl” is

[0662] selected from the group consisting of

[0663]

[0664]

[0665] As used wherein, unless otherwise denoted, the term “benzo-fused” shall denote a bicyclic ring system in which a benzene is fused with a second ring, wherein the second ring may be saturated, partially unsaturated or aromatic, and wherein the second ring contains four to more, preferably 4 to 8, more preferably 4 to 7 ring atoms, more preferably

[0666]

[0667] ,.

[0668] As used herein, unless otherwise noted, the term “9 to 11 membered benzofused carbocyclyl” shall denote any 9 to 11 membered bicyclic ring structure, wherein one of the rings is benzene, and wherein the second ring is a saturated, partially unsaturated, or aromatic ring comprising 5 to 7 carbon ring atoms. The “9 to 11 membered benzo-fused carbocyclyl” may be attached to any carbon atom that the result is a stable structure. In certain embodiments of the present invention, the 9 to 11 membered benzofuzed carbocyclyl is bound through a carbon atom of the benzene ring. In certain embodiments of the present invention, the 9 to 11 membered benzo-fuzed carbocyclyl is bound through a carbon atom of the second ring. Suitably examples include, but are not

[0669]

[0670] like. In certain embodiments of the present invention, the “9 to 11 membered benzo-

[0671] fused carbocyclyl” is selected from the group consisting

[0672]

[0673]

[0674] As used herein, unless otherwise noted, the term “9 to 11 membered benzofused heterocyclyl” shall denote any 9 to ele11ven membered bicyclic ring structure, wherein one of the rings is benzene, and wherein the second ring is saturated, partially unsaturated or aromatic, and wherein the second ring contains at least one heteroatom selected from the group consisting of 0, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of 0, N and S. The “9 to 11 membered benzo-fused heterocyclyl” may be attached to any of the carbon atom of the benzene ring such that the result is a stable structure. Suitable

[0675]

[0676]

[0677] When a particular group is "substituted" (e.g. Cx-yalkyl, Cx-Ycycloalkyl, heterocyclyl, heterocycloalkyl, benzo-fused carbocyclyl, benzo-fuzed heterocyclyl, etc.), said group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents. With reference to substituents, the term “independently” means that when more than one substituent is possible, such substituents may be the same or different from each other.

[0678] 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.

[0679] 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).

[0680] 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.

[0681] 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.

[0682] 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.

[0683] 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, a-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.

[0684] Representative bases which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1 H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

[0685] 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).

[0686] As used herein, the symbol or notation shall denote the presence of a stereogenic center.

[0687] Where the compounds of the present invention contain at least one chiral center, they may accordingly exist as enantiomers. Where the compounds of the present invention contain two or more chiral centers, they may additionally exist as diastereomers or stereoisomers. It is to be understood that all such isomers I stereoisomers and mixtures thereof are encompassed within the scope of the present invention. It is further understood that atropisomers (a specific type of stereoisomer resulting from steric or other hinderances to rotation) are also encompassed within the scope of the present invention.

[0688] 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%.

[0689] Throughout the specification and claims, wherein a compound or substituent group is drawn or named, the “*S” and “*R” or “S*” and “R*” designations associated with a given stereo-center indicate that although the compound or substituent group is present in an excess of one stereo-orientation at said stereo-center, the exact stereoconfiguration has not been determined. Further, wherein a compound or substituent group is drawn or named, the “S” and “R” designations indicate that the stereoorientation at said stereo-center was measured / determined and that the compound or group is present in an excess of the corresponding “S” or “R” stereo-orientation.

[0690] Wherein a compound or substituent group contains two stereo-centers which are drawn using

[0691]

[0692] “ and I or “ "HI “ bond symbols, and which are the further denoted as “RS”, it is intended to indicate that the compound is present in an excess of either the “cis” or “trans” orientation of said two stereo-centers, although the exact stereo-configuration has not been determined.

[0693] In some embodiments, the present invention is directed to compounds of formula (I) wherein the stereocenter denoted with a is present in the R- stereo-orientation. In some embodiments, the present invention is directed to compounds of formula (I) wherein the stereocenter denoted with a is present in an S- stereo-orientation. In some embodiments, the present invention is directed to compounds of formula (II) wherein the stereocenter denoted with a is present in the R- stereo-orientation. In some embodiments, the present invention is directed to compounds of formula (II) wherein the stereocenter denoted with a is present in an S- stereo-orientation. In some embodiments, the present invention is directed to compounds of formula (III) wherein the stereocenter denoted with a is present in the R- stereo-orientation. In some embodiments, the present invention is directed to compounds of formula (III) wherein the stereocenter denoted with a is present in an S- stereo-orientation.

[0694] 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.

[0695] 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.

[0696] 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 nonradioactive. Radiolabelled compounds of formula (I) may comprise one or more radioactive isotope(s) selected from the group of3H,11C,18F,122l,123l,125l,131I,75Br,76Br,77Br and82Br. Preferably, the radioactive isotope is selected from the group of3H,11C and18F.

[0697] Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a “phenyl-(Ci-C6alkylene)-amino-carbonyl-(Ci-Cealkylene)-” substituent refers to a group of the formula

[0698]

[0699] 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.

[0700] 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.

[0701] 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 saltform(s).

[0702] General Synthesis Schemes

[0703] The compounds of formula (I), compounds of formula (II) and compounds of formula (III) of the present invention may be prepared according to the general synthesis schemes and synthesis example procedures, as described herein.

[0704] The compounds of formula (I), compounds of formula (II), and compounds of formula (III) of the present invention may be prepared by coupling three substituent groups onto a central 3,5-di-C(O)-phenyl scaffold of structure (A)

[0705]

[0706] wherein the numbering indicates phenyl carbon atoms around said scaffold. More specifically, the compounds of the present invention may be prepared by coupling the following substituent groups, at the noted positions:

[0707] (a) an -R1group (herein referred to as the “bottom" substituent) directly to the carbon atom at the 1 -position of the phenyl, to yield a 1,1 -biphenyl core (for example, as described in Scheme 1, below);

[0708] (b) an -NH-C(R8)-C(O)-NH-(R7) group (herein referred to as the “right hand side” substituent), to the -C(O)- at the 3-position of the phenyl (for example, as described in Scheme 2, below); and

[0709] (c) a

[0710]

[0711] group (herein referred to as the “left hand side” substituent), to the -C(O)- at the 5-position of the phenyl (for example, as described in Scheme 3, below).

[0712] One skilled in the art will recognize that the “bottom”, “right hand side” and “left hand side” substituent groups may be introduced I coupled onto the central 3,5-di-C(O)-phenyl scaffold in any order, and in either a single coupling step or in multiple steps (as for example described in more detail in the Schemes 1-3, which follow herein). One skilled in the art will further recognize that depending on the order in which the “bottom”, “right hand side” and “left hand side” substituent groups are introduced / coupled onto the 3,5-di-C(O)-phenyl scaffold, reactive terminal groups and I or substituents may be protected at a suitable or desired step prior to any coupling step, and de-protected at any suitable subsequent step, according to known methods.

[0713] The Schemes which follow herein describe methods for individually coupling the “bottom”, “right hand side” and “left hand side” substituents onto the 3,5-di-(C(O)-phenyl scaffold, starting from a suitably substituted compound of formula (V)

[0714]

[0715] wherein PL1and PL2are each independently hydrogen or a suitably selected oxygen protecting group, wherein the oxygen protecting group is selected so as to be suitable for the desired reaction step (or sequence of reaction steps), as would be readily recognized by those skilled in the art. Suitable PL1and PL2oxygen protecting groups include for example, Ci-4alkyl (preferably methyl, ethyl or tert-butyl), benzyl, and the like. Further, PL3represents a suitably selected leaving group such as a halogen (preferably Br, Cl or I), -OS(O)2CFs, and the like, or a suitably selected reactive coupling group such as a group of the formula -B(R)2 (a boronic acid wherein each R is OH, a dialkyl boronic ester wherein each R is -O-Ci-4alky I, or a cyclic boronic ester of the

[0716] formula

[0717]

[0718] wherein the two R groups are taken together with the boron atom to which they are bound).

[0719] Preferably, PL1, PL2and PL3are not the same. Preferably, PL1and PL2are not the same and are chosen to allow for either selective de-protection of the 3-position or 5-position ester prior to a desired coupling reaction; or selective coupling at the 3-postion or 5-position of the 3,5-di-C(O)-phenyl scaffold. For example, when PL1is methyl or ethyl and PL2is terf-butyl, one skilled in the art will recognize that the PL1methyl or ethyl group may be selectively de-protected by reacting with a suitably selected base such as NaOH, LiOH, Ba(0H)2, and the like, according to known methods, without removal of the PL2te / Y-butyl group Alternatively, the PL2te / Y-butyl group may be selectively de-protected by reacting with a suitably selected acid such as H3PO4, TFA, HCI, and the like, according to known methods, without the removal of the PL1methyl or ethyl group.

[0720] Preferably, when coupling the “right hand substituent”, PL1is removed and replaced with hydrogen and PL2is selected to be a suitable oxygen protecting group. Preferably, when coupling the “left hand substituent”, PL2is removed and replaced with hydrogen and PL1is selected to be a suitable oxygen protecting group. Preferably, PL3is a halogen (more preferably, Br) or a reactive coupling group of the formula -B(R)2

[0721] (more preferably

[0722]

[0723] In one example, the compound of formula (I), compound of formula (II) or compound of formula (III) is prepared by coupling, in sequence, the “bottom”, “left hand side”, and “right hand side” substituent groups. In another example, the compound of formula (I), compound of formula (II) or compound of formula (III) is prepared by coupling, in sequence, the “bottom”, “right hand side”, and “left hand side” substituent groups. In another example, the compound of formula (I), compound of formula (II) or compound of formula (III) is prepared by coupling the “right hand side” and “left hand side” substituent groups (in any order) and then coupling the “bottom” substituent group.

[0724] The ’’bottom” substituent may be coupled onto the 3,5-di-C(O)-phenyl scaffold as described in Scheme 1, below.

[0725]

[0726] Scheme 1

[0727] Accordingly, a suitably substituted compound of formula (Va), wherein PL1and PL2are the same or different, and are each a suitably selected oxygen protecting groups such as C1-4alkyl (preferably methyl, ethyl or tert-butyl), benzyl, and the like, and wherein PL3is a suitably selected leaving group such as a halogen (preferably Br, Cl or I), -OS(O)2CFS, and the like, a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of formula (VI), wherein LG1is a suitably selected reactive coupling group such as a group of the formula -B(R)2 (a boronic acid wherein each R is OH, a dialkyl boronic ester wherein each R is -O-C1-

[0728] 4alkyl, or a cyclic boronic ester of the formula

[0729]

[0730] wherein the two R groups are taken together with the boron atom to which they are bound), a known compound or compound prepared by known methods; in the presence of a suitably selected palladium catalyst such as Pd(dppf)Cl2, CataCXium® A Pd G3, CataCXium® A Pd G4, Pd(PPh3)4, XPhos Pd G3, Pd(dtbpf)Cl2, Pd(t-BusP)2 and the like; in the presence of a suitably selected base such as K3PO4, Cs2CO3, Na2CO3, TEA, CsF, K2CO3, and the like; in a suitably selected solvent such as 1,4-dioxane, toluene, DMSO, THF, 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 (VII).

[0731] Alternatively, a suitably substituted compound of formula (Va), wherein PL1and PL2are the same or different, and are each a suitably selected oxygen protecting groups such as C1-4alkyl (preferably methyl, ethyl or tert-butyl), benzyl, and the like, and wherein PL3is a suitably selected reactive coupling group such as a group of the formula -B(R)2 (a boronic acid wherein each R is OH, a dialkyl boronic ester wherein

[0732] each R is -O-C1-4alkyl, or a cyclic boronic ester of the formula

[0733]

[0734] wherein the two R groups are taken together with the boron atom to which they are bound), a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of formula (VI) wherein LG1is a suitably selected leaving group such as a halogen (preferably Br or I), -OS(O)2CFs, and the like, a known compound or compound prepared by known methods; in the presence of a suitably selected palladium catalyst such as Pd(dppf)Cl2, CataCXium® A Pd G3, CataCXium® A Pd G4, Pd(PPh3)4, XPhos Pd G3, Pd(dtbpf)Cl2, Pd(t-BusP)2, and the like; in the presence of a suitably selected base such as K3PO4, Cs2CO3, Na2CO3, TEA, CsF, K2CO3, and the like; in a suitably selected solvent such as 1,4-dioxane, toluene, DMSO, THF, 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 (VII).

[0735] Alternatively, a suitably substituted compound of formula (Va), wherein PL1and PL2are the same or different, and are each a suitably selected oxygen protecting groups such as Ci-4alkyl (preferably methyl, ethyl or tert-butyl), and the like, and wherein PL3is a suitably selected leaving group such as a halogen (preferably Br, Cl or I), -OS(O)2CFS, and the like, a known compound or compound prepared by known methods; is reacted with a suitably substituted compound of formula (VIII), wherein WAis a suitably selected reactive group such as -C(O)CHs, -C(O)H, -C(O)OH, -NO2, -NH2, and the like, and wherein LG2is a suitably selected reactive coupling group, such as a group of the formula -B(R)2 (a boronic acid wherein each R is OH, a dialkyl boronic ester wherein each R is -O-C1-4alkyl, or a cyclic boronic ester of the formula

[0736]

[0737] wherein the two R groups are taken together with the boron atom to which they are bound), a known compound or compound prepared by known methods; in the presence of a suitably selected palladium catalyst such as Pd(dppf)Cl2, CataCXium®A Pd G3, CataCXium® A Pd G4, Pd(PPh3)4, XPhos Pd G3, Pd(dtbpf)CI2, Pd(t-Bu3P)2, and the like; in the presence of a suitably selected base such as K3PO4, Cs2CO3, TEA, CsF, Na2CO3, KOAc, and the like; in a suitably selected solvent such as 1,4-dioxane, toluene, DMSO, THF 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).

[0738] Alternatively, a suitably substituted compound of formula (Va), wherein PL1and PL2are the same or different, and are each a suitably selected oxygen protecting groups such as C1-4alkyl (preferably methyl, ethyl or tert-butyl), benzyl, and the like, and wherein PL3is a suitably selected reactive coupling group such as a group of the formula -B(R)2(a boronic acid wherein each R is OH, a dialkyl boronic ester wherein

[0739] each R is -O-C1-4alkyl, or a cyclic boronic ester of the formula

[0740]

[0741] wherein the two R groups are taken together with the boron atom to which they are bound), a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of formula (VIII), wherein WAis a suitably selected reactive group such as -C(O)CH3, -C(O)H, -C(O)OH, -NO2, -NH2, and the like, and wherein LG2is a suitably selected leaving group such as a halogen (preferably Br or I), -OS(O)2CF3, and the like, a known compound or compound prepared by known methods; in the presence of a suitably selected palladium catalyst such as Pd(dppf)CI2, CataCXium® A Pd G3, CataCXium® A Pd G4, Pd(PPh3)4, XPhos Pd G3, Pd(dtbpf)CI2, Pd(t-Bu3P)2, and the like; in the presence of a suitably selected base such as K3PO4, Cs2CO3, TEA, CsF, Na2CO3, KOAc, and the like; in a suitably selected solvent such as 1,4-dioxane, toluene, DMSO, THF 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).

[0742] The compound of formula (IX) is then further reacted to functionalize and I or convert the WAgroup to the desired -(L1)b-R3substituent.

[0743] For example, a compound of formula (IX) wherein WAis -NH2 (prepared for example by reacting the compound of formula (IX) wherein WAis -NO2 by reacting with a suitably selected reducing agent, such as Fe, Zn, H2, and the like; in the presence of a suitably selected additive such as NH4CI, AcOH, Pd / C, and the like; in a suitably selected solvent or mixture of solvents, such as MeOH, EtOH, H2O, THF, a mixture of MeOH, THF and water, a mixture of EtOH, THF, and water, and the like; at a temperature in the range of from about 0 °C to about 60 °C, preferably at about 25 °C);

[0744] may be reacted with a suitably substituted compound of formula R3-(Ci-4alkyl)o-i-C(O)OH, a known compound or compound prepared by known methods; in the presence of a suitably selected amide coupling reagent such as HATU, T3P®, EDC, TCFH, DCC, PyBOP, Si-DCC, Si-HOBT, 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, acetonitrile, DMA, 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 (X) wherein L1is -NH-C(O)- or -NH-C(O)-(Ci-4alkyl)-.

[0745] One skilled in the art will recognize that wherein R4comprises a terminal -NH2 substituent group, said terminal -NH2 may be similarly functionalized to yield alternate substituents, for example as described in Synthesis Example 53 and 69, which follow herein.

[0746] In another example, a compound of formula (IX), wherein WAis -C(O)H, may be reacted with a compound of formula R3-(Ci-4alkyl)o-i-NHRD, a known compound or compound prepared by known methods; in the presence of a reducing agent such as NaBH4, Na(OAc)3BH, Na(CN)BH3, LiBH4, and the like; in the presence of a suitably selected additive such as AcOH, TEA, ZnCl2, Ti(OPr)4, and the like; in a suitably selected solvent such as DCE, MeOH, THF, EtOH, DCM, DMF, and the like; at a temperature in the range of from about 0°C to about 60°C, preferably at about 25 °C; to yield the corresponding compound of formula (X) wherein L1is -CH2-NRD-(Ci-4alkyl)o-i. One skilled in the art will recognize that wherein WAor R4is -C(O)H substituent group, said -C(O)H may be similarly functionalized to yield alternate substituents, for example as described in synthesis Examples 60, 70-78, and 139-140, which follow herein.

[0747] In another example, a compound of formula (IX) wherein WAis -C(O)OH (prepared for example from the corresponding compound of formula (IX) wherein WAis -C(O)H by reacting with a suitably selected oxidizing agent, such as NaCIO2, PCC, H2O2, NaCIO, O2, and the like; in the presence of a suitably selected additive such as NaH2PO4, 2-methyl-2-butene, Na2HPO4, and the like; in a suitably selected solvent or mixture of solvents, such as DMSO, H2O, DMF, MeCN, a mixture of DMSO and water, a mixture of tBuOH and water, acetone and water, MeCN and water, MeOH and water, and the like; at a temperature in the range of from about 0 °C to about 80 °C, preferably at about 50 °C);

[0748] may be reacted with a suitably substituted compound of formula R3-(LA)o-i-NHRD,

[0749] wherein LAis -C i-4alky I-,

[0750]

[0751] , a known compound or compound prepared by known methods; in the presence of a suitably selected amide coupling reagent such as HATU, T3P®, EDC, TCFH, DCC, PyBOP, Si-DCC, Si-HOBT, 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, MeCN, DMA, and the like; at a temperature in the range of from about room temperature to about 80 °C, preferably at about room temperature; to yield the corresponding compound of formula (X) wherein

[0752]

[0753] One skilled in the art will recognize that wherein WAis -C(O)OH substituent, said -C(O)OH may be similarly functionalized to yield substituents such as -R3(wherein b is 0), for example as described in Synthesis Example 59, which follows herein. In another example, a compound of formula (IX), wherein WAis -C(O)CH3, may be reacted with Bredereck’s reagent (te / Y-butoxy bis(dimethylamino)methane) or DMF-DMA in a suitably selected solvent such as DMF, 1,4-dioxane, toluene, and the like; at a temperature in the range of from about 60°C to about 130°C, preferably at about 100 °C; to yield the corresponding compound wherein WAis converted to -C(O)-CHCH-N(CHS)2. The intermediate compound wherein WAis -C(O)-CHCH-N(CH3)2is then further reacted with hydrazine hydrate, a known compound, in a suitably selected solvent such as EtOH, MeOH, and the like; at a temperature in the range of from about 60°C to about 120°C, preferably at about 80 °C; to yield the corresponding compound of formula (X) wherein b is 0 and R3is 1H-pyrazol-5-yl.

[0754] One skilled in the art will recognize that wherein R4comprises a terminal -CH3 substituent group, said -CH3 may similarly be functionalized to yield alternate substituents, for example as described in Synthesis Example 26, which follows herein.

[0755] The ’’right hand side” substituent may be coupled onto the 3,5-di-C(O)-phenyl scaffold as described in Scheme 2, below.

[0756]

[0757] Scheme 2

[0758] Accordingly, a compound of formula (Vb), wherein PL2is a suitably selected oxygen protecting group such as Ci-4alkyl (preferably methyl, ethyl and tert-butyl), and wherein PL3is a suitably selected leaving group such as halogen (preferably Br, Cl or I), or a suitably selected reactive coupling group of the formula -B(R)2 (a boronic acid wherein each R is OH, a dialkyl boronic ester wherein each R is -O-C1-4alkyl, or a cyclic

[0759] boronic ester of the formula

[0760]

[0761] wherein the two R groups are taken together with the boron atom to which they are bound), a known compound or compound prepared by known methods; is reacted with a suitably substituted compound of formula (XI), a known compound or compound prepared by know methods; in the presence of a suitably selected amide coupling reagent such as HATU, T3P®, TCFH, EDC, DCC, PyBOP, Si-DCC, Si-HOBT, 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, THF, DMSO, DCM, DMA, and the like; at a temperature in the range of from about 0°C to about 60 °C, preferably at about room temperature; to yield the corresponding compound of formula (XII).

[0762] Alternatively, a compound of formula (Vb) wherein PL2is a suitably selected oxygen protecting group such as Ci-4alkyl (preferably methyl, ethyl and tert-butyl), and wherein PL3is a suitably selected leaving group such as halogen (preferably Br, Cl or I), or a suitably selected reactive coupling group of the formula -B(R)2 (a boronic acid wherein each R is OH, a dialkyl boronic ester wherein each R is -O-C1-4alkyl, or a cyclic

[0763] boronic ester of the formula

[0764]

[0765] wherein the two R groups are taken together with the boron atom to which they are bound), a known compound or compound prepared by known methods; is reacted with a suitably substituted compound of formula (XIII) wherein PG1is a suitably selected oxygen protecting group such as C1-2alkyl (preferably methyl, ethyl or tert-butyl), benzyl, and the like, a known compound or compound prepared by known methods; in the presence of a suitably selected amide coupling reagent such as HATU, T3P®, TCFH, DCC, EDC, PyBOP, Si-DCC, Si-HOBT, and the like; in the presence of a suitably selected base such as Et3N, DIPEA and the like; in a suitably selected solvent such as DMF, DCM, and the like; at a temperature in the range of from about 0°C to about 60 °C, preferably at room temperature; to yield the corresponding compound of formula (XIV). Preferably PG1and PL2are selected to allow for selective deprotection of PG1. For example, when PG1is a protecting group that can be removed under basic conditions, then PL2is preferably a protecting group which is not labile under basic conditions. In another example, when PG1is a protecting group that can be removed under acid conditions, then PL2is preferably a protecting group which is not labile under acid conditions.

[0766] The compound of formula (XIV) is reacted according to known methods, to remove the PG1protecting group; to yield the corresponding compound of formula (XV). For example, wherein PG1is te / Y-butyl, the compound of formula (XIV) is reacted with a suitably selected acid such as HCI, TFA, H3PO4, and the like; in a suitably selected solvent of mixture of solvents such as THF, MeOH, water, 1,4-dioxane, DCM, and the like; at a temperature in the range of from about 0°C to about 100 °C, preferably at about room temperature. In another example, wherein PG1is methyl or ethyl, the compound of formula (XIV) is reacted with a suitably selected base such as LiOH, NaOH, KOH, and the like; in a suitably selected solvent or mixture of solvents such as THF, MeOH, water, MeCN, 1,4-dioxane and the like; at a temperature in the range of from about 0°C to about 60 °C, preferably at about room temperature.

[0767] The compound of formula (XV) is reacted with a suitably substituted compound of formula (XVI), a known compound or compound prepared by know methods; in the presence of a suitably selected amide coupling reagent such as HATU, T3P®, TCFH, DCC, EDC, PyBOP, Si-DCC, Si-HOBT, 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, THF, DMA, DCM, 1,4-dioxane, acetonitrile, and the like; at a temperature in the range of from about 0°C to about 60 °C, preferably at about room temperature; to yield the corresponding compound of formula (XII).

[0768] -(L2)f-

[0769] One skilled in the art will recognize that wherein R8is, and wherein

[0770]

[0771] contains a terminal -NH2substituent, said -NH2substituent may be further functionalized, for example, as described in Synthesis Examples 3, 5-6, 11-12, 132, and 136-138, which follow herein.

[0772] One skilled in the art will further recognize that wherein R8is

[0773]

[0774] and

[0775] wherein

[0776]

[0777] contains a terminal halogen (preferably Br, Cl or I) substituent, said halogen may be further functionalized, for example, as described in Synthesis Examples 7-10, 127-130, and 133-135, which follow herein.

[0778] The ’’left hand side” substituent may be coupled onto the 3,5-di-C(O)-phenyl scaffold as described in Scheme 3, below.

[0779]

[0780] Scheme 3

[0781] Accordingly, a compound of formula (Vc), wherein PL1is a suitably selected oxygen protecting group such as C1-4alkyl (preferably methyl, ethyl or tert-butyl), benzyl, and the like, and wherein PL3is a suitably selected leaving group such as halogen (preferably Br, Cl or I), or a suitably selected reactive coupling group of the formula -B(R)2(a boronic acid wherein each R is OH, a dialkyl boronic ester wherein each R is - O-C1-4alkyl, or a cyclic boronic ester of the formula

[0782]

[0783] wherein the two R groups are taken together with the boron atom to which they are bound), a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of formula (XVII), a known compound or compound prepared by know methods; in the presence of a suitably selected amide coupling reagent such as HATU, T3P®, TCFH, EDC, DCC, PyBOP, Si-DCC, Si-HOBT, 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, THF, DMA, 1,4-dioxane, acetonitrile, and the like; at a temperature in the range of from about 0°C to about 60 °C, preferably at about room temperature; to yield the corresponding compound of formula (XVIII).

[0784] Alternatively, a suitably substituted compound of formula (Vc), wherein PL1is a suitably selected oxygen protecting group such as C1-4alkyl (preferably methyl, ethyl or tert-butyl), benzyl, and the like, and wherein PL3is a suitably selected leaving group such as halogen such I, Br, or Cl, preferably Br, or a suitably selected reactive coupling group of the formula -B(R)2 (a boronic acid wherein each R is OH, a dialkyl boronic

[0785] ester wherein each R is -O-C1-4alkyl, or a cyclic boronic ester of the formula

[0786]

[0787] wherein the two R groups are taken together with the boron atom to which they are bound), a known compound or compound prepared by known methods, is reacted with piperazine, a known compound; in the presence of a suitably selected amide coupling reagent such as HATU, T3P®, EDC, DCC, TCFH, PyBOP, Si-DCC, Si-HOBT, 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, DMA, THF, acetonitrile, DMSO, and the like; at a temperature in the range of from about 0°C to about 60 °C, preferably at about room temperature; to yield the corresponding compound of formula (XIX). One skilled in the art will recognize that, to facilitate the purification of compound of formula (XIX), one of the nitrogen atoms of the piperazine is preferably protected with a suitably selected nitrogen protecting group such as BOC, Fmoc, Alloc, Cbz, and the like. The compound of formula (XIX) is reacted with a compound of formula (XX), wherein Q3is a suitably selected leaving group such as a halogen (preferably, Br, Cl, or I, more preferably Br), OTf, OTs, and the like, a known compound or compound prepared by know methods; in the presence of a suitably selected palladium catalyst such as RuPhos Pd G4, rac-BINAP Pd G4, XPhos Pd G4, SPhos Pd G4 and the like; in the presence of a suitably selected base such as Cs2CO3, K3PO4, K2CO3, Na2CO3, NaOtBu, and the like; in a suitably selected solvent such as 1,4-dioxane, THF, Me-THF, DMF, and the like; at a temperature in the range of from about 60 to about 120 °C, preferably at about 100°C; to yield the corresponding compound of formula (XVIII).

[0788] Alternatively, the compound of formula (XIX) is reacted with a compound of formula (XX), wherein Q3is oxo, a known compound or compound prepared by know methods; in the presence of a suitably selected reducing agent such as NaBH4, Na(CN)BH3s, Na(OAc)3BH, and the like; in the presence of a suitably selected additive such as AcOH, TEA, Ti(OPr)4, Sheppard reagent, and the like; in a suitably selected solvent such as DCE, DCM, THF, MeOH, and the like; at a temperature in the range of from about 0°C to about 60°C, preferably at about 25 °C; to yield the corresponding compound of formula (XVIII).

[0789] One skilled in the art will recognize that wherein R12is phenyl, C4-8cycloalkyl, or 4 to 10 membered heterocyclyl, and wherein said phenyl, C4-8cycloalkyl, or 4 to 10 membered heterocyclyl contain at least one oxo substituent, said oxo substituent(s) may be further functionalized, for example, as described in in Synthesis Example 23, which follows herein.

[0790] One skilled in the art will recognize, that when desired or preferred, suitably selected leaving groups such as a halogen, such as Br, Cl, I and the like, preferably Br or I, may be converted to a reactive coupling group of the formula -B(R)2 (a boronic acid wherein each R is OH, a dialkyl boronic ester wherein each R is -O-C1-4alkyl, or a cyclic

[0791] boronic ester of the formula

[0792]

[0793] by reacting 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 as Pd(dppf)Cl2, PdCl2(PPh3)2, XPhos Pd G4, and the like; in the presence of a suitably selected base such as 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.

[0794] One skilled in the art will further recognize that various substituent groups and I or functional groups (for example -OH, -NH2, -C(O)OH, etc.) may be protected prior to any reaction step, and then de-protected at any subsequent step in the synthesis, as would be desired or necessary, according to methods well known to those skilled in the art.

[0795] 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.

[0796] 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. 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.

[0797] 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.

[0798] 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.

[0799] 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.

[0800] 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.

[0801] 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.

[0802] 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.

[0803] 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.

[0804] 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.

[0805] 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.

[0806] Additionally, chiral HPLC against a standard may be used to determine percent enantiomeric excess (%ee). The enantiomeric excess may be calculated as follows [ (Rmoles-Smoles) / (Rmoles+Smoles) ] X 100% where Rmoles and Smoles are the R and S mole fractions in the mixture such that Rmoles+Smoles = 1. The enantiomeric excess may alternatively be calculated from the specific rotations of the desired enantiomer and the prepared mixture as follows:

[0807] ee = ([α-obs] / [α-max]) X 100.

[0808] Methods of Treatment / Disorders Mediated by BFL-1 Receptor

[0809] 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 (I I) or a compound of formula (III).

[0810] 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).

[0811] 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.

[0812] 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).

[0813] 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).

[0814] 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.

[0815] 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.

[0816] 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.

[0817] Pharmaceutical Compositions

[0818] 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) ora compound of formula (III) as described herein and one or more pharmaceutically acceptable carriers or excipients.

[0819] 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.

[0820] 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.

[0821] 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.

[0822] 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.

[0823] The dosages, however, may be varied depending upon the requirement of the patients, the seventy of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.

[0824] 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 com 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 preformulation 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.

[0825] 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.

[0826] 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.

[0827] 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.

[0828] 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.

[0829] The liquid forms may include suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.

[0830] 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.

[0831] 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.

[0832] 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.

[0833] Examples

[0834] 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.

[0835] 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.

[0836] 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.

[0837] LC-MS: Unless otherwise indicated, the analytical LC-MS system used consisted of one of the following: 1) Shimadzu LC MS-2020 with electrospray ionization (ESI) in positive ion detection mode with a HALO C18 column, 30 x 5.0 mm, 2.7 pm. Mobile phase A was water containing 0.05% TFA and mobile phase B was acetonitrile containing 0.05% TFA with a flow rate of 1.5 mL / min. 2) Agilent 1260 Inifinity II with electrospray ionization (ESI) in positive ion detection mode with an InfinityLab Poroshell 120 EC-C18 column, 50 x 2.1 mm, 2.7 pm. Mobile phase A was water containing 0.1% TFA and mobile phase B was acetonitrile containing 0.1% TFA with a flow rate of 1.2 mL / min. Mobile phase gradients were optimized for the individual compounds.

[0838] Calculated mass corresponds to the exact mass.

[0839] 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®).

[0840] 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.

[0841] Intermediate Compound Synthesis Examples

[0842] Intermediate A: (R)-2-Amino-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide HCI.

[0843]

[0844] Step A: tert-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 (3.04 g, 45.0 mmol) and triethylamine (20.9 mL, 150 mmol) in DMF (100 mL) at 0°C was added HATU (13.7 g, 36.0 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water (100 mL) was added, and the reaction mixture was extracted with EtOAc (1000 mL). The combined organic extracts were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with DCM / petroleum ether (20 / 1, 220 mL) at room temperature and the solid was collected by filtration to yield the title compound. MS (ESI): mass calculated for C16H21F3N2O3, 346.2; m / z measured, 291.1 [M-56+H]+(loss of terf-butyl group).1H NMR (400 MHz, CDCI3) δ 7.56 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 7.8 Hz, 2H), 5.90 (br s, 1 H), 5.00 (br s, 1 H), 4.34 (br d, J = 7.5 Hz, 1 H), 3.23-3.14 (m, 1H), 3.12-3.03 (m, 1H), 2.76 (d, J= 4.8 Hz, 3H), 1.39 (s, 9H).

[0845] Step B: (R)-2-Amino-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide HCI. To a solution of tert-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, 28.0 mL, 112 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was filtered and the solid was dried under vacuum to yield the title compound as the hydrochloride salt, which was used directly in the next step. MS (ESI): mass calculated for C11H13F3N2O, 246.1; m / z measured, 247.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 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) 5 -60.86 (s, 1 F).

[0846] Intermediate B: 2-Amino-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide HCI.

[0847]

[0848] Step A: tert-Buty I (1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamate. To a mixture of 2-((tert-butoxycarbonyl)amino)-3-(4-(trifluoromethyl)phenyl)propanoic acid (200 mg, 0.600 mmol), CH3NH2•HCl (81 mg, 1.2 mmol), and DIPEA (233 mg, 1.80 mmol) in DCM (5 mL) was added T3P® (50% solution in EtOAc, 496 mg, 0.78 mmol). The reaction mixture was stirred at room temperature overnight. To the reaction mixture was then added sat. aq. NH4CI (15 ml_) and extracted with DCM (3x 15 ml_). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. Purification of the resultant 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 C16H21F3N2O3, 346.2; m / z measured, 291.1 [M-56+H]+(loss of tert-butyl group).1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 5.85 (br s, 1 H), 4.98 (br s, 1 H), 4.34 (br d, J = 7.2 Hz, 1 H), 3.25 - 3.01 (m, 2H), 2.77 (d, J = 4.6 Hz, 3H), 1.40 (s, 9H).19F NMR (376 MHz, CDCl3) δ -62.50 (s, 1F).

[0849] Step B: 2-Amino- / V-methyl-3-(4-(trifluoromethyl)phenyl)propanamide hydrochloride. To a mixture of tert-butyl (1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamate (180 mg, 0.52 mmol) in DCM (6 mL) was added HCI (4 M solution in 1,4-dioxane, 5.0 mL, 20 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum 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) 5 8.42 (br d, J = 4.5 Hz, 1H), 8.23 (brs, 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) δ -60.88 (br s, 1 F).

[0850] Intermediate C: Ethyl (R)-2-amino-3-(4-(trifluoromethyl)phenyl)propanoate.

[0851]

[0852] Step A: Ethyl (R)-2-((tert-butoxycarbonyl)amino)-3-(4-(trifluoromethyl)phenyl)propanoate. A mixture of Boc-4-(trifluoromethyl)-D-phenylalanine (10 g, 30 mmol) and Cs2CO3(29.3 g, 90.0 mmol) in DMF (200 mL) was stirred at room temperature for 15 minutes before iodoethane (3.6 mL, 45 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered, and the filter cake was washed with EtOAc (300 ml_). The filtrate was washed with brine (3x 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification of the resultant 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 C17H22F3NO4, 361.2; m / z measured, 262.2 [M-100+H]+(loss of Boc group).1H NMR (400 MHz, CDCI3) 67.57 (br d, J = 7.8 Hz, 2H), 7.33 - 7.25 (m, 2H), 5.05 (brs, 1H), 4.61 (br d, J = 6.8 Hz, 1H), 4.24 - 4.12 (m, 2H), 3.26 - 3.05 (m, 2H), 1.43 (s, 9H), 1.25 (br t, J = 7.2 Hz, 3H).19F NMR (376 MHz, CDCI3) 6 -62.52 (br s, 1 F).

[0853] Step B: Ethyl (R)-2-amino-3-(4-(trifluoromethyl)phenyl)propanoate. To a solution of ethyl (R)-2-((tert-butoxycarbonyl)amino)-3-(4-(trifluoromethyl)phenyl)propanoate (8.30 g, 22.6 mmol) in DCM (100 mL) was added TFA (10 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo. To the residue was added DCM (200 mL) and the pH was adjusted to ~8 with sat. aq. NaHCO3solution. The organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the title compound as a green oil. MS (ESI): mass calculated for C12H14F3NO2, 261.1; m / z measured, 262.1 [M+H]+.1H NMR (400 MHz, CDCI3) 67.61 - 7.54 (m, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.18 (q, J= 7.2 Hz, 2H), 3.91 - 3.64 (m, 1H), 3.24 - 3.05 (m, 1H), 3.05 - 2.84 (m, 1H), 1.25 (t, J= 7.2 Hz, 3H).19F NMR (376 MHz, CDCl3) δ -62.49 (s, 1F).

[0854] Intermediate D: (R)-2',5'-Dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid.

[0855]

[0856] 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 an atmosphere of N2. The reaction mixture was heated to 90 °C overnight. The reaction mixture was filtered, and the filter cake was washed 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 resultant residue by chromatography (FCC, silica gel, 0-10% EtOAc in petroleum ether) yielded the title compound as a white solid.1H NMR (400 MHz, CDCI3) 68.67 (t, J = 1.7 Hz, 1 H), 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).

[0857] Step B: 5-(Methoxycarbonyl)-2',5'-dimethyl-[1,1'-biphenyl]-3-carboxylicacid. 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 resultant residue by 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, CDCI3) 68.75 (s, 1H), 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).

[0858] 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 HCI (Intermediate A, 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, suspended in 1:1 (v / v) EtOAc / petroleum ether (40 mL), stirred for 15 minutes at room temperature, and filtered. The 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, CDCl3) 68.33 (s, 1H), 8.16 (s, 1H), 7.93 (s, 1H), 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, 1H), 4.88 - 4.79 (m, 1H), 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, CDCl3) 6 -62.52 (s, 1F).

[0859] 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 hours. 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]+. Intermediate E: (R)-2',5'-Dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(piperazine-1 -carbonyl)-[1, 1 ' -bi ph eny I ]-3-carboxamide.

[0860]

[0861] Step A: tert-Buty I (R)-4-(2',5'-dimethyl-5-((1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carbonyl)piperazine-1 -carboxylate. 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 D, 1.0 g, 2.0 mmol), Et3N (0.84 mL, 6.0 mmol), and HATU (915 mg, 2.41 mmol) in DMF (10 mL) was added 1-Boc-piperazine (440 mg, 2.34 mmol). The reaction was stirred at room temperature for 2.5 hours, then additional HATU (229 mg, 0.60 mmol) and 1-Boc-piperazine (112 mg, 0.600 mmol) were added. The reaction was stirred at room temperature for about 75 minutes. To the reaction mixture was then added EtOAc (-15 mL) and H2O (10 ml_), and the mixture was stirred for about 10 minutes. The layers were separated, and the aqueous layer was extracted with EtOAc (10 mL). The combined organic layers were consecutively washed with 0.2 N HCI, sat. aq. NaHCO3, brine, and concentrated in vacuo. Purification of the resultant residue by chromatography (FCC) yielded the title compound. MS (ESI): mass calculated for C36H41F3N4O5, 666.3; m / z measured, 611.1 [M-56+H]+(loss of tert-butyl group).1H NMR (400 MHz, CDCI3) 67.8-7.7 (m, 2H), 7.6-7.3 (m, 5H), 7.2-7.0 (m, 4H), 5.88-5.77 (m, 1 H), 4.79 (q, J = 7.2 Hz, 1 H), 3.75 (br s, 2H), 3.53 (br s, 2H), 3.41 (br s, 4H), 3.3-3.2 (m, 2H), 2.74 (d, J = 4.9 Hz, 3H), 2.35 (s, 3H), 2.19 (s, 3H), 1.47 (s, 9H).

[0862] Step B: (R)-2',5'-Dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(piperazine-1 -carbonyl)-[1, 1 ' -bi ph eny I ]-3-carboxamide. To a mixture of tert-butyl (R)-4-(2',5'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-bi ph eny I ]-3-carbonyl)piperazine-1-carboxylate (880 mg, 1.32 mmol) in DCM (8.8 mL) was added TFA (0.51 mL, 6.6 mmol). The reaction mixture was allowed to stand at room temperature. After 80 minutes, additional TFA (1.50 mL, 19.6 mmol) was added, and the reaction was allowed to stand at room temperature for about 2 hours. The reaction mixture was diluted with DCM (6.2 mL) and carefully neutralized with Na2CO3(2 M in H2O, 15 mL). The layers were separated, and the aqueous layer was extracted with DCM (1x). The combined organics were dried over Na2SO4and concentrated in vacuo to yield the title compound as a solid. MS (ESI): mass calculated for C31H33F3N4O3, 566.3; m / z measured, 567.2 [M+H]+.1H NMR (400 MHz, CDCI3) 67.77 - 7.68 (m, 2H), 7.57 - 7.52 (m, 2H), 7.47 - 7.33 (m, 3H), 7.24 - 7.10 (m, 3H), 7.00 (s, 1H), 5.98 - 5.88 (m, 1 H), 4.80 (q, J = 7.3 Hz, 1 H), 3.76 (br s, 2H), 3.40 (br s, 2H), 3.22 (d, J = 6.8 Hz, 2H), 3.03 - 2.91 (m, 2H), 2.88 (br s, 1 H), 2.80 (s, 3H), 2.73 (d, J = 4.9 Hz, 3H), 2.34 (s, 3H), 2.19 (s, 3H).

[0863] Intermediate F: 2',5'-Dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxylic acid.

[0864]

[0865] Step A: Methyl 2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1,1'-biphenyl]-3-carboxylate. To a mixture of 5-(methoxycarbonyl)-2',5'-dimethyl-[1,1'-biphenyl]-3-carboxylic acid (Intermediate D, Step B, 5.0 g, 17 mmol), 1-(4-(methylsulfonyl)phenyl)piperazine (4.5 g, 19 mmol), and HATU (8.5 g, 22 mmol) in DCM (100 mL) was added DIPEA (17.1 mL, 103 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (100 mL) and washed with brine (2x 50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. Purification of the resultant residue by chromatography (FCC, silica gel, 0-100% EtOAc in petroleum ether) yielded the title compound as a white solid. MS (ESI): mass calculated for C28H30N2O5S, 506.2; m / z measured, 507.2 [M+H]+.1H NMR (400 MHz, CDCI3) δ 8.12 (d, J = 5.9 Hz, 2H), 7.82 (d, J = 9.0 Hz, 2H), 7.62 (s, 1 H), 7.23 - 7.12 (m, 2H), 7.07 (s, 1 H), 6.97 (d, J = 9.0 Hz, 2H), 3.97 (s, 5H), 3.83 - 3.60 (m, 2H), 3.57 - 3.26 (m, 4H), 3.04 (s, 3H), 2.38 (s, 3H), 2.26 (s, 3H).

[0866] Step B: 2',5'-Dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1,1'-biphenyl]-3-carboxylic acid. To a mixture of methyl 2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1,1'-biphenyl]-3-carboxylate (7.7 g, 15 mmol) in 1:1 (v / v) MeOH / THF (50 mL) was added NaOH (1 M in water, 30.4 mL, 30.4 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and EtOAc (200 mL) and water (50 mL) were added to the residue. The pH was adjusted to pH ~ 3 by addition of 1 M aqueous HCI. The aqueous layer was extracted with EtOAc (2x 150 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to yield the title compound as a white solid. MS (ESI): mass calculated for C27H28N2O5S, 492.2; m / z measured, 493.2 [M+H]+.

[0867] 1H NMR (400 MHz, DMSO-d6) δ 8.00 - 7.89 (m, 2H), 7.74 - 7.63 (m, 3H), 7.22 (d, J = 7.8 Hz, 1H), 7.17 - 7.05 (m, 4H), 3.78 (brs, 2H), 3.50 (brs, 6H), 3.09 (s, 3H), 2.32 (s, 3H), 2.21 (s, 3H). Intermediate G: 2-(2',5'-Dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamido)-3-(4-(trifluoromethyl)phenyl)propanoic acid.

[0868]

[0869] Step A: Ethyl (R)-2-(2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamido)-3-(4-(trifluoromethyl)phenyl)propanoate. To a mixture of 2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1, 1 biphenyl]-3-carboxylic acid (Intermediate F, 152.7 mg, 0.305 mmol), ethyl (R)-2-amino-3-(4-(trifluoromethyl)phenyl)propanoate (Intermediate C, 79.6 mg, 0.31 mmol), and Et3N (0.13 mL, 0.91 mmol) in DCM (2.5 ml_) was added HATU (139 mg, 0.37 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (3x 10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. Purification of the resultant residue by chromatography (FCC, silica gel, 0-100% EtOAc in petroleum ether) yielded the title compound as a white powder. MS (ESI): mass calculated for C39H40F3N3O6S, 735.3; m / z measured, 736.2 [M+H]+.1H NMR (400 MHz, CDCI3) 67.85 - 7.79 (m, 3H), 7.75 (s, 1H), 7.57 - 7.52 (m, 3H), 7.29 (br d, J= 8.3 Hz, 2H), 7.22 - 7.17 (m, 1H), 7.16 - 7.11 (m, 1H), 7.04 (s, 1H), 6.95 (d, J= 8.8 Hz, 2H), 6.74 (d, J= 7.3 Hz, 1H), 5.13 - 5.05 (m, 1H), 4.23 (q, J = 7.2 Hz, 2H), 3.96 (br s, 2H), 3.80 - 3.61 (m, 2H), 3.50 - 3.26 (m, 6H), 3.03 (s, 3H), 2.36 (s, 3H), 2.23 (s, 3H), 1.31 - 1.27 (m, 3H).19F NMR (376 MHz, CDCl3) δ -62.49 (br s, 1 F).

[0870] Step B: 2-(2',5'-Dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1,1'-biphenyl]-3-carboxamido)-3-(4-(trifluoromethyl)phenyl)propanoic acid. To a mixture of ethyl (R)-2-(2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamido)-3-(4-(trifluoromethyl)phenyl)propanoate (220 mg, 0.27 mmol) in 1:1 (v / v) THF / MeOH (3 mL) was added NaOH (1 M in H2O, 0.57 mL, 0.57 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated, and the residue was diluted with H2O (10 mL). The pH was adjusted to 4 by addition of 1 M HCI and extracted with EtOAc (3x 10 ml_). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to yield the title compound as a yellow solid.1H NMR (400 MHz, CDCI3) 58.00 - 7.90 (m, 1H), 7.88 - 7.78 (m, 3H), 7.54 - 7.41 (m, 4H), 7.30 (br d, J = 8.0 Hz, 2H), 7.21 - 7.16 (m, 1H), 7.15 - 7.10 (m, 1H), 7.04 - 6.99 (m, 1H), 6.96 (d, J= 9.0 Hz, 2H), 5.18 - 5.02 (m, 1H), 4.06 - 3.85 (m, 2H), 3.68 (br s, 2H), 3.51 (brs, 2H), 3.43 - 3.31 (m, 2H), 3.26 - 3.16 (m, 1H), 3.10 (br dd, J = 6.9, 14.2 Hz, 1H), 3.03 (s, 3H), 2.36 - 2.30 (m, 3H), 2.22 (s, 3H).19F NMR (376 MHz, CDCI3) 6 -62.37 (s, 1F).

[0871] Intermediate H: 3-Bromo-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)benzamide.

[0872]

[0873] 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 hours. The solvent was evaporated under vacuum and the resulting residue was resuspended in H2O (150 mL). The pH of the mixture was adjusted to 4 with 1 M aq. HCI, then extracted with EtOAc (300 mL x3). The extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the resultant residue by silica gel flash column chromatography (0-50% EtOAc with 0.1%AcOH in petroleum ether) yielded the title compound as a solid.1H NMR (400 MHz, DMSO-d6) 5 13.71 (br s, 1 H), 8.42 (d, J = 1.5 Hz, 1H), 8.29 (d, J= 1.3 Hz, 2H), 3.91 (s, 3H).

[0874] Step B: Methyl 3-bromo-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)benzoate. To a solution of 3-bromo-5-(methoxycarbonyl)benzoic acid (5.04 g, 19.4 mmol), HATU (8.9 g, 23.3 mmol), and triethylamine (5.4 mL, 38.9 mmol) in DMF (70 mL) was added 2-amino- / \ / -methyl-3-(4-(trifluoromethyl)phenyl)propanamide HCI (Intermediate B, 6.60 g, 23.3 mmol). The reaction mixture was stirred at room temperature for 18 hours. Ethyl acetate (140 ml_) was added to the reaction mixture and the mixture was washed with water (1x100 mL) and brine (1x100 mL) then dried over anhydrous MgSCX filtered, and concentrated. The residue was resuspended in DCM (100 mL) and stirred for 30 minutes. The solid was dried under vacuum to yield the title compound. MS (ESI): mass calculated for C20H18BrF3N2O4, 486.0; m / z measured, 487.0 [M+H]+.

[0875] Step C: 3-Bromo-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)benzoic acid. Aqueous NaOH (3 M, 2.05 mL) was added to a solution of methyl 3-bromo-5-((1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)benzoate (1 g, 2.05 mmol) in 1:1:1 THF: MeOH: H2O (11.4 mL). The reaction mixture was stirred at room temperature for 3 hours. The pH of the reaction mixture was adjusted to 2 with 2 M HCI, and the resulting mixture extracted with EtOAc (20 mLx2). The extracts were combined, dried over anhydrous MgSO4, filtered, and concentrated to yield the title compound, which was used without further purification. MS (ESI): mass calculated for C19H16F3N2O4, 472.0; m / z measured, 473.0 [M+H]+.

[0876] Step D: 3-Bromo-N-(1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan- 2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)benzamide. To a solution of 3-bromo-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)benzoic acid (773 mg, 1.63 mmol), HATU (807.4 mg, 2.12 mmol), and Et3N (0.45 mL, 3.27 mmol) in DMF (10 mL) was added 1-[4-(methylsulfonyl)phenyl]piperazine (510 mg, 2.12 mmol). The reaction mixture was stirred at room temperature for 2 hours then diluted with EtOAc (50 mL). The mixture was washed with H2O (2x50 mL) and brine (1x50 mL) then dried over anhydrous sodium sulfate, filtered, and concentrated. The resultant residue was purified by flash column chromatography (silica, 40-100% EtOAc in hexanes) and the desired fractions were concentrated. The residue was suspended in EtOAc (3 mL), stirred, and filtered to yield the title compound as a solid. MS (ESI): mass calculated for C30H30BrF3N4O5S, 694.1; m / z measured, 695.0 [M+H]+.

[0877] Intermediate I: (R)- / V-(1-(Methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-3-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide.

[0878]

[0879] Step A: Methyl (R)-3-bromo-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)benzoate. To a solution of 3-bromo-5-(methoxycarbonyl)benzoic acid (Intermediate H, Step A, 500 mg, 1.86 mmol), (R)-2-amino-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide HCI (Intermediate A, 631.8 mg, 2.24 mmol) and DIPEA (1.58 mL, 9.31 mmol) in DMF (5 mL) was added HATU (920.7 mg, 2.42 mmol). The reaction mixture was stirred at room temperature for 2 hours. Water (50 mL) was added and the mixture was filtered. The filter cake was collected, resuspended in 1:1 petroleum ether: ethyl acetate (10 mL), stirred for 15 minutes at room temperature, and filtered, washing with 1:1 petroleum ether: ethyl acetate (20 mL). The resultant solid was collected and dried under vacuum to yield the title compound. MS (ESI): mass calculated for C20H18BrF3N2O4, 486.0; m / z measured, 487.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) 59.05 (d, J= 8.5 Hz, 1H), 8.33 (s, 1H), 8.25 (s, 1H), 8.17 (s, 1H), 8.10 (br d, J = 4.5 Hz, 1H), 7.62 (d, J= 8.3 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 4.76-4.67 (m, 1H), 3.89 (s, 3H), 3.23 (dd, J = 4.3, 13.8 Hz, 1H), 3.09-3.01 (m, 1H), 2.62 (d, J = 4.5 Hz, 3H).

[0880] Step B: (R)-3-Bromo-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)benzoic acid. Aqueous NaOH (1 M, 3.5 mL) was added to a solution of methyl (R)-3-bromo-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)benzoate (850 mg, 1.744 mmol) in 1:1 THF: MeOH (10 mL). The reaction mixture was stirred at room temperature for 1 hours. The pH of the reaction mixture was adjusted to 4-5 with 1 M aq. HCI, and the resulting mixture extracted with EtOAc (30 mLx3). The extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the title compound as a solid. MS (ESI): mass calculated for C19H16F3N2O4, 472.0; m / z measured, 473.1 [M+H]+.

[0881] 1H NMR (400 MHz, DMSO-d6) 5 13.56 (brs, 1H), 9.03 (d, J= 8.5 Hz, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 8.09 (br d, J = 4.6 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 4.76-4.67 (m, 1H), 3.32 (br s, 1H), 3.22 (br dd, J = 13.7, 4.3 Hz, 1H), 3.09-3.01 (m, 1 H), 2.62 (d, J = 4.5 Hz, 3H).

[0882] Step C: (R)-3-Bromo-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)benzamide. To a solution of (R)-3-bromo-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)benzoic acid (3.65 g, 7.58 mmol), HATU (3.75 g, 9.85 mmol), and DIPEA (7.5 mL, 45.47 mmol) in DMF (60 mL) was added 1-[4-(methylsulfonyl)phenyl]piperazine (2.37 g, 9.85 mmol). The reaction mixture was stirred at room temperature for 16 hours then diluted with H2O (30 mL). The mixture was extracted with EtOAc (3x100 mL), then washed with brine (2x20 mL) and the combined organic extracts concentrated under vacuum. The resultant residue was purified by flash column chromatography (silica, 50-100% EtOAc in petroleum ether) and the desired fractions were concentrated to yield the title compound as a solid. MS (ESI): mass calculated for C30H30BrF3N4O5S, 694.1; m / z measured, 697.1 [M+H]+.

[0883] Step D: (R)-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-3-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide. A suspension of (R)-3-bromo-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)benzamide (1.2 g, 1.73 mmol), bis(pinacolato)diboron (563 mg, 2.22 mmol), KOAc (510 mg, 5.20 mmol), and Pd(dppf)Cl2*DCM complex(150 mg, 0.182 mmol) in 1,4-dioxane (9 mL) was degassed with Argon for 15 minutes then evacuated and flushed with N2 before it was heated to 90°C for 8 hours. The mixture was cooled to room temperature and filtered through Celite®. The filtrate was concentrated and the resultant residue was purified by flash column chromatography (silica, 30-100% ethyl acetate: hexanes then 0-10% methanol in ethyl acetate) to yield the title compound as a foamy solid. MS (ESI): mass calculated for C36H42BF3N4O7S, 742.3; m / z measured, 660.8 [M-82+H]+(mass of the corresponding boronic acid).1H NMR (400 MHz, CDCI3) 5 8.14 (s, 1H), 7.99 (s, 1H), 7.96 (t, J= 1.7 Hz, 1H), 7.80 (d, J= 9.3 Hz, 2H), 7.56 (d, J = 7.8 Hz, 2H), 7.38 (d, J= 8.3 Hz, 2H), 7.08 (d, J= 7.8 Hz, 1H), 6.94 (d, J= 8.8 Hz, 2H), 6.01 (q, J = 4.4 Hz, 1H), 4.82 (q, J = 7.8 Hz, 1H), 4.07-3.80 (br m, 2H), 3.72-3.16 (br m, 8H), 3.02 (s, 3H), 2.75 (d, J = 4.4 Hz, 3H), 1.36 (s, 12H).

[0884] Intermediate J: 2',5'-Dimethyl-5-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylic acid.

[0885]

[0886] Step A: 3-(tert-Butyl) 5-methyl 2',5'-dimethyl-[1, T-biphenyl]-3,5-dicarboxylate. A mixture of 5-(methoxycarbonyl)-2',5'-dimethyl-[1, 1 '-biphenyl]-3-carboxylic acid (Intermediate D, Step B, 90.0 g, 317 mmol), Boc2O (145 mL, 633 mmol), and DMAP (58.0 g, 475 mmol) in THF (500 mL) was degassed and purged with N2 three times. The mixture was stirred at 25 °C for 12 hours under an atmosphere of N2. The reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc (2x 1.0 L). The combined organic layers were washed with 0.5 N HCI (2x 600 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the resultant 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) 68.64 - 8.58 (m, 1 H), 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).

[0887] Step B: 5-(tert-Butoxycarbonyl)-2',5'-dimethyl-[1,1'-biphenyl]-3-carboxylic acid. To a solution of S-(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 hours. The reaction mixture was concentrated under reduced pressure to remove THF / MeOH. The remaining residue was diluted with H2O (200 mL) and the pH was adjusted to 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) 68.70 (t, J = 1.4 Hz, 1 H), 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).

[0888] Step C: tert-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 (Intermediate B, 130 mg, 0.46 mmol), 5-(tert-butoxycarbonyl)-2',5'-dimethyl-[1,1'-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 hours. To the reaction mixture was added sat. aq. NH4CI (10 mL) and extracted with EtOAc (3x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. Purification of the resultant 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) 68.29 (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, 1 H), 7.07 - 7.00 (m, 2H), 5.96 (br d, 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).

[0889] 19F NMR (376 MHz, CDCI3) 5 -62.51 (s, 1F).

[0890] 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 tert-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 hours. 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) 5 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, 1H), 7.15 (br d, J= 8.0 Hz, 1H), 7.06 (s, 1H), 4.81 -4.69 (m, 1H), 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-d6) 5 -75.10 (br s, 1F).

[0891] Intermediate K: tert-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.

[0892]

[0893] A suspension of tert-butyl (R)-3-bromo-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)benzoate (2.0 g, 3.8 mmol), bis(pinacolato)diboron (1.44 g, 5.67 mmol), KOAc (1.48 g, 15.11 mmol), and Pd(dppf)Cl2 (276.5 mg, 0.38 mmol) in 1,4-dioxane (30 mL) under N2 was heated to 90°C for 16 hours. The reaction mixture was cooled to room temperature before H2O (30 mL) was added and the mixture was extracted with EtOAc (2x50 mL). The combined extracts were washed with brine (1x30 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 measured, 577.3 [M+H]+.

[0894] Intermediate L: (R)-3',6'-Dimethyl-5-((1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-2'-(1H-pyrazol-5-yl)-[1,1'-biphenyl]-3-carboxylic acid.

[0895]

[0896] Step A: 2-lodo-3,6-dimethylbenzaldehyde. To a solution of (2-iodo-3,6-dimethylphenyl) methanol (9.0 g, 34 mmol) in DCM (200 mL) at room temperature was added MnO2 (29.85 g, 343.4 mmol) and the reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was filtered through a pad of Celite® and the filter cake was washed with DCM (100 mL x3). The resultant filtrate was concentrated under reduced pressure to yield the title compound as a solid, which was used in the next step without further purification.

[0897] Step B: 1-(2-lodo-3,6-dimethylphenyl)ethan-1-ol. To a solution of 2-iodo-3,6-dimethylbenzaldehyde (6.0 g, 23.1 mmol) in anhydrous THF (30 mL) at 0°C was added methylmagnesium bromide (3M in diethyl ether, 8.46 mL, 23.4 mmol). The reaction mixture was stirred at 0°C under N2 for 2 hours. Upon completion, sat. aq. NH4CI (30 mL) was added and the mixture was extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, and concentrated to yield the title compound as a solid.

[0898] Step C: 1-(2-lodo-3,6-dimethylphenyl)ethan-1-one. To a solution of 1-(2-iodo-3,6-dimethylphenyl)ethan-1-ol (6.0 g, 22 mmol) in DCM (100 mL) at room temperature was added MnO2 (18.89 g, 217.3 mmol) and the reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was filtered through a pad of Celite® and the filter cake was washed with DCM (100 mL x4). The resultant filtrate was concentrated under reduced pressure to yield the title compound as a solid, which was used in subsequent step(s) without further purification.1H NMR (400 MHz, CDCI3) 67.08-7.03 (m, 1H), 7.02-6.94 (m, 1H), 2.49-2.46 (m, 3H), 2.34 (s, 3H), 2.17 (s, 3H).

[0899] Step D: tert-Butyl (R)-2'-acetyl-3',6'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylate. A suspension of tert-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 (Intermediate K, 1.3 g, 2.3 mmol), 1-(2-iodo-3,6-dimethylphenyl)ethan-1-one (741.8 mg, 2.71 mmol), PdCl2(dtbpf) (147.0 mg, 0.23 mmol), and Na2CO3(717.1 mg, 6.77 mmol) in 4:1 1,4-dioxane: H2O (20 mL) was heated to 60°C and stirred under N2 for 16 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. The resultant residue was purified by flash column chromatography (silica, 0-100% EtOAc in petroleum ether) to yield the title compound as an oil. MS (ESI): mass calculated for C33H35F3N2O5, 596.2; m / z measured, 597.3 [M+H]+.

[0900] Step E: tert-Butyl (R)-2'-(3-(dimethylamino)acryloyl)-3',6'-dimethyl-5-((1- (methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 biphenyl]-3-carboxylate. To a solution of tert-butyl (R)-2'-acetyl-3',6'-dimethyl-5-((1-(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 biphenyl]-3-carboxylate (1.1 g, 1.84 mmol) in DMF (20 ml_) was added tert-butoxy bis(dimethylamino)methane (1.9 mL, 9.22 mmol). The reaction mixture was heated to 80°C for 16 hours. The mixture was concentrated under vacuum and the resulting residue was purified by flash column chromatography (silica, 0-100% EtOAc in petroleum ether) to yield the title compound as an oil. MS (ESI): mass calculated for C36H40F3N3O5, 651.3; m / z measured, 652.4 [M+H]+.

[0901] Step F: tert-Butyl (R)-3',6'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-2'-(1H-pyrazol-5-yl)-[1,1'-biphenyl]-3-carboxylate. To a solution of tert-butyl (R)-2'-(3-(dimethylamino)acryloyl)-3',6'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, T-biphenyl]-3-carboxylate (900 mg, 1.31 mmol) in EtOH (10 mL) was added hydrazine hydrate (1.27 mL, 26.2 mmol). The reaction mixture was heated to 80°C and stirred for 48 hours then concentrated under vacuum. The resulting residue was purified by preparative RP-HPLC (Stationary phase: Xtimate C18, 5 pm, 150 x 25 mm; Mobile phase: (0.05% NH3H2O) (A) - MeCN (B), gradient elution: 55 - 85% B in A over 8 min, flow rate: 30 mL / min) to yield the title compound as a solid. MS (ESI): mass calculated for C34H35F3N4O4, 620.3; m / z measured, 621.3 [M+H]+.

[0902] Step G: (R)-3',6'-Dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-2'-(1H-pyrazol-5-yl)-[1,1'-biphenyl]-3-carboxy lie acid. To a solution of tert-butyl (R)-3',6'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-2'-(1H-pyrazol-5-yl)-[1,1'-biphenyl]-3-carboxylate (350 mg, 0.56 mmol) in DCM (3 mL) was added TFA (3 mL). The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated under vacuum to yield the title compound as a solid, which was used in subsequent steps without further purification. MS (ESI): mass calculated for C30H27F3N4O4, 564.2; m / z measured, 565.2 [M+H]+.

[0903] Intermediate M: (R)-2'-Formyl-3',6'-dimethyl-N-(1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0904]

[0905] Step A: 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-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (7.3 g, 20 mmol) over 1 minute. The reaction mixture was then stirred at room temperature overnight, then poured into a mixture of DCM and sat. aq. NaHCO3. The aqueous layer was extracted twice with DCM and the combined organic layers were washed with brine, dried over MgSC>4, 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) 5 10.41 (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).

[0906] Step B: (R)-2'-Formyl-3',6'-dimethyl-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide. A suspension of (R)-N-(1 -(methylamino)-l -oxo- 3-(4-(trifluoromethyl)phenyl)propan-2-yl)-3-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate I, 300 mg, 0.369 mmol), 2-formyl-3,6-dimethylphenyl trifluoromethanesulfonate (115 mg, 0.406 mmol), Pd(dppf)Cl2 (27 mg, 0.037 mmol), and K2CO3 (153.1 mg, 1.108 mmol) in 9:1 1,4-dioxane: H2O (15 mL) was heated to 80°C and stirred under N2 for 16 hours. The reaction mixture was cooled to room temperature and filtered, washing the filter cake with EtOAc. The filtrate was diluted with water (30 mL) and the mixture was extracted with EtOAc (15 mL x 3). Combined organic extracts were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative thin layer chromatography (silica, 10:1 DCM: MeOH) to yield the title compound as a solid. MS (ESI): mass calculated for C39H39F3N4O6S, 748.3; m / z measured, 749.2 [M+H]+.1H NMR (400 MHz, CDCI3) 59.90 (s, 1 H), 7.91 (br s, 1 H), 7.81 (br d, J = 8.3 Hz, 2H), 7.68 (br d, J= 9.3 Hz, 1H), 7.56 (br d, J = 7.0 Hz, 2H), 7.43-7.33 (m, 4H), 7.25 (br d, J= 8.0 Hz, 1H), 7.10 (brs, 1H), 6.98 (br d, J= 8.3 Hz, 2H), 5.73 (br s, 1H), 4.78 (br s, 1H), 3.95 (br s, 2H), 3.64 (br s, 2H), 3.41 (br s, 4H), 3.24 (br s, 2H), 3.03 (s, 3H), 2.75 (br s, 3H), 2.62 (s, 3H), 2.04 (br d, J = 4.5 Hz, 3H).

[0907] Intermediate N: (R)-3,6-Dimethyl-3'-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-5'-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1, 1 '-biphenyl]-2-carboxylic acid.

[0908]

[0909] To a solution of (R)-2'-formyl-3',6'-dimethyl-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1,1'-biphenyl]-3-carboxamide (Intermediate M, 502 mg, 0.67 mmol) in DMSO (40 mL) was added a solution of sodium phosphate monobasic (178.9 mg, 1.476 mmol) in H2O (25 mL). Sodium chlorite (80%, 154.8 mg, 1.369 mmol) was then added and the resulting mixture was warmed to 45°C and stirred for 1 hours. The mixture was diluted with EtOAc (40 mL), and the aqueous layer was extracted (3x40 mL). The combined organic extracts were washed twice with ice-cold H2O, dried over Na2SO4, and concentrated under reduced pressure to yield the title compound as a residue, which was used in subsequent steps without further purification. MS (ESI): mass calculated for C39H39F3N4O7S, 764.2; m / z measured, 765.3 [M+H]+.

[0910] Intermediate O: N-(1-(Methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-3-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide.

[0911]

[0912] A suspension of 3-bromo-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)benzamide (Intermediate H, 5 g, 7.19 mmol), bis(pinacolato)diboron (3.65 g, 14.38 mmol), KOAc (4.94 g, 50.32 mmol), and Pd(dppf)Cl2*DCM complex (293.5 mg, 0.36 mmol) in DMSO (35.9 m L) was degassed with Argon for 5 minutes then heated to 85°C for 16 hours. The mixture was cooled to room temperature, poured into H2O, and stirred for 30 minutes. The resulting solids were filtered to yield the title compound as a residue, which was used in subsequent steps without further purification. MS (ESI): mass calculated for C36H42BF3N4O7S, 742.3; m / z measured, 660.0 [M-82+H]+(mass of the corresponding boronic acid).

[0913] Compound Synthesis Examples

[0914] Example 1: 3-(2,5-Dimethylphenyl)-5-[4-(2-methoxy-4-methylsulfonyl-phenyl)piperazine-1 -carbonyl]-N-[(1 R)-2-(methylamino)-2-oxo-1 -[[4-(trifluoromethyl)phenyl]methyl]ethyl]benzamide.

[0915]

[0916] To a mixture of (R)-2',5'-dimethyl-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(piperazine-1 -carbonyl)-[1, 1 ' -bi ph eny I ]-3-carboxamide (Intermediate E) (50 mg, 0.083 mmol), 1-bromo-2-methoxy-4- (methylsulfonyl)benzene (28.6 mg, 0.108 mmol), and cesium carbonate (81 mg, 0.25 mmol) in 1,4-dioxane (1 ml_) was added a solution of RuPhos Pd G4 (7.1 mg, 0.0083 mmol) in 1,4-dioxane (1 mL) in a glovebox. The vial containing the reaction mixture was sealed, removed from the glovebox, magnetically stirred, and heated at 95 °C for 22.5 hours. After cooling to room temperature, the reaction mixture was diluted with methanol and filtered through an ISOLUTE® Si Thiol column. The filtrate was concentrated under reduced pressure 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 MeCN (B), gradient elution: 40 - 75% B in A over 12 min, flow rate: 25 mL / min) to yield the title compound as a solid. MS (ESI): mass calculated for C39H41F3N4O6S, 750.8; m / z measured, 751.4 [M+H]+.1H NMR (DMSO-d6) 58.84 (d, J= 8.3 Hz, 1H), 8.08 (q, J = 4.4 Hz, 1H), 7.87-7.83 (m, 2H), 7.62-7.58 (m, 2H), 7.56-7.50 (m, 3H), 7.43 (dd, J= 8.3, 2.0 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.22 (d, J= 7.8 Hz, 1H), 7.14 (d, J= 7.8 Hz, 1H), 7.07 (s, 1H), 7.07 (d, J= 8.4 Hz, 1H), 4.77-4.70 (m, 1H), 3.89 (s, 3H), 3.80 (brs, 2H), 3.60-3.42 (m, 2H), 3.25-3.03 (m, 9H), 2.62 (d, J = 4.4 Hz, 3H), 2.32 (s, 3H), 2.18 (s, 3H).

[0917] Example 2: (R)-5-(4-(4-(Dimethylphosphoryl)phenyl)piperazine-1 -carbonyl)-2',3',6'-trimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide.

[0918]

[0919] Step A: Methyl 3-bromo-5-(chlorocarbonyl)benzoate. To a solution of 3-bromo-5-(methoxycarbonyl)benzoic acid (Intermediate H, Step A, 150 g, 579 mmol) in DCM (1000 mL) was added (COCI)2 (101 mL, 1.16 mol) and DMF (89.1 pL, 1.16 mmol) at 20 °C. The reaction mixture was stirred at 40 °C for 2 hours and concentrated under reduced pressure to yield the title compound as a yellow oil which was used in the next step without further purification.

[0920] Step B: terf-Butyl 4-(3-bromo-5-(methoxycarbonyl)benzoyl)piperazine-1-carboxylate. To a solution of methyl 3-bromo-5-(chlorocarbonyl)benzoate (166 g, 891 mmol), TEA (105 m L, 1.08 mol) and DMAP (6.60 g, 54.0 mmol) in DCM (700 mL) was added tert-butyl piperazine-1 -carboxylate (150 g, 540 mmol, 1 eq) in DCM (300 mL) at 0 °C. The mixture was stirred at 20 °C for 12 hours. The reaction mixture diluted with H2O (500 mL) and extracted with DCM (500 mLx 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether (with 20% DCM) / Ethyl acetate =10 / 1 to 1 / 1) to yield the title compound as a white solid.1H NMR (400 MHz, CDCI3) 58.24 (t, J = 1.6 Hz, 1 H), 7.98 (t, J = 1.4 Hz, 1 H), 7.75 (t, J = 1.7 Hz, 1H), 3.94 (s, 3H), 3.79 - 3.28 (m, 8H), 1.47 (s, 9H).

[0921] Step C: terf-Butyl 4-(3-(methoxycarbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1 -carboxylate. A mixture of tert-butyl 4-(3-bromo-5-(methoxycarbonyl)benzoyl)piperazine-1 -carboxylate (90.0 g, 210 mmol), B2pin2 (60.6 g, 252 mmol), Pd(dppf)Cl2 (1.54 g, 2.11 mmol), KOAc (62.0 g, 631 mmol) in 1,4-dioxane (1000 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 100 °C for 12 hours under N2 atmosphere. The reaction mixture was diluted with H2O (500 mL) and extracted with EA (500 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 1 / 1) to yield the title compound as a white solid. MS (ESI): mass calculated for C24H35BN2O7, 474.3; m / z measured, 419.0 [M-56+H]+(loss of tert-butyl group).1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.15 (t, J= 1.8 Hz, 1H), 8.03 (s, 1H), 3.94 (s, 3H), 3.84 - 3.34 (m, 8H), 1.48 (s, 9H), 1.36 (s, 12H).

[0922] Step D: terf-Butyl 4-(5-(methoxycarbonyl)-2',3',6'-trimethyl-[1, T-biphenyl]-3-carbonyl)piperazine-1 -carboxylate. A mixture of tert-butyl 4-(3-(methoxycarbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1 -carboxylate (45.0 g, 94.8 mmol), 2-iodo-1,3,4-trimethylbenzene (26.8 g, 109 mmol), Pd(t-BusP)2 (2.42 g, 4.74 mmol) and, K3PO4(60.4 g, 284 mmol, 3 eq) in 1,4-dioxane (230 ml_) was degassed and purged with N2 three times. The mixture was then stirred at 90 °C for 12 hours under N2 atmosphere. The reaction mixture was diluted with H2O (300 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 5 / 1) to yield the title compound as a white solid. MS (ESI): mass calculated for C27H34N2O5, 466.3; m / z measured, 411.0 [M-56+H]+(loss of tert-butyl group).1H NMR (400 MHz, CDCl3) δ 8.10 (t, J= 1.6 Hz, 1H), 7.92 (t, J= 1.6 Hz, 1H), 7.37 (t, J= 1.6 Hz, 1H), 7.15 - 7.00 (m, 2H), 3.94 (s, 3H), 3.68 - 3.31 (m, 8H), 2.29 (s, 3H), 1.97 (s, 3H), 1.92 (s, 3H), 1.48 (s, 9H).

[0923] Step E: 5-(4-(tert-Butoxycarbonyl)piperazine-1-carbonyl)-2',3',6'-trimethyl-[1, T-biphenyl]-3-carboxylic acid. To a solution of tert-butyl 4-(5-(methoxycarbonyl)-2',3',6'-trimethyl-[1,1'-biphenyl]-3-carbonyl)piperazine-1 -carboxylate (32.0 g, 68.5 mmol) in MeOH (160 mL) and H2O (32 mL) was added LiOH•H2O (2.88 g, 68.5 mmol). The reaction mixture was stirred at 20 °C for 3 hours. The reaction mixture was quenched by adjusting the pH to 6 by addition of HCI (2 N) then concentrated under reduced pressure to remove MeOH and THF. Water (100 mL) was added and the aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound as a brown oil, which was used in the next step without further purification. MS (ESI): mass calculated for C26H32N2O5, 452.2; m / z measured, 397.0 [M-56+H]+(loss of tert-butyl group).1H NMR (400 MHz, DMSO-d6) 57.92-7.88 (m, 1H), 7.68-7.64 (m, 1H), 7.39-7.32 (m, 1H), 7.13 - 7.00 (m, 2H), 3.94 - 3.91 (m, 1H), 3.93 (s, 1H), 3.89 -3.85 (m, 1H), 3.59 (s, 8H), 2.24 (s, 3H), 1.90-1.86 (m, 4H), 1.86 (s, 3H), 1.39 (s, 9H).

[0924] Step F: tert-Butyl (R)-4-(2',3',6'-trimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carbonyl)piperazine-1 -carboxylate. To a solution of 5-(4-(tert-butoxycarbonyl)piperazine-1-carbonyl)-2',3',6'-trimethyl-[1,1'-biphenyl]-3-carboxylic acid (20.0 g, 44.1 mmol) and (R)-2-amino-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide HCI (Intermediate A, 18.5 g, 75.1 mmol, 1.7 eq) in DCM (200 mL) was added DIEA (30.7 mL, 176 mmol) followed by addition of T3P® (52.6 mL, 88.3 mmol, 50% purity) at -30 °C. The mixture was stirred at -30 °C for 3 hours. The reaction mixture was diluted with H2O (500 mL) and extracted with DCM (200 m L_ x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 50-80% Ethyl acetate / Petroleum ether) to yield the title compound as a brown solid. MS (ESI): mass calculated for C37H43F3N4O5, 680.3; m / z measured, 625.2 [M-56+H]+(loss of ferf-butyl group).1H NMR (400 MHz, CDCI3) 67.85 (s, 1H), 7.68 (s, 1H), 7.49 (m, 2H), 7.34 (m, 2H), 7.18 (s, 1H), 7.10 (m, 1H), 7.01 (m, 1H), 4.95 (s, 1H), 3.77 (s, 2H), 3.60 - 3.39 (m, 6H), 3.35 - 3.13 (m, 2H), 2.27 (m, 3H), 1.98 - 1.81 (m, 9H), 1.48 (s, 9H).

[0925] Step G: (R)-2',3',6'-Trimethyl-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(piperazine-1 -carbonyl)-[1, 1 ' -bi ph eny I ]-3-carboxamide. To te / Y-butyl (R)-4-(2',3',6'-trimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carbonyl)piperazine-1 -carboxylate (16.8 g, 22.3 mmol) was added HCI / 1,4-dioxane (4 M, 250 mL). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC to yield the title compound as a white solid. MS (ESI): mass calculated for C32H35F3N4O3, 580.3; m / z measured, 581.2 [M+H]+.1H NMR (400 MHz, D2O) 57.67 ( s, 1H), 7.18 (s 1H), 7.05 (s, 4H), 6.90 (s, 1H), 6.73 - 6.53 (m, 2H), 4.13 - 2.80 (m, 11 H), 2.63 (s, 3H), 1.91 (s, 3H), 1.78 - 1.35 (m, 6H).

[0926] 19F NMR (400 MHz, D2O) 5 -62.60 (s 1 F).

[0927] Step H: (R)-5-(4-(4-(Dimethylphosphoryl)phenyl)piperazine-1 -carbonyl)-2',3',6'-trimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, T-biphenyl]-3-carboxamide. In a glovebox under an atmosphere of N2, (R)-2',3',6'-trimethyl-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(piperazine-1-carbonyl)-[1,1'-biphenyl]-3-carboxamide (55 mg, 266 pmol), (4-bromophenyl)dimethylphosphine oxide (70.6 mg, 303 pmol), Cs2CO3(351 mg, 1.07 mmol), and rac-BINAP Pd G4 (26.8 mg, 26.6 pmol) were suspended in 1,4-dioxane (2.4 mL). The reaction mixture was then placed into a pre-heated 90 °C metal heating block and stirred for 19 hours. The reaction mixture was cooled to room temperature and poured into water (10 mL) and EtOAc (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2x 10 mL). The combined organic layers were washed with brine (10 ml_), dried over anhydrous MgSO4, filtered, and concentrated. Purification of the resultant residue by preparative RP-HPLC (Stationary phase: Waters XBridge BEH C18, 5pm, 19x100 mm; Mobile phase A: water + pH 10 NH4OH; Mobile Phase B: MeCN + pH 10 NH4OH; Gradient elution: 35 - 70% B in A over 12 minutes; Flow rate: 25 mL / min) yielded the title compound as a white solid. MS (ESI): mass calculated for C40H44F3N4O4P, 732.3; m / z measured, 732.9 [M+H]+.1H NMR (400 MHz, CDCI3) 67.89 (t, J = 1.5 Hz, 1 H), 7.6-7.7 (m, 3H), 7.57 (d, J = 8.3 Hz, 2H), 7.3-7.4 (m, 3H), 7.1-7.2 (m, 1H), 7.0-7.1 (m, 2H), 7.00 (dd, J = 2.0, 8.8 Hz, 2H), 5.88 (br s, 1H), 4.7-4.9 (m, 1H), 3.8-4.1 (m, 2H), 3.5-3.8 (m, 2H), 3.3-3.5 (m, 4H), 3.2-3.3 (m, 2H), 2.76 (d, J = 4.9 Hz, 3H), 2.31 (s, 3H), 1.98 (d, J= 3.9 Hz, 3H), 1.93 (d, J= 4.4 Hz, 3H), 1.73 (s, 3H), 1.70 (s, 3H).

[0928] Example 3: (R)-N-(3-(3-Acrylamido-4-(trifluoromethoxy)phenyl)-1 -(methylamino)-1-oxopropan-2-yl)-2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0929]

[0930] Step A: Methyl (R)-3-(3-amino-4-(trifluoromethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate. To a dried vial was added methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (165 mg, 0.501 mmol), NiBr2(dtbbpy)•4H2O (33.6 mg, 0.060 mmol) and manganese (82.6 mg, 1.50 mmol). The vial was vacuumed and back filled with argon (2X). To the vial was then added 5-bromo-2-(trifluoromethoxy)aniline (154 mg, 0.602 mmol) and DMA (2.5 mL). After 3 hours, the reaction mixture was filtered through Celite® and washed with EtOAc (30 mL). The solution was washed with aq. NH4CI (50 mL). The aqueous layer was extracted again with EtOAc (20 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried with Na2SO4, and concentrated. The residue was purified by column chromatography (silica gel, 0 - 25% EtOAc / heptane) to yield the title compound as a residue. MS (ESI): mass calculated for C16H21F3N2O5, 378.1; m / z measured, 279.0 [M-100+H]+(loss of Boc group).1H NMR (400 MHz, CDCl₃) δ 7.01 - 7.07 (m, 1 H), 6.56 - 6.60 (m, 1 H), 6.48 (dd, J=8.31, 1.96 Hz, 1 H), 4.89 - 5.12 (m, 1 H), 4.43 - 4.61 (m, 1 H), 3.81 - 3.94 (m, 2 H), 3.64 - 3.77 (m, 3 H), 2.82 - 3.09 (m, 2 H), 1.33 - 1.53 (m, 9 H).

[0931] Step B: tert-Butyl (R)-(3-(3-amino-4-(trifluoromethoxy)phenyl)-1-(methylamino)-1-oxopropan-2-yl)carbamate. A mixture of methyl (R)-3-(3-amino-4-(trifluoromethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (87 mg, 0.23 mmol) and 40% MeNH2 in water (179 mg, 2.3 mmol) in MeOH (1.0 mL) was stirred for 18 hours. The reaction mixture was concentrated, and the resulting mixture was diluted with EtOAc (10 mL) and washed with water (10 mL x 2). The organic layer was dried over Na2SO4and concentrated to yield the title compound as a residue. MS (ESI): mass calculated for C16H22F3N3O4, 377.2; m / z measured, 400.1 [M+Na]+.

[0932] Step C: (R)-2-Amino-3-(3-amino-4-(trifluoromethoxy)phenyl)-N-methylpropanamide. To a solution of tert-butyl (R)-(3-(3-amino-4-(trifluoromethoxy)phenyl)-1-(methylamino)-1-oxopropan-2-yl)carbamate (645 mg, 1.71 mmol) in MeOH (8 mL) was added 4N HCI in 1,4-dioxane (2.56 mL, 10.2 mmol). The reaction mixture was stirred for 4 hours. The mixture was concentrated, diluted with EtOAc (50 mL), and washed with aq. NaHCO3solution (50 mL). The organic layer was dried over Na2SO4and concentrated to yield the title compound as a residue. MS (ESI): mass calculated for C11H14F3N3O2, 277.1; m / z measured, 278.1 [M+H]+.

[0933] Step D: (R)-N-(3-(3-Amino-4-(trifluoromethoxy)phenyl)-1 -(methylamino)-l -oxopropan-2-yl)-2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamide. To a solution of 2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxylic acid (Intermediate F) (160 mg, 0.325 mmol), (R)-2-amino-3-(3-amino-4-(trifluoromethoxy)phenyl)-N-methylpropanamide (108 mg, 0.390 mmol)), and HATU (161 mg, 0.422 mmol) in DMF (3 mL) was added DIEA (0.28 mL, 1.62 mmol). The reaction mixture was stirred for 3 hours. The resulting mixture was filtered and purified by RP-HPLC (Kinetex EVO C18, 5 pm, 100 x 30 mm; Mobile phase: water (10 mM NH4OH) (A) - MeCN (B), gradient elution: 10-55% B in A over 8 min, flow rate 60 mL / min) to yield the title compound as a residue. MS (ESI): mass calculated for C38H40F3N5O6S, 751.3; m / z measured, 752.2 [M+H]+.1H NMR (400 MHz, CDCI3) 67.7-7.9 (m, 3H), 7.5-7.6 (m, 1H), 7.5-7.5 (m, 1H), 7.2-7.2 (m, 1H), 7.1-7.1 (m, 2H), 7.0-7.1 (m, 3H), 7.0-7.0 (m, 1H), 6.9-7.0 (m, 2H), 6.8-6.8 (m, 1H), 6.6-6.7 (m, 1H), 6.5-6.6 (m, 1H), 4.8-4.9 (m, 1H), 3.9-4.1 (m, 2H), 3.5-3.8 (m, 2H), 3.3-3.5 (m, 4H), 3.0-3.1 (m, 5H), 2.7-2.8 (m, 3H), 2.3-2.4 (m, 3H), 2.1-2.3 (m, 3H).

[0934] Step E: (R)-N-(3-(3-Acrylamido-4-(trifluoromethoxy)phenyl)-1 -(methylamino)-l -oxopropan-2-yl)-2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide. A mixture of (R)-N-(3-(3-amino-4-(trifluoromethoxy)phenyl)-1-(methylamino)-1-oxopropan-2-yl)-2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1,1'-biphenyl]-3-carboxamide (70 mg, 0.0931 mmol) and Et3N (0.065 mL, 0.466 mmol) in DCM (1.5 mL) was stirred at 0 °C for 5 minutes before acryloyl chloride (12.6 mg, 0.14 mmol) was added. The reaction mixture was stirred for 1 hour and then concentrated. The residue was dissolved in DMF (1 mL) and purified by RP-HPLC (Kinetex EVO C18, 5 pm, 100 x 30 mm; Mobile phase: water (10 mM NH4OH) (A) - MeCN (B), gradient elution: 10-50% B in A over 13 min, flow rate 60 mL / min) to yield the title compound as a residue. MS (ESI): mass calculated for C41H42F3N5O7S, 805.3; m / z measured, 828.2 [M+Na]+.1H NMR (400 MHz, CDCI3) 68.3-8.5 (m, 1H), 7.7-7.9 (m, 3H), 7.5-7.6 (m, 2H), 7.2-7.2 (m, 1H), 7.1-7.2 (m, 1H), 7.1-7.1 (m, 1H), 7.0-7.1 (m, 2H), 6.9-7.0 (m, 2H), 6.3-6.5 (m, 1H), 6.2-6.3 (m, 2H), 5.8-5.9 (m, 1H), 4.8-4.9 (m, 1H), 3.8-4.0 (m, 2H), 3.6-3.7 (m, 2H), 3.3-3.6 (m, 4H), 3.1-3.2 (m, 2H), 3.0-3.0 (m, 3H), 2.7-2.8 (m, 3H), 2.3-2.4 (m, 3H), 2.1-2.3 (m, 3H).

[0935] Example 4: 2',5'-Dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0936]

[0937] To a solution of 2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1, T-biphenyl]-3-carboxylicacid (Intermediate F, 150 mg, 305 pmol), 2-amino-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide HCI (Intermediate B, 103 mg, 365 pmol), and Et3N (127 pL, 914 pmol) in DMF (2.3 mL) was added HATU (151 mg, 396 pmol). The reaction mixture was stirred under and atmosphere of Argon at room temperature for 1 hour. The reaction mixture was poured into water (10 mL), sat. aq. NaHCO3(15 mL), and EtOAc (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous MgSO4, filtered, and concentrated. Purification of the resultant residue by chromatography (FCC, silica gel, 0-5% MeOH / DCM) yielded the title compound as a white solid. MS (ESI): mass calculated for C38H39F3N4O5S, 720.3; m / z measured, 721.3 [M+H]+.1H NMR (400 MHz, CDCI3) 67.8-7.8 (m, 3H), 7.76 (t, J = 1.7 Hz, 1 H), 7.55 (d, J = 7.8 Hz, 2H), 7.52 (t, J = 1.5 Hz, 1 H), 7.37 (d, J = 7.8 Hz, 2H), 7.2-7.2 (m, 1H), 7.1-7.2 (m, 1H), 7.06 (d, J= 7.8 Hz, 1H), 7.02 (s, 1H), 6.94 (d, J = 8.8 Hz, 2H), 5.79 (br d, J = 4.9 Hz, 1H), 4.7-4.9 (m, 1H), 3.8-4.1 (m, 2H), 3.5-3.8 (m, 2H), 3.3-3.5 (m, 4H), 3.2-3.3 (m, 2H), 3.02 (s, 3H), 2.75 (d, J = 4.9 Hz, 3H), 2.35 (s, 3H), 2.21 (s, 3H).

[0938] Example 5: (R, E)-N-(3-(3-(4-(Dimethylamino)but-2-enamido)-4-(trifluoromethoxy)phenyl)-1-(methylamino)-1-oxopropan-2-yl)-2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0939]

[0940] A mixture of (R)-N-(3-(3-amino-4-(trifluoromethoxy)phenyl)-1-(methylamino)-1-oxopropan-2-yl)-2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1,1'-biphenyl]-3-carboxamide (Example 3, Step D) (64 mg, 0.085 mmol), (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (85 mg, 0.511 mmol), and DIEA (0.22 mL, 1.28 mmol) in DCM (0.3 ml_) was stirred for 5 minutes, then T3P® (50% solution, 325 mg, 0.511 mmol) was added. The reaction mixture was stirred for 6 hours. The resulting mixture was filtered and purified by RP-HPLC (Kinetex EVO C18, 5 pm, 100 x 30 mm; Mobile phase: water (10 mM NH4OH) (A) - MeCN (B), gradient elution: 5-40% B in A over 13 min, flow rate 60 mL / min) to yield the title compound as a residue. MS (ESI): mass calculated for C44H49F3N6O7S, 862.3; m / z measured, 863.3 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.10-8.25 (m, 2H), 7.77-7.82 (m, 3H), 7.49-7.51 (m, 1H), 7.28-7.33 (m, 1H), 7.15-7.19 (m, 2H), 7.10-7.13 (m, 1H), 7.01-7.06 (m, 2H), 6.92-6.96 (m, 2H), 6.48-6.62 (m, 2H), 4.87-4.95 (m, 1H), 3.92-3.98 (m, 1H), 3.75-3.84 (m, 2H), 3.60-3.69 (m, 2H), 3.30-3.50 (m, 5H), 3.13-3.21 (m, 2H), 2.99-3.04 (m, 3H), 2.83-2.90 (m, 6H), 2.74-2.79 (m, 3H), 2.32-2.36 (m, 3H), 2.20 (s, 3H).

[0941] Example 6: (R)-N-(3-(3-(Buta-2,3-dienamido)-4-(trifluoromethoxy)phenyl)-1 -(methylamino)-1-oxopropan-2-yl)-2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0942]

[0943] A mixture of (R)-N-(3-(3-amino-4-(trifluoromethoxy)phenyl)-1-(methylamino)-1- oxopropan-2-yl)-2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1,1'-biphenyl]-3-carboxamide (Example 3, Step D) (50 mg, 0.0665 mmol), 2-butynoic acid (28 mg, 0.333 mmol), and DIEA (0.172 mL, 0.998 mmol) in DCM (0.2 ml_) was stirred for 5 minutes, then T3P® (50% solution, 296 mg, 0.466 mmol) was added. The reaction mixture was stirred for 2 hours. The resulting mixture was filtered and purified by RP-HPLC (Kinetex EVO C18, 5 pm, 100 x 30 mm; Mobile phase: water (10 mM NH4OH) (A) - MeCN (B), gradient elution: 15-50% B in A over 13 min, flow rate 60 mL / min) to yield the title compound as a residue. MS (ESI): mass calculated for C42H42F3N5O7S, 817.3; m / z measured, 840.3 [M+Na]+.1H NMR (400 MHz, CDCI3) 6 8.2-8.4 (m, 1H), 8.0-8.1 (m, 1H), 7.8-7.9 (m, 3H), 7.5-7.6 (m, 1H), 7.1-7.2 (m, 3H), 6.9- 7.1 (m, 4H), 6.1-6.2 (m, 1H), 5.7-5.8 (m, 1H), 5.4 (d, J=6.4 Hz, 2H), 4.8-4.9 (m, 1H), 3.9- 4.1 (m, 2H), 3.5-3.8 (m, 2H), 3.3-3.5 (m, 4H), 3.1-3.2 (m, 2H), 3.0-3.1 (m, 3H), 2.7-2.8 (m, 3H), 2.3-2.4 (m, 3H), 2.1-2.2 (m, 3H).

[0944] Example 7: (*R)-N-(3-(2-(2-Chloroacetamido)-4-(trifluoromethyl)phenyl)-1-(methylamino)-1-oxopropan-2-yl)-2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0945]

[0946] To a mixture of (*R)-N-(3-(2-amino-4-(trifluoromethyl)phenyl)-1-(methylamino)-1-oxopropan-2-yl)-2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1,1'- biphenyl]-3-carboxamide (Example 127, Step H) (44 mg, 60 mmol) and DIPEA (31 mL, 0.18 mmol) in DCM (3.5 mL) at 0°C under nitrogen was added a mixture of 2-chloroacetyl chloride (12 mL, 0.15 mmol) in DCM (0.5 mL). The reaction mixture was stirred 0 °C for 2 hours then quenched with sat. aq. NH4CI (10 mL) and extracted with DCM (10 mL x 3). The organic layers were separated, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative RP-HPLC (Stationary phase: Boston Prime C18, 5 pm, 150 x 30 mm; mobile phase: (0.05% aqueous NH4OH + 10 mM NH4HCO3) (A) - MeCN (B), gradient elution: 55 - 85% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as white solid. MS (ESI): mass calculated for C40H41CIF3N5O6S, 811.2; m / z measured, 812.5 [M+H]+.1H NMR (400 MHz, DMSO-de) 59.98 (s, 1 H), 8.93 (d, J = 8.2 Hz, 1 H), 8.12-8.03 (m, 1 H), 7.91 (s, 1 H), 7.89-7.83 (m, 2H), 7.69 (d, J = 8.9 Hz, 2H), 7.59-7.52 (m, 2H), 7.50-7.43 (m, 1H), 7.25-7.19 (m, 1H), 7.13 (br d, J = 7.7 Hz, 1H), 7.11-7.04 (m, 3H), 4.78-4.70 (m, 1 H), 4.45-4.33 (m, 2H), 3.78 (br s, 2H), 3.49 (br s, 4H), 3.45-3.40 (m, 2H), 3.25 (br dd, J = 14.5, 4.6 Hz, 1H), 3.12-3.04 (m, 4H), 2.61 (d, J = 4.5 Hz, 3H), 2.32 (s, 3H), 2.19 (s, 3H).19F NMR (376 MHz, DMSO-d6) 5 -61.02.

[0947] Example 8: (*S)-N-(3-(2-(2-Chloroacetamido)-4-(trifluoromethyl)phenyl)-1 -(methylamino)-1-oxopropan-2-yl)-2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0948]

[0949] To a mixture of (*S)-N-(3-(2-amino-4-(trifluoromethyl)phenyl)-1-(methylamino)-1-oxopropan-2-yl)-2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1,1'- biphenyl]-3-carboxamide (Example 127, Step H) (40 mg, 54 mmol) and DIPEA (28 mL, 0.16 mmol) in DCM (3.5 mL) at 0°C under nitrogen was added a mixture of 2-chloroacetyl chloride (11 mL, 0.13 mmol) in DCM (0.5 mL). The reaction mixture was stirred 0°C for 1 hour then quenched with sat. aq. NH4CI (10 mL), then extracted with DCM (10 mL x 3). The organic layers were separated, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative RP-HPLC (stationary phase: Boston Prime C18, 5 pm, 150 x 30 mm; mobile phase: (0.05% aqueous NH4OH + 10 mM NH4HCO3) (A) - MeCN (B), gradient elution: 50 - 0% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as white solid. MS (ESI): mass calculated for C40H41CIF3N5O6S, 811.2; m / z measured, 812.2 [M+H]+.1H NMR (400 MHz, DMSO-de) 59.98 (s, 1 H), 8.93 (d, J = 8.0 Hz, 1 H), 8.07 (q, J = 4.2 Hz, 1 H), 7.91 (s, 1 H), 7.87 (d, J = 6.5 Hz, 2H), 7.70 (d, J = 8.8 Hz, 2H), 7.59-7.53 (m, 2H), 7.50- 7.43 (m, 1H), 7.25-7.19 (m, 1H), 7.13 (d, J= 7.8 Hz, 1H), 7.08 (d, J= 8.8 Hz, 3H), 4.79-4.71 (m, 1H), 4.45-4.32 (m, 2H), 3.78 (brs, 2H), 3.50 (brs, 4H), 3.42-3.36 (m, 2H), 3.26 (br dd, J = 14.3, 5.0 Hz, 1H), 3.14-3.04 (m, 4H), 2.62 (d, J = 4.5 Hz, 3H), 2.32 (s, 3H), 2.19 (s, 3H).19F NMR (376 MHz, DMSO-d6) 5 -61.03.

[0950] Example 9: (*S)-N-(3-(3-(2-Chloroacetamido)-4-(trifluoromethyl)phenyl)-1 -(methylamino)-1-oxopropan-2-yl)-2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0951]

[0952] To a mixture of (*S)-N-(3-(3-amino-4-(trifluoromethyl)phenyl)-1-(methylamino)-1-oxopropan-2-yl)-2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1,1'-biphenyl]-3-carboxamide (Example 133, Step I) (100 mg, 136 mmol) in DCM (5 mL) was added DIPEA (140 mL, 0.82 mmol). The mixture was cooled to 0°C and a solution of 2-chloroacetyl chloride (21 mL, 0.27 mmol) in DCM (0.5 mL) was slowly added to the mixture. The reaction was stirred at 0°C for 1 hour and additional 2-chloroacetyl chloride (21 mL, 0.27 mmol) in DCM (0.5 m L) was added. After stirring at 0°C for an additional 1 hour, 2-chloroacetyl chloride (11 mL, 0.14 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum and the residue was dissolved in MeOH (3 mL). K2CO3 (100 mg) was added and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was purified by preparative RP-HPLC (stationary phase: Boston Prime C18, 5 pm, 150 x 30 mm; mobile phase: water (0.05% aqueous NH4OH + 10 mM NH4HCO3) (A) - MeCN (B), gradient elution: 50-80% B in A over 7 min, flow rate: 25 mL / min). The resultant residue was further purified by SFC: (Column:

[0953] DAICEL CHIRALCEL OJ 250 x 30 mm, 10 pm; mobile phase: CO2(A) - EtOH (0.1% aqueous NH4OH) (B); isocratic elution: 35% B in A; flow rate: 60 mL / min; column temp.: 35 °C; ABPR: 100 bar.) to yield the title compound as a white solid. MS (ESI): mass calculated for C40H41CIF3N5O6S, 811.2; m / z measured, 812.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1 H), 8.87 (d, J = 8.5 Hz, 1 H), 8.14 (d, J = 4.5 Hz, 1 H), 7.90 (d, J= 8.8 Hz, 2H), 7.70 (d, J= 8.8 Hz, 2H), 7.65 (d, J= 8.0 Hz, 1H), 7.54 (s, 1H), 7.49 (s, 1H), 7.45 (d, J= 8.0 Hz, 1H), 7.26-7.20 (m, 1H), 7.14 (d, J= 8.0 Hz, 1H), 7.09 (d, J = 8.8 Hz, 3H), 4.78-4.66 (m, 1 H), 4.27 (s, 2H), 3.79 (s, 2H), 3.51 (s, 4H), 3.40 (s, 2H), 3.22-3.14 (m, 1H), 3.13-3.03 (m, 4H), 2.62 (d, J = 4.5 Hz, 3H), 2.33 (s, 3H), 2.20 (s, 3H).

[0954] 19F NMR (376 MHz, DMSO-d6) δ -59.05.

[0955] Example 10: (*S, E)-N-(3-(3-(4-(Dimethylamino)but-2-enamido)-4-(trifluoromethyl)phenyl)-1-(methylamino)-1-oxopropan-2-yl)-2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0956]

[0957] To a mixture of (*S)-N-(3-(3-amino-4-(trifluoromethyl)phenyl)-1-(methylamino)-1-oxopropan-2-yl)-2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1,1'-biphenyl]-3-carboxamide (Example 133, Step I) (70 mg, 0.095 mmol) in DCM (2.5 mL) was added DIPEA (81 mL, 0.47 mmol). The mixture was cooled to 0°C and (E)-4-(dimethylamino)but-2-enoyl chloride (0.3 mL, 0.3 M in DCM, 0.1 mmol) was slowly added. The reaction was stirred at 0°C for 1 hour, then additional (E)-4-(dimethylamino)but-2-enoyl chloride (0.3 mL, 0.3 M in DCM, 0.1 mmol) was added and the reaction was stirred at 0°C for 1 hour. The mixture was quenched with water (2 mL) and extracted with DCM (3 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was purified by preparative RP-HPLC (stationary phase: Boston Prime C18, 5 pm, 150 x 30 mm; mobile phase: water (0.05% aqueous NH4OH + 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 C44H49F3N6O6S, 846.3; m / z measured, 847.4 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.83 (d, J= 8.9 Hz, 4H), 7.60-7.50 (m, 3H), 7.22-7.10 (m, 4H), 7.05 (s, 1H), 7.02-6.93 (m, 3H), 6.16 (s, 2H), 4.89 (s, 1H), 3.98 (s, 2H), 3.68 (s, 2H), 3.57-3.11 (m, 8H), 3.04 (s, 3H), 2.77 (d, J= 4.5 Hz, 3H), 2.38 (s, 9H), 2.23 (s, 3H).19F NMR (376 MHz, CDCl3) δ -60.37.

[0958] Example 11: (R)-N-(3-(3-(But-2-ynamido)-4-(trifluoromethyl)phenyl)-1 -(methylamino)-1-oxopropan-2-yl)-2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0959]

[0960] Step A: 5-Bromo-2-(trifluoromethyl)aniline. To a suspension of 4-bromo-2-nitro-1-(trifluoromethyl)benzene (1.0 g, 3.70 mmol), iron powder (1.1 g, 19.7 mmol), and NH4CI (1.19 g, 22.3 mmol) in MeOH / THF / H2O (v / v / v, 1 / 2 / 1, 20 mL) was added 1 M aq. HCl (0.1 ml_, 0.1 mmol). The reaction mixture was stirred at 70°C for 1 day. The hot mixture was directly filtered, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was concentrated to dryness under vacuum, then diluted with sat. aq. NaHCO3(20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under vacuum. The residue was purified by column chromatography (SiO2, 0-3% ethyl acetate in petroleum ether) to yield the title compound as a yellow oil. MS (ESI): mass calculated for C7H5BrF3N, 239.0; m / z measured, 239.8 [M+H]+.1H NMR (400 MHz, DMSO-d6) 57.25 (d, J= 8.5 Hz, 1H), 7.03 (s, 1H), 6.75 (d, J= 8.5 Hz, 1H), 5.89 (s, 2H).19F NMR (376 MHz, DMSO-d6) δ -61.81 (s, 1F).

[0961] Step B: (R)-Methyl 3-(3-amino-4-(trifluoromethyl)phenyl)-2-((tert-butoxycarbonyl)amino) propanoate. A mixture of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (770 mg, 2.34 mmol), 5-bromo-2-(trifluoromethyl)aniline (700 mg, 2.89 mmol), Mn powder (385 mg, 7.01 mmol), dtbbpy (77.0 mg, 287 pmol) and NiBr2(62.0 mg, 284 pmol) in a 50 mL round bottom flask was exchanged with Argon, then DMA (15 m L) was added. After purging with Argon, the reaction mixture was placed in a pre-heated oil bath (50°C) and stirred for 2 hours. The reaction mixture was filtered, and the filter cake was rinsed with ethyl acetate (10 mL). The filtrate was diluted with ethyl acetate (40 mL) and washed with 3% aq. LiCI (50 mL x 3). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to dryness under vacuum. The residue was purified by column chromatography (SiO2, 0-16% ethyl acetate in petroleum ether) to yield the title compound (650 mg) as a light yellow oil. MS (ESI): mass calculated for C16H21F3N2O4, 362.1; m / z measured, 263.2 [M-100+H]+(loss of Boc group).1H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J= 8.0 Hz, 1H), 7.23 (d, J= 8.0 Hz, 1H), 6.67 (s, 1H), 6.50 (d, J= 8.0 Hz, 1H), 5.48 (s, 2H), 4.20-4.11 (m, 1H), 3.62 (s, 3H), 2.95-2.84 (m, 1H), 2.75 (dd, J= 13.4, 9.9 Hz, 1H), 1.34 (s, 9H).19F NMR (376 MHz, DMSO-d6) δ -61.10 (s, 1F).

[0962] Step C: (R)-3-(3-Amino-4-(trifluoromethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid. To a mixture of (R)-methyl 3-(3-amino-4-(trifluoromethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (600 mg, 1.58 mmol) in MeOH / THF (v / v, 1 / 1, 12 mL) was added 1 M aq. NaOH (1.9 mL, 1.9 mmol). The mixture was stirred at room temperature for 2 hours, then 1 M aq. HCI was added to adjust the pH to 6. The mixture was diluted with brine (30 mL), then extracted with ethyl acetate (30 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under vacuum to yield the title compound as a light yellow oil. MS (ESI): mass calculated for C15H19F3N2O4, 348.1; m / z measured, 249.0 [M-100+H]+(loss of Boc group).1H NMR (400 MHz, DMSO-d6) δ 7.11 (d, J= 8.1 Hz, 1H), 6.60 (s, 1H), 6.43 (d, J= 8.0 Hz, 1H), 5.88 (s, 1H), 5.29 (s, 2H), 3.69 (s, 1H), 2.96-2.86 (m, 1H), 2.84-2.74 (m, 1H), 1.34 (s, 9H).

[0963] Step D: (R)-tert-Butyl (3-(3-amino-4-(trifluoromethyl)phenyl)-1-(methylamino)-1-oxopropan- 2-yl)carbamate. To a solution of (R)-3-(3-amino-4-(trifluoromethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (560 mg, 1.57 mmol), CH3NH2•HCl (212 mg, 3.14 mmol), and Et3N (1.0 mL, 7.18 mmol) in DMF (11 mL) was added HATU (775 g, 2.04 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with ethyl acetate (20 mL), washed with 3% aq. LiCI (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under vacuum. The residue was purified by column chromatography (SiO2, 0-31% ethyl acetate in petroleum ether) to yield the title compound as a yellow oil. MS (ESI): mass calculated for C16H22F3N3O3, 361.2; m / z measured, 261.9 [M-100+H]+(loss of Boc group).1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 4.4 Hz, 1 H), 7.20 (d, J = 8.1 Hz, 1H), 6.83 (d, J= 8.5 Hz, 1H), 6.64 (s, 1H), 6.50 (d, J= 8.1 Hz, 1H), 5.43 (s, 2H), 4.11-4.04 (m, 1H), 2.84 (dd, J= 13.5, 4.8 Hz, 1H), 2.65-2.60 (m, 1H), 2.57 (d, J = 4.4 Hz, 3H), 1.31 (s, 9H).19F NMR (376 MHz, DMSO-d6) δ -61.00 (s, 1F).

[0964] Step E: (R)-2-Amino-3-(3-amino-4-(trifluoromethyl)phenyl)- / \ / -methylpropanamide. HCI (4M in 1,4-dioxane, 7 mL, 28 mmol) was added to a solution of (R)-tert-butyl (3-(3-amino-4-(trifluoromethyl)phenyl)-1 -(methylamino)-l -oxopropan-2-yl)carbamate (480 mg, 1.30 mmol) and DCM (7 mL). The mixture was stirred at room temperature for 2 hours then concentrated to dryness under vacuum. The residue was diluted with DCM (10 mL), adjusted to pH 7 with sat. aq. NaHCO3, and then extracted with DCM (10 mL x 2). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under vacuum to yield the title compound as a yellow oil. MS (ESI): mass calculated for C11H14F3N3O, 261.1; m / z measured, 261.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J = 4.4 Hz, 1 H), 7.22 (d, J = 8.1 Hz, 1H), 6.65 (s, 1H), 6.48 (d, J = 8.1 Hz, 1H), 5.46 (s, 2H), 3.31 (d, J= 5.1 Hz, 1H), 2.91-2.77 (m, 1H), 2.59 (d, J = 4.6 Hz, 3H), 2.50-2.45 (m, 1H).

[0965] Step F: (R)- / V-(3-(3-Amino-4-(trifluoromethyl)phenyl)-1-(methylamino)-1-oxopropan-2-yl)-2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1,1'-biphenyl]-3-carboxamide. To a solution of 2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxylic acid (Intermediate F, 35 mg, 68.7 pmol), (R)-2-amino-3-(3-amino-4-(trifluoromethyl)phenyl)- / V-methylpropanamide (23 mg, 83.7 pmol), and Et3N (28.8 pL, 208 pmol) in DMF (1.3 mL) was added HATU (35 mg, 92.1 pmol). The reaction mixture was stirred at room temperature for 2 hours then diluted with H2O (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under vacuum. The residue was purified by preparative RP-HPLC (Stationary phase: Boston Prime C18, 5 pm, 150 x 30 mm; Mobile phase: water (NH3H2O + NH4HCOs) (A) - MeCN (B), gradient elution: 50 - 80% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as an off-white powder. MS (ESI): mass calculated for C38H40F3N5O5S, 735.3; m / z measured, 736.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 8.2 Hz, 1 H), 8.03 (d, J = 4.5 Hz, 1 H), 7.90 (s, 2H), 7.70 (d, J= 8.9 Hz, 2H), 7.54 (s, 1H), 7.26-7.21 (m, 1H), 7.16 (dd, J= 15.7, 8.0 Hz, 2H), 7.11-7.05 (m, 3H), 6.73 (s, 1H), 6.59 (d, J= 8.0 Hz, 1H), 5.46 (s, 2H), 4.71-4.60 (m, 1H), 3.79 (s, 2H), 3.51 (s, 4H), 3.40 (s, 2H), 3.10 (s, 3H), 3.03 (dd, J =13.5, 4.5 Hz, 1H), 2.94-2.85 (m, 1 H), 2.61 (d, J = 4.4 Hz, 3H), 2.33 (s, 3H), 2.20 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -61.01 (s, 1F).

[0966] Step G: (R)- / V-(3-(3-(But-2-ynamido)-4-(trifluoromethyl)phenyl)-1 -(methylamino)-1-oxopropan-2-yl)-2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1,1'-biphenyl]-3-carboxamide. A solution of but-2-ynoyl chloride (17 mg, 0.17 mmol) in DCM (0.5 mL) was added to a solution of (R)-N-(3-(3-amino-4-(trifluoromethyl)phenyl)-1-(methylamino)-1-oxopropan- 2-yl)-2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1,1'-biphenyl]-3-carboxamide (70 mg, 0.094 mmol) and sat. aq. NaHCO3(2 mL) in DCM (1.5 mL) at 0°C. After 2 hours, additional but-2-ynoyl chloride (17 mg, 0.17 mmol) in DCM (0.5 mL) was added and the mixture was warmed to room temperature and stirred for 2 hours. The mixture was quenched with H2O (5 mL), then extracted with DCM (5 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, concentrated to dryness in vacuo, and the residue purified by preparative RP-HPLC (stationary phase: Boston Prime C18, 5 pm, 150 x 30 mm; mobile phase: water (0.05% aqueous NH4OH + 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 an off-white solid. MS (ESI): mass calculated for C42H42F3N5O6S, 801.3; m / z measured, 802.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.86 (d, J = 8.3 Hz, 1H), 8.12 (d, J = 4.3 Hz, 1H), 7.91 (d, J= 8.0 Hz, 2H), 7.69 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.3 Hz, 1 H), 7.54 (s, 1 H), 7.45 (d, J = 7.3 Hz, 1 H), 7.39 (s, 1H), 7.22 (d, J= 7.8 Hz, 1H), 7.13 ( d, J= 7.8 Hz, 1H), 7.10-7.04 (m, 3H), 4.70 (s, 1H), 3.78 ( s, 2H), 3.50 (s, 4H), 3.40 (s, 2H), 3.19-3.12 (m, 1H), 3.09 (s, 4H), 2.62 (d, J = 4.3 Hz, 3H), 2.33 (s, 3H), 2.20 (s, 3H), 2.00 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -59.13.

[0967] Example 12: (R, E)-N-(3-(3-(But-2-enamido)-4-(trifluoromethyl)phenyl)-1- (methylamino)-1-oxopropan-2-yl)-2',5'-dimethyl-5-(4-(4- (methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0968]

[0969] To a solution of (R)-N-(3-(3-amino-4-(trifluoromethyl)phenyl)-1-(methylamino)-1-oxopropan-2-yl)-2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1,1'- biphenyl]-3-carboxamide (Example 11, Step F) (70 mg, 0.094 mmol) and sat. aq. NaHCO3(2 m L) in DCM (1.5 m L) was added a solution of (E)-but-2-enoyl chloride (50 mL, 0.54 mmol) in DCM (0.5 ml_) at 0°C. After 1 hour, additional (E)-but-2-enoyl chloride (50 mL, 0.54 mmol) was added and the reaction mixture was allowed to warm to room temperature, then stirred at room temperature for 3 hours. The mixture was quenched with H2O (5 mL), then extracted with DCM (5 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, concentrated to dryness in vacuo and the resultant residue purified by preparative RP-HPLC (stationary phase: Boston Prime C18, 5 pm, 150 x 30 mm; mobile phase: water (0.05% aqueous NH4OH + 10 mM NH4HCO3) (A) - MeCN (B), gradient elution: 50 - 80% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C42H44F3N5O6S, 803.3; m / z measured, 804.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1 H), 8.84 (d, J = 8.3 Hz, 1 H), 8.12 (d, J = 4.5 Hz, 1 H), 7.90 (d, J = 12.5 Hz, 2H), 7.69 (d, J= 8.8 Hz, 2H), 7.61 (d, J = 8.3 Hz, 1H), 7.51 (d, J= 17.8 Hz, 2H), 7.40 (d, J = 8.0 Hz, 1H), 7.26-7.18 (m, 1H), 7.13 (d, J= 7.8 Hz, 1H), 7.08 (d, J= 7.0 Hz, 3H), 6.80-6.66 (m, 1H), 6.17 (d, J = 14.8 Hz, 1H), 4.71 (s, 1H), 3.78 (s, 2H), 3.49 (s, 6H), 3.22-3.12 (m, 1H), 3.11-3.02 (m, 4H), 2.62 (d, J = 4.3 Hz, 3H), 2.32 (s, 3H), 2.19 (s, 3H), 1.82 (d, J = 6.3 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -58.97.

[0970] Example 13: 2',5'-Dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-N-(1 -(oxetan-3-ylamino)-1 -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide.

[0971]

[0972] To a solution of 2-(2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1, 1 '-biphenyl]-3-carboxamido)-3-(4-(trifluoromethyl)phenyl)propanoic acid (Intermediate G) (51 mg, 0.072 mmol) in DMF (1.5 ml_) was added 3-oxetanamine (10.5 pL, 0.15 mmol), HATU (42.5 mg, 0.11 mmol) and TEA (31 pL, 0.22 mmol). The reaction mixture was stirred at room temperature for 3 hours then was diluted with water and extracted with EtOAc (3X). The combined organics layers were washed with brine (2X), dried over sodium sulfate, filtered, and concentrated. The residue was purified by RP-HPLC (KINETEX 5pM EVO C18, LC Column 100x30.0 mm, 45-100% ACN (in 10 mM NH4OH / H2O) to yield the title compound as white solid. MS (ESI): mass calculated for C40H41F3N4O6S, 762.3; m / z measured, 763.3 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.7-7.8 (m, 4H), 7.5-7.6 (m, 3H), 7.36 (d, 2H, J=7.8 Hz), 7.1-7.2 (m, 2H), 7.0-7.1 (m, 2H), 6.94 (d, 2H, J=8.8 Hz), 6.79 (br d, 1 H, J=6.8 Hz), 4.8-5.0 (m, 4H), 4.37 (t, 1 H, J=6.4 Hz), 4.25 (t, 1H, J=6.4 Hz), 3.3-4.1 (m, 8H), 3.2-3.3 (m, 2H), 3.02 (s, 3H), 2.35 (s, 3H), 2.20 (s, 3H).19F NMR (376 MHz, CDCl3) δ -62.49 (s, 1F).

[0973] Example 14: 2',5'-Dimethyl-N-(1 -((1 -methylazetidin-3-yl)amino)-1 -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0974]

[0975] To a solution of 2-(2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1, 1 '-biphenyl]-3-carboxamido)-3-(4-(trifluoromethyl)phenyl)propanoic acid (Intermediate G) (50 mg, 0.071 mmol) in DMF (1.5 ml_) were added 1-methylazetidin-3-amine (13 pL, 0.15 mmol), and HATU (41.9 mg, 0.11 mmol) and TEA (30 pL, 0.21 mmol). The reaction mixture was stirred at room temperature for 4 hours, then diluted with water and extracted with EtOAc (3X). The combined organics layers were washed with brine (2X), dried over sodium sulfate, filtered, and concentrated. The residue was purified by RP-HPLC (KINETEX 5pM EVO C18, LC Column 100x30.0 mm, 45-100% ACN (in 10 mM NH4OH / H2O) to yield the title compound as white solid. MS (ESI): mass calculated for C41H44F3N5O5S, 775.3; m / z measured, 776.4 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.7-7.9 (m, 4H), 7.5-7.6 (m, 3H), 7.38 (d, 2H, J=7.8 Hz), 7.18 (d, 1H, J=1.0 Hz), 7.13 (d, 1H, J=1.0 Hz), 6.9-7.1 (m, 4H), 6.14 (d, 1H, J=7.8 Hz), 4.7-4.8 (m, 1H), 4.3-4.4 (m, 1H), 3.2-4.0 (m, 11 H), 3.1-3.2 (m, 1H), 3.02 (s, 3H), 2.79 (t, 1H, J=6.4 Hz), 2.61 (t, 1H, J=6.6 Hz), 2.35 (s, 3H), 2.24 (s, 3H), 2.21 (s, 3H).19F NMR (376 MHz, CDCl3) δ -62.51 (s, 1F).

[0976] Example 15: N-(1-((2-(Dimethylamino)ethyl)amino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0977]

[0978] To a solution of 2-(2',5'-dimethyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1, 1 '-biphenyl]-3-carboxamido)-3-(4-(trifluoromethyl)phenyl)propanoic acid (Intermediate G) (50.7 mg, 0.072 mmol) in DMF (1.5 ml_) were added dimethyl ethylenediamine (16 pL, 0.15 mmol), HATU (42.7 mg, 0.11 mmol) and TEA (31 pL, 0.22 mmol). The reaction mixture was stirred at room temperature for 3 hours, then diluted with water and extracted with EtOAc (3X). The combined organics layers were washed with brine (2X), dried over sodium sulfate, filtered, and concentrated. The residue was purified by RP-HPLC (KINETEX 5pM EVO C18, LC Column 100x30.0 mm, 40-100% ACN (in 10 mM NH4OH / H2O) to yield the title compound as white solid. MS (ESI): mass calculated for C41H46F3N5O5S, 777.3 m / z measured; 778.3 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.7-7.8 (m, 3H), 7.5-7.6 (m, 2H), 7.53 (s, 1H), 7.40 (d, 2H, J=7.8 Hz), 7.1-7.2 (m, 3H), 7.03 (s, 1H), 6.94 (d, 2H, J=8.8 Hz), 6.12 (br s, 1H), 4.8-4.9 (m, 1H), 3.94 (brs, 2H), 3.66 (brs, 2H), 3.4-3.5 (m, 3H), 3.1-3.3 (m, 5H), 3.02 (s, 3H), 2.36 (s, 3H), 2.2-2.3 (m, 1H, J=5.8, 5.8, 12.3 Hz), 2.22 (s, 3H), 2.1-2.2 (m, 1H, J=12.3 Hz), 2.06 (s, 6H).19F NMR (376 MHz, CDCl3) δ -62.46 (s, 1F).

[0979] Example 16: (R)-2',5'-Dimethyl-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-sulfamoylphenyl)piperazine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0980]

[0981] The title compound was prepared according to the procedure described in Example 20, substituting 4-(piperazin-1-yl)benzenesulfonamide for 1-(4-(methylsulfonyl)phenyl)piperazine. MS (ESI): mass calculated for C37H38F3N5O5S, 721.8; m / z measured: 722.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J= 8.6 Hz, 1H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J= 1.7 Hz, 2H), 7.66 (d, J= 8.6 Hz, 2H), 7.52 (s, 4H), 7.45 (d, J = 1.7 Hz, 1 H), 7.16 (d, J = 8.0 Hz, 1 H), 7.07 (d, J = 6.5 Hz, 2H), 6.98 (d, J= 8.5 Hz, 2H), 6.90 (s, 2H), 4.76 (d, J= 5.5 Hz, 1H), 3.80 (s, 2H), 3.62 (s, 2H), 3.37 (s, 4H), 3.17 (dd, J= 13.7, 4.9 Hz, 1H), 3.09 (dd, J= 13.6, 10.0 Hz, 1H), 2.67 (d, J = 4.5 Hz, 3H), 2.36 (s, 3H), 2.24 (s, 3H).

[0982] Example 17: (R)-2',5'-Dimethyl-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(N-methylsulfamoyl)phenyl)piperazine-1-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0983]

[0984] The title compound was prepared according to the procedure described in Example 20, substituting / V-methyl-4-(piperazin-1-yl)benzenesulfonamide for 1-(4-(methylsulfonyl)phenyl)piperazine. MS (ESI): mass calculated for C38H40F3N5O5S, 735.8; m / z measured: 736.2 [M+H]+.1H NMR (600 MHz, Acetonitrile-d3) 57.76 (t, J = 1.6 Hz, 1 H), 7.72 (t, J = 1.7 Hz, 1 H), 7.69 - 7.62 (m, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.50 (t, J= 1.6 Hz, 1H), 7.47 (d, J = 7.9 Hz, 3H), 7.21 (d, J = 7.8 Hz, 1H), 7.14 (dd, J= 7.8, 1.8 Hz, 1H), 7.10 - 7.06 (m, 1H), 7.03 - 6.97 (m, 2H), 6.75 (d, J= 5.2 Hz, 1H), 5.24 (q, J = 5.3 Hz, 1H), 4.81 (td, J= 8.9, 5.3 Hz, 1H), 3.83 (s, 2H), 3.54 (s, 2H), 3.43 (s, 2H), 3.36 (dd, J= 14.0, 5.3 Hz, 2H), 3.30 (s, 2H), 3.10 (dd, J= 14.0, 9.4 Hz, 1H), 2.67 (d, J = 4.8Hz, 3H), 2.46 (d, J= 5.3 Hz, 3H), 2.34 (s, 3H), 2.20 (s, 3H).

[0985] Example 18: 2'-Chloro-5'-methyl-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0986]

[0987] To a 2-dram vial charged with 2-chloro-5-methylphenylboronic acid was added 3-bromo-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)benzamide (Intermediate H, 70 mg, 0.1 mmol) and CataCXium® A Pd G4 (3.7 mg, 0.005 mmol) in 1,4-dioxane (0.8 mL) under inert atmosphere. Cesium carbonate (1.5 M in H2O, 0.2 mL) was then added, and the reaction was stirred at 80 °C for 16 hours. The reaction was then cooled to room temperature, SiliaMetS™ DMT (40 mg) was added, and the reaction was stirred at room temperature for 3 hours. The reaction was diluted with 1 mL of EtOAc, filtered through a plug of Na2SO4and Celite® and the plug was rinsed with EtOAc (0.5 mL x 4). The collected filtrates were then dried using a Genevac and purified RP-HPLC (Stationary phase: Waters XBridge BEH C18, 5 pm, 19x100 mm; Mobile phase: Modifier 0.16% NH4OH; Water(A)- MeCN (B), gradient elution: 40 - 75% B inA over 9 min, flow rate: 25 mL / min) to yield the title compound as a residue. MS (ESI): mass calculated for C37H36CIF3N4O5S, 740.2; m / z measured, 741.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J=8.3 Hz, 1 H) 8.12 (q, J=4.4 Hz, 1 H) 7.93 (s, 2 H) 7.70 (d, J=8.8 Hz, 2 H) 7.60 - 7.65 (m, 3 H) 7.52 - 7.56 (m, 2 H) 7.47 - 7.51 (m, 1 H) 7.26 - 7.32 (m, 2 H) 7.09 (d, J=9.3 Hz, 2 H) 4.70 - 4.77 (m, 1 H) 3.78 (br s, 2 H) 3.37 - 3.57 (m, 6 H) 3.17 - 3.24 (m, 1 H) 3.10 (s, 3 H) 3.04 - 3.09 (m, 1 H) 2.60 - 2.64 (m, 3 H) 2.36 (s, 3 H).

[0988] Example 19: 2'-(Hydroxymethyl)-6'-methyl-N-(1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-

[0989] carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0990]

[0991] To a 2-dram vial charged with Intermediate I (74.6 mg, 0.1 mmol) was added (2-bromo-3-methylphenyl)methanol (40 mg, 0.2 mmol) and CataCXium® A Pd G4 (3.7 mg, 0.005 mmol) in 1,4-dioxane (0.8 mL) under inert atmosphere. Cesium carbonate (1.5 M in H2O, 0.2 mL) was then added, and the reaction was stirred at 80 °C for 16 hours. The reaction was cooled to room temperature, diluted with DMSO, filtered, concentrated, and the resultant residue purified by RP-HPLC (Stationary phase: Waters XBridge BEH C18, 5 pm, 19x100 mm; Mobile phase: Modifier 0.16% NH4OH; Water(A)- MeCN (B), gradient elution: 30 - 65% B inA over 9 min, flow rate: 25 mL / min) to yield the title compound as a residue. MS (ESI): mass calculated for C38H39F3N4O6S, 736.2; m / z measured, 737 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J=8.3 Hz, 1 H) 8.09 -8.14 (m, 1 H) 7.88 - 7.90 (m, 1 H) 7.74 (dt, J=4.6, 1.6 Hz, 1 H) 7.69 (d, J=9.3 Hz, 2 H) 7.61 (dd, J=8.3, 4.4 Hz, 2 H) 7.52 (d, J=8.3 Hz, 2 H) 7.40 - 7.43 (m, 1 H) 7.39 (t, J=1.5 Hz, 1 H) 7.33 (t, J=7.6 Hz, 1 H) 7.24 (brd, J=8.3 Hz, 1 H) 7.09 (d, J=8.8 Hz, 2 H) 5.05 (td, J=5.3, 1.2 Hz, 1 H) 4.68 - 4.76 (m, 1 H) 3.98 - 4.21 (m, 2 H) 3.74 (br s, 2 H) 3.42 - 3.56 (m, 4 H) 3.19 (br dd, J=13.5, 3.7 Hz, 1 H) 3.10 (s, 3 H) 3.05 (br d, J=13.2 Hz, 1 H) 2.59 - 2.63 (m, 3 H) 1.98 (d, J=15.2 Hz, 3 H).

[0992] Example 20: (R)-2',5'-Dimethyl-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0993]

[0994] 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 D) (240 mg, 0.47 mmol), 1-(4-(methylsulfonyl)phenyl)piperazine (136 mg, 0.565 mmol) and DIPEA (0.49 ml_, 2.8 mmol) in DMF (2 mL) was added HATU (230 mg, 0.61 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was purified directly by RP-HPLC (50-80% ACN in 0.05% aqueous NH4OH) to yield the title compound as an off-white solid. MS (ESI): mass calculated for C38H39F3N4O5S, 720.3; m / z measured, 721.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.84-7.79 (m, 3H), 7.77 (s, 1H), 7.57 (d, J= 8.1 Hz, 2H), 7.54 (s, 1H), 7.39 (d, J= 7.9 Hz, 2H), 7.21-7.17 (m, 1H), 7.16-7.12 (m, 1H), 7.03 (s, 1H), 7.00 (d, J= 7.6 Hz, 1H), 6.96 (d, J = 9.1 Hz, 2H), 5.69 (br d, J = 5.0 Hz, 1 H), 4.82-4.75 (m, 1 H), 3.96 (br s, 2H), 3.65 (br s, 2H), 3.56-3.29 (m, 4H), 3.29-3.18 (m, 2H), 3.03 (s, 3H), 2.76 (d, J = 4.8 Hz, 3H), 2.37 (s, 3H), 2.22 (s, 3H).19F NMR (376 MHz, CDCl3) δ -62.46 (s, 1F).

[0995] Example 21: (R)-2',5'-Dimethyl-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(6-(morpholinosulfonyl)pyridin-3-yl)piperazine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[0996]

[0997] Step A: 4-((5-Bromopyridin-2-yl)sulfonyl)morpholine. To a solution of 5-bromo-pyridine-2-sulfonyl chloride (50 mg, 0.20 mmol) in DCM (1.0 mL) was added morpholine (19 pL, 0.21 mmol). The reaction mixture was stirred at room temperature for 3 hours, then poured into saturated aqueous NaHCO3(5 ml_) and extracted with EtOAc (3x10 ml_). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by prep-TLC (2:1 petroleum etherEtOAc) to yield the title compound as a white solid. MS (ESI): mass calculated for C9H11BrN2O3S, 306.0; m / z measured, 308.8 [M+H]+.1H NMR (400 MHz, CDCI3) 68.78 (d, J = 2.3 Hz, 1H), 8.07 (dd, J= 8.3, 2.3 Hz, 1H), 7.84 (d, J= 8.3 Hz, 1H), 3.84-3.70 (m, 4H), 3.41-3.27 (m, 4H).

[0998] Step B: terf-Butyl 4-(6-(morpholinosulfonyl)pyridin-3-yl)piperazine-1 -carboxylate. A suspension of 4-((5-bromopyridin-2-yl)sulfonyl)morpholine (130 mg, 0.42 mmol), 1-Boc-piperazine (118 mg, 0.635 mmol), and Cs2CO3(414 mg, 1.27 mmol) in toluene (5.2 mL) was sparged with N2 for 2 minutes before Pd2(dba)3(38.8 mg, 0.423 mmol) and XantPhos (49.0 mg, 0.0846 mmol) were added. The reaction mixture was again purged with N2 then heated to 100°C for 16 hours. The mixture was cooled to room temperature and filtered, rinsing with EtOAc. The filtrate was concentrated and purified by silica gel flash column chromatography (0-60% EtOAc in petroleum ether) to yield the title compound as a white solid. MS (ESI): mass calculated for C18H28N4O5S, 412.2; m / z measured, 413.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 2.9 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.19 (dd, J = 8.8, 3.0 Hz, 1H), 3.80-3.69 (m, 4H), 3.67-3.55 (m, 4H), 3.44-3.31 (m, 4H), 3.30-3.16 (m, 4H), 1.50 (s, 9H).

[0999] Step C: 4-((5-(Piperazin-1-yl)pyridin-2-yl)sulfonyl)morpholine HCI. To a solution of te / Y-butyl 4-(6-(morpholinosulfonyl)pyridin-3-yl)piperazine-1 -carboxylate (30 mg, 0.059 mmol) in DCM (1.0 mL) was added HCI (4M in 1,4-dioxane, 1.0 mL, 4.0 mmol). The reaction mixture was stirred at room temperature for 16 hours, the volatiles were then evaporated under reduced pressure to yield the title compound as a yellow solid, which was used in the next step without further purification. MS (ESI): mass calculated for C13H20N4O3S, 312.1; m / z measured, 313.1 [M+H]+.

[1000] Step D: (R)-2',5'-Dimethyl-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(6-(morpholinosulfonyl)pyridin-3-yl)piperazine-1-carbonyl)-[1,1'-biphenyl]-3-carboxamide. The title compound was prepared according to the procedure described in Example 20, substituting 4-((5-(piperazin-1-yl)pyridin-2-yl)sulfonyl)morpholine HCI for 1-(4-(methylsulfonyl)phenyl)piperazine. MS (ESI): mass calculated for C40H43F3N6O6S, 792.3; m / z measured, 793.3 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 2.9 Hz, 1 H), 7.86-7.79 (m, 2H), 7.78-7.74 (m, 1 H), 7.58 (d, J = 8.1 Hz, 2H), 7.55 (s, 1H), 7.39 (d, J= 7.9 Hz, 2H), 7.25-7.18 (m, 2H), 7.16-7.11 (m, 1H), 7.04 (s, 1 H), 6.97 (br d, J = 7.6 Hz, 1 H), 5.64 (br d, J = 5.2 Hz, 1 H), 4.83-4.72 (m, 1 H), 3.99 (br s, 2H), 3.83-3.68 (m, 6H), 3.42 (br s, 4H), 3.33-3.15 (m, 6H), 2.77 (d, J = 4.8 Hz, 3H), 2.37 (s, 3H), 2.22 (s, 3H);19F NMR (376 MHz, CDCI3) 6 -62.47 (s, 1F).

[1001] Example 22: 2',5'-Dimethyl-N-((R)-1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonimidoyl)phenyl)piperazine-1-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[1002]

[1003] Step A: 3-Methyl-1,4,2-dioxazol-5-one. To a solution of acetohydroxamic acid (375 mg, 5.00 mmol) in DCM (50 mL) was added CDI (811 mg, 5.00 mmol) in one portion at room temperature. The reaction mixture was stirred for 90 minutes before it was quenched with 1 M HCI (30 mL) and extracted with DCM (30 mL x 2). The combined extracts were dried over anhydrous MgSC>4, filtered, and concentrated to yield the title compound (360 mg) as a light yellow oil, which was used in subsequent steps without further purification.1H NMR (400 MHz, CDCl3) δ 2.36 (s, 3H).

[1004] Step B: / \ / -((4-Bromophenyl)(methyl)(oxo)-A6-sulfaneylidene)acetamide. In a glovebox, two reaction vials were each charged with 5,10,15,20-tetraphenyl-21 / - / ,23H-porphine ruthenium(ll) carbonyl (13.6 mg, 0.0183 mmol), 1-bromo-4-(methylsulfinyl)benzene (200 mg, 0.913 mmol), and a solution of 3-methyl-1,4,2-dioxazol-5-one (92.3 mg, 0.913 mmol) in toluene (3.7 mL). The reaction vials were sealed and removed from the glovebox, then irradiated with a UV Kessil lamp at room temperature for 3 hours. The contents of the reaction vials were combined, concentrated, and purified by silica gel flash column chromatography (EtOAc / heptane) to yield the title compound as an oil. MS (ESI): mass calculated for C9H10BrNO2S, 275.0; m / z measured, 276.0 [M+H]+.1H NMR (400 MHz, CDCI3) δ 7.88–7.80 (m, 2H), 7.78–7.70 (m, 2H), 4.12 (q, J = 7.2 Hz, 1H), 3.32 (s, 3H), 2.15 (s, 3H), 2.05 (s, 2H), 1.26 (t, J= 7.1 Hz, 2H).

[1005] Step C: terf-Butyl 4-(4-(N-acetyl-S-methylsulfonimidoyl)phenyl)piperazine-1-carboxylate. In a glovebox, a reaction vial was charged with 1-Boc-piperazine (425 mg, 2.28 mmol), XPhos Pd G4 (131 mg, 0.152 mmol), Cs2CO3(1.49 g, 4.56 mmol), and a solution of N-((4-bromophenyl)(methyl)(oxo)-A6-sulfaneylidene)acetamide (420 mg, 1.52 mmol) in DMF (7.60 mL). The vial was sealed, removed from the glovebox, and the reaction mixture heated to 80°C with stirring for 4 hours. The reaction mixture was diluted with EtOAc and sat. aq. NaHCO3, and the layers were separated. The organic layer was washed with brine, dried over MgSC>4, and concentrated to yield the title compound as a residue, which was used in the subsequent step without further purification. MS (ESI): mass calculated for C18H27N3O4S, 381.2; m / z measured, 382.1 [M+H]+.

[1006] Step D: lmino(methyl)(4-(piperazin-1-yl)phenyl)-A6-sulfanone. To a solution of tert-buty I 4-(4-(N-acetyl-S-methylsulfonimidoyl)phenyl)piperazine-1 -carboxylate (580 mg, 1.52 mmol) in DCM (15.2 mL) was added HCI (12M, 3.17 mL, 38.0 mmol) dropwise at room temperature. The reaction mixture was stirred for 4 hours, then concentrated to yield the title compound as a residue, which was used in the subsequent step without further purification.

[1007] Step E: 2',5'-Dimethyl-N-((R)-1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonimidoyl)phenyl)piperazine-1-carbonyl)-[1,1'-biphenyl]-3-carboxamide. A reaction vial containing (R)-2',5'-dimethyl-5-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, T-biphenyl]-3-carboxylic acid (Intermediate D) (50 mg, 0.099 mmol), Si-DCC (265 mg, 0.247 mmol), Si-HOBt (250 mg, 0.198 mmol) was charged with a solution of imino(methyl)(4-(piperazin-1-yl)phenyl)-A6-sulfanone (28.4 mg, 0.119 mmol) in DCM (1.4 mL). The reaction mixture was stirred at room temperature for 16 hours, then triethylamine (0.101 mL, 0.741 mmol) was added and the reaction mixture was heated to 50°C for another 108 hours. The reaction mixture was filtered and DMAP (14.5 mg, 0.119 mmol) and EDCI*HCI (26.5 mg, 0.138 mmol) were added, and the resulting mixture was stirring at room temperature for 20 hours. Saturated aqueous NaHCO3was added and the mixture was transferred to a separatory funnel with EtOAc. The layers were separated and the organic layer was dried over MgSO4, filtered, and concentrated. The resultant residue was purified by RP-HPLC (Stationary phase: Waters XSelect CSH C18, 5p, 19x100 mm; Mobile phase: Modifier 0.16% TFA; Water(A)- MeCN (B), gradient elution: 25 - 60% B in A over 12 min, flow rate: 25 mL / min) to yield the title compound as a solid. MS (ESI): mass calculated for C38H40F3N5O4S, 719.3; m / z measured, 720.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.87 (dd, J = 9.0, 3.8 Hz, 2H), 7.73 (dt, J = 7.5, 1.6 Hz, 2H), 7.69–7.62 (m, 1H), 7.53 (dd, J= 19.7, 6.6 Hz, 3H), 7.37 (t, J= 7.3 Hz, 2H), 7.22–7.05 (m, 4H), 7.02 (s, 1H), 6.94 (dd, J= 9.2, 1.7 Hz, 2H), 6.22–6.12 (m, 1H), 6.08–5.94 (m, 1H), 4.82 (p, J= 7.4 Hz, 2H), 4.14-3.26 (m, 14H), 3.21 (dd, J= 7.1, 4.7 Hz, 3H), 2.76 (dd, J= 4.8, 1.7 Hz, 2H), 2.59 (d, J = 53.3 Hz, 13H), 2.36 (s, 3H), 2.09-2.01 (m, 1H), 1.25 (s, 1H).

[1008] Example 23: 5-(4-(4-Hydroxy-1, 1 -dioxidothiochroman-6-yl)piperazine-1 -carbonyl)-2',5'-dimethyl-N-((R)-1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3-carboxamide.

[1009]

[1010] Step A: 6-Fluorothiochroman-4-one 1,1 -dioxide. Oxone (2.5 g, 4.07 mmol) was added in portions to a mixture of 6-fluorothiochroman-4-one (500 mg, 2.74 mmol) in EtOH / H2O (v / v, 1 / 1, 20 ml_) at 0°C. The reaction mixture was heated to 60°C and stirred for 16 hours, then cooled to room temperature. The mixture was quenched with sat. aq. Na2SO3(10 mL) at 0°C and the organic solvent was evaporated in vacuo. The aqueous phase was diluted with H2O (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The resultant residue was purified by flash column chromatography (SiO2, 0-50% ethyl acetate in petroleum ether) to yield the title compound as white solid.1H NMR (400 MHz, DMSO-d6) δ 8.06 (dd, J = 8.7, 5.0 Hz, 1 H), 7.85-7.79 (m, 1 H), 7.75 (dd, J= 9.1, 2.7 Hz, 1H), 4.07-4.01 (m, 2H), 3.31-3.26 (m, 2H).19F NMR (376 MHz, DMSO-cfe) 5 -103.91 (s, 1F).

[1011] Step B: terf-Butyl 4-(1,1-dioxido-4-oxothiochroman-6-yl)piperazine-1 -carboxylate.

[1012] 7erf-butyl piperazine-1 -carboxylate (383 mg, 2.06 mmol) was added slowly to a solution of 6-fluorothiochroman-4-one 1,1 -dioxide (400 mg, 1.87 mmol) and Et3N (363 mg, 3.59 mmol) in DMSO (8 mL) at 0°C. The reaction mixture was heated to 90°C and stirred for 4 hours, then cooled to room temperature and concentrated to dryness in vacuo. The resultant residue was purified by RP-HPLC (Stationary phase: Xtimate C18, 10 pm, 150 x 40 mm; Mobile phase: water (FA) (A) - MeCN (B), gradient elution: 35 - 65% B inA over 7 min, flow rate: 60 mL / min) to yield the title compound as a yellow powder. MS (ESI): mass calculated for C18H24N2O5S, 380.1; m / z measured, 324.9 [M-56+H]+(loss of tert-butyl group).1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J= 8.8 Hz, 1H), 7.47 (d, J = 2.7 Hz, 1H), 7.18 (dd, J = 8.8, 2.7 Hz, 1H), 3.68-3.58 (m, 6H), 3.45-3.36 (m, 6H), 1.50 (s, 9H).

[1013] Step C: 6-(Piperazin-1-yl)thiochroman-4-one 1,1 -dioxide HCI. A mixture of tertbutyl 4-(1,1-dioxido-4-oxothiochroman-6-yl)piperazine-1 -carboxylate (100 mg, 0.26 mmol) in 4 M HCI / 1,4-dioxane (2.0 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated to yield the title compound as a yellow solid, which was used in the subsequent step without further purification. MS (ESI): mass calculated for C13H16N2O3S, 280.1; m / z measured, 280.8 [M+H]+.

[1014] Step D: (R)-5-(4-(1,1-Dioxido-4-oxothiochroman-6-yl)piperazine-1-carbonyl)-2',5'-dimethyl- N-(1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3- carboxamide. The title compound was prepared according to the procedure described in Example 20, substituting 6-(piperazin-1-yl)thiochroman-4-one 1,1 -dioxide HCI for 1-(4-(methylsulfonyl)phenyl)piperazine. MS (ESI): mass calculated for C40H39F3N4O6S, 760.3; m / z measured, 761.1 [M+H]+.

[1015] Step E: 5-(4-(4-Hydroxy-1,1-dioxidothiochroman-6-yl)piperazine-1-carbonyl)-2',5'-dimethyl-N-((R)-1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-[1, 1 '-biphenyl]-3- carboxamide. Sodium borohydride (30 mg, 0.79 mmol) was added slowly to a solution of (R)-5-(4-(1,1-dioxido-4- oxothiochroman-6-yl)piperazine-1-carbonyl)-2',5'- dimethyl-N-(1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)-[1, T-biphenyl]-3-carboxamide (50 mg, 0.064 mmol) in MeOH (2.0 ml_) at 0°C. The reaction mixture was stirred at room temperature for 2 hours before it was quenched with sat. aq. NH4CI (5 ml_) at 0°C and extracted with ethyl acetate (10 mL x 3). The combined extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The resultant residue was purified by RP-HPLC (Stationary phase: Welch Xtimate C18, 5 pm, 150 x 25 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) -MeCN (B), gradient elution: 45 - 75% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as an off-white powder. MS (ESI): mass calculated for C40H41F3N4O6S, 762.3; m / z measured, 763.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.85 (d, J = 8.6 Hz, 1 H), 8.09 (br d, J = 4.5 Hz, 1 H), 7.86 (s, 2H), 7.65-7.58 (m, 2H), 7.57-7.49 (m, 4H), 7.26-7.19 (m, 1H), 7.14 (d, J= 7.7 Hz, 1H), 7.06 (br d, J= 9.5 Hz, 3H), 5.74 (br s, 1 H), 4.79-4.64 (m, 2H), 3.78 (br s, 2H), 3.57-3.46 (m, 3H), 3.45-3.38 (m, 3H), 3.21 (br dd, J = 13.8, 4.3 Hz, 2H), 3.12-3.02 (m, 1H), 2.70-2.63 (m, 1H), 2.61 (d, J = 4.5 Hz, 3H), 2.44-2.41 (m, 1H), 2.32 (s, 3H), 2.30-2.24 (m, 1H), 2.18 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -60.72 (s, 1F).

[1016] Example 24: 2',6'-Dimethyl-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[1017]

[1018] A suspension of 3-bromo- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)benzamide (Intermediate H, 100 mg, 0.14 mmol), 2,6-dimethylphenylboronic acid (32 mg, 0.22 mmol), Na2CO3(61 mg, 0.58 mmol), and Pd(PPh3)4(17 mg, 0.014 mmol) in 1:1 1,4-dioxane: H2O (1.0 mL) under N2 was heated to 120°C in a microwave for 40 minutes. The reaction mixture was diluted with EtOAc (2 mL) and the layers were separated. The organic layer was dried over MgSO4, filtered, and concentrated. The resultant residue was purified by RP-HPLC (Stationary phase: Waters XBridge BEH C18, 5p, 19x100 mm; Mobile phase: Modifier 0.16% NH4OH; Water(A)- MeCN (B), gradient elution: 40 - 75% B in A over 5 min, flow rate: 25 mL / min) to yield the title compound as a solid. MS (ESI): mass calculated for C38H39F3N4O5S, 720.3; m / z measured, 721.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J= 8.8 Hz, 1H), 8.12 (q, J = 4.4 Hz, 1 H), 7.88 (t, J = 1.5 Hz, 1 H), 7.75-7.64 (m, 3H), 7.60 (d, J = 7.8 Hz, 2H), 7.52 (d, J= 8.3 Hz, 2H), 7.41-7.35 (m, 1H), 7.26-7.13 (m, 3H), 7.09 (d, J= 9.3 Hz, 2H), 4.78-4.67 (br m, 1H), 3.85-3.67 (br m, 2H), 3.58-3.34 (br m, 6H), 3.24-3.13 (m, 1H), 3.09 (s, 3H), 3.08-3.00 (m, 1 H), 2.61 (d, J = 4.4 Hz, 3H), 2.00 (s, 3H), 1.96 (s, 3H).

[1019] Example 25: 4'-Fluoro-2',5'-dimethyl-N-(1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[1020]

[1021] The title compound was prepared according to the procedure described in Example 24, substituting 4-fluoro-2,5-dimethylphenylboronic acid for 2,6-dimethylphenylboronic acid. MS (ESI): mass calculated for C38H38F4N4O5S, 738.2; m / z measured, 739.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J= 8.8 Hz, 1H), 8.12 (q, J = 4.4 Hz, 1 H), 7.90-7.80 (m, 2H), 7.70 (d, J = 9.3 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.58-7.48 (m, 3H), 7.23-7.12 (m, 2H), 7.09 (d, J= 9.3 Hz, 2H), 4.79-4.68 (m, 1H), 3.89-3.68 (br m, 2H), 3.59-3.30 (br m, 6H), 3.26-3.15 (m, 1H), 3.10 (s, 3H), 3.09-3.01 (m, 1 H), 2.62 (d, J = 4.4 Hz, 3H), 2.25 (s, 3H), 2.20 (s, 3H).

[1022] Example 26: (R)-5'-(Hydroxymethyl)-2'-methyl-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[1023]

[1024] (R)-2',5'-dimethyl-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1, 1 ' -bi phenyl ]-3-carboxamide (Example 20) (50 mg, 0.069 mmol) was subjected to Hypha PolyCYPs® CYP166 according to manufacturer’s instructions. The extract was purified by RP-HPLC (Stationary phase: Waters XBridge BEH C18, 5p, 19x100 mm; Mobile phase: Modifier 0.16% NH4OH; Water(A)- MeCN (B), gradient elution: 25 - 75% B in A over 13 min, flow rate: 25 mL / min) to yield the title compound as a solid. MS (ESI): mass calculated for C38H39F3N4O6S, 736.3; m / z measured, 737.3 [M+H]+.1H NMR (400 MHz, CDCI3) 68.05 (br d, J= 7.8 Hz, 1H), 7.86-7.75 (m, 3H), 7.73 (t, J= 1.6 Hz, 1H), 7.54 (d, J= 8.1 Hz, 2H), 7.46 (t, J= 1.5 Hz, 1H), 7.41 (d, J= 8.3 Hz, 2H), 7.27-7.22 (m, 2H), 7.15 (s, 1H), 6.93 (d, J = 9.1 Hz, 2H), 6.35 (q, J = 4.4 Hz, 1 H), 4.83 (q, J = 7.8 Hz, 1 H), 4.76 (d, J = 12.7 Hz, 1H), 4.65 (d, J = 12.7 Hz, 1H), 4.06-3.78 (br m, 2H), 3.70-3.04 (br m, 9H), 3.02 (s, 3H), 2.55 (d, J = 4.9 Hz, 3H), 2.19 (s, 3H).

[1025] Example 27: 2',5'-Dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(6-(methylsulfonyl)pyridin-3-yl)piperazine-1-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[1026]

[1027] Step A: terf-Butyl 4-(6-(methylsulfonyl)pyridin-3-yl)piperazine-1 -carboxylate. To a mixture of 5-bromo-2-(methylsulfonyl)pyridine (300 mg, 1.27 mmol), te / Y-butyl piperazine-1 -carboxylate (284 mg, 1.52 mmol) and Cs2CO3(1.24 g, 3.81 mmol) in toluene (6 ml_) were added RuPhos (59.3 mg, 0.127 mmol) and Pd2(dba)3(58.2 mg, 0.063 mmol). The reaction mixture was heated to 100°C and stirred under N2 for 16 hours, then cooled to room temperature. The mixture was filtered, and the filter cake was washed with ethyl acetate (20 mL). The filtrate was diluted with H2O (30 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic extracts were combined, washed with brine (20 mL), dried with Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (SiO2, 0-70% ethyl acetate in petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C15H23N3O4S, 341.1; m / z measured, 341.9 [M+H]+.1H NMR (400 MHz, CDCl3) 68.32 (d, J =3.0 Hz, 1 H), 7.93 (d, J = 8.8 Hz, 1 H), 7.22 (dd, J = 8.8, 3.0 Hz, 1H), 3.66-3.59 (m, 4H), 3.42-3.34 (m, 4H), 3.16 (s, 3H), 1.49 (s, 9H).

[1028] Step B: 1-(6-(Methylsulfonyl)pyridin-3-yl)piperazine. HCI (4M in 1,4-dioxane, 0.8 mL) was added to a solution of terf-butyl 4-(6-(methylsulfonyl)pyridin-3-yl)piperazine-1-carboxylate (50 mg) in DCM (5 mL). The reaction mixture was stirred at room temperature for 16 hours, then diluted with H2O (18 mL) and washed with DCM (15 mL). The aqueous layer was adjusted to pH 7-8 with sat. aq. NaHCO3and extracted with DCM (600 mL x 3). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under vacuum to yield the title compound as a white solid, which was used in the next step without further purification. MS (ESI): mass calculated for C10H15N3O2S, 241.1; m / z measured, 241.9 [M+H]+.1H NMR (400 MHz, CDCl3) 68.32 (d, J= 3.0 Hz, 1H), 7.92 (d, J= 8.8 Hz, 1H), 7.20 (dd, J= 8.9, 2.9 Hz, 1H), 3.40-3.32 (m, 4H), 3.16 (s, 3H), 3.10-3.01 (m, 4H).

[1029] Step C: 2',5'-Dimethyl- / V-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(6-(methylsulfonyl)pyridin-3-yl)piperazine-1-carbonyl)-[1,1'-biphenyl]-3-carboxamide. To a solution of 2',5'-dimethyl-5-((1-(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamoyl)-[1, 1 '-biphenyl]-3-carboxylic acid (Intermediate J) (66 mg, 0.13 mmol), HATU (76 mg, 0.20 mmol), and Et3N (55 pL, 0.40 mmol) in DMF (0.99 mL) was added 1-(6-(methylsulfonyl)pyridin-3-yl)piperazine (49 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and purified directly by RP-HPLC (Stationary phase: Waters XSelect CSH C18, 5p, 19x100 mm; Mobile phase: Modifier 0.16% TFA; Water(A)- MeCN (B), gradient elution: 35 - 70% B in A over 12 min, flow rate: 25 mL / min) to yield the title compound as a solid. MS (ESI): mass calculated for C37H38F3N5O5S, 721.3; m / z measured, 722.2 [M+H]+.1H NMR (400 MHz, CD3OD) 58.64 (d, J = 7.8 Hz, 1 H), 8.30 (d, J = 2.9 Hz, 1 H), 7.80 (d, J = 8.8 Hz, 1 H), 7.71 (dt, J = 5.9, 1.5 Hz, 2H), 7.52-7.44 (m, 3H), 7.42-7.34 (m, 3H), 7.09 (d, J = 7.8 Hz, 1 H), 7.06-6.99 (m, 1 H), 6.96 (br s, 1 H), 4.82-4.70 (m, 1 H), 3.94-3.77 (br m, 2H), 3.65-3.31 (br m, 6H), 3.29-3.20 (m, 1H), 3.08-2.97 (m, 4H), 2.62 (s, 3H), 2.25 (s, 3H), 2.10 (s, 3H).

[1030] Example 28: (R)-2',3',6'-Trimethyl-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[1031]

[1032] In a microwave vial under N2, a suspension of (R)-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-3-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate I) (150 mg, 0.20 mmol), 2-bromo-1,3,4-trimethylbenzene (80 mg, 0.40 mmol), Na2CO3(86 mg, 0.81 mmol), and Pd(PPh3)4 (23 mg, 0.020 mmol) in 3:1 1,4-dioxane: H2O (1.8 ml_) was heated to 120°C in a microwave for 30 minutes. The reaction mixture was diluted with EtOAc (2 ml_), and the layers were separated. The organic layer was removed, dried over MgSC>4, and concentrated. The resultant residue was purified by silica gel flash column chromatography (0-4% MeOH in DCM), and then by SFC to yield the title compound as a solid. MS (ESI): mass calculated for C39H41F3N4O5S, 734.3; m / z measured, 735.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J= 8.3 Hz, 1H), 8.12 (q, J = 4.4 Hz, 1H), 7.91-7.85 (m, 1H), 7.73-7.64 (m, 1H), 7.60 (d, J= 8.3 Hz, 2H), 7.52 (d, J= 8.3 Hz, 2H), 7.33 (q, J = 2.0 Hz, 1H), 7.16-7.01 (m, 4H), 4.78-4.67 (m, 1H), 3.85-3.68 (br m, 2H), 3.57-3.35 (br m, 6H), 3.24-3.14 (m, 1H), 3.09 (s, 3H), 3.08-3.01 (m, 1 H), 2.61 (d, J = 4.9 Hz, 3H), 2.25 (d, J = 2.9 Hz, 3H), 1.98-1.81 (m, 6H).

[1033] Example 29: (R)-5'-(Hydroxymethyl)-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-2'-(trifluoromethyl)-[1, 1 '-biphenyl]-3-carboxamide.

[1034]

[1035] A suspension of (R)-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-3-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate I) (100 mg, 0.14 mmol), (3-bromo-4-(trifluoromethyl)phenyl)methanol (48 mg, 0.19 mmol), CS2COS (130 mg, 0.41 mmol), and Pd(dppf)Cl2(10 mg, 0.14 mmol) in 19:1 1,4-dioxane: H2O (0.68 ml_) was sparged with Argon for 15 minutes. The vial was then heated to 100°C and stirred for 16 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the resultant residue purified directly by silica gel flash column chromatography (30-100% EtOAc in heptanes) to yield the title compound as a foamy solid. MS (ESI): mass calculated for C38H36F6N4O6S, 790.2; m / z measured, 813.2 [M+Na]+.1H NMR (400 MHz, CDCI3) δ 8.31 (br d, J = 6.9 Hz, 1 H), 7.86 (s, 1 H), 7.76 (d, J = 9.3 Hz, 2H), 7.72 (s, 1 H), 7.67 (d, J = 8.3 Hz, 1 H), 7.55-7.30 (m, 6H), 7.25 (s, 1 H), 6.92 (d, J = 8.8 Hz, 2H), 6.69 (br d, J = 4.9 Hz, 1 H), 4.94-4.61 (m, 3H), 4.03-3.73 (br m, 2H), 3.66-3.09 (br m, 8H), 3.01 (s, 3H), 2.48 (d, J = 4.9 Hz, 3H).

[1036] Example 30: (R)-3'-Chloro-2',6'-dimethyl-N-(1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide TFA.

[1037]

[1038] A suspension of (R)-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-3-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate I) (240 mg, 0.24 mmol), 2-bromo-4-chloro-1,3-dimethylbenzene (50 mg, 0.23 mmol), XPhos Pd G3(30 mg, 0.035 mmol), and Cs2CO3(240 mg, 0.74 mmol) in 10:1 1,4-dioxane: H2O (10 mL) was heated to 80°C and stirred for 16 hours under N2. The reaction mixture was cooled to room temperature, filtered, and rinsed with EtOAc (3x10 mL). The filtrate was concentrated, and the resultant residue was purified by RP-HPLC (Stationary phase: Boston Prime C18, 5 pm, 150 x 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 55 - 85% B in A over 7 min, flow rate: 25 mL / min) and then further purified by RP-HPLC (Stationary phase: Welch Xtimate C18, 3 pm, 100 x 40 mm; Mobile phase: water (TFA) (A) - MeCN (B), gradient elution: 38 - 68% 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 C38H38ClF3N4O5S, 754.2; m / z measured, 755.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J= 8.5 Hz, 1H), 8.16-8.08 (m, 1H), 7.92 (d, J= 1.4 Hz, 1H), 7.73-7.66 (m, 3H), 7.63-7.57 (m, 2H), 7.56-7.47 (m, 2H), 7.44-7.38 (m, 2H), 7.22 (dd, J = 8.2, 1.8 Hz, 1H), 7.09 (d, J= 9.1 Hz, 2H), 4.78-4.69 (m, 1H), 3.76 (brs, 2H), 3.54-3.52 (m, 1H), 3.53-3.36 (m, 5H), 3.20 (br dd, J = 13.6, 4.5 Hz, 1H), 3.09 (s, 3H), 3.08-3.02 (m, 1H), 2.61 (d, J = 4.4 Hz, 3H), 2.01 (d, J= 15.3 Hz, 3H), 1.95 (d, J= 16.1 Hz, 3H).

[1039] Example 31: (R)-4'-Fluoro-5'-(hydroxymethyl)-2'-methyl-N-(1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[1040]

[1041] A mixture of (R)-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)- 3-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate I) (130 mg residue, 0.14 mmol), (5-bromo-2-fluoro-4-methylphenyl)methanol (35.9 mg, 0.16 mmol) and Na2CO3(43.4 mg, 0.41 mmol) in 1,4-dioxane / H2O (v / v, 4 / 1, 2 ml_) was degassed with N2. Pd(dppf)Cl2 (10 mg, 0.014 mmol) was added, and the mixture was purged with N2. The reaction mixture was heated to 80°C and stirred for 16 hours. The reaction mixture was diluted with water (5 mL), and the aqueous layer was extracted with ethyl acetate (5 mL x 3). The organic layers were separated, dried over Na2SO4, and concentrated to dryness. The resultant residue was purified by RP-HPLC (Stationary phase: Boston Prime C18, 5 pm, 150 x 30 mm; Mobile phase: water (0.05% NH3H2O + 10 mM NH4HCO3) (A) - MeCN (B), gradient elution: 38 - 68% B inA over 1.8 min, flow rate: 25 mL / min) to yield the title compound as an off-white powder. MS (ESI): mass calculated for C38H38F4N4O6S, 754.2; m / z measured, 755.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.89 (br d, J = 8.3 Hz, 1H), 8.11 (brd, J = 4.5 Hz, 1H), 7.88 (br d, J= 5.7 Hz, 2H), 7.70 (d, J= 8.9 Hz, 2H), 7.65-7.61 (m, 2H), 7.56-7.52 (m, 3H), 7.34 (d, J= 7.7 Hz, 1H), 7.17 (d, J= 11.1 Hz, 1H), 7.09 (d, J = 9.1 Hz, 2H), 5.30 (t, J = 5.7 Hz, 1 H), 4.78-4.69 (m, 1 H), 4.57 (d, J = 5.5 Hz, 2H), 3.79 (brs, 2H), 3.50 (br s, 3H), 3.33 (br s, 3H), 3.21 (br dd, J = 13.6, 4.2 Hz, 1H), 3.10 (s, 4H), 2.62 (d, J = 4.5 Hz, 3H), 2.23 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -60.71 (s, 1F), -121.91 (s, 1F).

[1042] Example 32: (R)-5'-(Hydroxymethyl)-2',4'-dimethyl-N-(1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1, 1 '-biphenyl]-3-carboxamide.

[1043]

[1044] Step A: (5-Bromo-2,4-dimethylphenyl)methanol. BH3 (1M solution in THF, 1.1 ml_, 1.1 mmol) was added to a solution of 5-bromo-2,4-dimethylbenzoic acid (50 mg, 0.22 mmol) in THF (1 ml_) at 0°C under N2. The resulting mixture was warmed to room temperature and stirred for 2 hours. MeOH (0.5 mL) was added and the mixture was concentrated under vacuum. The resultant residue was purified by column chromatography (SiO2, 0-50% ethyl acetate in petroleum ether) to yield the title compound as a white solid. MS (ESI): mass calculated for C9H11BrO, 214.0; m / z measured, 198.8 [M-16+H]+.1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 7.05 (s, 1H), 4.64 (d, J = 5.7 Hz, 2H), 2.36 (s, 3H), 2.27 (s, 3H), 1.54 (t, J = 5.8 Hz, 1H).

[1045] Step B: (R)-5'-(Hydroxymethyl)-2',4'-dimethyl-N-(1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-[1,1'-biphenyl]-3-carboxamide. Pd(dppf)Cl2 (10.1 mg, 0.014 mmol) was added to a mixture of (5-bromo-2,4-dimethylphenyl)methanol (30 mg, 0.14 mmol), (R)-N-(1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-3-(4-(4-(methylsulfonyl) phenyl)piperazine-1-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate I) (134 mg, 0.14 mmol) and K2CO3 (58 mg, 0.42 mmol) in 1,4-dioxane / H2O (v / v, 5 / 1, 1.2 mL) under N2. The reaction mixture was heated to 100°C for 16 hours, then cooled to room temperature. The mixture was filtered through a pad of Celite® and the filter cake was washed with ethyl acetate (20 mL). The filtrate was evaporated under vacuum and the resultant residue was purified by RP-HPLC (Stationary phase: Phenomenex Gemini NX C18, 3 pm, 75 x...

Claims

What is claimed:

1. A compound of Formula (I), whereinwhereinR1is selected from the group consisting of(a) phenyl; wherein the phenyl is optionally substituted with one or more substituent independently selected from the group consisting of halogen, hydroxy, -CN, -NO2, Ci-4alkyl, fluoro substituted Ci-4alkyl, hydroxy substituted Ci-4alkyl, C2-4alkenyl, fluoro substituted C^alkenyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-4alkyl), -(Ci-4alkyl)-O-(Ci-4alkyl), -C(O)-(Ci-4alkyl), -C(O)OH, -C(O)O-(Ci-4alkyl), -C(O)-NRARB, -NRARB, -(Ci-4alkyl)-NRARB, -NRA-C(O)-(Ci-3alkyl), -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; and RBis selected from the group consisting of hydrogen, Ci-4alkyl, hydroxy substituted C1-4alkyl, and -(Ci-4alkyl)-O-(Ci-4alkyl);whereinb is an integer from 0 to 1;L1is selected from the group consisting of -(Ci-4alkyl)-, -(Ci-4alkyl)-O-, -O-(Ci-4alkyl)-, -(Ci-4alkyl)-O-(Ci-4alkyl)-, -C(O)O-(Ci-4alkyl)-, -C(O)-NRD-, -C(O)-NH-(Ci-4alkyl)-NRD-SO2-; wherein RDis selected from the group consisting of hydrogen, and C1-2alkyl;provided that when L1is -C(O)O-(Ci-4alkyl)-, -C(O)-NH-(Ci-4alkyl)-, -C(O)-NH / \ z°\-C(O)-NH^^, or -C(O)-NH-^ then the -C(O)- portion of L1is bound directly to the phenyl;provided further that when L1is -NRD-C(O)-(Ci-4alkyl)-, then the -NRD- portion of L1is bound directly to the phenyl;provided further that when L1is -(Ci-4alkyl)-NRD-SO2-, then the -(Ci-4alkyl)-portion of L1is bound directly to the phenyl;R3is selected from the group consisting of C3-6cycloalkyl, aryl, and 4 to 10 membered heterocyclyl;wherein the C3-6cycloalkyl, aryl, or 4 to 10 membered heterocyclyl is optionally substituted with one or more substituent independently selected from the group consisting of halogen, hydroxy, oxo, Ci-4alkyl, fluoro substituted Ci-4alkyl, hydroxy substituted Ci-4alkyl, -O-(Ci-4alkyl), -(Ci-4alkyl)-O-(Ci-4alkyl) and -NRERF; wherein REand RFare each independently selected from the group consisting of hydrogen and Ci-4alkyl;c is an integer from 0 to 3;each R4is independently selected from the group consisting of halogen, hydroxy, -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)-(Ci-4alkyl), -C(O)OH, -C(O)O-(Ci-4alkyl), -C(O)-NRGRH, -NRGRH, and -(Ci-4alkyl)-NRGRH;wherein RGis selected from the group consisting of hydrogen, and Ci-4alkyl; and RHis selected from the group consisting of hydrogen, Ci-4alkyl, hydroxy substituted Ci-4alkyl, and -(Ci-4alkyl)-O-(Ci-4alkyl);and (c) 9 to 11 membered benzo-fused carbocyclyl or 9 to 11 membered benzofused heterocyclyl; wherein the 9 to 11 membered benzo-fused carbocyclyl or 9 to 11 membered benzo-fused heterocyclyl is bound through the benzo-fused portion;wherein the 9 to 11 membered benzo-fused carbocyclyl, or 9 to 11 membered benzo-fused heterocyclyl is optionally substituted with one or more substituentindependently selected from the group consisting of halogen, hydroxy, oxo, -CN, Ci-4alkyl, fluoro substituted Ci-4alkyl, hydroxy substituted Ci-4alkyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-4alkyl), -(Ci-4alkyl)-O-(Ci-4alkyl), -(Ci-4alkyl)-C(O)OH, -(Ci-4alkyl)-C(O)O-(Ci-4alkyl), and -NRJRK;wherein RJand RKare each independently selected from the group consisting of hydrogen, and Ci-4alkyl;or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

2. A compound as in Claim 1, whereinR1is selected from the group consisting of(a) phenyl; wherein the phenyl is optionally substituted with one to four substituent independently selected from the group consisting of halogen, hydroxy, -CN, -NO2, Ci-salkyl, fluoro substituted Ci-2alkyl, hydroxy substituted Ci-salkyl, C2-salkenyl, fluoro substituted C2-3alkenyl, -O-(Ci-salkyl), -O-(fluoro substituted Ci-2alkyl), -(C1-2alkyl)-O-(Ci-2alkyl), -C(O)-(Ci-2alkyl), -C(O)OH, -C(O)O-(Ci-2alkyl), -C(O)-NRARB, -NRARB, -(Ci-2alkyl)-NRARB, -NRA-C(O)-(Ci-2alkyl), -NH-C(O)-(Ci-2alkyl)-NRARB, -NH-C(O)-(Ci-2alkyl)-NH-C(O)-(Ci-2alkyl), -CH(CN)-NRARB, and -CH(CN)-NH-C(O)-(Ci-2alkyl);wherein RAis selected from the group consisting of hydrogen, and Ci-2alkyl; and RBis selected from the group consisting of hydrogen, Ci-2alkyl, hydroxy substituted C1- i-2alkyl);whereinb is an integer from 0 to 1;L1is selected from the group consisting of -(Ci-3alkyl)-, -(C1-2alkyl)-O-, -O-(Ci-2alkyl)-, -(Ci-2alkyl)-O-(Ci-3alkyl)-, -C(O)O-(Ci-2alkyl)-, -C(O)-NRD-, -C(O)-NH-(Ci-3alkyl)-SO2-; wherein RDis selected from the group consisting of hydrogen, and Ci-2alkyl;provided that when L1is -C(O)O-(Ci-2alkyl), -C(O)-NH-(Ci-3alkyl)-, -C(O)-NHz°\or -C(O)-NH^'Xthen the -C(O)- portion of L1is bound directly to the phenyl;provided further that when L1is -NRD-C(O)-(Ci-2alkyl)-, then the -NRD- portion of L1is bound directly to the phenyl;provided further that when L1is -(Ci-2alkyl)-NRD-SO2-, then the -(Ci-2alkyl)-portion of L1is bound directly to the phenyl;R3is selected from the group consisting of C3-5cycloalkyl, aryl, and 4 to 9 membered heterocyclyl; wherein the C3-5cycloalkyl aryl, or 4 to 9 membered heterocyclyl is optionally substituted with one or three substituent independently selected from the group consisting of halogen, hydroxy, oxo, Ci-2alkyl, fluoro substituted Ci-2alkyl, hydroxy substituted Ci-2alkyl, -O-(Ci-2alkyl), -(C1-2alkyl)-O-(Ci-2alkyl) and -NRERF;wherein REand RFare each independently selected from the group consisting of hydrogen and Ci-2alkyl;c is an integer from 0 to 3;each R4is independently selected from the group consisting of halogen, hydroxy, -CN, Ci-2alkyl, fluoro substituted Ci-2alkyl, hydroxy substituted Ci-2alkyl, -O-(Ci-2alkyl), -O-(fluoro substituted Ci-2alkyl), and -(C1-2alkyl)-O-(Ci-2alkyl);and (c) 9 to 11 membered benzo-fused carbocyclyl or 9 to 11 membered benzofused heterocyclyl; wherein the 9 to 11 membered benzo-fused carbocyclyl, or 9 to 11 membered benzo-fused heterocyclyl is bound through the benzo-fused portion;wherein the 9 to 11 membered benzo-fused carbocyclyl or 9 to 11 membered benzo-fused heterocyclyl is optionally substituted with one or four substituent independently selected from the group consisting of halogen, hydroxy, oxo, -CN, Ci-2alkyl, fluoro substituted Ci-2alkyl, hydroxy substituted Ci-2alkyl, -O-(Ci-2alkyl), -O-(fluoro substituted Ci-2alkyl), -(Ci-2alkyl)-O-(Ci-4alkyl), -(Ci-3alkyl)-C(O)OH, -(Ci-3alkyl)-C(O)O-(Ci-4alkyl), and -NRJRK;wherein RJand RKare 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, whereinR1is selected from the group consisting of(a) phenyl; wherein the phenyl is optionally substituted with one to four substituent independently selected from the group consisting of halogen, hydroxy, -CN, -NO2, Ci-3alkyl, fluoro substituted Ci-2alkyl, hydroxy substituted Ci-3alkyl, fluoro substituted C2.3alkenyl, -O-(Ci-3alkyl), -O-(fluoro substituted Ci-2alkyl), -(Ci-2alkyl)-OCH3, -C(O)-(Ci-2alkyl), -C(O)OH, -C(O)O-(Ci-2alkyl), -C(O)-NRARB, -NRARB, -(Ci-2alkyl)-NRARB, -NRA-C(O)-(Ci-2alkyl), -NHC(O)-(Ci-2alkyl)-NRARB, -NH-C(O)-(CH2)-NH-C(O)-(Ci-2alkyl), -CH(CN)-NRARB, and -CH(CN)-NH-C(O)-(Ci-2alkyl);wherein RAis selected from the group consisting of hydrogen, and Ci-2alkyl; and RBis selected from the group consisting of hydrogen, Ci-2alkyl, hydroxy substituted Ci-2alkyl, and -(Ci-2alkyl)-O-(Ci-2alkyl);l^J(Ll)b-R3(b) (R4)c; whereinb is an integer from 0 to 1;L1is selected from the group consisting of -(Ci-3alkyl)-, -(Ci-2alkyl)-O-, -O-(Ci-S02-; wherein RDis selected from the group consisting of hydrogen, and Ci-2alkyl;provided that when L1is -C(O)O-(Ci-2alkyl)-, -C(O)-NH-(Ci-3alkyl)-, -C(O)-NHthen the -C(O)- portion of L1is bound directly to the phenyl;provided further that when L1is -NRD-C(O)-(Ci-2alkyl)-, then the -NRD- portion of L1is bound directly to the phenyl;provided that when L1is -(Ci-2alkyl)-NRD-SO2-, then the -(Ci-2alkyl)- portion of L1is bound directly to the phenyl;R3is selected from the group consisting of C3-4cycloalkyl, aryl, and 4 to 9 membered heterocyclyl; wherein the C3-4cycloalkyl, aryl, or 4-9 membered heterocyclyl is optionally substituted with one or two substituent independently selected from the group consisting of halogen, hydroxy, oxo, Ci-2alkyl, fluoro substituted Ci-2alkyl, hydroxy substituted Ci-2alkyl, -O-(Ci-2alkyl), -(C1-2alkyl)-O-(Ci-2alkyl), and -NRERF;wherein REand RFare each independently selected from the group consisting of hydrogen and Ci-2alkyl;c is an integer from 0 to 2;each R4is independently selected from the group consisting of halogen, Ci-2alkyl, and hydroxy substituted Ci-2alkyl;and (c) 9 to 11 membered benzo-fused carbocyclyl or 9 to 11 membered benzofused heterocyclyl; wherein the 9 to 11 membered benzo-fused carbocyclyl, or 9 to 11 membered benzo-fused heterocyclyl is bound through the benzo-fused portion;wherein the 9 to 11 membered benzo-fused carbocyclyl and 9 to 11 membered benzo-fused heterocyclyl is optionally substituted with one or four substituent independently selected from the group consisting of halogen, hydroxy, oxo, -CN, Ci-2alkyl, -O-(Ci-2alkyl), -(C1-2alkyl)-O-(Ci-2alkyl), -(Ci-2alkyl)-C(O)OH, and -NRJRK;wherein RJand RKare each independently selected from the group consisting of hydrogen, and Ci-2alkyl;or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

4. A compound as in Claim 1, whereinR1is selected from the group consisting of981z681z061zor a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

5. A compound as in Claim 4, whereint76t7961zor a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

6. A compound as in Claim 4, wherein861z661zor a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

7. A compound as in Claim 4, whereinor 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 celllymphoma (MCL), lymphoplasmatic lymphoma, precursor B -lymphoblastic lymphoma, lymphoma of the central nervous system, small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia (CLL), precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma, sarcoma of the soft tissue, gliosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma, breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma.

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-1receptor 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) nonHodgkin'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), whereinwhereine is an integer from 0 to 3;each R6is independently selected from the group consisting of halogen, hydroxy, -CN, -NO2, Ci-4alkyl, hydroxy substituted Ci-4alkyl, fluoro substituted Ci-4alkyl, C2-4alkenyl, fluoro substituted C2-4alkenyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-4alkyl), -(C1-4alkyl)-O-(C1-4alkyl), -C(O)OH, -C(O)-(C1-4alkyl), -C(O)O-(C1-4alkyl), -C(O)-NRMRN, -NRMRN, -(C1-4alkyl)-NRMRN, -NH-C(O)-(C1-3alkyl)-NRMRN, -NH-C(O)-(C1-3alkyl)-NH-C(O)-(C1-4alkyl), -CH(CN)-NRMRN, and -CH(CN)-NH-C(O)-(C1-4alkyl);wherein RMis selected from the group consisting of hydrogen, and C1-4alkyl; and RNis selected from the group consisting of hydrogen, C1-4alkyl, hydroxy substituted C1-4alkyl, and -(C1-4alkyl)-O-(C1-4alkyl);R7is selected from the group consisting of C1-4alkyl, hydroxy substituted C1-4alkyl, fluoro substituted C1-4alkyl, -O-(C1-4alkyl), -(C1-4alkyl)-O-(C1-4alkyl), -(C1-4alkyl)-NRCRP, -SO2-(C1-2alkyl), C3-5cycloalkyl, 4 to 6 membered heterocycloalkyl, and -(C1-4alkyl)-(4 to 6 membered heterocycloalkyl);wherein RCand RPare each independently selected from the group consisting of hydrogen, and Ci-4alkyl;and wherein the C3-5cycloalkyl or 4 to 6 membered heterocycloalkyl, whether alone or as part of a substituent group, is optionally substituted with one or moresubstituents independently selected from the group consisting of halogen, hydroxy, -CN, C1-4alkyl, and fluorinated substituted C1-4alkyl;whereinf is an integer from 0 to 1;L2is selected from the group consisting of -(C1-4alkyl)-, -(fluorinated C1-4alkyl)-, -(C1-4alkyl)-NH- and -(C1-4alkyl)-O-;provided that when L2is -(Ci-4alkyl)-NH- or-(Ci-4alkyl)-O-, then the -NH- and -0- B )portion of L2is bound directly to;B )wherein is selected from the group consisting of Ce-scycloalkyl, aryl, and 5 to 7 membered heterocyclyl; wherein the C6-8cycloalkyl, aryl, or 5 to 7 membered heterocyclyl or is optionally substituted with one or more substituent independently selected from the group consisting of halogen, hydroxy, oxo, Ci-4alkyl, fluoro substituted Ci-4alkyl, -(Ci-4alkyl)-CN, -0-(Ci-4alkyl), -O-(fluoro substituted Ci-4alkyl), -C(0)-(Ci-4alkyl), -C(O)-CH=CH2, -C(=CH2)-CN, -NRQRR, -NRQC(O)-R10, and C3-5cycloalkyl;wherein each RQand RRis independently selected from the group consisting of hydrogen, and C1-4alkyl;and wherein R10is selected from the group consisting of Ci-4alkyl, halogen substituted Ci-2alkyl, C2-4alkenyl, C2-4alkynyl, and -CH=CH-CH2-NRSRT; wherein RSand RTare each independently selected from the group consisting of hydrogen, and Ci-2alkyl; alternatively, Rsand RTare taken together with the nitrogen atom to which they are bound to form pyrrolidin-1 -yl, piperidin-1 -yl, piperazin-1 -yl or morpholin-4-yl;or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

28. A compound as in Claim 27, whereine is an integer from 0 to 3;each R6is independently selected from the group consisting of halogen, hydroxy, -CN, Ci-2alkyl, hydroxy substituted Ci-2alkyl, fluoro substituted Ci-2alkyl, -O-(Ci-2alkyl), -O-(fluoro substituted Ci-2alkyl), and -(C1-2alkyl)-O-(Ci-2alkyl);R7is selected from the group consisting of Ci-2alkyl, hydroxy substituted Ci2alkyl, fluoro substituted Ci-2alkyl, -(C1-2alkyl)-O-(Ci-2alkyl), -O-(Ci-2alkyl), -(Ci-2alkyl)-NRCRP, -SO2-(Ci-2alkyl), C3-5cycloalkyl, 4 to 6 membered heterocycloalkyl, and -(C1-2alkyl)-(4 to 6 membered heterocycloalkyl); wherein RCand RPare each independently selected from the group consisting of hydrogen, and C1-2alkyl;wherein the C3-5cycloalkyl or 4 to 6 membered heterocycloalkyl, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-2alkyl, and fluorinated substituted Ci-2alkyl;; whereinf is an integer from 0 to 1;L2is selected from the group consisting of -(C1-2alkyl)-, -(fluorinated C1-2alkyl)-, -(C1-2alkyl)-N- and -(C1-2alkyl)-O-;provided that when L2is -(C1-2alkyl)-N- or -(C1-2alkyl)-O-, then the -N- and -O-portion of L2is bound directly towhereinis selected from the group consisting of Ce-scycloalkyl, phenyl, and 5 to 7 membered heterocyclyl; wherein the C6-8cycloalkyl, phenyl, or 5 to 7 membered heterocyclyl is optionally substituted with one or three substituent independently selected from the group consisting of halogen, hydroxy, oxo, Ci-3alkyl, fluoro substituted Ci-3alkyl, -(Ci-3alkyl)-CN, -O-(Ci-3alkyl), -O-(fluoro substituted Ci-3alkyl), -NRQRR, -C(0)-(Ci-3alkyl), -C(O)CH=CH2, -C(=CH2)CN, and -NRQC(O)-R10and C3-4cycloalkyl;wherein each RQand RRis independently selected from the group consisting of hydrogen, and C1-3alkyl;wherein R10is selected from the group consisting of halogen substituted C1-2alkyl, C2-3alkenyl, C2-3alkynyl, and -CH=CH-CH2-NRSRT; wherein RSand RTare each independently selected from the group consisting of hydrogen, and C1-2alkyl; alternatively, Rsand RTare taken together with the nitrogen atom to which they are bound to form pyrrolidin-1 -yl, piperidin-1 -yl, piperazin-1 -yl or morpholin-4-yl;or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

29. A compound as in Claim 27, whereine is an integer from 0 to 3;each R6is independently selected from the group consisting of halogen, hydroxy, Ci-2alkyl, hydroxy substituted Ci-2alkyl, and fluoro substituted Ci-2alkyl;R7is selected from the group consisting of Ci-2alkyl, hydroxy substituted Ci-2alkyl, fluoro substituted Ci-2alkyl, -(Ci-2alkyl)-O-(Ci-2alkyl), -O-(Ci-2alkyl), -(Ci-2alkyl)-NRCRP, -SO2-(Ci-2alkyl), C3-4cycloalkyl, 4 to 6 membered heterocycloalkyl, and -(Ci-2alkyl)-(6 membered heterocycloalkyl);wherein RCand RPare each independently selected from the group consisting of hydrogen, and Ci-2alkyl;wherein the C3-4cycloalkyl or 4 to 6 membered heterocycloalkyl, whether alone or as part of a substituent group, is optionally substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy, Ci-2alky I, and fluorinated substituted Ci-2alkyl;; whereinf is an integer from 0 to 1;L2is selected from the group consisting of -(Ci-2alkyl)-, and -(Ci-2alkyl)-O-; provided that when L2is -(Ci-2alkyl)-O-, then the -0- portion of L2is bounddirectlywhereinis selected from the group consisting of Ce-scycloalkyl, phenyl, and 5 to 7 membered heterocyclyl; wherein the C6-8cycloalkyl, phenyl, or 5 to 7 membered heterocyclyl is optionally substituted with one or three substituent independently selected from the group consisting of halogen, hydroxy, oxo, Ci-salkyl, fluoro substituted Ci-2alkyl, -(Ci-2alkyl)-CN, -O-(Ci-2alkyl), -O-(fluoro substituted Ci-2alkyl), -NRQRR, -C(O)-(Ci-2alkyl), -C(O)CH=CH2, -C(=CH2)CN, and -NRQ-C(O)-R10and cyclopropyl;wherein each RQand RRis independently selected from the group consisting of hydrogen, and Ci-3alkyl;wherein R10is selected from the group consisting of halogen substituted C1-2alkyl, C2-salkenyl, C2-salkynyl, and -CH=CH-CH2-NRSRT; wherein RSand RTare each independently selected from the group consisting of hydrogen, and Ci-2alkyl;or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

30. A compound as in Claim 27, whereine is an integer from 2 to 3;each R6is independently selected from the group consisting of -CH3, -CH2OH, and -CF3;R7is selected from the group consisting of -CH3, -CH2CH3, -CH2CH2OH, -or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

31. A compound as in Claim 30, whereine is an integer from 2 to 3;each R6is independently selected from the group consisting of -CH3, -CH2OH, and -CF3;R7is selected from the group consisting of -CH3, -CH2CH3, -CH2CH2OH, -or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

32. A compound as in Claim 30, whereine is an integer from 2 or 3;each R6is independently selected from the group consisting of -CH3, -CH2OH, and -CF3;R7is selected from the group consisting of -CH3, -CH2CH2OH, -CH2CH2-N(CH3)2,R8is selected from the group consistingor a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

33. A compound as in Claim 30, whereine is 2;each R6is methyl;R7is methyl;R8is selected from the group consistingor 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 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.

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) nonHodgkin'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-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)48. The compound of any one 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) nonHodgkin'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) colorectalcarcinoma, (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), whereinwhereine is and integer from 0 to 3;each R6is independently selected from the group consisting of halogen, hydroxy, -CN, -NO2, Ci-4alkyl, hydroxy substituted Ci-4alkyl, fluoro substituted Ci-4alkyl, C2-4alkenyl, fluoro substituted C2-4alkenyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-4alkyl), -(C1-4alkyl)-O-(C1-4alkyl), -C(O)OH, -C(O)-(C1-4alkyl), -C(O)O-(C1-4alkyl), -C(O)-NRMRN, -NRMRN, -(C1-4alkyl)-NRMRN, -NH-C(O)-(C1-3alkyl)-NRMRN, -NH-C(O)-(C1-3alkyl)-NH-C(O)-(C1-4alkyl), -CH(CN)-NRMRN, and -CH(CN)-NH-C(O)-(C1-4alkyl);wherein RMis selected from the group consisting of hydrogen, and C1-4alkyl; and RNis selected from the group consisting of hydrogen, C1-4alkyl, hydroxy substituted C1-4alkyl, and -(C1-4alkyl)-O-(C1-4alkyl);R12is selected from the group consisting of phenyl, C4-8cycloalkyl, and 4 to 10 membered heterocyclyl; wherein the phenyl, C4-8cycloalkyl, or 4 to 10 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, -CN, -NO2, Ci-4alkyl, hydroxy substituted Ci-4alkyl, fluoro substituted Ci-4alkyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-4alkyl), -C(O)-(Ci-4alkyl), -C(O)-(fluoro substituted Ci-4alkyl), -NRWRX, -(Ci-4alkyl)-NRwRx, -C(O)-NRWRX, -NRw-SO2-(Ci-4alkyl), -SO2-(Ci-4alkyl), -SO2-(fluorosubstituted Ci-4alkyl), -SO2-NRWRX, -S(O)(NH)(Ci-4alkyl), -SO2-(5 to 6 membered heterocycloalkyl) and P(O)(CH3)2;wherein Rwand Rxare each independently selected from the group consisting of hydrogen, and Ci-4alkyl;or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

53. A compound as in Claim 52, whereine is and integer from 2 to 3;each R6is independently selected from the group consisting of halogen, hydroxy, Ci-2alkyl, hydroxy substituted Ci-2alkyl, fluoro substituted Ci-2alkyl, -O-(Ci-2alkyl), and -O-(fluoro substituted Ci-2alkyl);R12is selected from the group consisting of C4-7cycloalkyl, phenyl, and 4 to 10 membered heterocyclyl; wherein the C4-7cycloalkyl, phenyl, or 4 to 10 membered heterocyclyl is optionally substituted with one to four substituents independently selected from the group consisting of halogen, hydroxy, oxo, -CN, -NO2, Ci-4alkyl, hydroxy substituted Ci-3alkyl, fluoro substituted Ci-3alkyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-3alkyl), -C(O)-(Ci-3alkyl), -C(O)-(fluoro substituted Ci-3alkyl), -NRWRX, -(Ci-3alkyl)-NRwRx, -C(O)-NRWRX, -NRw-SO2-(Ci-3alkyl), -SO2-(Ci-3alkyl), -SO2-(fluoro substituted Ci-3alkyl), -SO2-NRWRX, -S(O)(NH)(Ci-3alkyl), -SO2-(6 membered saturated heterocycloalkyl) and P(O)(CH3)2;wherein Rwand Rxare each independently selected from the group consisting of hydrogen, and Ci-3alkyl;or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

54. A compound as in Claim 52, whereine is and integer from 2 to 3;each R6is independently selected from the group consisting of hydrogen, and -CH3;R12is selected from the group consisting of C4-6cycloalkyl, phenyl, and 4 to 10 membered heterocyclyl; wherein the C4-6cycloalkyl, phenyl, or 4 to 10 membered heterocyclyl is optionally substituted with one to four substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, -CN, -NO2, Ci-4alkyl, hydroxy substituted Ci-2alkyl, fluoro substituted Ci-2alkyl, -O-(Ci-4alkyl), -O-(fluoro substituted Ci-2alkyl), -C(O)-(Ci-2alkyl), -C(O)-(fluoro substituted Ci-2alkyl), -N(CH3)2, -(Ci-2alkyl)-NH2, -C(O)-NH2, -C(O)-N(CH3)2, -NH-SO2-(Ci-2alkyl), -SO2-(Ci-3alkyl), -SO2-(fluoro substituted Ci-2alkyl), -SO2-NRWRX, -S(O)(NH)(Ci-2alkyl), -SO2-(6 membered saturated heterocycloalkyl), and P(O)(CH3)2;wherein Rwand Rxare each independently selected from the group consisting of hydrogen, and Ci-3alkyl;or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

55. A compound as in Claim 52, wheree is 2 or 3; each R6is methyl;R12is selected from the group consisting629or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

56. A compound as in Claim 55, whereine is 2 or 3; each R6is methyl;12R is se lected from the group consistingor a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

57. A compound as in Claim 55, whereine is 2 or 3; each R6is methyl;R12is selected from the group consistingor a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

58. A compound as in Claim 55, whereine is 2 or 3; each R6is methyl;R12is selected from the group consistingor 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 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).

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 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.

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) nonHodgkin'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 cancer mediated by the BFL-1 receptor is (a) AIDS-related lymphoma, (b) Hodgkin lymphoma, (c) nonHodgkin'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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