(phthalazin-3-yl)amine derivatives as BFL-1 inhibitors for the treatment of cancer

Abstract

The present invention is directed to (phthalazin-3-yl)amine derivatives of formula (I) as BFL-1 inhibitors for use in methods of treatment of leukemias, lymphomas and other cancers.

Description

PHTHALAZINE DERIVATIVES USEFULAS BFL-1 INHIBITORSCross-Reference to Related Applications.This application claims priority from United States Provisional Application Serial No. 63 / 706,801 filed October 14, 2024, the contents of which is incorporated by reference in its entirety.Field of the Invention

[0001] The present invention is directed towards phthalazine 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 related cancers.Background of the Invention

[0002] Non-Hodgkin lymphoma (NHL) is a heterogeneous group of malignancies, from B- or T-cell origin, accounting for about 4% of all malignancies in the US (Bibikova et al., Blood. 2019; 134 (Supplement^ : 2571). Worldwide, diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of NHL, accounting for 30% to 40% of all newly diagnosed cases (Sehn LH & Gascoyne RD, Blood. 2015;125(1):22- 32). DLBCL typically presents as an aggressive lymphoma, evolving over months and resulting in symptomatic disease that is fatal without treatment (Ibid).

[0003] Outcomes in DLBCL have improved dramatically over the last decade with the addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (R CHOP). This regimen remains the current standard of care. However, R CHOP treatment fails in about 30% to 50% of patients with DLBCL (Coiffier B & Sarkozy C,. Hematology Am Soc Hematol Educ Program. 2016;2016(1):366-378). Less than half of these patients can be cured with stem cell transplantation (Gisselbrecht et al., J Clin Oncol. 2010; 28(27): 4184-4190), and those who are not cured will typically die from their disease (Crump et al., Blood. 2017; 130(16): 1800-1808). Since the best chance for cure is front-line treatment, there have been many attempts to improve upon R CHOP but so far, these treatments have failed to significantly improve outcomes (Goy A., J Clin Oncol. 2017;35(31 ):3519-3522). Recently, several studies have explored theaddition 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 et al., 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.

[0004] 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.

[0005] Acute myelogenous leukemia (AML) is a clonal disease of the blood and bone marrow resulting from mutations that occur in normal hematopoietic stem cells. AML is a heterogenous disease in that it presents with a range of cytogenetic, morphological and immunophenotypic features, and is characterized by an accumulation of clonal, abnormal myeloid progenitor cells, known as myeloblasts. These cells demonstrate disruption of normal myeloid differentiation and excessive proliferation, resulting in the decreased formation of hematopoietic cells. Disease remission can be achieved with standard induction chemotherapy, but refractory and relapsed disease remains a challenge due to persistence of leukemic stem cells. Patients refractory to salvage therapy are treated pal liati vely , as current treatment options are extremely limited. These patients have a median survival of 2 months. Therefore, AML represents an unmet medical need with >20,000 new cases per year in the US with 5-year overall survival below 30% (Stein ET et al., Health Qual Life Outcomes. 2018; 16: 193).

[0006] 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, newlydiagnosed AML patients ineligible for induction chemotherapy based on age and comorbidities, and newly diagnosed intermediate / high / very high risk MDS patients.

[0007] Intrinsic apoptosis (programmed cell death) is regulated by the B Cell lymphoma 2 (BCL-2) protein family. Anti-apoptotic family members sequester their pro- apoptotic counterparts through a highly conserved BH3 binding groove. Disruption of this balance will lead to mitochondrial pore formation and subsequent cell death. To evade apoptosis, tumors often upregulate the expression of one or more anti-apoptotic family members. As such anti-apoptotic family members have become attractive targets for anti-cancer drug development. The most advanced small molecule inhibitor targeting the anti-apoptotic protein BCL-2, Venetoclax, effectively improves clinical outcomes in newly diagnosed, relapsed and refractory acute myeloid leukemia (AML) patients, with complete response rates (with and without complete blood count recovery) ranging between 34-90% and 21-33%, respectively. (Griffioen et al., Cancers. 2022; 14 (14): 3456)

[0008] BFL-1 (‘Bcl-2 related gene expressed in fetal liver’ (Choi et al., Oncogene. 1995; 11 : 1693-1698), gene name BCL2A1 (B-cell lymphoma 2-related protein A1)) is a lesser-known anti-apoptotic family member, physiologically mainly expressed in the hematopoietic system. BFL-1 was found to be a direct transcriptional target of nuclear factor-KB (NF-KB) (Lee et al., PNAS. 1999; 96: 9136-9141). Two BFL-1 isoforms are reported; the full length BFL-1 containing 175 amino acids and a shorter 163 amino acids BFL-1 isoform (as a result of alternative splicing of the BFL-1 gene), BFL-1 S, predominantly expressed in the lymph nodes (Ko et al., Oncogene. 2003; 22: 2457- 2465).

[0009] In comparative transcriptome analysis of acute myeloid leukaemia (AML) patient samples, BCL2A1 (BFL-1) was identified as the most differentially expressed gene, enriched in samples resistant to Venetoclax treatment (Zhang et al., Nature Cancer. 2020; 1 : 826-839 & Bisaillon et al., Leukemia. 2020; 34: 63-74).

[0010] BFL-1 overexpression has been reported in many types of B cell lymphoma. Diffuse large B cell lymphoma (DLBCL) patient sample analysis shows, with regards to expression of anti-apoptotic family members, expression levels of BFL-1 are second only to MCL-1 (Reddy et al., Cell. 2017; 171 , 481-494). Expression of BFL-1 wasshown to be upregulated in MYC / BCL2 double hit lymphoma cell lines treated with Venetoclax / n vivo (Esteve-Arenys et al., Oncogene. 2018; 37: 1830-1844). BFL-1 positive lymphomas are also shown to be less sensitive to inhibition of BCL-2 and MCL- 1 (Boiko et al., Blood. 2021 ; 137 (21): 2947-2957). Targeting BFL-1 is therefore a possible strategy for the treatment of cancers such as AML, MDS, and DLBCL.

[0011] There remains a need for inhibitors of the BFL-1 protein, which may be useful for the treatment of cancer, more particularly for the treatment of leukemias and related cancers.Summary of the InventionThe present invention is directed to compounds of Formula (I)or a pharmaceutically acceptable salt or stereoisomer thereof, wherein 0HOyNHR1is selected from: H, -C(OH)(Ci-4alkyl)2, -C(=O)NH-Ci-4alkyl, or ~-L ;R2is selected from: phenyl, benzyl, pyridyl, or py rimidinyl , wherein each phenyl, benzyl, pyridyl, or pyrimidinyl is substituted with one, two or three members each independently selected from fluorinated-Ci-4alkyl, O-fluorinated-Ci-4alkyl, NH2, andL is absent or CH2;R3is phenyl substituted with two or three Ci-4alkyl members; andR4is selected from:

[0012] The present invention is further directed to processes for the preparation of the compounds of Formula (I). The present invention is further directed to a product prepared according to the process described herein.

[0013] The present invention is further directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product prepared according to any of the process(es) described herein. The present invention is further directed to a pharmaceutical composition made by mixing the product prepared according to any of the process(es) described herein and a pharmaceutically acceptable carrier. The present invention is further directed to a process for making a pharmaceutical composition comprising mixing the product prepared according to any of the process(es) described herein and a pharmaceutically acceptable carrier.

[0014] Exemplifying the invention are methods of treating a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein 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.

[0015] Exemplifying the invention are methods of treating a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein 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 CellLymphoma (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.

[0016] In an embodiment, the present invention is directed to a compound of Formula (I) for use as a medicament. In another embodiment, the present invention is directed to a compound of Formula (I) for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein 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)).

[0017] In another embodiment, the present invention is directed to a compound of Formula (I) for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein 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).

[0018] In another embodiment, the present invention is directed to a composition comprising a compound of Formula (I) for the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein 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)).

[0019] In another embodiment, the present invention is directed to a composition comprising a compound of Formula (I) for the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein 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 celllymphoma, 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).

[0020] 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.

[0021] 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.

[0022] 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 protein, wherein the cancer mediated by the BFL-1 protein 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.

[0023] 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 protein, wherein the cancer mediated by the BFL-1 protein is a lymphoma selected from the group consisting of AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), subtypes of NHL such as Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell DLBCL, double-hit lymphoma and double-expressor lymphoma; anaplastic large cell lymphoma, marginal B cell lymphoma and primary mediastinal B-cell lymphoma, immunoblastic large cell lymphoma, Burkitt lymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoplasmatic lymphoma, precursor B -lymphoblastic lymphoma, lymphoma of the central nervous system, small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL); T-cell NHL suchas 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.

[0024] The present invention is further directed to processes for the preparation of the compounds of Formula (I). The present invention is further directed to a product prepared according to the process described herein.

[0025] The present invention is further directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (I) as described herein. The present invention is further directed to a pharmaceutical composition made by mixing a compound of formula (I) as described herein and a pharmaceutically acceptable carrier. The present invention is further directed to a process for making a pharmaceutical composition comprising mixing a compound of formula (I) as described herein and a pharmaceutically acceptable carrier.Detailed Description of the InventionThe present invention is directed to compounds of Formula (I)wherein R1, R2, R3, R4, and L, are as herein defined. The compounds of the present invention are useful for the treatment of disorders and diseases or conditions mediatedby the BFL-1 protein, including, but not limited to leukemias, lymphomas and related cancers.

[0026] Additional embodiments of the present invention, include those wherein the substituents selected for one or more of the variables defined herein (i.e. R1, R2, R3, R4, and L) are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein.

[0027] In another embodiment of the present invention is any single compound or subset of compounds selected from the representative compounds listed in Table 1 below.

[0028] Representative compounds of Formula (I) of the present invention are as listed in Table 1 below. Unless otherwise noted, wherein a stereogenic center is present in the listed compound, the compound was prepared as a mixture of stereoconfigurations. Wherein the compound contains at least one stereocenter, and the compound was prepared in a stereogenic excess of a specific stereoisomer, the *S- and *R- designations in are intended to indicate that the exact stereo-configuration of the center has not been determined. Wherein the compound contains at least one stereocenter, and the compound was prepared in a stereogenic excess of a specific stereoisomer, the S- and R- designations in are intended to indicate that measured stereo-configuration of the center.

[0029] Certain examples contain chemical structures that are depicted or labelled as an (*R) or (*S When (*R) or (*S) is used in the name of a compound or in the chemical representation of the compound, it is intended to convey that the compound is a pure single isomer at that stereocenter; however, absolute configuration of that stereocenter has not been established. For example, [(4*R)-3,3-Difluoro-4-(6- methylsulfonyl-3-pyridyl)-1 -pi peridy l]-[1 -[[(1 R)-2-hydroxy-2-methyl-1 -[[4- (trifluoromethyl)phenyl]methyl]propyl]amino]-7-(2,3,6-trimethylphenyl)phthalazin-5- yl]methanone:

[0031] 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 of Table 1 , below.

[0032] Table 1 : Representative Compounds for Formula (I)0033] and stereoisomers, and pharmaceutically acceptable salts thereof.

[0034] In certain embodiments, the present invention is directed to one or more compounds of Formula (I) independently selected from the group consisting ofacceptable salts thereof.

[0035] In certain embodiments, the present invention is directed to compounds ofFormula (I), wherein R2is

[0036] In certain embodiments, the present invention is directed to compounds ofFormula (I), wherein

[0037] In certain embodiments, the present invention is directed to compounds of Formula (I), wherein L is absent.

[0038] In certain embodiments, the present invention is directed to compounds of Formula (I), wherein L is CH2.

[0039] In certain embodiments, the present invention is directed to compounds of Formula (I), wherein R1is H.

[0040] In certain embodiments, the present invention is directed to compounds of Formula (I), wherein R1is -C(OH)(CHs)2.

[0041] In certain embodiments, the present invention is directed to compounds of Formula (I), wherein R1is -C(=O)NH-CHs.

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

[0043] In certain embodiments, the present invention is directed to compounds of Formula (I), which, when tested for BFL-1 protein inhibition according to the procedure as described in Biological Example 1 , which follows hereinafter, exhibit a Ki of less than or equal to about 1 pM, preferably less than or equal to about 100 nM, more preferably less than or equal to about 10 nM, more preferably less than or equal to about 1 nM.AspectsAspect 1 . A compound of Formula (I),whereinR1is selected from:R2is selected from: phenyl, benzyl, pyridyl, or py rimidinyl , wherein each phenyl, benzyl, pyridyl, or pyrimidinyl is substituted with one, two or three members each independently selected from fluorinated-Ci-4alkyl, O-fluorinated-Ci-4alkyl, NH2, andS 'NO2; or -J- ;L is absent or CH2;R3is phenyl substituted with two or three Ci-4alkyl members; andR4is selected from:stereoisomer or pharmaceutically acceptable salt thereof.Aspect 2. A compound as in Aspect 1 , wherein R2isor a stereoisomer or pharmaceutically acceptable salt thereof.Aspect 3. A compound as in Aspect 1 , whereinor a stereoisomer or pharmaceutically acceptable salt thereof.Aspect 4. A compound as in Aspect 1 , wherein L is absent; or a stereoisomer or pharmaceutically acceptable salt thereof.Aspect 5. A compound as in Aspect 1 , wherein L is CH2; or a stereoisomer or pharmaceutically acceptable salt thereof.Aspect 6. A compound as in Aspect 1 , wherein R1is H; or a stereoisomer or pharmaceutically acceptable salt thereof.Aspect 7. A compound as in Aspect 1 , wherein R1is -C(OH)(CHs)2; or a stereoisomer or pharmaceutically acceptable salt thereof.Aspect 8. A compound as in Aspect 1 , wherein R1is -C(=O)NH-CHs; or a stereoisomer or pharmaceutically acceptable salt thereof.Aspect 9. A compound as in Aspect 1 , wherein L is CH2 and R4isstereoisomer or pharmaceutically acceptable salt thereof.Aspect 10. A compound selected from the group consisting of:[7-(2,5-Dimethylphenyl)-1-[2-[4-(trifluoromethyl)phenyl]ethylamino]phthalazin-5- yl]-[4-(4-methylsulfonylphenyl)piperazin-1-yl]methanone;[1 -[[(1 R)-2-Hydroxy-2-methyl-1 -[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]-7-(2,3,6-trimethylphenyl)phthalazin-5-yl]-[4-(methylsulfonylmethyl)-1 - piperidyl]methanone;[1 -[[(1 R)-2-Hydroxy-2-methyl-1 -[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]- 7-(2,3,6-trimethylphenyl)phthalazin-5-yl]-[4-(4-methylsulfonylphenyl)piperazin-1- yl]methanone;[1 -[[(1 R)-2-Hydroxy-2-methyl-1 -[[6-(trifluoromethyl)-3- pyridyl]methyl]propyl]amino]-7-(2,3,6-trimethylphenyl)phthalazin-5-yl]-[4-(4- methylsulfonylphenyl)piperazin-1-yl]methanone;[(4*R)-3,3-Difluoro-4-(6-methylsulfonyl-3-pyridyl)-1 -pi peridy l]-[ 1 -[[(1 R)-2-hydroxy- 2-methyl-1-[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]-7-(2,3,6- trimethylphenyl)phthalazin-5-yl]methanone;[(4*S)-3,3-Difluoro-4-(6-methylsulfonyl-3-pyridyl)-1 -piperidy l]-[ 1 -[[(1 R)-2-hydroxy- 2-methyl-1-[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]-7-(2,3,6- trimethylphenyl)phthalazin-5-yl]methanone;(*R)-N-Methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1-carbonyl]-7-(2,3,6- trimethylphenyl)phthalazin-1-yl]amino]-2-[4-(trifluoromethoxy)phenyl]acetamide;(*S)-N-Methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1-carbonyl]-7-(2,3,6- trimethylphenyl)phthalazin-1-yl]amino]-2-[4-(trifluoromethoxy)phenyl]acetamide;(*R)-N-Methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1-carbonyl]-7-(2,3,6- trimethylphenyl)phthalazin-1-yl]amino]-2-[2-(trifluoromethyl)pyrimidin-5-yl]acetamide;(*S)-N-Methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1-carbonyl]-7-(2,3,6- trimethylphenyl)phthalazin-1-yl]amino]-2-[2-(trifluoromethyl)pyrimidin-5-yl]acetamide;(*R)-3-((1*S,3*S,6*R)-7,7-Difluorobicyclo[4.1.0]heptan-3-yl)-N-methyl-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1- yl)amino)propenamide;(*S)-3-((1*S,3*S,6*R)-7,7-Difluorobicyclo[4.1.0]heptan-3-yl)-N-methyl-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1- yl)amino)propenamide;(*R)-3-((1*R,3*R,6*S)-7,7-Difluorobicyclo[4.1.0]heptan-3-yl)-N-methyl-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1- yl)amino)propenamide;(*S)-3-((1 *R,3*R,6*S)-7,7-Difluorobicyclo[4.1 ,0]heptan-3-yl)-N-methyl-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1- yl)amino)propenamide;(R)-2-((5-((*S)-3,3-Difluoro-4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1- carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propenamide;(R)-2-((5-((*R)-3,3-Difluoro-4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1- carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propenamide;(2R)-N-Methyl-2-[[5-[4-(6-methylsulfonyl-3-pyridyl)piperidine-1-carbonyl]-7-(2,3,6- trimethylphenyl)phthalazin-1-yl]amino]-3-[2-(trifluoromethyl)pyrimidin-5-yl]propenamide;(R)-2-((5-((*S)-2,2-Dioxidooctahydropyrazino[2, 1 -c][1 ,4]thiazine-8-carbonyl)-7- (2,3,6-trimethylphenyl)phthalazin-1-yl)amino)-N-methyl-3-(2-(trifluoromethyl)pyrimidin-5- yl)propenamide;(R)-2-((5-((*R)-2,2-Dioxidooctahydropyrazino[2,1-c][1 ,4]thiazine-8-carbonyl)-7- (2,3,6-trimethylphenyl)phthalazin-1-yl)amino)-N-methyl-3-(2-(trifluoromethyl)pyrimidin-5- yl)propenamide;(2R)-N-Methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1-carbonyl]-7-(2,3,6- trimethylphenyl)phthalazin-1-yl]amino]-3-[6-(trifluoromethyl)-3-pyridyl]propenamide;(2R)-3-[3-Amino-4-(trifluoromethyl)phenyl]-N-methyl-2-[[5-[4-(4- methylsulfonylphenyl)piperazine-1-carbonyl]-7-(2,3,6-trimethylphenyl)phthalazin-1- yl]amino]propenamide;(2R)-N-Methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1-carbonyl]-7-(2,3,6- trimethylphenyl)phthalazin-1-yl]amino]-3-[2-nitro-4-(trifluoromethyl)phenyl]propenamide;(R)-3-(2-Amino-4-(trifluoromethyl)phenyl)-N-methyl-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1- yl)amino)propenamide;(R)-N-((1 r,3R)-3-Hydroxy-3-methylcyclobutyl)-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1- yl)amino)-3-(4-(trifluoromethyl)phenyl)propenamide; and(R)-N-((1s,3S)-3-Hydroxy-3-methylcyclobutyl)-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1 - yl)amino)-3-(4-(trifluoromethyl)phenyl)propenamide; or a stereoisomer or pharmaceutically acceptable salt thereof.Aspect 11 . A compound selected from the group consisting of:acceptable salt thereof.Aspect 12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Aspect 1 .Aspect 13. A pharmaceutical composition made by mixing a compound of Aspect 1 and a pharmaceutically acceptable carrier.Aspect 14. A process for making a pharmaceutical composition comprising mixing a compound of Aspect 1 and a pharmaceutically acceptable carrier.Aspect 15. A method of treating a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is a leukemia or a lymphoma, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of Aspect 1.Aspect 16. The method of Aspect 15, 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).Aspect 17. The method of Aspect 15, wherein the leukemia is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).Aspect 18. The method of Aspect 15, 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.Aspect 19. The method of Aspect 15, wherein the lymphoma is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).Aspect 20. The use of the compound of Aspect 1 for the preparation of a medicament for the treatment a cancer mediated by the BFL-1 protein, wherein the cancer mediate by the BFL-1 protein is (a) a leukemia, or (b) a lymphoma, in a subject in need thereof.Aspect 21 . The use as in Aspect 20, 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).Aspect 22. The use as in Aspect 20, 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.Aspect 23. The compound of Aspect 1 , for use in a method for the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is (a) a leukemia or (b) a lymphoma, in a subject in need thereof.Aspect 24. The compound of Aspect 1 , for use in a method for the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein 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)Aspect 25. The compound of Aspect 1 , for use in a method for the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1protein 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.Aspect 26. The compound of Aspect 1 , for use as a medicament.Aspect 27. The compound of Aspect 1 , for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is (a) a leukemia or (b) a lymphoma, in a subject in need thereof.Aspect 28. The compound of Aspect 1 , for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein 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)Aspect 29. The compound of Aspect 1 , for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein 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.Aspect 30. A composition comprising a compound of Aspect 1 , for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is (a) a leukemia or (b) a lymphoma.Aspect 31 . A composition comprising a compound of Aspect 1 , for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein 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)Aspect 32. A composition comprising a compound of Aspect 1 , for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein 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.Aspect 33. A compound, composition, method of treatment or method of preparation as herein described.Definitions and Abbreviations

[0044] Abbreviations used in the specification, for example in the Schemes, Synthesis Examples and Biological Examples, are as listed in the Table 2, below:Table 2: Abbreviations

[0045] As used herein, unless otherwise noted, “halogen” shall mean chloro, bromo, fluoro and iodo, preferably bromo, fluoro or chloro, more preferably fluoro or chloro.

[0046] As used herein, unless otherwise noted, the term “Cx-yalkyl” wherein X and Y are integers, whether used alone or as part of a substituent group, include straight and branched chains containing between X and Y carbon atoms. For example, Ci -4alky I radicals include straight and branched chains of between 1 and 4 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl.

[0047] As used herein, unless otherwise noted, the term “fluorinated-Cx-Yalkyl” shall mean any Cx-yalkyl group as defined above substituted with one or more fluoro groups, preferably one to three fluoro group. Suitably examples include, but are not limited to - CH2F, CHF2, -CF3, -CH2-CF3, -CF2-CH3, -CH2-CH2-CH2F, -CH2-CH2-CF3, -C(CH3)2CF3, -C(CFS)3, and the like.

[0048] As used herein, unless otherwise noted, the term “Cx-vcycloalkyl”, wherein X and Y are integers, shall mean any stable X- to Y-membered monocyclic, bicyclic, polycyclic, bridged, or spiro-cyclic saturated ring system, preferably a monocyclic, bicyclic, bridged or spiro-cyclic saturated ring system. For example, “Cs-scycloalkyl” refers to a cycloalkyl having from 3 to 8 carbon atoms in the ring(s), “Cs-ecycloalkyl” refers to a cycloalkyl having from 3 to 6 carbon atoms in the ring, “C3-4cycloalkyl” refers to a cycloalkyl having from 3 to 4 carbon atoms in the ring. The term "cycloalkyl" also encompasses cycloalkyl group, as defined above, which has been fused to a benzene ring. Examples of cycloalkyl groups include the following entities, in the form of properly bonded moieties:, and the like.

[0049] As used herein, the term “phenyl” represents the following moiety:As used herein, the term “benzyl” represents the following moiety:As used herein, the term “pyridyl” represents the following moiety:As used herein, the term “pyrimidinyl” represents the following moiety:

[0053] When a particular group is "substituted" (e.g. Cx-yalkyl, aryl, 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.

[0054] Lines drawn into ring systems indicate that the bond may be attached to any of the suitable and available ring atoms. The term “variable point of attachment” means that a group is allowed to be attached at more than one alternative position in a structure. The attachment will always replace a hydrogen atom on one of the ring atoms. In other words, all permutations of bonding are represented by the single diagram, as shown in the illustrations below.

[0055] Those skilled in the art will recognize that if more than one such substituent is present for a given ring, the bonding of each substituent is independent of all of the others. The groups listed or illustrated above are not exhaustive.

[0056] One skilled in the art will further recognize that in the chemical structures provided herein, a methyl substituent group may be denoted as “Me or as “ ”. For example, a 4-methyl-pyridin-2-yl substituent may be drawn asrespectively.

[0057] One skilled in the art will recognize that any of the compounds of Formula (I) 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) orcommon organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.

[0058] In some embodiments, the present invention is directed to pharmaceutically acceptable salts of the compounds of Formula (I).

[0059] For use in medicine, the salts of the compounds of the present invention refer to non-toxic “pharmaceutically acceptable salts”. Other salts may, however, be useful in the preparation of the compounds of the present invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.

[0060] 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.

[0061] Representative acids which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: acidsincluding acetic acid, 2, 2 -di chloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, (+)-camphonc acid, camphorsulfonic acid, (+)-(1 S)-camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1 ,2-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-tartanc acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid.

[0062] 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.

[0063] It is further intended that the present invention includes the compounds of Formula (I), described herein, including all isomers thereof (including, but not limited to stereoisomers, enantiomers, diastereomers, tautomers, isotopologues, isotopomers, and the like).

[0064] As used herein, the symbol or notation shall denote the presence of a stereogenic center.

[0065] 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.

[0066] 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%

[0067] As used herein, unless otherwise noted, the term “isotopologues” shall mean molecules that differ only in their isotopic composition. More particularly, an isotopologue of a molecule differs from the parent molecule in that it contains at least one atom which is an isotope (i.e. has a different number of neutrons from its parent atom). For example, isotopologues of water include, but are not limited to, "light water" (HOH or H2O), "semi-heavy water" with the deuterium isotope in equal proportion to protium (HDO or1H2HO), “heavy water” with two deuterium isotopes of hydrogen per molecule (c / 2O or2H2O), "super-heavy water" or tritiated water (T2O or3H2O), where the hydrogen atoms are replaced with tritium (3H) isotopes, two heavy-oxygen waterisotopologues (H218O and H217O) and isotopologues where the hydrogen and oxygen atoms may each independently be replaced by isotopes, for example the doubly labeled water isotopologue c / 218O.

[0068] As used herein, unless otherwise noted, the term “isotopomer” shall mean isomers with isotopic atoms, having the same number of each isotope of each element but differing in their position. Isotopomers include both constitutional isomers and stereoisomers solely based on isotopic location. For example, CHsCHDCHsand CH3CH2CH2D are a pair of constitutional isotopomers of n-propane; whereas (R)- CH3CHDOH and (S)-CH3CHDOH or (Z)-CH3CH=CHD and (E)-CH3CH=CHD are examples of isotopic stereoisomers of ethanol and n-propene, respectively.

[0069] The present invention is further directed to compounds of Formula (I) 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 isotopical ly enriched form. For example, a reference to hydrogen includes within its scope1H,2H (D), and3H (T). Similarly, references to carbon and oxygen include within their scope respectively12C,13C and14C and16O and18O. The isotopes may be radioactive or non-radioactive. Radiolabelled compounds of Formula (I) may comprise one or more radioactive isotope(s) selected from the group of3H,11C,18F,122l,123l,125l,1311,75Br,76Br,77Br and82Br. Preferably, the radioactive isotope is selected from the group of3H,11C and18F.

[0070] 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.

[0071] 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.

[0072] As used herein, unless otherwise noted, the term “substantially free of a corresponding salt form(s)” when used to described a compound of the present invention shall mean that mole percent of the corresponding salt form(s) in the isolated free acid or free base of said compound, is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably less than about 0.1 mole percent. In an embodiment of the present invention, the compound of Formula (I) is present in a form which is substantially free of corresponding salt form(s).General Synthesis SchemesSCHEME 1

[0073] According to SCHEME 1 , methyl 5-bromo-2-(bromomethyl)-3-iodobenzoate is commercially available or is prepared in two steps from methyl 3-amino-5-bromo-2- methylbenzoate employing methods known to one skilled in the art or as described in WO201 9148005. Methyl 5-bromo-2-formyl-3-iodobenzoate is commercially available or prepared by reacting methyl 5-bromo-2-(bromomethyl)-3-iodobenzoate with N- methylmorpholine N-oxide (NMO), in a suitable solvent such as ACN, and the like. Methyl 5-bromo-2-formyl-3-iodobenzoate is cyclized employing NaOH, in a suitable solvent such as MeOH / water to provide 6-bromo-3-hydroxy-4-iodoisobenzofuran-1 (3H)- one. 6-Bromo-3-hydroxy-4-iodoisobenzofuran-1 (3H)-one is reacted with hydrazine hydrate, in a suitable solvent such as EtOH, and the like; to provide 7-bromo-5- iodophthalazin-1-ol (in a similar manner, 5-bromo-7-iodophthalazin-1-ol is prepared from methyl 3-bromo-5-iodo-2 -methylbenzoate). Palladium-catalyzed cyanation of 7-bromo-5-iodophthalazin-1-ol is achieved employing zinc cyanide as the nucleophile, Pd(PPhs)4, in a suitable solvent such as DMF, at a temperature of about 80 °C, for a period of 2 hrs, to provide 7-bromo-1 -hydroxyphthalazine-5-carbonitrile. Hydrolysis of 7- bromo-1-hydroxyphthalazine-5-carbonitrile employing a suitable base such as NaOH, LiOH, and the like; in a suitable solvent such as water, THF, MeOH, ethanol (EtOH), or a mixture thereof; at 100 °C, for a period of 2 hrs; provides 7-bromo-1- hydroxyphthalazine-5-carboxylic acid. In a similar manner, 5-bromo-7-iodophthalazin-1- ol is prepared from methyl 3-bromo-5-iodo-2-methylbenzoate.SCHEME 2

[0074] According to SCHEME 2, 7-bromo-1-hydroxyphthalazine-5-carboxylic acid is esterified under Fischer esterification conditions such as a suitable acid such as H2SO4, in a suitable solvent such as MeOH, and the like, to afford methyl 7-bromo-1- hydroxyphthalazine-5-carboxylate. Methyl 7-bromo-1 -hydroxyphthalazine-5-carboxylate is reacted in a metal-mediated cross coupling reaction with a commercially available or synthetically accessible appropriately substituted aryl boronic acid of formula R3-B(OH)2 (or pinacol boronic ester and boronate ester), where R3is as defined in claim 1 ; in the presence of a palladium catalyst such as Pd-118, PdCl2(dtbpf), Pd(PPhs)4, b / s(triphenylphosphine)palladium(l l)chloride (PdCl2(PPh3)2), bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex withdichloromethane, (2-dicyclohexylphosphino-2',6'-diisopropoxy-1 , 1 '-biphenyl)[2-(2'- amino-1 , 1 '-biphenyl)]palladium(l I) methanesulfonate (RuPhos Pd G3), [1 ,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (Pd(dppf)Cl2), XPhos Pd G2, Pd(dppf)Cl2, CataXCiumA Pd G3, and the like; a base such as KF, K3PO4, aq. Na2COs, CS2CO3, and the like; in a suitable solvent such as 1 ,4-dioxane, dimethylformamide (DMF), acetonitrile (ACN), water, or a mixture thereof; at temperatures ranging from 60 to 120 °C; for a period of about 16 to 48 hours to provide a compound of formula (V).

[0075] In an alternate method 5-bromo-7-iodophthalazin-1-ol is reacted in a Suzuki coupling as previously described with a compound of formula (IV) to provide a compound of (X). A compound of formula (X) is reacted under palladium-catalyzed carbonylation conditions using a suitable palladium catalyst such as [1 ,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (PdCl2(dppf)), and the like; in a suitable solvent such as methanol and the like; under an atmosphere of carbon monoxide; to provide a compound of formula (VIII). Saponification of the ester compound of formula (VIII) to the acid compound of formula (V) is achieved employing conditions known to one skilled in the art. For example, employing a suitable base such as NaOH, LiOH, and the like; in a suitable solvent such as water, THF, methanol (MeOH), or a mixture thereof; at room temperature; for a period of about 1 -3 h.SCHEME 3

[0076] According to SCHEME 3, an optionally substituted 4-8 membered cyclic amine such as piperidine, piperazine, and the like; is reacted under Pd-catalyzed amination conditions with an optionally substituted aryl halide such as 1 -bromo-4- (methylsulfonyl)benzene. For example, piperazine is reacted with 1 -bromo-4- (methylsulfonyl)benzene; a palladium catalyst such as Pd2(dba)s, Pd(OAc)2, and the like; a ligand such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), or (±)-2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthalene (rac-BINAP); a base such asCS2CO3, LHMDS, NaOtBu, K3PO4, and the like; in a suitable solvent such as toluene, THF, DMF, dioxane, or a mixture thereof; at temperatures ranging from 80-150 °C, employing microwave or conventional heating; for a period of 0.5 h to 18 h; to provide 1- (4-(methylsulfonyl)phenyl)piperazine.SCHEME 4

[0077] According to SCHEME 4, 5-bromo-2-(methylsulfonyl)pyridine is reacted in a palladium catalyzed metal mediated cross coupling reaction as previously described with an appropriately substituted boronic acid such as terf-butyl 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2 / - / )-carboxylate to provide terf-butyl 6- (methylsulfonyl)-3',6'-dihydro-[3,4'-bipyridine]-1 '(2' / - / )-carboxylate. terf-Butyl 6- (methylsulfonyl)-3',6'-dihydro-[3,4'-bipyridine]-1 '(2'H)-carboxylate is reacted under hydrogenation conditions with a platinum catalyst such as wet PtC ; in a suitable solvent such as MeOH; in the presence of HCI, under a balloon of H2; at room temperature; for a period of 12-18 hours; to provide 2-(methylsulfonyl)-5-(piperidin-4- yl)pyridine.SCHEME 5

[0078] According to SCHEME 5, tert-butyl 3,3-difluoro-4-oxopiperidine-1 - carboxylate is reacted with a mild triflating agent such as N- phenylbis(trifluoromethanesufonimide) (Tf2NPh), a base such as NaH, TEA, DIEA, and the like, in a suitable solvent such as THF, DCM, and the like; to provide tert-butyl 3,3- difluoro-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1 (2 / - / )-carboxylate. Tert-Butyl 3,3-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1 (2 / - / )- carboxylate is reacted in a metal-mediated cross coupling reaction as previously described, with a commercially available or synthetically accessible appropriately substituted heteroaryl boronic acid such as (6-(methylsulfonyl)pyridin-3-yl)boronic acid, to provide tert-buty I 3', 3'-difluoro-6-(methy Isulfony l)-3' , 6'-dihydro-[3 ,4'-bi py ridi ne]-1 '(2' / - / )- carboxylate. Tert-Butyl 3',3'-difluoro-6-(methylsulfonyl)-3',6'-dihydro-[3,4'-bipyridine]- 1 '(2' / - / )-carboxylate is reduced under hydrogenation conditions known to one skilled in the art, for example, using catalyst such as Pd / C or the like; in a suitable solvent such as THF, MeOH, EtOAc or a mixture thereof; under an atmosphere of hydrogen for a period of 4-24 h; to provide tert-butyl 3,3-difluoro-4-(6-(methylsulfonyl)pyridin-3- yl)piperidine-1 -carboxylate. Deprotection of the BOC group is achieved according to procedures known to one skilled in the art and employing established methodologies, such as those described in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 3 ed., John Wiley & Sons, 1999, pgs 518-525. For example, deprotection under acidic conditions such as trifluoroacetic acid (TFA) / CH2Cl2, HCI / Dioxane, and the like, at room temperature for a period of 2 h, provides 5-(3,3- difluoropiperidin-4-yl)-2-(methylsulfonyl)pyridine.SCHEME 6

[0079] According to SCHEME 6, a compound of formula (VI) is prepared by conventional amide bond forming techniques such as coupling reactions which are well known to those skilled in the art. For example, reaction of a compound of formula (V) where R3is phenyl substituted with two or three Ci-4alkyl members; with a commercially available or synthetically accessible amine as described in the SCHEMES above; a suitable coupling agent such as / \ / , / \ / W'W-tetramethyl-O-(1 / - / -benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), 1-[bis(dimethylamino)methylene]-1 / - / -1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 2,4,6-tripropyl-1 , 3, 5, 2,4,6- trioxatriphosphorinane-2,4,6-trioxide (T3P®), TCFH, and the like; in a suitable solvent such as DCM, THF, DMF and the like, optionally in the presence of a tertiary amine such as NMI, N-methylmorpholine, N-ethyldiisopropylamine (DIEA, DIPEA), or triethylamine (TEA), at a temperature ranging from about 0 °C to 60 °C, to provide compound a of formula (VI). Chlorination of a compound of formula (VI) is achieved employing conditions known to one skilled in the art, for example, a compound of formula (VI) is treated with a chlorinating agent such as POCh, and the like, at temperatures ranging from 25-100 °C, to provide a compound of formula (VII).

[0080] According to SCHEME 7, a compound of formula (V) is esterified employing conditions previously described to provide a compound of formula (VIII). A compound of formula (VIII) is chlorinated employing conditions previously described to provide a compound of formula (IX).SCHEME 82. Deprotection

[0081] According to SCHEME 8, a commercially available or synthetically accessible compound of formula (Xa) or (Xb), where R2is an optionally substituted phenyl or heteroaryl and L is CH2 is protected employing methods known to one skilled in the art. For example, a compound of formula (XI) where Rais Ci-4alkyl, and PG is a suitable nitrogen protecting group such as te / Y-butoxycarbonyl (BOC), is prepared according to procedures known to one skilled in the art such as by treatment with Boc anhydride, a suitable base such as TEA, DIEA, and the like; in a suitable solvent such as EtOAc, DCM, THF and the like. A compound of formula (XI) where Rais Ci-4alkyl, and PG is a suitable nitrogen protecting group such as te / Y-butoxycarbonyl (BOC), is prepared according to procedures known to one skilled in the art such as by reaction of a compound of formula (Xb) with a suitable alkylating agent, such as iodoethane, employing a base such as NaH, K2CO3, Na2COs, TEA, CS2CO3, and the like, in a suitable solvent such as DMF, ACN, DCM, at temperatures ranging from 0 °C to 85 °C. A compound of formula (XI) where Rais Ci ealkyl and PG is BOC; is reacted with a Grignard reagent such as MeMgBr, in a suitable solvent such as THF, ether, or a mixture thereof; and the like; at temperatures of about 0 °C, for period of about 2-6 hrs; to provide a compound of formula (XII). Deprotection of BOC group on a compound of formula (XII) is achieved according to procedures known to one skilled in the art and employing established methodologies, such as those described in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 3 ed., John Wiley & Sons, 1999, pgs 518-525. For example, deprotection under acidic conditions such as trifluoroacetic acid (TFA) / CH2Cl2, HCI / Dioxane, and the like, at room temperature for a period of 2 h, provides a compound of formula (XIII), where R1is C(CHs)2(OH).

[0082] A compound of formulaprepared in two steps from a compound of formula (Xb). In a first step, a compound of formula (Xb) is reacted in an amide bond forming reaction with 3-amino-1 - methylcyclobutanol employing conventional amide bond forming techniques as described herein or as known to one skilled in the art. In a second step, deprotection ofthe BOC protecting group is achieved employing methods previously described to provide a compound of formula (XIII).SCHEME 9

[0083] According to SCHEME 9, an arylhalide or heteroaryl halide compound of formula (XXX), where X is Br, such as 1-bromo-4-(trifluoromethoxy)benzene or 5- bromo-2-(trifluoromethyl)pyrimidine is reacted under palladium-catalyzed a-arylation conditions with a protected glycine such as ethyl n-(diphenylmethylene)glycinate; with a palladium catalyst such as CataCXium A-Pd-G4, and the like; a suitable base such as K3PO4, and the like; in a suitable solvent such as toluene, and the like; at temperatures ranging from 80 °C to 100 °C; to provide a compound of formula (XXXI) where L is absent. Deprotection of a Schiff base compound of formula (XXXI) with a suitable acid such as HCI; a suitable solvent such as EtOH, and the like; provides a corresponding amino ester compound of formula (XXXII). An ester compound of formula (XXXII) is converted into a secondary amides by an aminolysis reaction with methylamine; in a suitable solvent such as MeOH, and the like; to provide a compound of formula (XIII), where R1is -C(=O)NH(CH3) and L is absent.

[0084] In a similar fashion, a commercially available or synthetically accessible alkyl halide such as 3-(bromomethyl)-7,7-difluorobicyclo[4.1.0]heptane is reacted with protected glycine such as ethyl n-(diphenylmethylene)glycinate in a suitable solventsuch as ACN, and the like; with a suitable base such as CS2CO3, and the like; in the presence of TBAI; to provide ethyl 2-amino-3-(7,7-difluorobicyclo[4.1.0]heptan-3- yl)propanoate. Aminolysis reaction with methylamine and ethyl 2-amino-3-(7,7- difluorobicyclo[4.1.0]heptan-3-yl)propanoate under conditions previously described provides 2-amino-3-(7,7-difluorobicyclo[4.1.0]heptan-3-yl)- / \ / -methylpropanamide.

[0085] In an alternate method, a compound of formula (XXX), where X is Br, is reacted in a Ni-catalyzed cross-electrophile coupling between aryl or heteroaryl bromides and primary alkyl iodides by employing an alkyl iodide such as methyl (S)-2- ((te / Y-butoxycarbonyl)amino)-3-iodopropanoate; a ligand such as dtbbpy, and the like; a nickel catalyst such as NiBr2; with Mn powder; in a suitable solvent such as DMA to provide a compound of formula (XI), where L is CH2, Rais CH3, and PG is BOC. Subsequent aminolysis and deprotection employing methods previously described provides a compound of formula (XIII).SCHEME 10

[0086] According to SCHEME 10, direct amination of a compound of formula (VI), with a compound of formula (XIII), where L is CH2, R1is H, and R2is an optionally substituted phenyl, is achieved employing BOP (benzotriazol- 1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate), a suitable base such as CS2CO3, and the like; in a suitable solvent such as ACN, and the like; at temperatures ranging from rt to 60 °C; for a period of 12-18 hr, provides a compound of Formula (I).SCHEME 11

[0087] According to SCHEME 11 , a compound of formula (VII) is reacted in an amination reaction with either a commercially available or synthetically accessible compound of formula (XIV) (chiral auxiliary of a compound of formula (XIII), where R1is -C(CHS)2(OH)) or compound of formula (XIII), employing methods described herein to provide a compound of formula (XV) or (XVII). Removal of the chiral auxiliary and hydrolysis of the ester on compound of formula (XV) (and compound of formula (XVII)) is achieved using a suitable base such as NaOH, LiOH, KOH, and the like; in a suitable solvent such as MeOH, EtOH, THF, MeCN, H2O, or a mixture thereof. Installation of the R4moiety is achieved employing amide bond forming techniques such as coupling reactions with compounds of formulas (XVIII) or (XIV) with commercially available or synthetically accessible (as previously described) cyclic amines; which are well known to those skilled in the art, or as previously described to provide a compound of Formula (I).SCHEME 12

[0088] According to SCHEME 12, a heteroaryl halide compound of formula (VII) is reacted under Pd-catalyzed amination conditions with an amine of formula (XIII); apalladium catalyst such as Sphos Pd G4, XantPhos Pd G4, rac-BINAP Pd G4; with or without a ligand such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), or (±)-2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthalene (rac-BINAP); a base such as CS2CO3, LHMDS, NaOtBu, K3PO4, and the like; in a suitable solvent such as toluene, THF, DMF, 1 ,4-dioxane, or a mixture thereof; at temperatures ranging from 80-150 °C, employing microwave or conventional heating; for a period of 0.5 h to 18 h; to provide a compound of Formula (I).

[0089] Wherein when a compound of Formula (I), where the R2moiety displays a nitro substituent, the nitro is reduced to an amino group employing hydrogenation conditions known to one skilled in the art.

[0090] One skilled in the art will recognize that various substituent groups and I or functional groups on said substituent groups (for example -OH, -NH2, -C(O)OH, etc.) may be protected prior to any reaction step, and then de-protected at a later step in the synthesis, as would be desirable or necessary, according to methods well known to those skilled in the art.

[0091] 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.

[0092] 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, saidreaction step may also be carried out in a mixture of the suitable solvents or solvent systems.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] During any of the processes for preparation of the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective 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.

[0099] 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.

[0100] 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.

[0101] Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, beresolved 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.

[0102] Additionally, chiral HPLC against a standard may be used to determine percent enantiomeric excess (%ee). The enantiomeric excess may be calculated as follows[ (Rmoles-Smoles) / (Rmoles+Smoles) ] X 100% where Rmoles and Smoles are the R and S mole fractions in the mixture such that Rmoles+Smoles = 1 . The enantiomeric excess may alternatively be calculated from the specific rotations of the desired enantiomer and the prepared mixture as follows: ee = ([a-obs] I [a-max]) X 100.Methods of Treatment I Cancers Mediated by BFL-1 protein

[0103] The present invention is further directed to methods of treating a cancers mediated by the BFL-1 protein (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).

[0104] As used herein, unless otherwise noted the term “cancer mediated by the BFL-1 protein” 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).

[0105] 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.

[0106] In certain embodiments, the cancer mediated by the BFL-1 protein is a leukemia. In certain embodiments, the cancer mediate by the BFL-1 protein 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 protein is a leukemia is acute myeloid leukemia (AML).

[0107] In certain embodiments, the cancer mediated by the BFL-1 protein is a lymphoma. In certain embodiments, the cancer mediated by the BFL-1 protein 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-expressorlymphoma; 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 protein 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 protein 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 protein 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 protein is a leukemia is Diffuse Large Cell Lymphoma (DLBCL).

[0108] 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" includestreatment which lowers the incidence of development or progression of a disease, disorder or condition.

[0109] 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.

[0110] 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.Pharmaceutical Compositions

[0111] The present invention is further directed to pharmaceutical compositions comprising, consisting of or consisting essentially of a compound of Formula (I) as described herein. The present invention is further directed to pharmaceutical compositions comprising, consisting of or consisting essentially of a compound of Formula (I) as described herein and one or more pharmaceutically acceptable carriers or excipients.

[0112] 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.

[0113] 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.

[0114] The present invention further comprises pharmaceutical compositions containing a compound of Formula (I), with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing one or more of the compounds of the presentinvention 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.

[0115] 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 suspensionsmay 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 300 mg / day, or any amount or range therein.

[0116] The dosages, however, may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.

[0117] 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 pre-formulation composition is then subdivided into unit dosage forms of the type described above containing from about 0.01 mg to about 1 ,000 mg, or any amount or range therein, of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form yielding the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] The liquid forms may include suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methylcellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.

[0123] To prepare a pharmaceutical composition of the present invention, a compound of Formula (I) 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 ofpreparation 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.

[0124] 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 thromboembolic disorders, inflammatory disorders or diseases or conditions in which plasma kallikrein activity is implicated is required.

[0125] 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.Examples

[0126] 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.

[0127] 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 MgSCU or Na2SO4. Where a synthesis product is listed as having been isolated as a residue, it will be understood by those skilled in the art that the term “residue” does not limit the physical state in which the product was isolated and may include, for example, a solid, an oil, a foam, a gum, a syrup, and the like.

[0128] 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.

[0129] LC-MS: Unless otherwise indicated, the analytical LC-MS system used consisted of one of the following: 1) Shimadzu LCMS-2020 with electrospray ionization (ESI) in positive ion detection mode with a HALO C18 column, 30 x 5.0 mm, 2.7 pm. Mobile phase A was water containing 0.05% TFA and mobile phase B was acetonitrile containing 0.05% TFA with a flow rate of 1.5 mL / min. 2) Agilent 1260 Inifinity II with electrospray ionization (ESI) in positive ion detection mode with an Infinity Lab Poroshell 120 EC-C18 column, 50 x 2.1 mm, 2.7 pm. Mobile phase A was water containing 0.1 % TFA and mobile phase B was acetonitrile containing 0.1% TFA with a flow rate of 1.2 mL / min. Mobile phase gradients were optimized for the individual compounds. Calculated mass corresponds to the exact mass.

[0130] Preparative HPLC: Unless otherwise noted, preparative HPLC purifications were performed with Waters Auto purification system. The column was selected from one of the following: Waters C18, 19 x150 mm, 5 pm; XBridge Prep OBD C18 Column, 30x150mm 5pm; XSelect CSH Prep C18 OBD Column, 5pm,19*150mm; XBridgeShield RP18 OBD Column, 30x150mm, 5pm; Xselect CSH Fluoro Phenyl, 30 x 150 mm, 5 pm; or YMC-Actus Triart C18, 30 x 150 mm, 5 pm. The mobile phases consisted of mixtures of acetonitrile (5-95%) in water containing 0.1 % FA or 10 mmol / L NH4HCO3. Flow rates were maintained at 25 mL / min and the UV detector used two channels 254 nm and 220 nm. Mobile phase gradients were optimized for the individual compounds.

[0131] Chiral chromatography: Chiral analytical chromatography was performed on one of Chiralpak AS, AD, Chiralcel OD,OJ Chiralpak IA, IB, IC, ID, IE, IF, IG, I H columns (Daicel Chemical Industries, Ltd.) (R,R)-Whelk-O1 , (S,S)-Whelk-O1 columns (Regis technologies, Inc. ) CHIRAL Cellulose-SB, SC, SA columns (YMC Co., Ltd.) as noted, at different column size (50x4.6mm, 100x4.6mm, 150x4.6mm, 250x4.6mm, 50x3.0mm, 100x3.0mm), with percentage of either ethanol in hexane (%Et / Hex) or isopropanol in hexane (%IPA / Hex) as isocratic solvent systems, or using supercritical fluid (SFC) conditions.

[0132] 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®), using ethyl acetate (EtOAc) / hexanes, ethyl acetate (EtOAc) / Petroleum ether, CH2CI2 / MeOH, or CH2CI2 / 10% 2N NH3in MeOH, as eluent.

[0133] 1H NMR: Unless otherwise noted,1H NMR spectra were acguired using 400 MHz spectrometers in CDCI3, CD3OD, or DMSO-de solutions. The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (5) are expressed in parts per million (ppm). 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), g (guartet), dd (double doublet), dt (double triplet), m (multiplet), br (broad).

[0134] Chemical names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye).INTERMEDIATESIntermediate A: Methyl 7-bromo-1-hydroxyphthalazine-5-carboxylate.

[0135] Step A: Methyl 5-bromo-3-iodo-2-methylbenzoate. To a solution of methyl 3- amino-5-bromo-2 -methyl benzoate (1000 g, 4.10 mol) in HCI (6 M, 5.00 L) was added a solution of NaNO2 (311 g, 4.51 mol) in H2O (1500 m L) at ~0 to -5 °C. After stirring for 30 minutes, the resulting solution was added dropwise to a solution of KI (700 g, 4.22 mol) and I2 (10.0 g, 39.4 mmol) in H2O (3000 ml_) at 90 °C. The mixture was stirred for 3 hours at 90 °C. The reaction was quenched with saturated aqueous Na2S20s (1000 mL), and then extracted with MTBE (2 x 500 mL). The combined extracts were washed with brine (2 x 500 mL), dried with anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 0%) to afford the title compound as a yellow solid.1H NMR (400MHz, DMSO-cfe): 5 8.20 (d, J = 2.0 Hz, 1 H) 7.82 (d, J = 2.0 Hz, 1 H) 3.84 (s, 3 H) 2.45 - 2.49 (m, 3 H).

[0136] Step B: Methyl 5-bromo-2-(bromomethyl)-3-iodobenzoate. To a mixture of methyl 5-bromo-3-iodo-2-methylbenzoate (1.1 kg, 3.10 mol) in CCI4 (16.50 L) was added NBS (1.38 kg, 7.75 mol) and BPO (50.0 g, 155 mmol, 75% purity) at 25 °C. The mixture was stirred at 100 °C for 12 hours. The reaction was quenched by saturated aqueous solution of sodium sulfite (3x10 L). The aqueous phase was extracted with DCM (2x20 L). The combined organic extracts were washed with brine (2x5 L), dried with anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 0~3%) to afford the title compound as a red oil.1H NMR (400MHz, CDCI3): 5 8.19 (d, J = 2.0 Hz, 1 H), 8.05 (d, J = 2.0 Hz, 1 H), 5.08 (s, 2H), 3.97 (s, 3H).

[0137] Step C: Methyl 5-bromo-2-formyl-3-iodobenzoate. To a solution of methyl 5- bromo-2-(bromomethyl)-3-iodobenzoate (2000 g, 4.61 mol) in CH3CN (20 L) was added NMO (1.08 kg, 9.22 mol, 973 mL) and 4A molecular sieves (2000 g). The reaction was stirred at 25°C for 12 h. The resulting mixture was filtered, and the filter cake was washed with DCM (2 x 20 L). The filtrate was quenched with saturated aqueousNa2S2O3 (10 L) and concentrated in vacuo to afford the title compound as a red oil.1H NMR (400 MHz, CDCI3) 5 10.05 (s, 2H), 8.19 (d, J = 1.5 Hz, 1 H), 7.97 (d, J = 1.3 Hz, 1 H), 3.66 (s, 3H).

[0138] Step D: 6-Bromo-3-hydroxy-4-iodoisobenzofuran-1 (3H)-one. To a suspension of methyl 5-bromo-2-formyl-3-iodobenzoate (300 g, 813 mmol) in MeOH (1 .5 L) and THF (1 .5 L) was added NaOH (1 M, 1 .50 L). The reaction mixture was stirred at 25 °C for 12 hours. The pH of the resulting mixture was adjusted to ~5-6 with HCI and then diluted with DCM (15 L). The mixture was washed with water (2 x 10 L). The organic phase was washed with brine (20 L), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0 to 15% EtOAc in petroleum ether) to afford the title compound as a yellow solid.1H NMR (400 MHz, DMSO-cfe) 5 8.40 (d, J = 1 .6 Hz, 1 H) 8.29 (d, J = 1 .6 Hz, 1 H) 8.03 (d, J = 1.6 Hz, 1 H) 6.43 (s, 1 H).

[0139] Step E: 7-Bromo-5-iodophthalazin-1-ol. To a solution of 6-bromo-3-hydroxy- 4-iodoisobenzofuran-1 (3H)-one (300 g, 845 mmol) in EtOH (3000 mL) was added NH2NH2.H2O (84.6 g, 1.69 mol) at 25°C. The reaction was stirred at 80°C for 12 h. The reaction mixture was filtered, and the solids were washed with EtOH (3 x 2000 mL). The filter cake was collected and dried in vacuo. The residue was triturated with EtOH (500 mL) at 25°C for 2 h to afford the title compound as a yellow solid.1H NMR (400 MHz, DMSO-cfe) 5 13.17-12.71 (m, 1 H), 8.61 (d, J = 2.0 Hz, 1 H), 8.31 (d, J = 1.6 Hz, 1 H), 8.25 (s, 1 H).

[0140] Step F: 7-Bromo-1-hydroxyphthalazine-5-carbonitrile. To a solution of 7- bromo-5-iodophthalazin-1-ol (150 g, 427 mmol) in DMF (3000 mL) was added Pd(PPhs)4 (24.7 g, 21.4 mmol) and the suspension was degassed under vacuum and purged with N2 several times. Zn(CN)2 (25.1 g, 214 mmol) was then added under N2 and the reaction was stirred at 80°C for 12 h. The reaction mixture was poured into water (20 L) and the resulting mixture was filtered. The filtrate was concentrated under reduced pressure then poured into saturated Na2COs (5 L) and extracted with EtOAc (3 x 3000 mL). The combined organic layers were washed with brine (2 x 2000 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the titlecompound as a yellow solid.1H NMR (400 MHz, DMSO-cfe) 5 13.21 (s, 1 H), 8.75 (d, J = 2.0 Hz, 1 H), 8.56 (d, J = 1.6 Hz, 1 H), 8.37 (s, 1 H).

[0141] Step G: 7-Bromo-1-hydroxyphthalazine-5-carboxylic acid. To a solution of 7- bromo-1-hydroxyphthalazine-5-carbonitrile (250 g, 1000 mmol) in 1 ,4-dioxane (1000 mL) and H2O (1000 mL) was added NaOH (80.0 g, 2.00 mol). The reaction was stirred at 100 °C for 12 hours. The resulting mixture was concentrated in vacuo and diluted with water (2000 mL). The aqueous mixture was extracted with DCM (3 x 1000 mL) then HCI (4 M, 500 mL) was added to acidify to pH~2. The resulting precipitate was triturated with MeOH (2000 mL) at 25 °C for 2 hours to afford the title compound as a yellow solid.1H NMR (400 MHz, DMSO-d6) 6 13.01 (s, 1 H), 9.06 (s, 1 H), 8.52 (d, J = 2.0 Hz, 1 H), 8.47 (d, J = 2.4 Hz, 1 H).

[0142] Step H: Methyl 7-bromo-1-hydroxyphthalazine-5-carboxylate. To a solution of 7-bromo-1-hydroxyphthalazine-5-carboxylic acid (50.0g, 186 mmol) in MeOH (1200 mL) was added H2SO4 (182 g, 1.86 mol, 99.1 mL). The reaction mixture was degassed and then heated to 100 °C and stirred for 12 hours under N2. The resulting mixture was filtered at 70 °C and the solids were collected. The residue was triturated with water (300 mL) at 25 °C for 30 minutes to obtain a gray solid. The gray solid was further triturated with MeOH (300 mL) at 25 °C for 30 minutes to afford the title compound as a white solid. MS (ESI): mass calcd. for CioH?BrN203, 282.0; m / z measured, 284.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) 513.04 (s, 1 H), 8.92 (s, 1 H), 8.53 (d, J = 2.0 Hz, 1 H), 8.45 (d, J = 2.0 Hz, 1 H), 3.95 (s, 3H).Intermediate B: 5-Bromo-7-iodophthalazin-1-ol.

[0143] The title compound was prepared in a manner analogous to the procedure described in Intermediate , Steps B-E, using methyl 3-bromo-5-iodo-2-methylbenzoate instead of methyl 5-bromo-3-iodo-2-methylbenzoate in Step B. MS (ESI): mass calcd.for C8H4BrlN2O, 349.9; m / z measured, 352.9 [M+H]+.1H NMR (400 MHz, DMS0-d6) 6 13.06 (br s, 1 H), 8.58 (d, J = 1.6 Hz, 1 H), 8.49 (d, J = 1.0 Hz, 1 H), 8.37 (s, 1 H).Intermediate C: 1-Hydroxy-7-(2,3,6-trimethylphenyl)phthalazine-5-carboxylic acid.

[0144] To a solution of methyl 7-bromo-1-hydroxyphthalazine-5-carboxylate (Intermediate , 48.0 g, 169 mmol) and 4,4,5,5-tetramethyl-2-(2,3,6-trimethylphenyl)- 1 ,3,2-dioxaborolane (83.5 g, 339 mmol) in DMF (1500 mL) was added a solution of K3PO4 (126 g, 593 mmol) in H2O (300 mL). The reaction mixture was degassed three times under N2 and then CataCXium A-Pd-Gs (12.35 g, 16.96 mmol) was added. The reaction mixture was stirred at 100 °C for 12 hours and then the resulting mixture was filtered. The filtrate was poured into water (5000 mL), NaOH was added to adjust the pH to 12 and the mixture was stirred for 30 minutes. The aqueous phase was extracted with DCM (2 x 1000 mL). The aqueous phase was adjusted the pH to 2 (HCI, 4 M, 500 mL) and extracted with EtOAc (2 x 1000 mL). The combined organic extracts were washed with brine (2x500 mL), dried with anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title compound as a white solid. MS (ESI): mass calcd. for C18H16N2O3, 308.1 ; m / z measured, 309.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) <5 13.89 (s, 1 H), 12.95 (s, 1 H), 9.17 (s, 1 H), 8.17 - 8.08 (m, 2H), 7.21 - 6.92 (m, 2H), 2.25 (s, 3H), 1.90 (s, 3H), 1.85 (s, 3H).Intermediate D: Methyl 1-chloro-7-(2,3,6-trimethylphenyl)phthalazine-5-carboxylate.

[0145] Step A: Methyl 1 -hydroxy-7-(2,3,6-trimethylphenyl)phthalazine-5- carboxylate.

[0146] To a solution of 1 -hydroxy-7-(2,3,6-trimethylphenyl)phthalazine-5-carboxylic acid (Intermediate , 30.0 g, 97.3 mmol) in MeOH (600 ml_) was added H2SO4 (95.4 g, 973 mmol, 51.9 ml_). The mixture was degassed and then heated to 100 °C for 12 hours under N2. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The resulting residue was triturated with H2O (300 m L) at 25 °C for 0.5 h to obtain a gray solid. The gray solid was further triturated with MeOH (300 mL) at 25 °C for 0.5 h to afford the title compound as a white solid. MS (ESI): mass calcd. for C19H18N2O3, 322.1 ; m / z measured, 323.1 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 6 12.98 (s, 1 H), 9.05 (s, 1 H), 8.17 (s, 1 H), 8.12 (d, J = 1.2 Hz, 1 H), 7.18 - 7.12 (m, 1 H), 7.11 - 7.05 (m, 1 H), 3.93 (s, 3H), 2.26 (s, 3H), 1 .90 (s, 3H), 1.85 (s, 3H).

[0147] Step B: Methyl 1 -chloro-7-(2,3,6-trimethylphenyl)phthalazine-5-carboxylate. To methyl 1-hydroxy-7-(2,3,6-trimethylphenyl)phthalazine-5-carboxylate (45.0 g, 140 mmol) was added POCI3 (62.0 g, 3.01 mol, 280 mL) at 25 °C. The reaction mixture was heated to 100 °C and stirred for 12 hours. The reaction mixture was concentrated in vacuo. The resulting residue was diluted with DCM (1000 mL) and washed with sat. NaHCOs (2000 mL). The organic phase was washed with brine (2x500 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 20% EtOAc in petroleum ether) to afford the title compound as a light-yellow solid. MS (ESI): mass calcd. for C19H17CIN2O2, 340.1 ; m / z measured, 341.3 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 6 10.38 (s, 1 H), 8.36 (d, J = 1.6 Hz, 1 H), 8.28 (s, 1 H), 7.24 - 7.16 (m, 1 H), 7.14 - 7.08 (m, 1 H), 4.00 (s, 3H), 2.27 (s, 3H), 1 .92 (s, 3H), 1.87 (s, 3H).Intermediate E: 1-(4-(Methylsulfonyl)phenyl)piperazine.

[0148] A suspension of bromo-4-methanesulfonyl benzene (200 g, 851 mmol), piperazine (733 g, 8.51 mol), Pd2(dba)s (23. g, 26 mmol), BINAP (21 g, 34 mmol) and NaOtBu (123 g, 1.28 mol) in toluene (2 L) was degassed and purged with N2 (3x) and the mixture was stirred at 110 °C for 12 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (5 L) and acidified with HCI to pH ~3-4. The aqueous mixture was extracted twice with DCM (5 L). The aqueous layer was then adjusted to pH -10-11 with Na2COs and extracted twice with DCM (5 L). The resulting organics were washed twice with brine (10 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound as a yellow solid. MS (ESI): mass calcd. for C11H16N2O2S, 240.1 ; m / z measured, 241.2 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 67.69 - 7.62 (m, 2H), 7.05 (d, J = 9.2 Hz, 2H), 3.27 - 3.20 (m, 4H), 3.08 (s, 3H), 2.84 - 2.78 (m, 4H).Intermediate F: 2-(Methylsulfonyl)-5-(piperidin-4-yl)pyridine.

[0149] Step A: ferf-Butyl 6-(methylsulfonyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)- carboxylate. A mixture of 5-bromo-2-(methylsulfonyl)pyridine (500 mg, 2.12 mmol), tert- butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2 / - / )- carboxylate (852 mg, 2.76 mmol), CataCXium A-Pd-G3 (160 mg, 220 .mol), K3PO4 (1.4 g, 6.60 mmol) in 1 ,4-dioxane (18 ml_) and H2O (2 ml_) was degassed three times and purged with N2. The reaction mixture was heated to 80 °C overnight. The resulting mixture was diluted with water (20 m L) and extracted with EtOAc (3 x 20 m L). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0-50 % ethyl acetate in petroleum ether) to afford the title compound.1H NMR (400 MHz, DMSO-c / e) 5 8.88 (d, J = 1.9 Hz, 1 H), 8.16 (dd, J = 2.3, 8.2 Hz, 1 H), 8.01 (d, J = 8.3 Hz, 1 H), 6.49 (br s, 1 H), 4.07 (br s, 2H), 3.57 (br t, J = 5.5 Hz, 2H), 3.28 (s, 3H), 2.54 (br dd, J = 1 .7, 5.8 Hz, 2H), 1.44 (s, 9H).

[0150] Step B: 2-(Methylsulfonyl)-5-(piperidin-4-yl)pyridine. To a solution of tertbutyl 6-(methylsulfonyl)-3',6'-dihydro-[3,4'-bipyridine]-T(2'H)-carboxylate (3.70g, 10.9 mmol) in MeOH (10 ml_) was added wet PtO2 (2.70 g, 11.9) and 37% aq. HCI (fuming, 1 mL) under N2. The suspension was degassed in vacuo and purged with H2 several times. The reaction mixture was stirred under a H2 balloon at 35 °C for 24 h. The resulting suspension was filtered through a pad of Celite®and the pad was rinsed with MeOH (3 x 20 mL). The filtrate was concentrated to dryness in vacuo to afford the title compound as yellow solid. MS (ESI): mass calcd. for C11H16N2O2S, 240.1 ; m / z measured, 241.1 [M+H]+.Intermediate G: 5-(3,3-Difluoropiperidin-4-yl)-2-(methylsulfonyl)pyridine.

[0151] Step A: tert-Butyl 3,3-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)-3,6- dihydropyridine-1 (2 / - / )-carboxylate. To a solution of NaH (2.6 g, 65 mmol, 60% w / w) in anhydrous THF (100 mL) was added a solution of terf-butyl 3,3-difluoro-4-oxopiperidine- 1 -carboxylate (7.5 g, 32 mmol) in anhydrous THF (50 mL) dropwise at 0 °C under N2 balloon and the resulting mixture was stirred at 0 °C for 30 minutes. Tf2NPh (17 g, 47 mmol) was added and the reaction mixture was stirred at 45 °C for 48 hours. Saturated aqueous NH4CI (150 mL) was added, and the mixture was extracted twice with ethyl acetate (300 mL). The combined extracts were washed with brine (200 mL), dried (Na2SO4) and filtered. The resulting organics were concentrated under reduced pressure and the residue was purified by chromatography (FCC, SiO2, 0 - 30% EtOAc in petroleum ether) to afford the title compound as a yellow oil.

[0152] Step B: terf-Butyl 3',3'-difluoro-6-(methylsulfonyl)-3',6'-dihydro-[3,4'- bipyridine]-1'(2'H)-carboxylate. To a solution of tert-butyl 5,5-difluoro-4- (((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1 (2 / - / )-carboxylate (9.5 g, 25 mmol) in 1 ,4-dioxane / H2O (v / v, 4 / 1 , 200 mL) was added (6-(methylsulfonyl)pyridin-3-yl)boronic acid (5.2 g, 25 mmol), K2CO3 (7.2 g, 52 mmol) and Pd-118 (1.7 g, 2.6 mmol) under N2atmosphere. The mixture was stirred at room temperature overnight. The reaction was quenched with water (100 m L) and the aqueous phase was extracted with ethyl acetate (2 x 200 ml_). The combined organic layers were washed with brine (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2gradient elution: 0 - 80% EtOAc in petroleum ether) and then further purified by RP-HPLC (Stationary phase: Xtimate C18 150x40mm, 10 .m; Mobile phase A: water (0.05% NHsH2O), Mobile phase B: MeCN, gradient elution: 39 - 69% B in A over 7 min, flow rate: 55 mL / min). The desired fractions were collected, and the pH of the mixture was adjusted with saturated NaHCOs to pH~8. The aqueous mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a yellow oil.1H NMR (400MHz, CDCh) £8.81 (s, 1 H), 8.14 - 8.04 (m, 2H), 6.51 (br s, 1 H), 4.30 (br s, 2H), 4.01 (br t, J=11 .0 Hz, 2H), 3.27 (s, 3H), 1 .54 (s, 9H).

[0153] Step C: tert-Butyl 3,3-difluoro-4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1- carboxylate. To a solution of tert-butyl 3',3'-difluoro-6-(methylsulfonyl)-3',6'-dihydro-[3,4'- bipyridine]-1'(2'H)-carboxylate (300 mg, 801 mol) in THF:MeOH (v / v, 1 / 1 , 6 mL) was added Pd / C (10% purity, 130 mg, 122 mol) under N2. The suspension was degassed under vacuum and purged with H2several times. The reaction mixture was stirred under a H2balloon (15 psi) at room temperature for 6 hours. The resulting suspension was filtered through a pad of Celite® and the filter cake was rinsed with ethyl acetate (3 x 15 mL). The filtrate was concentrated to dryness in vacuo and the residue was subjected to column chromatography (SiO2, 0 - 50% ethyl acetate in petroleum ether) to afford the title compound as a white solid. MS (ESI): mass calcd. for CieH22F2N2O4S, 376.1 ; m / z measured, 377.2 [M+H]+.1H NMR (400MHz, CDCh) 5 8.66 (d, J = 1.2 Hz, 1 H), 8.10 (d, J = 8.2 Hz, 1 H), 7.94 (br d, J = 8.2 Hz, 1 H), 4.65 - 4.26 (m, 2H), 3.25 (s, 3H), 3.24 - 3.00 (m, 2H), 2.98 - 2.80 (m, 1 H), 2.22 (dq, J = 4.2, 13.0 Hz, 1 H), 1.98 - 1.88 (m, 1 H), 1.51 (s, 9H);19F NMR (376 MHz, CDCh) £-103.04 - -106.56 (m, 1 F), -113.97 - -118.66 (m, 1 F).

[0154] Step D: 5-(3,3-Difluoropiperidin-4-yl)-2-(methylsulfonyl)pyridine TFA. To a solution of tert-butyl 3, 3-difluoro-4-(6-(methy Isulfony l)py ridi n-3-y l)pi peridi ne-1 - carboxylate (290 mg, 688 .mol) in DCM (14 mL) was added TFA (10 g, 88 mmol). Thereaction mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated to dryness in vacuo to afford the title compound as a white solid. MS (ESI): mass calcd. for C11H14F2N2O2S, 276.1 ; m / z measured, 277.2 [M+H]+.Intermediate H: (1-Chloro-7-(2,3,6-trimethylphenyl)phthalazin-5-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone.

[0155] Step A: (1-Hydroxy-7-(2,3,6-trimethylphenyl)phthalazin-5-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone. To a solution of 1-hydroxy-7-(2,3,6- trimethylphenyl)phthalazine-5-carboxylic acid (Intermediate , 30.0 g, 97.3 mmol) in DMF (1200 mL) was added T3P (124 g, 195 mmol, 116 mL, 50% purity), DIEA (62.8 g, 486 mmol, 84.7 mL) and 1-(4-(methylsulfonyl)phenyl)piperazine (Intermediate , 46.8 g, 195 mmol). The reaction mixture was stirred at 60 °C for 12 hours. The resulting mixture was poured into water (6000 mL) and filtered. The solids were collected and dissolved in DCM (500 mL). The organic phase was washed with brine (2 x 300 mL), dried with anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with MTBE: MeOH (300 mL: 30 mL) at 25 °C for 30 minutes afford the title compound as a yellow solid. MS (ESI): mass calcd. for C29H30N4O4S, 530.2; m / z measured, 531.2 [M+H]+.1H NMR (400MHz, CDCI3) 5 12.89 (s, 1 H), 8.26 (s, 1 H), 7.98 (s, 1 H), 7.77 - 7.62 (m, 3H), 7.17 - 7.12 (m, 1 H), 7.10 - 7.05 (m, 3H), 4.01 - 3.74 (m, 2H), 3.56 (d, J = 4.8 Hz, 2H), 3.38 (s, 3H), 3.08 (s, 2H), 3.07 (s, 4H), 2.26 (s, 3H), 1.94 (s, 3H), 1.89 (s, 3H).

[0156] Step B: To (1-hydroxy-7-(2,3,6-trimethylphenyl)phthalazin-5-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone (41 g, 77 mmol) was added POCI3 (473 g, 3.09 mol, 287 mL) at 25 °C. The mixture was heated to 100 °C and stirred for 30 minutes. The reaction mixture was concentrated in vacuo. The residue was diluted with DCM (1000 mL) and the mixture was washed with sat. NaHCOs (2000 mL) andbrine (2 x 500 m L), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 70%) and then triturated with EtOAc (200 mL): THF (20 mL) at 25 °C for 30 minutes to afford the title compound as a pink solid. MS (ESI): mass calcd. for C29H29CIN4O3S, 548.2; m / z measured, 549.1 [M+H]+.1H NMR (400MHz, DMSO-cfe) 6 9.61 (s, 1 H), 8.07 (s, 1 H), 8.00 (d, = 1.2 Hz, 1 H), 7.70 (s, 1 H), 7.68 (s, 1 H), 7.20 - 7.16 (m, 1 H), 7.14 - 7.05 (m, 3H), 3.99 - 3.76 (m, 2H), 3.60 (t, J = 4.8 Hz, 2H), 3.40 (s, 4H), 3.09 (s, 3H), 2.27 (s, 3H), 1.96 (s, 3H), 1.91 (s, 3H).Intermediate I: (7-(2,5-Dimethylphenyl)-1 -hydroxyphthalazin-5-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone.

[0157] Step A. 5-Bromo-7-(2,5-dimethylphenyl)phthalazin-1-ol. Pd(dppf)Cl2 (145 mg, 198 mmol) was added to a mixture of 5-bromo-7-iodophthalazin-1-ol (Intermediate , 1.39 g, 3.95 mmol), (2,5-dimethylphenyl)boronic acid (474 mg, 3.16 mmol) and K2CO3 (1.09 g, 7.90 mmol) in 1 ,4-dioxane / H2O (v / v, 5 / 1 , 174 mL) under N2. The reaction mixture was heated at 80 °C overnight, then cooled to room temperature. The mixture was quenched with saturated aqueous NH4CI (155 mL) and extracted with ethyl acetate (3x165 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by RP-HPLC (Stationary phase: Xtimate C18, 5 pm, 150 x 40 mm; Mobile phase A: water (0.05% NH3H2O), Mobile phase B: MeCN, gradient elution: 50 - 80% B in A over 8 minutes, flow rate: 55 mL / min) to afford the title compound as yellow solid. MS (ESI): mass calcd. for Ci6Hi3BrN2O, 328.0; m / z measured, 329.0 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 6 13.00 (s, 1 H), 8.45 (s, 1 H), 8.20 (d, J=1.6 Hz, 1 H), 8.10 (s, 1 H), 7.27-7.21 (m, 1 H), 7.20- 7.13 (m, 2H), 2.33 (s, 3H), 2.22 (s, 3H).

[0158] Step B. Methyl 7-(2,5-dimethylphenyl)-1-hydroxyphthalazine-5-carboxylate. To a mixture of 5-bromo-7-(2,5-dimethylphenyl)phthalazin-1 -ol (350 mg, 1.06 mmol) and EtsN (330 mg, 3.26 mmol) in MeOH (30 mL) was added Pd(dppf)Cl2 (78 mg, 0.11 mmol). The reaction was stirred under an atmosphere of CO (g) (50 psi) and heated at 80 °C overnight. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 30% ethyl acetate in petroleum ether) to afford the title compound as yellow solid. MS (ESI): mass calcd. for C18H16N2O3, 308.1 ; m / z measured, 308.9 [M+H]+.1H NMR (400MHz, CDCI3) 5 10.63 (br s, 1 H), 9.37-9.24 (m, 1 H), 8.64 (d, J = 1.5 Hz, 1 H), 8.48 (d, J = 1.8 Hz, 1 H), 7.24-7.20 (m, 1 H), 7.19-7.15 (m, 1 H), 7.11 (s, 1 H), 4.03 (s, 3H), 2.39 (s, 3H), 2.27 (s, 3H).

[0159] Step C. 7-(2,5-Dimethylphenyl)-1-hydroxyphthalazine-5-carboxylic acid. To a solution of methyl 7-(2,5-dimethylphenyl)-1-hydroxyphthalazine-5-carboxylate (150 mg, 0.476 mmol) in THF / MeOH (v / v, 1 / 1 , 5.5 mL) was added 1 M aq. NaOH (2.38 mL, 2.38 mmol). The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was diluted with H2O (10 mL), acidified (1 M HCI) to pH~3-4 and then filtered. The filter cake was washed with H2O (5 mL) and the resulting solids were collected and dried under vacuum to afford the title compound as yellow solid. MS (ESI): mass calcd. for C17H14N2O3, 294.1 ; m / z measured, 295.1 [M+H]+.1H NMR (400MHz, DMSO-56) 6 12.93 (s, 1 H), 9.15 (s, 1 H), 8.34 (s, 2H), 7.66-7.41 (m, 1 H), 7.31-7.23 (m, 1 H), 7.22-7.12 (m, 2H), 2.33 (s, 3H), 2.22 (s, 3H).

[0160] Step D. (7-(2,5-Dimethylphenyl)-1 -hydroxyphthalazin-5-yl)(4-(4- (methylsulfonyl)phenyl) piperazin-1 -yl)methanone. To a mixture of 7-(2,5- dimethylphenyl)-1-hydroxyphthalazine-5-carboxylic acid (120 mg, 0.387 mmol), 1 -(4- (methylsulfonyl)phenyl)piperazine (Intermediate , 98 mg, 0.407 mmol) and DIEA (150 mg, 1.16 mmol) in DMF (4 mL) was added T3P (50% solution in ethyl acetate, 296 mg, 0.465 mmol). The reaction mixture was stirred at room temperature overnight. The resulting mixture was quenched by slow addition of H2O (30 mL). The mixture was diluted with H2O (30 mL) and then stirred at room temperature for 20 minutes. The suspension was filtered, and the filter cake was washed with H2O (3x5 mL). The resulting solids were collected and dried under vacuum to afford the title compound asyellow solid. MS (ESI): mass calcd. for C28H28N4O4S, 516.2; m / z measured, 517.2 [M+H]+.Intermediate J: (R)-3-Amino-2-methyl-4-(4-(trifluoromethyl)phenyl)butan-2-ol HCI.

[0161] Step A: Ethyl (R)-2-((te / Y-butoxycarbonyl)amino)-3-(4- (trifluoromethyl)phenyl)propanoate. To a mixture of (R)-2-((terf-butoxycarbonyl)amino)- 3-(4-(trifluoromethyl)phenyl)propanoic acid (1 g, 3 mmol) in acetonitrile (20 mL) was added CS2CO3 (2.9 g, 9 mmol). The mixture was stirred at room temperature for 30 mins, lodoethane (0.41 mL, 6.0 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (40 g, gradient elution: 0 -10% ethyl acetate in heptane) to afford the title compound. MS (ESI): mass calcd. for C17H22F3NO4, 361 .2; m / z measured, 262.2 [M+H-100]+.

[0162] Step B: te / Y-butyl (R)-(3-hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan- 2-yl)carbamate. To a mixture of ethyl (R)-2-((te / Y-butoxycarbonyl)amino)-3-(4- (trifluoromethyl)phenyl)propanoate (992 mg, 2.74 mmol) in THF (15 mL) at 0 °C under N2, was added MeMgBr (4.57 mL, 3 M, 13.7 mmol). The mixture was stirred at 0 °C for 2 hours. Saturated aqueous NH4CI (15 mL) was added to the mixture dropwise at 0 °C under N2. The resulting mixture was extracted with EtOAc (3x15 mL). The combined organic layers were washed with brine (15 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography over silica gel (40 g, 0-60% EtOAc in Heptane) to afford the title compound. MS (ESI): mass calcd. for C17H24F3NO3, 347.2; m / z measured, 248.1 [M+H-100]+.

[0163] Step C: (R)-3-Amino-2-methyl-4-(4-(trifluoromethyl)phenyl)butan-2-ol HCI. To a mixture of terf-butyl (R)-(3-hydroxy-3-methyl-1 -(4-(trifluoromethyl)phenyl)butan-2- yl)carbamate (865 mg, 2.49 mmol) in DCM (2 mL) was added HCI / 1 ,4-dioxane (12.4mL, 49.8 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was suspended in hexanes. The resulting precipitate was collected and dried in vacuo to afford the title compound. MS (ESI): mass calcd. for C12H16F3NO, 247.1 ; m / z measured, 248.3 [M+H]+.Intermediate K: (R)-3-Amino-2-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)butan-2-ol dihydrochloride.

[0164] Step A: Methyl (R)-2-((te / Y-butoxycarbonyl)amino)-3-(6- (trifluoromethyl)pyridin-3-yl)propanoate. To a solution of methyl (R)-2-amino-3-(6- (trifluoromethyl)pyridin-3-yl)propanoate (1.00 g, 3.51 mmol) and DIEA (0.726 mL, 4.21 mmol) in DCM (35 mL) was added di-te / Y-butyl dicarbonate (0.827 mL, 3.86 mmol). The reaction mixture was heated to 60 °C overnight. The resulting mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc. The organic phase was washed with saturated aqueous NaHCOs and concentrated under reduced pressure to afford the title compound. MS (ESI): mass calcd. for C15H19F3N2O4, 348.1 ; m / z measured, 349.1 [M+H]+.1H NMR (400 MHz, CDCI3) 68.6-8.4 (m, 1 H), 7,54 (s, 2H), 5.2-4.9 (m, 1 H), 4.7-4.5 (m, 1 H), 3.76 (s, 3H), 3.4-3.2 (m, 1 H), 3.2-3.0 (m, 1 H) 1.41 (s, 11 H).

[0165] Step B: te / Y-butyl (R)-(3-hydroxy-3-methyl-1-(6-(trifluoromethyl)pyridin-3- yl)butan-2-yl)carbamate. To a mixture of methyl (R)-2-((terf-butoxycarbonyl)amino)-3-(6- (trifluoromethyl)pyridin-3-yl)propanoate (1.00 g, 2.87 mmol) in THF (14 mL) at 0 °C under N2, was added MeMgBr (3.38 mL, 11 .5 mmol). The reaction mixture was stirred at 0 °C for 4 hours. Saturated aqueous NH4CI was added to the mixture dropwise. The resulting mixture was extracted with EtOAc. The organic layer was separated and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography over silica gel (40 g, 0-50% EtOAc in Heptane) to afford the title compound as a white solid. MS (ESI): mass calcd. for C16H23F3N2O3, 348.2; m / z measured, 349.1 [M+H]+.1H NMR (400 MHz, CDCI3) 68.6-8.5 (m, 1 H), 7.8-7.7 (m, 1 H),77-7.5 (m, 1 H), 47-4.4 (m, 1 H), 3.8-37 (m, 1 H), 3.2-3.1 (m, 1 H), 2.8-2.6 (m, 1 H), 2.0- 1.8 (m, 1 H), 1.34 (d, 7H, J = 17.6 Hz), 1.26 (s, 9H).

[0166] Step C: (R)-3-Amino-2-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)butan-2-ol dihydrochloride. To a mixture of tert-butyl (R)-(3-hydroxy-3-methyl-1-(6- (trifluoromethyl)pyridin-3-yl)butan-2-yl)carbamate (950 mg, 2.73 mmol) in DCM (5 ml_) was added HCI / 1 ,4-dioxane (6.8 mL, 27.3 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was evaporated, and the residue was suspended in Et20. The resulting precipitate was collected and dried in vacuo to afford the title compound. MS (ESI): mass calcd. for C11 H15F3N2O, 248.1 ; m / z measured, 249.0 [M+H]+.1H NMR (CD3OD, 400 MHz) 58.8-8.6 (m, 1 H), 8.1-8.0 (m, 1 H), 7.9-77 (m, 1 H), 3.5-3.4 (m, 1 H), 3.0-2.8 (m, 1 H), 1.43 (s, 3H), 1.34 (s,3H).Intermediate L: 2-Amino- / V-methyl-2-(4-(trifluoromethoxy)phenyl)acetamide.

[0167] Step A: Ethyl 2-((diphenylmethylene)amino)-2-(4- (trifluoromethoxy)phenyl)acetate. To a solution of ethyl 2- ((diphenylmethylene)amino)acetate (1.10 g, 4.11 mmol) and 1-bromo-4- (trifluoromethoxy)benzene (1.10 g, 4.52 mmol) in toluene (27 mL) was added K3PO4 (2.62 g, 12.3 mmol), butyldi-1-adamantylphosphine (73.6 mg, 0.205 mmol), and CataCXium A-Pd-G4 (305 mg, 0.411 mmol). The reaction mixture was stirred at 100 °C overnight and then the resulting mixture was filtered. The filtrate was concentrated in vacuo and the residue was purified (FCC, SiO2, 3-30% EtOAc / heptane) to afford the title compound as a yellow oil. MS (ESI): mass calcd. for C24H20F3NO3, 427.1 ; m / z measured, 428.2 [M+H]+.

[0168] Step B: Ethyl 2-amino-2-(4-(trifluoromethoxy)phenyl)acetate. To a solution of ethyl 2-((diphenylmethylene)amino)-2-(4-(trifluoromethoxy)phenyl)acetate in EtOH (1.6 mL) was added HCI (2M, 2 mL, 4 mmol). The reaction mixture was stirred at room temperature for ~ 5 minutes. The resulting mixture was concentrated under reduced pressure and the residue was diluted with EtOAc. The organic phase was washed withsaturated aqueous NaHCOs, dried (NaSC ), filtered and concentrated. The residue was purified by chromatography (SiO2, 100% EtOAc) to afford the title compound. MS (ESI): mass calcd. for C11 H12F3NO3, 263.1 ; m / z measured, 264.1 [M+H]+.

[0169] Step C: 2-Amino- / V-methyl-2-(4-(trifluoromethoxy)phenyl)acetamide. To a solution of ethyl 2-amino-2-(4-(trifluoromethoxy)phenyl)acetate (640 mg, 2.43 mmol) in MeOH (2.4 mL) was added methylamine, 40% w / w aq. soln. (2 mL). The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was diluted with EtOAc and then filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a colorless oil. MS (ESI): mass calcd. for C10H11 F3N2O2, 248.1 ; m / z measured, 249.2 [M+H]+.Intermediate M: 2-Amino- / V-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)acetamide.

[0170] The title compound was made in a manner analogous to Intermediate, Steps A-C using 5-bromo-2-(trifluoromethyl)pyrimidine instead of 1-bromo-4-(trifluoromethoxy)benzene in Step A. MS (ESI): mass calcd. for C8H9F3N4O, 234.1 ; m / z measured, 235.1 [M+H]+.Intermediate N: 2-Amino-3-(7,7-difluorobicyclo[4.1.0]heptan-3-yl)- / \ / - methylpropanamide.

[0171] Step A: Ethyl 2-amino-3-(7,7-difluorobicyclo[4.1.0]heptan-3-yl)propanoate.To a solution of ethyl n-(diphenylmethylene)glycinate ( 297 mg, 1.11 mmol) and 3- (bromomethyl)-7,7-difluorobicyclo[4.1.0]heptane (250 mg, 1.11 mmol) in ACN (5.5 mL)was added CS2CO3 (1.08 g, 3.33 mmol) and TBAI (20 mg, 0.056 mmol). The mixture was heated to 85 °C overnight. The resulting mixture was filtered and concentrated under reduced pressure. To the residue was added HCI (2 M in EtOH). The resulting mixture was diluted with EtOAc and the organic phase was washed with saturated aqueous NaHCOs. Purification by chromatography (silica gel, 20% EtOH / EtOAc) afforded the title compound as a light brown oil.1H NMR (400 MHz, CDCI3) 64.2-4.0 (m, 1 H), 3.5-3.4 (m, 1 H), 2.0-1.9 (m, 1 H), 1.5-0.8 (m, 3H).

[0172] Step B: 2-Amino-3-(7,7-difluorobicyclo[4.1.0]heptan-3-yl)-N- methylpropanamide. To a solution of ethyl 2-amino-3-(7,7-difluorobicyclo[4.1.0]heptan- 3-yl)propanoate (110 mg, 0.445 mmol) in MeOH (1.1 mL) was added methylamine (40% w / w aqueous solution, 1.1 mL). The mixture was heated at 50 °C for 3 hours. The resulting mixture was concentrated under reduced pressure to afford the title compound. MS (ESI): mass calcd. for C11H18F2N2O, 232.1 ; m / z measured, 233.0 [M+H]+.Intermediate A: (R)-2-Amino- / V-methyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)propanamide.

[0173] Step A. Methyl (R)-2-((te / Y-butoxycarbonyl)amino)-3-(2- (trifluoromethyl)pyrimidin-5-yl)propanoate. To a mixture of 5-bromo-2- (trifluoromethyl)pyrimidine (3.55 g, 15.6 mmol), dtbbpy (405 mg, 1.51 mmol), NiBr2 (330 mg, 1.51 mmol), methyl (S)-2-((te / Y-butoxycarbonyl)amino)-3-iodopropanoate (5.0 g, 15 mmol) and Mn powder (2.5 g, 45.51 mmol) under Ar, was added DMA (80 mL). The reaction mixture was heated 50 °C and stirred for 3 hours. The resulting mixture was filtered through a pad of Celite®and the filter cake was rinsed with ethyl acetate (100 mL). The filtrate was diluted with saturated aqueous NH4CI (120 mL) and extracted with ethyl acetate (3 x 120 mL). The combined organic extracts were washed with brine (3 x 150 mL), dried (Na2SO4), filtered and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient elution: 0 - 100% ethyl acetate in petroleum ether) to afford the title compound as yellow solid. MS (ESI): masscalcd. for C14H18F3N3O4, 349.1 ; m / z measured, 293.8 [M+H-56]+.1H NMR (400MHz, CDCI3) <58.70 (s, 2H), 5.18 (d, J=6.2 Hz, 1 H), 4.64 (d, J=5.8 Hz, 1 H), 3.80 (s, 3H), 3.35 (dd, J=5.2, 14.1 Hz, 1 H), 3.11 (dd, J=6.1 , 13.9 Hz, 1 H), 1.42 (s, 9H);19F NMR (376MHz, CDCI3) <5 -70.26 (s, 1 F).

[0174] Step B. te / Y-Butyl (R)-(1 -(methylamino)-1-oxo-3-(2-(trifluoromethyl)pyrimidin- 5-yl)propan-2-yl)carbamate. To a solution of methyl (R)-2-((te / Y-butoxycarbonyl)amino)- 3-(2-(trifluoromethyl)pyrimidin-5-yl)propanoate (2.4 g, 6.7 mmol) in MeOH (48 ml_) was added 40% aq. MeNH2 (5.12 g, 65.9 mmol). The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with H2O (25 mL) and extracted with ethyl acetate (3x20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 60% ethyl acetate in petroleum ether) to afford the title compound as a white solid. MS (ESI): mass calcd. for C14H19F3N4O3, 348.1 ; m / z measured, 247.9 [M+H-100]+.1H NMR (400MHz, CDCI3) 6 8.76 (s, 2H), 6.27 (br s, 1 H), 5.21 (br s, 1 H), 4.51 - 4.37 (m, 1 H), 3.32 - 3.19 (m, 1 H), 3.02 (br dd, J=7.4, 13.9 Hz, 1 H), 2.81 (br d, J=4.3 Hz, 3H), 1.38 (s, 9H);19F NMR (376MHz, CDCI3) 5 -70.24 (s, 1 F).

[0175] Step C. (R)-2-amino- / V-methyl-3-(2-(trifluoromethyl)pyrimidin-5- yl)propanamide. To a solution of terf-butyl (R)-(1-(methylamino)-1-oxo-3-(2- (trifluoromethyl)pyrimidin-5-yl)propan-2-yl)carbamate (2.2 g, 6.2 mmol) in DCM (40 mL) was added 4 M HCI / 1 ,4-dioxane (17 mL). The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated to dryness in vacuo. The pH was adjusted to pH 8 with 25% aq. NH3 and the residue was purified by RP- HPLC (Stationary phase: Xtimate C18, 10 pm, 150 x 40 mm; Mobile phase A: water (NH3H2O + NH4HCO3) Mobile phase B: MeCN (B), gradient elution: 2 - 32% B in A over 8 min, flow rate: 55 mL / min) to afford the title compound as a white solid. MS (ESI): mass calcd. for C9H11F3N4O, 248.1 ; m / z measured, 248.8 [M+H]+.1H NMR (400MHz, CDCI3) <58.78 (s, 2H), 7.12 (br s, 1 H), 3.70 (dd, J=4.6, 7.6 Hz, 1 H), 3.25 (dd, J=4.5, 14.2 Hz, 1 H), 3.04 (dd, J=7.5, 14.2 Hz, 1 H), 2.82 (d, J=5.0 Hz, 3H);19F NMR (376MHz, CDCI3) <5 -70.20 (s, 1 F).Intermediate 0: (R)-2-Amino- / V-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propanamide.

[0176] Step A: Methyl (R)-2-((te / Y-butoxycarbonyl)amino)-3-(6- (trifluoromethyl)pyridin-3-yl)propanoate. To a solution of methyl (R)-2-amino-3-(6- (trifluoromethyl)pyridin-3-yl)propanoate HCI (600 mg, 2.11 mmol) and EtsN (640 mg, 6.32 mmol) in DCM (6 mL) was added di-te / Y-butyl dicarbonate (690 mg, 3.16 mmol) dropwise at room temperature. The mixture was stirred at room temperature overnight. The mixture was diluted with H2O (30 mL) and extracted with DCM (3x35 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 - 70% ethyl acetate in petroleum ether) to afford the title compound as a white solid. MS (ESI): mass calcd. for C15H19F3N2O4, 348.1 ; m / z measured, 349.2 [M+H]+.1H NMR (400 MHz, CDCI3) 58.51 (s, 1 H), 7.71-7.67 (m, 1 H), 7.65-7.61 (m, 1 H), 5.10 (d, J = 7.3 Hz, 1 H), 4.65 (d, J = 6.8 Hz, 1 H), 3.77 (s, 3H), 3.29 (dd, J = 5.3, 13.8 Hz, 1 H), 3.11 (br dd, J = 6.3, 13.8 Hz, 1 H), 1.42 (s, 9H);19F NMR (376 MHz, CDCI3) 6 -67.86 (s, 1 F).

[0177] Step B: (R)-2-((te / Y-Butoxycarbonyl)amino)-3-(6-(trifluoromethyl)pyridin-3- yl)propanoic acid. To a solution of methyl (R)-2-((terf-butoxycarbonyl)amino)-3-(6- (trifluoromethyl)pyridin-3-yl)propanoate (700 mg, 1.92 mmol) in MeOH (20 mL) was added NaOH (1.9 mL, 1.9 mmol, 1 M aqueous). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum to afford the title compound as a white solid. MS (ESI): mass calcd. for C14H17F3N2O4, 334.1 ; m / z measured, 334.9 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 68.43 (s, 1 H), 7.75 (s, 2H), 5.86 (d, J = 5.1 Hz, 1 H), 3.73 (d, J = 5.2 Hz, 1 H), 3.21 -3.13 (m, 2H), 3.01 (dd, J = 5.2, 13.1 Hz, 1 H), 1.33 (s, 9H);19F NMR (376 MHz, DMSO-cfe) 6 -66.09 (s, 1 F).

[0178] Step C: tert-butyl (R)-(1 -(methylamino)-1-oxo-3-(6-(trifluoromethyl)pyridin-3- yl)propan-2-yl)carbamate. To a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-(6- (trifluoromethyl)pyridin-3-yl)propanoic acid (745 mg) and methylamine hydrochloride (186 mg, 2.76 mmol) in DMF (10 mL) at room temperature was added DIEA (1.71 g,13.2 mmol) and HATU (1.09 g, 2.87 mmol). The reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with H2O (25 m L) and extracted with DCM (3x30 m L) . The combined organic extracts were dried (Na2SO4), filtered and concentrated to dryness under vacuum. The residue was purified by column chromatography (SiO2, gradient elution: 0-70% ethyl acetate in petroleum ether) to afford the title compound as a white solid. MS (ESI): mass calcd. for C15H20F3N3O3, 347.1 ; m / z measured, 347.9 [M+H]+.

[0179] Step D: (R)-2-Amino- / V-methyl-3-(6-(trifluoromethyl)pyridin-3- yl)propanamide. To a solution of terf-butyl (R)-(1-(methylamino)-1-oxo-3-(6- (trifluoromethyl)pyridin-3-yl)propan-2-yl)carbamate (700 mg) in DCM (15 mL) was added. HCI (3.8 mL, 4M in 1 ,4-dioxane) was added The reaction mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with H2O (20 mL) and washed with DCM (40 mL). The pH of the aqueous phase was adjusted to pH ~7-8 with saturated aqueous NaHCOs. The aqueous phase was extracted with ethyl acetate (5 x 200 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to dryness under vacuum. The residue was separated by SFC: (Stationary phase: DAICEL CHIRALPAK AD 250 x 30 mm, 10 pm; Mobile phase A: CO2 , Mobile phase B: EtOH (0.1 % NH3H2O); isocratic elution: 45% B in A; flow rate: 80 mL / min; column temp.: 40 °C; ABPR: 100 bar.) to afford the title compound. MS (ESI): mass calcd. for C10H12F3N3O, 247.1 ; m / z measured, 247.9 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 6 8.56 (s, 1 H), 7.89-7.75 (m, 3H), 3.36 (dd, J = 5.1 , 8.2 Hz, 1 H), 2.98 (dd, J = 5.0, 13.5 Hz, 1 H), 2.76-2.68 (m, 1 H), 2.55 (d, J = 4.6 Hz, 3H);19F NMR (376 MHz, DMSO-cfe) 6 - 66.02 - -66.17 (m, 1 F).Intermediate P: (R)-2-Amino-3-(3-amino-4-(trifluoromethyl)phenyl)- / \ / - methylpropanamide.

[0180] Step A: Methyl (R)-2-((te / Y-butoxycarbonyl)amino)-3-(3-nitro-4- (trifluoromethyl)phenyl)propanoate. To a suspension of Zn powder (3.0 g, 46 mmol) in DMF (25 ml_) was added I2 (200 mg, 788 pmol) under N2 at room temperature. After stirring for 20 minutes, methyl (S)-2-((terf-butoxycarbonyl)amino)-3-iodopropanoate (5.0 g, 15 mmol) in DMF (15 mL) was added via syringe. The reaction mixture was stirred for 30 mins. To the resulting mixture was added a solution 4-bromo-2-nitro-1- (trifluoromethyl)benzene (4.9 g, 18 mmol), Pd2(dba)s (400 mg, 437 pmol) and Sphos (300 mg, 731 pmol) in DMF (25 mL) via syringe. The reaction mixture was stirred at 50 °C overnight. The resulting mixture was filtered through a pad of Celite®and the filter cake was rinsed with EtOAc (100 mL). The filtrate was washed with 3% aq. LiCI (5x100 mL), dried (Na2SO4), filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2 gradient elution: 0 - 10% EtOAc in petroleum ether) to afford the title compound.1H NMR (400MHz, CDCI3) 5 7.69 (d, J = 8.0 Hz, 1 H), 7.59 (s, 1 H), 7.45 (d, J = 7.9 Hz, 1 H), 5.02 (br s, 1 H), 4.57 (br d, J = 6.2 Hz, 1 H), 3.71 (s, 3H), 3.28 (br dd, J = 5.1 , 13.5 Hz, 1 H), 3.06 (br dd, J = 6.9, 13.4 Hz, 1 H), 1.34 (s, 9H).

[0181] Step B: te / Y-Butyl (R)-(1 -(methylamino)-3-(3-nitro-4-(trifluoromethyl)phenyl)- 1 -oxopropan-2-yl)carbamate. To a solution of methyl (R)-2-((tert- butoxycarbonyl)amino)-3-(3-nitro-4-(trifluoromethyl)phenyl)propanoate (1.4 g, 3.5 mmol) in EtOH (14 mL) was added CH3NH2 / H2O (7.1 g, 91 mmol ). The reaction mixture was stirred at 25°C for 8 h. The resulting mixture was concentrated to dryness in vacuo to afford the title compound as a white solid. MS (ESI): mass calcd. for C16H20F3N3O5, 391.1 ; m / z measured, 336.1 [M+H-56]+.1H NMR (400 MHz, CDCI3) 5 7.75 (d, J = 6.4 Hz, 2H), 7.60 (d, J = 8.1 Hz, 1 H), 6.31 (br s, 1 H), 5.22 (br d, J = 8.9 Hz, 1 H), 4.43 (br d, J = 7.3 Hz, 1 H), 3.38-3.25 (m, 1 H), 3.16-3.03 (m, 1 H), 2.81 (d, J = 4.9 Hz, 3H), 1.39 (s, 9H).

[0182] Step C: te / Y-Butyl (R)-(3-(3-amino-4-(trifluoromethyl)phenyl)-1- (methylamino)-1 -oxopropan-2-yl)carbamate. A solution of te / Y-butyl (R)-(1 - (methylamino)-3-(3-nitro-4-(trifluoromethyl)phenyl)-1-oxopropan-2-yl)carbamate (340 mg, 0.869 mmol) in MeOH (17 mL) was reduced using an H-cube, 1mL / min, 30 °C, 1barr, single pass. MS (ESI): mass calcd. for C16H22F3N3O3, 361.2; m / z measured, 262.0 [M+H-100]+.

[0183] Step D: (R)-2-Amino-3-(3-amino-4-(trifluoromethyl)phenyl)- / \ / - methylpropanamide. To a solution of terf-butyl (R)-(3-(3-amino-4- (trifluoromethyl)phenyl)-1-(methylamino)-1-oxopropan-2-yl)carbamate (320 mg, 0.866 mmol) was added TFA (1.0 mL, 13 mmol). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with EtOAc and saturated aqueous NaHCOs. The aqueous phase was extracted with EtOAc and the combined organic extracts were dried, filtered, and concentrated under reduced pressure to afford the title compound. MS (ESI): mass calcd. for C11H14F3N3O, 261.1 ; m / z measured, 262.0 [M+H]+.Intermediate Q: (R)-2-Amino- / V-methyl-3-(4-(trifluoromethyl)phenyl)propanamide HCI.

[0184] Step A. te / Y-Butyl (R)-(1 -(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamate. To a solution of (R)-2-((tert- butoxycarbonyl)amino)-3-(4-(trifluoromethyl)phenyl)propanoic acid (1.0 g, 3.0 mmol), CH3NH2 HCI (405 mg, 6.00 mmol) and HATU (1.37 g, 3.60 mmol) in DMF (10 mL) at 0°C was added triethylamine (1.52 g, 15.0 mmol). The reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc (30 mL) and washed with water (2x15 mL). The organic phase was washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, gradient eluent: petroleum ether / ethyl acetate=100 / 0 to 50 / 50) to afford the title compound as a white solid. MS (ESI): mass calcd. for C16H21F3N2O3, 346.2; m / z measured, 247.0 [M+H-100]+.1H NMR (400 MHz, CDCI3) 6 7.56 (d, J = 7.9 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 5.91 (br s, 1 H), 5.01 (br s, 1 H), 4.34 (d, J = 7.5 Hz, 1 H), 3.24-3.12 (m, 1 H), 3.11-3.00 (m, 1 H), 2.76 (d, J = 4.6 Hz, 3H), 1.39 (s, 9H);19F NMR (376 MHz, CDCI3) 6 -62.54 (s, 1 F).

[0185] Step B. (R)-2-amino-N-methyl-3-(4-(trifluoromethyl)phenyl)propenamide HCI. To a solution of tert-butyl (R)-(1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)carbamate (800 mg, 2.21 mmol) in DCM (10 ml_) was added HCI (4M in dioxane, 2.2 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was filtered, and the solids were collected and dried under vacuum to provide the title compound. MS (ESI): mass calcd. for C11 H13F3N2O, 246.1 ; m / z measured, 247.2 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 68.63 (br s, 1 H), 8.38 (br s, 2H), 7.69 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 4.01 (d, J = 5.5 Hz, 1 H), 3.23-3.04 (m, 2H), 2.59 (d, J = 4.5 Hz, 3H);19F NMR (376 MHz, DMSO-cfe) 6 - 60.93 (br s, 1 F).Intermediate R: (R)-2-Amino- / V-methyl-3-(2-nitro-4-(trifluoromethyl)phenyl)propanamide.

[0186] To a mixture of (R)-2-amino- / \ / -methyl-3-(4- (trifluoromethyl)phenyl)propanamide (Intermediate , 500 mg, 2.00 mmol) in cone. H2SO4 (5 mL) was added KNO3 (350 mg, 3.46 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The mixture was poured into ice-water (50 mL) and 50% aq. NaOH (15 mL) was added. The aqueous phase was extracted with ethyl acetate (3x30 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to afford the title compound as a yellow oil. MS (ESI): mass calcd. for C11 H12F3N3O3, 291.1 ; m / z measured, 292.1 [M+H]+.1H NMR (400 MHz, CDCI3) 68.20 (s, 1 H), 7.86-7.79 (m, 1 H), 7.63 (d, J = 8.0 Hz, 1 H), 7.02 (br s, 1 H), 3.71 (br dd, J = 5.1 , 7.7 Hz, 1 H), 3.55 (dd, J = 4.8, 13.6 Hz, 1 H), 3.13 (dd, J = 8.0, 13.6 Hz, 1 H), 2.83 (d, J = 4.8 Hz, 3H);19F NMR (376 MHz, CDCI3) 6 -62.90 (s, 1 F).Intermediate S: (R)-2-Amino- / \ / -((1 r,3R)-3-hydroxy-3-methylcyclobutyl)-3-(4- (trifluoromethyl)phenyl)propanamide.

[0187] Step A: te / Y-Butyl ((R)-1-(((1 ,3-trans)-3-hydroxy-3-methylcyclobutyl)amino)- 1 -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamate. To a suspension of (R)-2- ((te / Y-butoxycarbonyl)amino)-3-(4-(trifluoromethyl)phenyl)propanoic acid (200 mg, 0.600 mmol) and HATU (251 mg, 0.660 mmol) in DMF (2.4 ml_, 0.25 M) was added DIPEA (0.40 ml_, 2.32 mmol) and trans-3-amino-1 -methylcyclobutanol HCI (100 mg, 0.727 mmol). The reaction was stirred overnight at room temperature. The resulting mixture was diluted with EtOAc and saturated aqueous NaHCOs. The aqueous phase was extracted with EtOAc(3x), and the combined organic layers were washed with H2O and brine, dried (NaSC ), and concentrated under reduced pressure to afford the title compound as a tan solid. MS (ESI): mass calcd. for C20H27F3N2O4, 416.2; m / z measured, 361.1 [M+H-56]+.

[0188] Step B: (R)-2-Amino- / V-((1 ,3-trans)-3-hydroxy-3-methylcyclobutyl)-3-(4- (trifluoromethyl)phenyl)propenamide. To a suspension of te / Y-Butyl ((R)-1-(((1 ,3-trans)- 3-hydroxy-3-methylcyclobutyl)amino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2- yl)carbamate (260 mg, 0.590 mmol) in 1 ,4-dioxane (4.4 mL) was added HCI (4M in 1 ,4- dioxane, 1.5 mL, 6 mmol) The reaction mixture was stirred at room temperature for 4 hours. The resulting mixture was concentrated under reduced pressure and then diluted with EtOAc and dilute aqueous NaOH. The aqueous phase was extracted with EtOAc (3x), and the combined organic layers were washed with brine, dried (MgSO4), and concentrated under reduced pressure to afford the title compound as a yellow solid. MS (ESI): mass calcd. for C15H19F3N2O2, 316.1 ; m / z measured, 317.1 [M+H]+.1H NMR (400 MHz, CDCI3) 57.58 (d, J = 7.8 Hz, 2H), 7.42-7.28 (m, 3H), 4.48 (sxt, J = 7.6 Hz, 1 H), 3.60 (dd, J = 8.6, 4.2 Hz, 1 H), 3.28 (dd, J = 13.7, 3.9 Hz, 1 H), 2.89-2.80 (m, 1 H), 2.56-2.42 (m, 2H), 2.01-1.85 (m, 2H), 1.38 (s, 3H).Intermediate T: (R)-2-Amino- / \ / -((1 ,3-c / s)-3-hydroxy-3-methylcyclobutyl)-3-(4- (trifluoromethyl)phenyl)propenamide.

[0189] The title compound was prepared in a manner analogous to Intermediate ,Steps A-B using cis-3-hydroxy-3-methylcyclobutylamine HCI instead of trans-3-amino-1- methylcyclobutanol HCI in Step A and DCM instead of 1 ,4-dioxane in Step B. MS (ESI): mass calcd. for C15H19F3N2O2, 316.1 ; m / z measured, 317.3 [M+H]+.1H NMR (400 MHz, DMSO-cfe) <58.81 - 8.72 (m, 1 H), 8.36 (br s, 3H), 7.69 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.0Hz, 2H), 5.03 (br s, 1 H), 3.96 (br s, 1 H), 3.73 (qd, J=7.9, 15.9 Hz, 1 H), 3.11 (br d, J=6.9 Hz, 2H), 2.25 - 2.08 (m, 2H), 1 .97 - 1 .87 (m, 1 H), 1 .73 - 1 .66 (m, 1 H), 1 .20 (s, 3H);19F NMR (376MHz, DMSO-cfe) 6 -60.87 (s, 1 F).EXAMPLESExample 1 : [7-(2,5-Dimethylphenyl)-1-[2-[4-(trifluoromethyl)phenyl]ethylamino]phthalazin-5-yl]-[4-(4-methylsulfonylphenyl)piperazin- 1 -yl]methanone.

[0190] To a solution of (7-(2,5-dimethylphenyl)-1-hydroxyphthalazin-5-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone (Intermediate , 100 mg, 0.188 mmol), 2-(4-(trifluoromethyl)phenyl)ethan-1-amine (71.3 mg, 0.377 mmol), and CS2CO3 (307 mg, 0.942 mmol) , in CH3CN (3 m L) was added BOP (167 mg, 0.377 mmol. The reaction mixture was stirred at 60°C overnight and then quenched with saturated aqueous NH4CI (10 mL). The aqueous phase was extracted with ethyl acetate (3x10 mL) and the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified RP- HPLC (Stationary phase: Welch XtimateC18, 5 pm, 150 x 25 mm; Mobile phase A: water (0.225% FA) Mobile phase B: MeCN, gradient elution: 37 - 67% B in A over 6 min, flow rate: 25 mL / min). The residue was further purified by RP- HPLC (Stationary phase: Boston Prime C18, 5 pm, 150 x 30 mm; Mobile phase A: water (0.05% NH3H2O + 10 mM NH4HCO3), Mobile phase B: MeCN, gradient elution: 60 - 90% B in A over 7 min, flow rate: 25 mL / min) to afford the title compound as a white powder. MS (ESI): mass calcd. for C37H36F3N5O3S, 687.2; m / z measured, 688.3 [M+H]+.1H NMR (400 MHz, CDCI3) 5 9.02 (s, 1 H), 7.81 (d, J=8.8 Hz, 2H), 7.74 (s, 2H), 7.56 (d, J=7.9 Hz, 2H), 7.39 (br d, J=8.0 Hz, 2H), 7.24 - 7.20 (m, 1 H), 7.19 - 7.15 (m, 1 H), 7.05 (s, 1 H), 6.94 (br d, J=8.9 Hz, 2H), 5.56 (br s, 1 H), 4.21 (br s, 1 H), 4.06 (br s, 3H), 3.56 (br s, 2H), 3.44 (br s, 2H), 3.28 (br s, 2H), 3.20 (br s, 2H), 3.02 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H).Example 2: [1-[[(1R)-2-Hydroxy-2-methyl-1-[[4- (trifluoromethyl)phenyl]methyl]propyl]amino]-7-(2,3,6-trimethylphenyl)phthalazin-5-yl]-[4- (methylsulfonylmethyl)-1-piperidyl]methanone.

[0191] Step A: (R)-5,5-Dimethyl-4-(4-(trifluoromethyl)benzyl)oxazolidin-2-one. To a solution of (R)-3-amino-2-methyl-4-(4-(trifluoromethyl)phenyl)butan-2-ol HCI (Intermediate , 85.6 mg, 0.302 mmol) and DIPEA (52 pL, 0.30 mmol) in THF (2 mL) was added 1 ,1'-carbonyldiimidazole (49 mg, 0.30 mmol). The reaction mixture was stirred under nitrogen at ambient temperature overnight. The resulting mixture was concentrated under reduced pressure and the residue was purified by chromatography (4 g SiO2, 0-100% EtOAc in heptane over 15 min) to afford the title compound.1H NMR (CDCI3, 400 MHz) 57.62 (d, 2H, J=7.8 Hz), 7.33 (d, 2H, J=7.8 Hz), 4.9-5.1 (m, 1 H), 3.71 (dd, 1 H, J=3.9, 11.2 Hz), 2.9-2.9 (m, 1 H), 2.7-2.8 (m, 1 H), 1.50 (s, 3H), 1.47 (s, 3H).19F NMR (CDCI3, 376 MHz) 5 -65.00.

[0192] Step B: Methyl (R)-1-(5,5-dimethyl-2-oxo-4-(4-(trifluoromethyl)benzyl)oxazolidin-3-yl)-7-(2,3,6-trimethylphenyl)phthalazine-5- carboxylate. To a mixture of methyl 1-chloro-7-(2,3,6-trimethylphenyl)phthalazine-5- carboxylate (Intermediate , 34.3 mg, 0.101 mmol), (R)-5,5-dimethyl-4-(4- (trifluoromethyl)benzyl)oxazolidin-2-one (27.5 mg, 0.101 mmol), XantPhos Pd G4 (4.8 mg, 5.0 pmol) and CS2CO3 (46 mg, 0.141 mmol) under N2 was added toluene (1 mL) via syringe. The mixture was stirred for ~5 minutes while sparging with nitrogen and then heated to 120 °C overnight. The resulting mixture was diluted with H2O (3m L) and EtOAc (3 mL). The aqueous phase was further extracted with EtOAc (3x 3 mL). The combined organic layers were washed with water (3x) and brine (3x), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, 0-100% EtOAc in heptane over 15 minutes) to afford the title compound.1H NMR (CDCI3, 400 MHz) 5 10.53 (dd, 1 H, J=1.0, 2.0 Hz), 8.43 (dd, 1 H, J=1.7, 7.6 Hz), 8.1-8.1 (m, 1 H), 7.4-7.5 (m, 2H), 7.3-7.4 (m, 2H), 7.2-7.2 (m, 1 H), 7.1- 7.1 (m, 1 H), 5.3-5.4 (m, 1 H), 4.06 (s, 3H), 3.35 (br dd, 1 H, J=5.1 , 13.5 Hz), 2.84 (ddd, 1 H, J=5.4, 8.9, 14.1 Hz), 2.35 (d, 3H, J=2.9 Hz), 2.0-2.1 (m, 3H), 1.98 (d, 3H, J=19.6 Hz), 1.61 (s, 3H), 1.35 (d, 3H, J=4.4 Hz).19F NMR (CDCI3, 376 MHz) 5 -65.10, -65.11.

[0193] Step C: (R)-1 -((3-Hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan-2- yl)amino)-7-(2,3,6-trimethylphenyl)phthalazine-5-carboxylic acid. To methyl (R)-1-(5,5- dimethyl-2-oxo-4-(4-(trifluoromethyl)benzyl)oxazolidin-3-yl)-7-(2,3,6- trimethylphenyl)phthalazine-5-carboxylate (24 mg, 0.041 mmol) in EtOH (1 mL) was added NaOH (16 mg, 0.41 mmol) and the reaction was stirred at 80 °C for 30 minutes. The mixture was cooled to room temperature, diluted with H2O, and acidified (1 N HCI) to pH~3. The aqueous phase was extracted with EtOAc (4 x 4 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford the title compound. MS (ESI): mass calcd. for C30H30F3N3O3, 537.2; m / z measured, 538.2 [M+H]+.

[0194] Step D: [1 -[[(1 R)-2-Hydroxy-2-methyl-1 -[[4- (trifluoromethyl)phenyl]methyl]propyl]amino]-7-(2,3,6-trimethylphenyl)phthalazin-5-yl]-[4- (methylsulfonylmethyl)-1-piperidyl]methanone. To a suspension of (R)-1-((3-hydroxy-3- methyl-1-(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-7-(2,3,6-trimethylphenyl)phthalazine-5-carboxylic acid (22.5 mg, 0.0398 mmol) and 4- [(methylsulfonyl)methyl]piperidine hydrochloride (10.8 mg, 0.0505 mmol) in DMF (0.7 ml_) was added DIPEA (24 pL, 0.139 mmol) and HATU (19.6 mg, 0.0517 mmol). The vial was flushed with Ar (g), capped, and stirred at room temperature overnight. The reaction was quenched with 0.3 mL water and filtered through a 0.45 pm PTFE syringe filter, rinsing the vial with DMF (3x 0.3 mL). Purification by RP- HPLC (Stationary phase: Waters XBridge BEH C18, 5pm, 19x150 mm; Mobile phase A: Water + pH 10 Ammonium Hydroxide, Mobile phase B: MeCN + pH 10 Ammonium Hydroxide, gradient elution: 45 - 80% B in A over 8 min, flow rate: 25 mL / min) afforded the title compound as an off-white powder. MS (ESI): mass calcd. for C37H43F3N4O4S, 696.3; m / z measured, 697.2 [M+H]+.1H NMR (400MHz, DMSO-d6) <58.63 (s, 1 H), 8.20 (s, 1 H), 7.4-7.5 (m, 3H), 7.35 (br d, 2H, J=7.1 Hz), 7.1-7.2 (m, 1 H), 7.1 -7.1 (m, 1 H), 6.8-6.9 (m, 1 H), 4.8-4.9 (m, 1 H), 4.72 (br dd, 1 H, J=1.1 , 2.5 Hz), 3.2-3.3 (m, 1 H), 3.11 (br d, 2H, J=6.3 Hz), 3.0-3.1 (m, 3H), 2.94 (s, 3H), 2.54 (s, 2H), 2.30 (d, 3H, J=8.4 Hz), 2.2-2.3 (m, 1 H), 1 .94 (br d, 3H, J=3.8 Hz), 1 .91 (s, 3H), 1 .7-1 .9 (m, 1 H), 1 .3-1 .5 (m, 2H), 1 .30 (s, 3H), 1.27 (s, 3H) ppm.Example 3: [1-[[(1R)-2-Hydroxy-2-methyl-1-[[4- (trifluoromethyl)phenyl]methyl]propyl]amino]-7-(2,3,6-trimethylphenyl)phthalazin-5-yl]-[4- (4-methylsulfonylphenyl)piperazin-1-yl]methanone.

[0195] (1 -Chloro-7-(2,3,6-trimethylphenyl)phthalazin-5-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone (Intermediate , 100 mg, 0.182 mmol), (R)-3-amino-2-methyl-4-(4-(trifluoromethyl)phenyl)butan-2-ol (Intermediate , 62.0 mg, 0.219 mmol), rac-BINAP Pd G4 (14.2 mg, 0.0141 mmol), CS2CO3 (178 mg, 0.546 mmol), and 1 ,4-dioxane (3.6 mL) were added to a vial. The vial was evacuated andfilled three times with argon. The reaction was stirred at 100 °C for 24 hours. The reaction mixture was filtered through Celite ® and a silica plug before purifying by basic HPLC (Stationary phase: Xtimate C18, 5 pm, 150 x 40 mm; Mobile phase: H2O (0.05% NH3H2O) (A) - MeCN (B), gradient elution: 46-76% B in A over 8 min, flow rate: 60 mL / min) to afford the title compound. MS (ESI): mass calcd. for C41H44F3N5O4S, 759.3; m / z measured, 760.2 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 51H NMR (400 MHz, DMSO-de) 5 8.67 (s, 1 H), 8.35 (br s, 1 H), 7.68 (d, J = 8.80 Hz, 2H), 7.63 (d, J = 2.45 Hz, 1 H), 7.37 - 7.52 (m, 4H), 7.02 - 7.21 (m, 5H), 4.71 - 5.02 (m, 2H), 3.86 (br s, 2H , 3.54 (br s, 2H), 3.17 - 3.30 (m, 5H), 3.08 (s, 3H) , 2.95 - 3.04 (m, 1 H) , 2.29 (d, J = 11.74 Hz, 3H), 1.94 (br d, J = 15.16 Hz, 6H), 1.24 (br d, J = 15.65 Hz, 6H).Example 4: [1 -[[(1 R)-2-Hydroxy-2-methyl-1 -[[6-(trifluoromethyl)-3- pyridyl]methyl]propyl]amino]-7-(2,3,6-trimethylphenyl)phthalazin-5-yl]-[4-(4- methylsulfonylphenyl)piperazin-1-yl]methanone.

[0196] (1 -Chloro-7-(2,3,6-trimethylphenyl)phthalazin-5-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone (Intermediate , 120 mg, 0.219 mmol), (R)-3-amino-2-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)butan-2-ol (Intermediate , 77 mg, 0.24 mmol), rac-BINAP Pd G4 (22 mg, 0.022 mmol), K3PO4 (185 mg, 0.874 mmol), BINAP (14 mg, 0.022 mmol) and THF (1 .4 mL) were added to a vial. The vial was evacuated and filled three times with argon. The reaction was stirred at 90°C for 8 h. The reaction mixture was concentrated in vacuo and then eluted from a Biotage SNAP Duo (SiO2, 10 g, 20% EtOH / EtOAc). The resulting residue was purified by RP-HPLC (Stationary phase: Phenomenex Gemini 5 pM C8 110A 150 x 30 mm; Mobile phase A: 10 mM ammonium carbonate, 0.1 % ammonium hydroxide in water; Mobile Phase B: 10 mM ammonium carbonate, 0.1 % ammonium hydroxide in 90% acetonitrile 10% water; Gradient elution: 40 - 100% B in A over 10 minutes) to afford the title compound. MS(ESI): mass calcd. for C40H43F3N6O4S, 760.3; m / z measured, 761.0 [M+H]+.1H NMR (400 MHz, CDCI3) £8.8-9.1 (m, 1 H), 8.4-8.6 (m, 1 H), 7.8-7.9 (m, 3H), 7.4-7.6 (m, 3H), 7.1-7.2 (m, 1 H), 7.0-7.1 (m, 1 H), 6.9-7.0 (m, 2H), 5.3-5.5 (m, 1 H), 4.6-5.0 (m, 1 H), 3.9- 4.3 (m, 2H), 3.01 (s, 11 H), 2.2-2.4 (m, 3H), 1.89 (s, 6H), 1.3-1.5 (m, 6H).Example 5: [(4*R)-3,3-Difluoro-4-(6-methylsulfonyl-3-pyridyl)-1 -pi peridy I ]-[1 -[[(1 R)-2- hydroxy-2-methyl-1-[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]-7-(2,3,6- trimethylphenyl)phthalazin-5-yl]methanone.

[0197] Step A. Methyl (R)-1 -((3-hydroxy-3-methyl-1 -(4- (trifluoromethyl)phenyl)butan-2-yl)amino)- 7-(2,3,6-trimethylphenyl)phthalazine-5- carboxylate. To a suspension of methyl 1 -chloro-7-(2,3,6-trimethylphenyl)phthalazine- 5-carboxylate (Intermediate , 150 mg, 440 mol), (R)-3-amino-2-methyl-4-(4- (trifluoromethyl)phenyl)butan-2-ol HCI (Intermediate , 150 mg, 529 .mol) and CS2CO3 (450 mg, 1.38 mmol) in 1 ,4-dioxane (6 ml_) was added Sphos Pd G4 (30 mg, 38 mol) at room temperature in a glovebox. The reaction mixture was stirred at 100 °C overnight, then cooled to room temperature. The resulting mixture was filtered, and the filter cake was rinsed with ethyl acetate (40 m L). The filtrate was concentrated to dryness in vacuo and the residue was purified by prep-TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1 ) to afford the title compound as yellow solid. MS (ESI): mass calcd. for C31H32F3N3O3, 551.2; m / z measured, 552.4 [M+H]+.1H NMR (400MHz, CDCI3) <59.93 (s, 1 H), 8.25 (d, J=1.4 Hz, 1 H), 7.62 - 7.51 (m, 1 H), 7.36 (d, J=8.1 Hz, 2H), 7.24 (s, 3H), 7.19 - 7.14 (m, 1 H), 7.08 (d, J=7.7 Hz, 1 H), 5.31 (s, 1 H), 4.55 (s, 1 H), 4.02 (s, 3H), 3.33 - 3.21 (m, 1 H), 3.19 - 3.04 (m, 1 H), 2.31 (d, J=2.1 Hz, 3H), 1.91 - 1.81 (m, 6H), 1.42 (s, 6H);19F NMR (376 MHz, CDCI3) 5 -62.39 - -62.58 (m, 1 F).

[0198] Step B. (R)-1 -((3-Hydroxy-3-methyl-1 -(4-(trifluoromethyl)phenyl)butan-2- yl)amino)- 7-(2,3,6-trimethylphenyl)phthalazine-5-carboxylic acid. To a suspension of methyl (R)-1 -((3-hydroxy-3-methyl-1 -(4-(trifluoromethyl)phenyl) butan-2-yl)amino)-7- (2,3,6-trimethylphenyl)phthalazine-5-carboxylate (140 mg, 254 .mol) in THF / H2O (v / v, 1 / 1 , 2.5 mL) was added 1.5 M aq. NaOH (1.50 ml_, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with H2O (3 mL), then acidified to pH 5 with 1 M aq. HCI. The aqueous phase was extracted with ethyl acetate (2 x 5 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as yellow solid. MS (ESI): mass calcd. for C30H30F3N3O3, 537.2; m / z measured, 538.2 [M+H]+.1H NMR (400 MHz, DMSO-cfe) <59.58 (s, 1 H), 8.68 - 8.53 (m, 1 H), 8.10 (br s, 1 H), 7.49 - 7.44 (m, 2H), 7.43 - 7.38 (m, 2H), 7.21 - 7.17 (m, 1 H), 7.16 - 7.08 (m, 1 H), 4.80 - 4.66 (m, 1 H), 3.25 - 3.14 (m, 2H), 3.07 - 2.96 (m, 1 H), 2.29 (d, J=11 .7 Hz, 3H), 1.94 - 1 .87 (m, 6H), 1 .24 (br d, J=12.3 Hz, 6H);19F NMR (376 MHz, DMSO-cfe) 5 -60.78 (d, J = 6.9 Hz, 1 F).

[0199] Step C. (3,3-Difluoro-4-(6-(methylsulfonyl)pyridin-3-yl)piperidin-1-yl)(1 -((( / )- 3-hydroxy-3- methyl-1-(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-7-(2,3,6- trimethylphenyl)phthalazin-5-yl)methanone. To a suspension of (R)-1 -((3-hydroxy-3- methyl-1-(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-7-(2,3,6- trimethylphenyl)phthalazine-5-carboxylic acid (140 mg), 5-(3,3-difluoropiperidin-4-yl)-2- (methylsulfonyl)pyridine TFA(lntermediate , 180 mg) and NMI (200 mg, 2.44 mmol) in DMF (2.5 mL) was added TCFH (110 mg, 392 mol). The reaction mixture was stirred at room temperature for 2 days. The resulting mixture was diluted with brine (5 mL), then extracted with ethyl acetate (2 x 5 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiO2, DCM / THF = 3 / 1) to afford a yellow solid. The MS (ESI): mass calcd. for C41H42F5N5O4S, 795.3; m / z measured, 796.4 [M+H]+.

[0200] Step D. ((*R)-3,3-Difluoro-4-(6-(methylsulfonyl)pyridin-3-yl)piperidin-1-yl)(1- (((R)-3 -hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-7-(2,3,6- trimethylphenyl)phthalazin-5-yl)methanone. (3,3-difluoro-4-(6-(methylsulfonyl)pyridin-3- yl)pi peridi n-1 -y I) ( 1 -(((R)-3-hydroxy-3-methyl- 1 -(4-(trifluoromethyl)phenyl)butan-2- yl)amino)-7-(2,3,6-trimethylphenyl)phthalazin-5-yl) methanone (140 mg) was separatedby SFC: (Stationary phase: DAICEL CHIRALPAK IG, 10 pm, 250 x 30 mm; Mobile phase A: CO2 Mobile phase B: 45% EtOH (0.1% NH3H2O) flow rate: 80 mL / min; column temp.: 40 °C; ABPR: 100 bar.) to afford the title compound as the first eluting compound (retention time 4.408 min). MS (ESI): mass calcd. for C41H42F5N5O4S, 795.3; m / z measured, 796.3 [M+H]+.1H NMR (400 MHz, CD3CN) 68.86 - 8.65 (m, 2H), 8.07 - 7.99 (m, 2H), 7.83 (brd, J=6.1 Hz, 1H), 7.64-7.46 (m, 1H), 7.41 -7.34 (m, 4H), 7.17-7.06 (m, 2H), 6.13-6.02 (m, 1H), 5.28-5.01 (m, 1H), 5.01 -4.83 (m, 1H), 4.61 -4.46 (m, 1 H), 3.87 - 3.40 (m, 3H), 3.33 - 3.21 (m, 2H), 3.17 - 3.15 (m, 3H), 3.14 - 2.74 (m, 3H), 2.33-2.27 (m, 3H), 1.93 - 1.82 (m, 6H), 1.36- 1.32 (m, 3H), 1.30 - 1.27 (m, 3H);19F NMR (376 MHz, CD3CN) 6 -62.73 - -62.85 (m, 1F), -104.13 - -106.67 (m, 1F), -115.51 (brdd, J=230.3, 242.8 Hz, 1F); and [(4*S)-3,3-difluoro-4-(6-methylsulfonyl-3-pyridyl)-1- piperidy l]-[ 1 -[[(1 R)-2-hydroxy-2-methyl-1 -[[4- (trifluoromethyl)phenyl]methyl]propyl]amino]-7-(2,3,6-trimethylphenyl)phthalazin-5- yl]methanone, (Example 6) as the second eluting compound (retention time 4.914 min).Example 6: [(4*S)-3,3-Difluoro-4-(6-methylsulfonyl-3-pyridyl)-1 -pi peridy l]-[ 1 -[[(1 R)-2- hydroxy-2-methyl-1-[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]-7-(2,3,6- trimethylphenyl)phthalazin-5-yl]methanone.

[0201] The title compound was isolated from SFC purification of Example 5. MS (ESI): mass calcd. for C41H42F5N5O4S, 795.3; m / z measured, 796.3 [M+H]+.1H NMR (400MHz, CD3CN) 68.76 - 8.64 (m, 2H), 8.04 - 7.99 (m, 2H), 7.90 (br d, J=6.4 Hz, 1 H), 7.51 -7.46 (m, 1H), 7.41 -7.30 (m, 4H), 7.15-7.05 (m, 2H), 6.53 -6.16 (m, 1H), 5.22- 5.01 (m, 1H), 4.99-4.78 (m, 1H), 4.67 - 4.47 (m, 1H), 3.76-3.53 (m, 2H), 3.47 - 3.30 (m, 1H), 3.26-3.20 (m, 2H), 3.17 (brd, J=1.7 Hz, 3H), 3.10 (brd, J=11.7 Hz, 1H), 3.03 - 2.90 (m, 2H), 2.29 (br d, J=5.2 Hz, 3H), 1.92 - 1.79 (m, 6H), 1.33 - 1.21 (m, 6H);19FNMR (376MHz, CD3CN) 6 -62.73 - -62.92 (m, 1 F), -103.90 - -107.00 (m, 1 F), -114.47 - - 117.23 (m, 1 F).Example 7: (*R)- / \ / -Methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1-carbonyl]-7-(2,3,6-trimethylphenyl)phthalazin-1-yl]amino]-2-[4-(trifluoromethoxy)phenyl]acetamide.

[0202] The title compound was prepared in a manner analogous to Example 4 using 2-amino- / V-methyl-2-(4-(trifluoromethoxy)phenyl)acetamide (Intermediate) instead of (R)-3-amino-2-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)butan-2-ol (Intermediate ). The title compound was purified by SFC. MS (ESI): mass calcd. for C39H39F3N6O5S, 760.3; m / z measured, 761.2 [M+H]+.1H NMR (400 MHz , DMSO-cfe,) <58.89 (s, 1 H), 8.5-8.4 (m, 1 H), 8.4-8.3 (m, 1 H), 8.0-7.9 (m, 1 H), 7.67 (s, 5H), 7.4-7.3 (m, 2H), 7.2-6.9 (m, 4H), 6.1-5.9 (m, 1 H), 4.1 -3.7 (m, 2H), 3.6-3.5 (m, 2H), 3.4-3.3 (m, 2H), 3.08 (s, 3H), 2.61 (d, 3H, J=4.4 Hz), 2.27 (d, 3H, J=7.3 Hz), 2.0-1.8 (m, 6H).Example 8: (*S)- / V-Methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6-trimethylphenyl)phthalazin-1-yl]amino]-2-[4-(trifluoromethoxy)phenyl]acetamide.

[0203] The title compound was isolated from SFC purification of Example 9. MS (ESI): mass calcd. for C39H39F3N6O5S, 760.3; m / z measured, 761.2 [M+H]+.Example 9: (*R)- / V-Methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7- (2,3,6-trimethylphenyl)phthalazin-1-yl]amino]-2-[2-(trifluoromethyl)pyrimidin-5- yl]acetamide.

[0204] The title compound was prepared in a manner analogous to Example 4 using 2-amino- / V-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)acetamide (Intermediate) instead of (R)-3-amino-2-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)butan-2-ol (Intermediate ). The title compound was isolated by SFC. MS (ESI): mass calcd. for C37H37F3N8O4S, 746.3; m / z measured, 747.2 [M+H]+.1H NMR (400 MHz, CD3OD) 8 9.03 (s, 2H), 8.8-8.9 (m, 1 H), 8.1-8.2 (m, 1 H), 7.6-7.7 (m, 3H), 6.8-7.2 (m, 4H), 5.9-6.2 (m, 1 H), 3.2-4.1 (m, 7H), 2.93 (s, 3H), 2.71 (s, 3H), 2.1-2.3 (m, 3H), 1.7-2.0 (m, 7H).Example 10: (*S)- / V-Methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7- (2,3,6-trimethylphenyl)phthalazin-1-yl]amino]-2-[2-(trifluoromethyl)pyrimidin-5- yl]acetamide.

[0205] The title compound was isolated from SFC purification of Example 9. MS (ESI): mass calcd. for C37H37F3N8O4S, 746.3; m / z measured, 747.2 [M+H]+.Example 11 : (*R)-3-((1*S,3*S,6*R)-7,7-Difluorobicyclo[4.1.0]heptan-3-yl)- / V-methyl-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-7-(2,3,6- trimethylphenyl)phthalazin-1-yl)amino)propanamide.

[0206] The title compound was prepared in a manner analogous to Example 4 using 2-amino-3-(7,7-difluorobicyclo[4.1 .0]heptan-3-yl)- / V-methylpropanamide (Intermediate) instead of (R)-3-amino-2-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)butan-2- ol (Intermediate ). The title compound was isolated by SFC. MS (ESI): mass calcd. for C40H46F2N6O4S, 744.3; m / z measured, 745.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 8.84 (s, 1 H), 8.5-8.3 (m, 1 H), 8.1-7.9 (m, 1 H), 7.67 (s, 3H), 7.6-7.4 (m, 1 H), 7.3-6.9 (m, 4H), 4.9-4.7 (m, 1 H), 4.1-3.5 (m, 5H), 3.08 (s, 3H), 2.6-2.6 (m, 3H), 2.3-2.2 (m, 3H), 1.96 (s, 19H).Example 12: (*S)-3-((1*S,3*S,6*R)-7,7-Difluorobicyclo[4.1.0]heptan-3-yl)- / V-methyl-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-7-(2,3,6- trimethylphenyl)phthalazin-1-yl)amino)propenamide.

[0207] The title compound was prepared in a manner analogous to Example 4 using 2-amino-3-(7,7-difluorobicyclo[4.1 .0]heptan-3-yl)- / V-methylpropanamide (Intermediate) instead of (R)-3-amino-2-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)butan-2- ol (Intermediate ). MS (ESI): mass calcd. for C40H46F2N6O4S, 744.3; m / z measured, 745.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 68.9-8.8 (m, 1 H), 8.5-8.3 (m, 1 H), 8.1-7.9 (m, 1 H), 7.69 (d, 3H, J=9.3 Hz), 7.5-7.4 (m, 1 H), 7.2-7.0 (m, 4H), 4.9-4.7 (m, 1 H), 4.0-3.8 (m, 2H), 3.7-3.5 (m, 2H), 3.08 (s, 3H), 2.6-2.5 (m, 3H), 2.28 (s, 3H), 2.1 -0.7 (m, 19H).Example 13: (*R)-3-((1*R,3*R,6*S)-7,7-Difluorobicyclo[4.1.0]heptan-3-yl)- / V-methyl-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-7-(2,3,6- trimethylphenyl)phthalazin-1-yl)amino)propenamide.

[0208] The title compound was prepared in a manner analogous to Example 4 using 2-amino-3-(7,7-difluorobicyclo[4.1 .0]heptan-3-yl)- / V-methylpropanamide (Intermediate) instead of (R)-3-amino-2-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)butan-2- ol (Intermediate ). MS (ESI): mass calcd. for C40H46F2N6O4S, 744.3; m / z measured, 745.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 68.9-8.8 (m, 1 H), 8.5-8.3 (m, 1 H), 8.1-7.9 (m, 1 H), 7.67 (s, 3H), 7.5-7.4 (m, 1 H), 7.3-6.9 (m, 4H), 4.9-4.8 (m, 1 H), 4.1-3.7 (m, 2H), 3.6-3.5 (m, 2H), 3.2-3.0 (m, 4H), 2.6-2.5 (m, 3H), 2.3-2.2 (m, 3H), 2.1-1.2 (m, 18H), TOOT (m, 1 H).Example 14: (*S)-3-((1*R,3*R,6*S)-7,7-Difluorobicyclo[4.1.0]heptan-3-yl)- / V-methyl-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-7-(2,3,6- trimethylphenyl)phthalazin-1-yl)amino)propenamide.

[0209] The title compound was prepared in a manner analogous to Example 4 using 2-amino-3-(7,7-difluorobicyclo[4.1 .0]heptan-3-yl)- / V-methylpropanamide (Intermediate) instead of (R)-3-amino-2-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)butan-2- ol (Intermediate ). MS (ESI): mass calcd. for C40H46F2N6O4S, 744.3; m / z measured, 745.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 69.0-8.8 (m, 1 H), 8.6-8.3 (m, 1 H), 8.2-7.9 (m, 1 H), 7.67 (s, 3H), 7.5-7.4 (m, 1 H), 7.3-6.9 (m, 4H), 4.9-4.8 (m, 1 H), 4.1-3.5 (m, 5H), 3.08 (s, 4H), 2.6-2.5 (m, 3H), 2.3-2.2 (m, 3H), 1.96 (s, 20H).Example 15: (R)-2-((5-((*S)-3,3-Difluoro-4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1-yl)amino)- / \ / -methyl-3-(4- (trifluoromethyl)phenyl)propenamide.

[0210] The title compound was prepared in a manner analogous to Example 5, Steps A-C using BINAP Pd G4 instead of Sphos Pd G4 and (R)-2-amino- / \ / -methyl-3-(4- (trifluoromethyl)phenyl)propanamide (Intermediate ) instead of (R)-3-amino-2-methyl-4- (4-(trifluoromethyl)phenyl)butan-2-ol HCI (Intermediate ) in Step A. The product from Step C was separated by SFC (Stationary phase: DAICEL CHIRALPAK IC, 10 pm, 250 x 30 mm; Mobile phase A: CO2 , Mobile phase B: EtOH; isocratic elution: 50% B in A; flow rate: 150 mL / min; column temp.: 40 °C; ABPR: 100 bar) to afford the title compound as the second eluting compound (retention time, 2.816 min). MS (ESI): mass calcd. for C40H39F5N6O4S, 794.3; m / z measured, 795.3 [M+H]+.1H NMR (400MHz, CDCI3) 59.01 - 8.84 (m, 1 H), 8.68 (br s, 1 H), 8.11 - 7.97 (m, 2H), 7.89 (br s, 1 H), 7.61 - 7.40 (m, 5H), 7.20 - 7.03 (m, 2H), 7.01 - 6.89 (m, 1 H), 6.36 (br s, 1 H), 5.29 - 4.87 (m, 2H), 3.86 - 3.36 (m, 4H), 3.33 - 3.00 (m, 5H), 2.66 (br d, J=4.6 Hz, 3H), 2.36 - 2.28 (m, 3H), 2.12 - 2.08 (m, 2H), 2.00 (br s, 3H), 1.91 (br s, 3H);19F NMR (376 MHz, CDCI3) 6 - 62.89 (br s, 1 F), -104.43 - -107.12 (m, 1 F), -115.54 (br s, 1 F); and (R)-2-((5-((*R)-3,3-difluoro-4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1 -carbonyl)-7-(2,3,6- trimethylphenyl)phthalazin-1-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propenamide (Example 16) as the first eluting compound (retention time, 2.814 min).Example 16: (R)-2-((5-((*R)-3,3-Difluoro-4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propenamide.

[0211] The title compound was isolated from SFC purification of Example 15. MS (ESI): mass calcd. for C40H39F5N6O4S, 794.3; m / z measured, 795.3 [M+H]+.1H NMR (400MHz, CDCI3) 69.02 - 8.80 (m, 1 H), 8.69 (s, 1 H), 8.11 - 7.94 (m, 2H), 7.88 (br s, 1 H), 7.60 - 7.38 (m, 4H), 7.38 - 7.37 (m, 1 H), 7.13 (br d, J=18.1 Hz, 2H), 6.88 (br s, 1 H), 6.23 (br s, 1 H), 5.20 - 4.84 (m, 2H), 3.86 - 3.31 (m, 4H), 3.16 (s, 5H), 2.66 (d, J=4.8 Hz, 3H), 2.31 (s, 3H), 2.12 - 2.09 (m, 2H), 2.01 (br d, J=8.1 Hz, 3H), 1.89 (br s, 3H);19F NMR (376MHz, CDCI3) 5 -62.89 (br s, 1 F), -105.16 - -107.87 (m, 1 F), -115.52 (s, 1 F).Example 17: (2R)- / V-Methyl-2-[[5-[4-(6-methylsulfonyl-3-pyridyl)piperidine-1-carbonyl]-7- (2,3,6-trimethylphenyl)phthalazin-1-yl]amino]-3-[2-(trifluoromethyl)pyrimidin-5- yl]propenamide.

[0212] The title compound was prepared in a manner analogous to Example 5 Steps A-C, using BINAP Pd G4 instead of Sphos Pd G4 and (R)-2-Amino- / \ / -methyl-3- (2-(trifluoromethyl)pyrimidin-5-yl)propenamide (Intermediate A) instead of (R)-3-amino- 2-methyl-4-(4-(trifluoromethyl)phenyl)butan-2-ol HCI (Intermediate ) in Step A and 2- (methylsulfonyl)-5-(piperidin-4-yl)pyridine dihydrochloride (Intermediate ) instead of 5- (3,3-difluoropiperidin-4-yl)-2-(methylsulfonyl)pyridine (Intermediate ), HATU instead of TCFH and DIEA instead of NMI in Step C. MS (ESI): mass calcd. for C38H39F3N8O4S, 760.3; m / z measured, 761.3 [M+H]+.1H NMR (400MHz, DMSO-cfe) <59.01 - 8.94 (m, 2H), 8.82 - 8.69 (m, 2H), 8.37 - 8.26 (m, 1 H), 8.21 - 8.07 (m, 2H), 8.02 - 7.95 (m, 1 H), 7.89 - 7.58 (m, 2H), 7.21 - 7.16 (m, 1 H), 7.16 - 7.07 (m, 1 H), 5.14 (d, J=4.6 Hz, 1 H), 4.79 (d, J=14.8 Hz, 1 H), 3.26 (s, 6H), 3.18 - 2.90 (m, 2H), 2.62 (d, J=5.2 Hz, 3H), 2.32 - 2.23 (m, 3H), 2.06 - 1.79 (m, 9H), 1.79 - 1.37 (m, 2H);19F NMR (376MHz, DMSO-cfe) 6 - 68.74 - -68.97 (m, 1 F).Example 18: (R)-2-((5-((*S)-2,2-Dioxidooctahydropyrazino[2, 1 -c][1 ,4]th iazi ne-8- carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1-yl)amino)- / V-methyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)propenamide.

[0213] The title compound was prepared in a manner analogous to Example 5 Steps A-C, using BINAP Pd G4 instead of Sphos Pd G4 and (R)-2-Amino- / \ / -methyl-3- (2-(trifluoromethyl)pyrimidin-5-yl)propenamide (Intermediate A) instead of (R)-3-amino- 2-methyl-4-(4-(trifluoromethyl)phenyl)butan-2-ol HCI (Intermediate ) in Step A and octahydropyrazino[2,1 -c][1 ,4]thiazine 2,2-dioxide instead of 5-(3,3-difluoropiperidin-4- yl)-2-(methylsulfonyl)pyridine (Intermediate ), HATU instead of TCFH and DIEA instead of NMI in Step C. The product from Step C was separated by SFC (Stationary phase: DAICEL CHIRALPAK IC, 10 pm, 250 x 30 mm; Mobile phase A: CO2 , Mobile phase B: IPA (0.1 %NH3H2O); isocratic elution: 30% B in A; flow rate: 150 mL / min; column temp.: 40 °C; ABPR: 100 bar) to afford the title compound as the second eluting compound (retention time, 2.276 min). MS (ESI): mass calcd. for C34H37F3N8O4S, 710.3; m / z measured, 711 .3 [M+H]+.1H NMR (400MHz, CD3CN) 68.99 - 8.74 (m, 3H), 7.86 (br s, 1 H), 7.65 - 7.46 (m, 1 H), 7.19 - 7.12 (m, 1 H), 7.10 - 7.05 (m, 1 H), 6.93 (br s, 1 H), 6.31 (br s, 1 H), 5.24 (br s, 1 H), 4.72 - 4.48 (m, 1 H), 3.43 (br s, 1 H), 3.35 - 3.21 (m, 2H), 3.17 (br d, J=14.1 Hz, 2H), 3.13 - 3.05 (m, 1 H), 2.99 (br d, J=11 .8 Hz, 3H), 2.86 - 2.70 (m, 3H), 2.67 (br d, J=4.3 Hz, 4H), 2.57 - 2.39 (m, 1 H), 2.30 (s, 3H), 2.12 - 2.09 (m, 3H), 2.00 - 1 .97 (m, 3H);19F NMR (376MHz, MeCN-cfe) 5 -70.75 (br s, 1 F); and (R)-2-((5- ((*R)-2,2-dioxidooctahydropyrazino[2,1-c][1 ,4]thiazine-8-carbonyl)-7-(2,3,6- trimethylphenyl)phthalazin-1-yl)amino)- / V-methyl-3-(2-(trifluoromethyl)pyrimidin-5- yl)propenamide (Example 19) as the first eluting compound (retention time, 2.249 min).Example 19: (R)-2-((5-((*R)-2,2-Dioxidooctahydropyrazino[2, 1 -c][1 ,4]thiazine-8- carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1-yl)amino)- / \ / -methyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)propenamide.

[0214] The title compound was isolated from SFC purification of Example 18. MS (ESI): mass calcd. for C34H37F3N8O4S, 710.3; m / z measured, 711.3 [M+H]+.1H NMR (400MHz, CD3CN) 69.01 - 8.76 (m, 3H), 7.87 (br d, J=11 .8 Hz, 1 H), 7.69 - 7.43 (m, 1 H), 7.19 - 7.12 (m, 1 H), 7.11 - 7.05 (m, 1 H), 6.93 (br s, 1 H), 6.30 (br s, 1 H), 5.23 (br s, 1 H), 4.69 - 4.45 (m, 1 H), 3.42 (br d, J=11 .8 Hz, 1 H), 3.35 - 3.22 (m, 2H), 3.17 (br d, J=13.2 Hz, 2H), 3.13 - 3.05 (m, 1 H), 3.04 - 2.88 (m, 3H), 2.85 - 2.70 (m, 3H), 2.67 (br d, J=4.5 Hz, 4H), 2.57 - 2.39 (m, 1 H), 2.30 (s, 3H), 2.13 - 2.05 (m, 3H), 1.99 (br s, 3H);19F NMR (376MHz, MeCN-cfe) 5 -70.75 (br s, 1 F).Example 20: (2R)- / \ / -Methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7- (2,3,6-trimethylphenyl)phthalazin-1-yl]amino]-3-[6-(trifluoromethyl)-3- pyridyl]propenamide.

[0215] The title compound was prepared in a manner analogous to Example 3 using Sphos Pd G3 instead of rac-BINAP Pd G4 and (R)-2-amino- / \ / -methyl-3-(6- (trifluoromethyl)pyridin-3-yl)propenamide (Intermediate) instead of (R)-3-amino-2- methyl-4-(4-(trifluoromethyl)phenyl)butan-2-ol (Intermediate ) and with the addition of 4A molecular sieves. MS (ESI): mass calcd. for C39H40F3N7O4S, 759.3; m / z measured, 760.4 [M+H]+.1H NMR (400MHz, DMSO-cfe) 68.82 (s, 1 H), 8.74 (s, 1 H), 8.35 (s, 1 H), 8.19 (d, J=4.2 Hz, 1 H), 8.03 (d, J=7.3 Hz, 1 H), 7.78 (dd, J=3.8, 7.6 Hz, 1 H), 7.72 (d, J=8.5 Hz, 1 H), 7.68 (d, J=8.9 Hz, 3H), 7.19 - 7.15 (m, 1 H), 7.14 - 7.09 (m, 1 H), 7.06 (d, J=8.8 Hz, 2H), 5.07 (s, 1 H), 4.01 - 3.73 (m, 2H), 3.55 (s, 2H), 3.33 - 3.18 (m, 6H), 3.08 (s, 3H), 2.62 (d, J=4.3 Hz, 3H), 2.29 (d, J=3.1 Hz, 3H), 2.02 - 1.93 (m, 3H), 1.89 (d, J=16.5 Hz, 3H);19F NMR (376MHz, DMSO-cfe) 6 -66.21 (d, J=5.6 Hz, 1 F).Example 21 : (2R)-3-[3-Amino-4-(trifluoromethyl)phenyl]- / \ / -methyl-2-[[5-[4-(4- methylsulfonylphenyl)piperazine-1-carbonyl]-7-(2,3,6-trimethylphenyl)phthalazin-1 - yl]amino]propenamide.

[0216] The title compound was made in a manner analogous to Example 4 using (R)-2-amino-3-(3-amino-4-(trifluoromethyl)phenyl)- / \ / -methylpropanamide (Intermediate ) instead of (R)-3-amino-2-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)butan-2-ol (Intermediate ).1H NMR (400 MHz, DMSO-d6) d 8.82 (s, 1 H), 8.3-8.4 (m, 1 H), 8.0-8.2 (m, 1 H), 7.67 (s, 4H), 7.0-7.2 (m, 5H), 6.7-6.8 (m, 1 H), 6.6-6.7 (m, 1 H), 5.3-5.5 (m, 2H), 4.9-5.1 (m, 1 H), 3.4-4.1 (m, 5H), 3.08 (s, 6H), 2.60 (d, 3H, J=4.4 Hz), 2.28 (s, 3H), 1.8- 2.1 (m, 7H).Example 22: (2R)- / \ / -Methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7- (2,3,6-trimethylphenyl)phthalazin-1-yl]amino]-3-[2-nitro-4- (trifluoromethyl)phenyl]propenamide.

[0217] The title compound was prepared in a manner analogous to Example 3 using Bl NAP Pd G3 instead of rac-BINAP Pd G4, K3PO4 instead of CS2CO3 and (R)-2- amino- / V-methyl-3-(2-nitro-4-(trifluoromethyl)phenyl)propenamide (Intermediate ) instead of (R)-3-amino-2-methyl-4-(4-(trifluoromethyl)phenyl)butan-2-ol (Intermediate )and with the addition of 4A molecular sieves. MS (ESI): mass calcd. for C40H40F3N7O6S, 803.3; m / z measured, 804.3 [M+H]+.1H NMR (400MHz, DMSO-cfe) <58.84 (s, 1 H), 8.28 - 8.23 (m, 2H), 8.03 (br s, 1 H), 7.96 - 7.90 (m, 1 H), 7.77 (br d, J=7.4 Hz, 1 H), 7.72 - 7.67 (m, 4H), 7.18 - 7.15 (m, 1 H), 7.12 - 7.06 (m, 3H), 5.22 (br s, 1 H), 3.96 - 3.78 (m, 2H), 3.65 - 3.53 (m, 3H), 3.49 - 3.39 (m, 3H), 3.30 - 3.19 (m, 2H), 3.08 - 3.08 (m, 1 H), 3.08 (s, 2H), 2.55 (d, J=4.5 Hz, 3H), 2.28 (d, J=3.5 Hz, 3H), 1.99 - 1.93 (m, 3H), 1.89 (d, J=19.4 Hz, 3H);19F NMR (376MHz, DMSO-cfe) 6 -61 .31 (d, J=4.2 Hz, 1 F).Example 23: (R)-3-(2-Amino-4-(trifluoromethyl)phenyl)- / \ / -methyl-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1- yl)amino)propenamide.

[0218] To a solution of (2R)W-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine- 1 -carbonyl]-7-(2,3,6-trimethylphenyl)phthalazin-1-yl]amino]-3-[2-nitro-4- (trifluoromethyl)phenyl]propenamide (Example 23, 120 mg, 56.38 pmol) in THF (8 ml_) was added 10% wet Pd / C (150 mg) and 20% wet Pd(OH)2 / C (100 mg) under N2. The mixture was stirred under H2 (15 psi) at room temperature overnight. The resulting mixture was filtered through a pad of Celite® and the filter cake was washed with MeOH (3x5 m L). The filtrate was concentrated to dryness in vacuo. The residue was purified by RP-HPLC (Stationary phase: Welch Xtimate C18, 5 pm, 150 x 25 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 50 - 80% B in A over 7 min, flow rate: 25 mL / min) to afford the title compound as white powder. MS (ESI): mass calcd. for C40H42F3N7O4S, 773.3; m / z measured, 774.3 [M+H]+.1H NMR (400MHz, DMSO-cfe) 58.84 (s, 1 H), 8.36 (br d, J=6.9 Hz, 1 H), 8.14 (br d, J=3.0 Hz, 1 H), 7.73 - 7.65 (m, 4H), 7.24 (br s, 1 H), 7.19 - 7.15 (m, 1 H), 7.11 (dd, J=2.8, 7.8 Hz, 1 H), 7.06 (br d, J=8.9 Hz, 2H), 6.89 (s, 1 H), 6.67 (br t, J=6.3 Hz, 1 H), 5.74 (br s, 2H), 4.99 (br s, 1 H),4.02 - 3.76 (m, 2H), 3.56 (br s, 2H), 3.29 (s, 4H), 3.09 - 3.07 (m, 1 H), 3.08 (s, 2H), 3.06 - 2.96 (m, 2H), 2.61 (d, J=4.5 Hz, 3H), 2.28 (d, J=2.9 Hz, 3H), 2.02 - 1.94 (m, 3H), 1.91 (d, J=19.9 Hz, 3H);19F NMR (376MHz, DMSO-cfe) 5 = -61.08 (d, J=2.8 Hz, 1 F).Example 24: (R)- / V-((1r,3R)-3-Hydroxy-3-methylcyclobutyl)-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1- yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide.

[0219] The title compound was prepared in a manner analogous to Example 3 using, K3PO4 instead of CS2CO3, THF instead of 1 ,4-dioxane and (R)-2-amino- / \ / - ((1r,3R)-3-hydroxy-3-methylcyclobutyl)-3-(4-(trifluoromethyl)phenyl)propenamide (Intermediate ) instead of (R)-3-amino-2-methyl-4-(4-(trifluoromethyl)phenyl)butan-2-ol (Intermediate ). MS (ESI): mass calcd. for C44H47F3N6O5S, 828.3; m / z measured, 829.3.1H NMR (400 MHz, CDCI3) 59.02 (s, 1 H), 7.86-7.70 (m, 3H), 7.62-7.49 (m, 2H), 7.45 (d, J = 7.8 Hz, 2H), 7.41-7.28 (m, 2H), 7.14 (d, J = 7.8 Hz, 1 H), 7.10-7.00 (m, 1 H), 6.94 (d, J = 9.3 Hz, 2H), 6.43-6.18 (br m, 1 H), 5.52-5.34 (m, 1 H), 4.51 -4.31 (m, 1 H), 4.29-3.88 (br m, 2H), 3.64-3.15 (br m, 8H), 3.00 (s, 3H), 2.51-2.33 (br m, 2H), 2.29 (d, J = 9.3 Hz, 3H), 2.09-1.73 (m, 9H), 1.26 (s, 3H).Example 25: (R)- / V-((1 s,3S)-3-Hydroxy-3-methylcyclobutyl)-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1- yl)amino)-3-(4-(trifluoromethyl)phenyl)propenamide.

[0220] The title compound was prepared in a manner analogous to Example 3 using Sphos Pd G3 instead of rac-BINAP Pd G4 and (R)-2-amino- / \ / -((1 s,3S)-3-hydroxy- 3-methylcyclobutyl)-3-(4-(trifluoromethyl)phenyl)propenamide (Intermediate ) instead of (R)-3-amino-2-methyl-4-(4-(trifluoromethyl)phenyl)butan-2-ol (Intermediate ) and with the addition of 4A molecular sieves.Biological Example 1 :BFL-1 BIM (WIAQ peptide) homogeneous time-resolved fluorescence assay

[0221] Effect of a test compound on BFL-1 and a-helical Bcl-2 homology-3 (BH3) domains of pro-apoptotic proteins was determined using the homogeneous time- resolved fluorescence (HTRF) binding assay. The assay used the BIM BH3 peptide (H2N-(C / Cy5Mal) WIAQELRRIGDEFN-OH (New England Peptide, order #P612077) as the binding partner for BFL-1. Test compounds that interacted with BFL-1 (6His.Tev.Avi.Bfl1.1-153, Proteros, ClonelD#: PROT_Bfl1_01 ) were identified through displacement of the BIM BH3 peptide (H2N-(C / Cy5Mal) WIAQELRRIGDEFN-OH.

[0222] The assay reaction buffer contained 10 mM Tris, pH 7.5 (Teknova, #T1075), 150 mM NaCI (VWR, #E529), 0.1 mM TCEP (Thermo Fisher, # 77720), 0.0025% Tween-20 (Thermo Fisher, #85113), and 0.1 mg / mL BSA (Sigma, #A7030). Serial diluted test compounds (at concentrations of 10 pM, 3.33 pM, 1.11 pM, 370 nM, 123 nM, 41 nM, 13.7 nM, 4.6 nM, 1 .5 nM, and 0.51 nM) were spotted into white 384-well Proxiplates (Perkin Elmer, #6008289). An 8 nM BFL-1 solution prepared in the reaction buffer was dispensed into the assay wells for a final concentration of 4 nM. The assay plate was incubated for 30 mins at room temperature. Detection reagents containingCy5-BIM peptide and Mab Anti-6HIS Tb cryptate Gold (Tb-anti-His) (Perkin Elmer, #61 HI2TLB) were prepared in the reaction buffer (0.5 nM Tb-anti-His and 120 nM BIM peptide in 1X reaction buffer; 1X reaction buffer = 10 mM Tris, pH 7.5, 150 mM NaCI, 0.1 mM TCEP, 0.0025% Tween-20, and 0.1 mg / mL BSA) and dispensed into the assay wells for a final concentration of 60 nM Cy5-BIM peptide and 0.25 nM Tb-Anti-His. The assay plate was incubated for 60 mins at room temperature. The HTRF signal of the assay was read on a PHERAstar FSX microplate reader (BMG LabTech) using an HTRF optic module, and concentrations that achieved half-maximal inhibition relative to DMSO control (ICso) were determined using Genedata Screener® software.Biological Example 2:BFL-1 BID BH3 homogeneous time-resolved fluorescence assay

[0223] Effect of a test compound on BFL-1 and a-helical Bcl-2 homology-3 (BH3) domains of pro-apoptotic proteins was determined using the homogeneous time- resolved fluorescence (HTRF) binding assay. The assay used the BID BH3 peptide (H2N-(C / Cy5Mal) EDIIRNIARHLAQVGDSMDR-OH (New England Peptide, order #P612077) as the binding partner for BFL-1 . Test compounds that interacted with BFL- 1 (6His.Tev.Avi.Bfl1.1-153, Proteros, ClonelD#: PROT_Bfl1_01) were identified through displacement of the BID BH3 peptide (H2N-(C / Cy5Mal) EDIIRNIARHLAQVGDSMDR- OH.

[0224] The assay reaction buffer contained 10 mM Tris, pH 7.5 (Teknova, #T1075), 150 mM NaCI (VWR, #E529), 0.1 mM TCEP (Thermo Fisher, #77720), 0.0025% Tween-20 (Thermo Fisher, #85113), and 0.1 mg / mL BSA (Sigma, #A7030). Test compounds were serially diluted at concentrations including one or more of the 10-point dilution series A or B listed in Table 3, below, Table 3: Test Compound Serial Dilutions

[0225] and were spotted into white 384-well Proxiplate (Perkin Elmer, #6008289). A 2 nM BFL-1 solution prepared in the reaction buffer was dispensed into the assay wells for a final concentration of 1 nM. The assay plate was incubated for 30 mins at room temperature. Detection reagents containing Cy5-BID peptide and Mab Anti-6HIS Tb cryptate Gold (Tb-anti-His) (Perkin Elmer, #61 HI2TLB) were prepared in the reaction buffer (0.5nM Tb-anti-His and 20nM BID peptide in 1X reaction buffer; with 1X reaction buffer = 10 mM Tris, pH 7.5, 150 mM NaCI, 0.1 mM TCEP, 0.0025% Tween-20, and 0.1 mg / mL BSA) and dispensed into the assay wells for a final concentration of 10 nM Cy5-Bid peptide and 0.25 nM Tb-anti-His. The assay plate was incubated for 60 mins at room temperature. The HTRF signal of the assay was read on a PHERAstar FSX microplate reader (BMG LabTech) using an HTRF optic module, and concentrations that achieved half-maximal inhibition relative to DMSO control (ICso) were determined using Genedata Screener® software.Calculation of Ki values for BID and BIM assays

[0226] The Percent-of-Control (Generic) Normalization Method in GenedataScreener® was used to calculate % inhibition for curve fitting:Central Reference = Neutral Control (high control): 1 %DMSO onlyScale Reference = Blank Control (low control):1 pM NH2-EDIIRNIARHLAQVGDSMDR-OHScale Reference Control type = Stimulator%COntrOl inhibition (%lnh)=100* [ (Lsample-Lneutral) / (Lsiank-Lneutral) ]

[0227] The 4-points curve fit equation below was used to fit the dose response curves to determine ICso:y= Sinf + [ (So-Sinf) I (1 +(X / S5o)h) ] where x=concentration, y = activity, So=activity at bottom plateau of curve, Sinf=activity at top plateau of curve, S5o=inflection point, halfway between So and Sinf and h is hill slope.Ki was calculated using the Cheng-Prusoff equation:Ki = ICso 1 (1 + ([L] / KD)), where [L] = the concentration of labeled ligand, Ki = the inhibition constant, defined as the equilibrium concentration of competitive inhibitor that would occupy 50% of receptor sites if no competing labeled ligand was present, I Cso = the concentration of competitive inhibitor that displaces 50% of the specifically bound labeled ligand, and KD = the affinity constant, defined as the equilibrium concentration of labeled ligand that occupies 50% of receptor sites in the absence of competition.

[0228] For the BIM assay of Biological Example 1 , it was experimentally determined [L] = 60 nM and KD = 61 nM, thus Ki = I Cso 12. For the BID assay of Biological Example 2, it was experimentally determined that [L] = 10 nM and KD = 0.3 nM, thus Ki = ICso / 34.3.

[0229] Representative compounds of the present invention were tested according to the procedures as described in Biological Example 1 and Biological Example 2 above, with results as listed in Table 4, below. Ki values > 2 nM were calculated based on measurements from the BIM assay described in Biological Example 1. Ki values < 2 nM were calculated based on measurements from the BID assay described in Biological Example 2. Where a compound was tested more than once, the Ki value listed below represents the average of the individual measurements.Table 4.Formulation Example 1 :Solid, Oral Dosage Form - Prophetic Example

[0230] As a specific embodiment of an oral composition, 100 mg of any of Compound ID No. 5, 15, 16, 17 or 24, prepared as described in Examples 5, 15, 16, 17 or 24, respectively, is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.

[0231] While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and / or modifications as come within the scope of the following claims and their equivalents.

[0232] Throughout this application, various publications are cited. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.

Claims

What is claimed:

1. A compound of Formula (I),whereinR1is selected from:R2is selected from: phenyl, benzyl, pyridyl, or py rimidinyl , wherein each phenyl, benzyl, pyridyl, or pyrimidinyl is substituted with one, two or three members each independently selected from fluorinated-Ci-4alkyl, O-fluorinated-Ci-4alkyl, NH2, andL is absent or CH2;R3is phenyl substituted with two or three Ci-4alkyl members; andR4is selected from:stereoisomer or pharmaceutically acceptable salt thereof.

2. A compound as in Claim 1 , wherein R2isor a stereoisomer or pharmaceutically acceptable salt thereof.or a stereoisomer or pharmaceutically acceptable salt thereof.

4. A compound as in any one of Claims 1-3, wherein L is absent; or a stereoisomer or pharmaceutically acceptable salt thereof.

5. A compound as in any one of Claims 1-3, wherein L is CH2; or a stereoisomer or pharmaceutically acceptable salt thereof.

6. A compound as in any one of Claims 1-5, wherein R1is H; or a stereoisomer or pharmaceutically acceptable salt thereof.

7. A compound as in any one of Claims 1-5, wherein R1is -C(OH)(CHs)2; or a stereoisomer or pharmaceutically acceptable salt thereof.

8. A compound as in any one of Claims 1-5, wherein R1is -C(=O)NH-CH3; or a stereoisomer or pharmaceutically acceptable salt thereof.

9. A compound as in any one of Claims 1-3 and 5-8, wherein L is CH2 and R4isstereoisomer or pharmaceutically acceptable salt thereof.

10. A compound selected from the group consisting of:[7-(2,5-Dimethylphenyl)-1-[2-[4-(trifluoromethyl)phenyl]ethylamino]phthalazin-5- yl]-[4-(4-methylsulfonylphenyl)piperazin-1-yl]methanone;[1 -[[(1 R)-2-Hydroxy-2-methyl-1 -[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]- 7-(2,3,6-trimethylphenyl)phthalazin-5-yl]-[4-(methylsulfonylmethyl)-1- piperidyl]methanone;[1 -[[(1 R)-2-Hydroxy-2-methyl-1 -[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]- 7-(2,3,6-trimethylphenyl)phthalazin-5-yl]-[4-(4-methylsulfonylphenyl)piperazin-1- yl]methanone;[1 -[[(1 R)-2-Hydroxy-2-methyl-1 -[[6-(trifluoromethyl)-3- pyridyl]methyl]propyl]amino]-7-(2,3,6-trimethylphenyl)phthalazin-5-yl]-[4-(4- methylsulfonylphenyl)piperazin-1-yl]methanone;[(4*R)-3,3-Difluoro-4-(6-methylsulfonyl-3-pyridyl)-1 -pi peridy l]-[ 1 -[[(1 R)-2-hydroxy- 2-methyl-1-[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]-7-(2,3,6- trimethylphenyl)phthalazin-5-yl]methanone;[(4*S)-3,3-Difluoro-4-(6-methylsulfonyl-3-pyridyl)-1 -piperidy l]-[ 1 -[[(1 R)-2-hydroxy- 2-methyl-1-[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]-7-(2,3,6- trimethylphenyl)phthalazin-5-yl]methanone;(*R)-N-Methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1-carbonyl]-7-(2,3,6- trimethylphenyl)phthalazin-1-yl]amino]-2-[4-(trifluoromethoxy)phenyl]acetamide;(*S)-N-Methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1-carbonyl]-7-(2,3,6- trimethylphenyl)phthalazin-1-yl]amino]-2-[4-(trifluoromethoxy)phenyl]acetamide;(*R)-N-Methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1-carbonyl]-7-(2,3,6- trimethylphenyl)phthalazin-1-yl]amino]-2-[2-(trifluoromethyl)pyrimidin-5-yl]acetamide;(*S)-N-Methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1-carbonyl]-7-(2,3,6-trimethylphenyl)phthalazin-1 -yl]amino]-2-[2-(trifluoromethyl)pyrimidin-5-yl]acetamide;(*R)-3-((1*S,3*S,6*R)-7,7-Difluorobicyclo[4.1.0]heptan-3-yl)-N-methyl-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1- yl)amino)propenamide;(*S)-3-((1*S,3*S,6*R)-7,7-Difluorobicyclo[4.1.0]heptan-3-yl)-N-methyl-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1- yl)amino)propenamide;(*R)-3-((1*R,3*R,6*S)-7,7-Difluorobicyclo[4.1.0]heptan-3-yl)-N-methyl-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1- yl)amino)propenamide;(*S)-3-((1 *R,3*R,6*S)-7,7-Difluorobicyclo[4.1 ,0]heptan-3-yl)-N-methyl-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1- yl)amino)propenamide;(R)-2-((5-((*S)-3,3-Difluoro-4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1- carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propenamide;(R)-2-((5-((*R)-3,3-Difluoro-4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1- carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propenamide;(2R)-N-Methyl-2-[[5-[4-(6-methylsulfonyl-3-pyridyl)piperidine-1-carbonyl]-7-(2,3,6- trimethylphenyl)phthalazin-1-yl]amino]-3-[2-(trifluoromethyl)pyrimidin-5-yl]propenamide;(R)-2-((5-((*S)-2,2-Dioxidooctahydropyrazino[2, 1 -c][1 ,4]thiazine-8-carbonyl)-7- (2,3,6-trimethylphenyl)phthalazin-1-yl)amino)-N-methyl-3-(2-(trifluoromethyl)pyrimidin-5- yl)propenamide;(R)-2-((5-((*R)-2,2-Dioxidooctahydropyrazino[2,1-c][1 ,4]thiazine-8-carbonyl)-7- (2,3,6-trimethylphenyl)phthalazin-1-yl)amino)-N-methyl-3-(2-(trifluoromethyl)pyrimidin-5- yl)propenamide;(2R)-N-Methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1-carbonyl]-7-(2,3,6- trimethylphenyl)phthalazin-1-yl]amino]-3-[6-(trifluoromethyl)-3-pyridyl]propenamide;(2R)-3-[3-Amino-4-(trifluoromethyl)phenyl]-N-methyl-2-[[5-[4-(4- methylsulfonylphenyl)piperazine-1-carbonyl]-7-(2,3,6-trimethylphenyl)phthalazin-1-yl]amino]propenamide;(2R)-N-Methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1-carbonyl]-7-(2,3,6- trimethylphenyl)phthalazin-1-yl]amino]-3-[2-nitro-4-(trifluoromethyl)phenyl]propenamide;(R)-3-(2-Amino-4-(trifluoromethyl)phenyl)-N-methyl-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1- yl)amino)propenamide;(R)-N-((1 r,3R)-3-Hydroxy-3-methylcyclobutyl)-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1- yl)amino)-3-(4-(trifluoromethyl)phenyl)propenamide; and(R)-N-((1s,3S)-3-Hydroxy-3-methylcyclobutyl)-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-7-(2,3,6-trimethylphenyl)phthalazin-1- yl)amino)-3-(4-(trifluoromethyl)phenyl)propenamide; or a stereoisomer or pharmaceutically acceptable salt thereof.11 . A compound selected from the group consisting of:acceptable salt thereof.

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any one of Claims 1-11.

13. A pharmaceutical composition made by mixing a compound of any one of Claims 1 -11 and a pharmaceutically acceptable carrier.

14. A process for making a pharmaceutical composition comprising mixing a compound of any one of Claims 1-11 and a pharmaceutically acceptable carrier.

15. A method of treating a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein 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 1-11.

16. The method of Claim 15, 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).

17. The method of Claim 15, wherein the leukemia is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

18. The method of Claim 15, 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.

19. The method of Claim 15, wherein the lymphoma is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

20. The use of the compound of any one of Claims 1 -11 for the preparation of a medicament for the treatment a cancer mediated by the BFL-1 protein, wherein the cancer mediate by the BFL-1 protein is (a) a leukemia, or (b) a lymphoma, in a subject in need thereof.

21. The use as in Claim 20, 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).

22. The use as in Claim 20, 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.

23. The compound of any one of Claims 1-11 , for use in a method for the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is (a) a leukemia or (b) a lymphoma, in a subject in need thereof.

24. The compound of any one of Claims 1-11 , for use in a method for the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein 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. The compound of any one of Claims 1-11 , for use in a method for the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is (a) AIDS-related lymphoma, (b) Hodgkin lymphoma, (c) non-Hodgkin's lymphoma (NHL), (d) T-non-Hodgkin lymphoma (T-NHL), (e) Diffuse Large Cell Lymphoma (DLBCL), (f) activated B-cell DLBCL, (g) germinal center B-cell DLBCL, (h) double-hit lymphoma, (i) double-expressor lymphoma, (j) anaplastic large cell lymphoma, (k) marginal B cell lymphoma, (I) primary mediastinal B-cell lymphoma, (m) immunoblastic large cell lymphoma, (n) Burkitt lymphoma, (o) follicular lymphoma, (p) hairy cell leukemia, (q) Hodgkin's disease, (r) mantle cell lymphoma (MCL), (s) lymphoplasmatic lymphoma, (t) precursor B -lymphoblastic lymphoma, (u) lymphoma of the central nervous system, (v) small lymphocytic lymphoma (SLL), (w) chronic lymphocytic leukemia (CLL), (x) precursor T-lymphoblastic lymphoma / leukemia, (y) peripheral T-cell lymphoma (PTCL), (z) cutaneous T-cell lymphoma (CTCL), (aa) angioimmunoblastic T-cell lymphoma, (ab) extranodal natural killer T-cell lymphoma, (ac) enteropathy type T-cell lymphoma, (ad) subcutaneous panniculitis-like T-cell lymphoma, (ae) anaplastic large cell lymphoma, (af) sarcoma of the soft tissue, (ag)gliosarcoma, (ah) osteosarcoma, (ai) malignant fibrous histiocytoma, (aj) lymphosarcoma, (ak) rhabdomyosarcoma, (al) breast cancer, (am) colorectal carcinoma, (an) gastric cancer, (ao) gliosarcoma, (ap) head & neck cancer, (aq) hepatocellular carcinoma, (ar) lung cancer, (as) multiple myeloma, (at) neuroblastoma, (au) ovarian cancer, (av) pancreatic cancer, (aw) prostate cancer, or (ax) renal cell carcinoma.

26. The compound of any one of Claims 1-11 , for use as a medicament.

27. The compound of any one of Claims 1-11 , for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is (a) a leukemia or (b) a lymphoma, in a subject in need thereof.

28. The compound of any one of Claims 1-11 , for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein 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)29. The compound of any one of Claims 1-11 , for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein 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.

30. A composition comprising a compound of any one of Claims 1 -11 , for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is (a) a leukemia or (b) a lymphoma.

31. A composition comprising a compound of any one of Claims 1 -11 , for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein 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)32. A composition comprising a compound of any one of Claims 1 -11 , for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein 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 celllymphoma, (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.

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

Images