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

Abstract

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

Description

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

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority from United States Provisional Application Serial No. 63 / 706,799 filed October 14, 2024, the contents of which is incorporated by reference in its entirety.

[0004] Field of the Invention

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

[0006] Background of the Invention

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

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

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

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

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

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

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

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

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

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

[0017] Summary of the Invention

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

[0019] R1is selected from the group consisting of hydrogen, halogen, hydroxy, C1-4alkyl, fluorinated C1-4alkyl, hydroxy substituted Ci 4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, - (C1-2alkyl)-O-(C1-4alkyl), -O-(C1-2alkyl)-O-(C1-4alkyl), -SO2-(C1-4alkyl), -ON, -NRARB, -(C1-2alkyl)-NRARB, -C(O)-NRARB, C3-5cycloalkyl, -(C1-2alkyl)-(C3-5Cycloalkyl), -SO2-(C3-5cycloalkyl), 4 to 6 membered heterocycloalkyl, -(C1-2alkyl)-(4 to 6 membered heterocycloalkyl), -C(O)-(5 to 6 membered heterocycloalkyl), 5 to 6 membered heteroaryl, and -(C1-2alkyl)-(5 to 6 membered heteroaryl); wherein the C3-5cycl alkyl, 4 to 6 membered heterocycloalkyl or 5 to 6 membered heterocycloalkyl, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, O-2alkyl, and fluorinated C1-2alkyl; and wherein RAand RBare each independently selected from the group

[0020] 4 consisting of hydrogen, C1-4alkyl and fluorinated C1-2alkyl;

[0021] R2is selected from the group consisting of fluorinated C1-4alkyl, hydroxy substituted C1-4alkyl, -NRCRD, -(C1-2alkyl)-NRcRD, -CH(NRcRE)-(fluorinated C1-3alkyl), - C(O)-NRc-CN, -C(O)-NRCRD, -(C1-4alkyl)-C(O)-NRcRD, -C(O)-NRc-(C1-2alkyl)-NRDRE, - R11, -(C1-2alkyl)-R11, -(hydroxy substituted C1-2alkyl)-R11, -C(O)-NRC-R11, -(C1-2alkyl)- C(O)-NRC-R11, -C(O)-NRc-(C1-2alkyl)-R11, -C(O)-R11, -(C1-2alkyl)-NRc-R11, and -( C1-2alkyl)-NRc-(C1-2alkyl)-R11; wherein R11is C3-5cycloalkyl, 4 to 8 membered heterocycloalkyl and 5 to 6 membered heteroaryl; and wherein the C3-5cycloalkyl, 4 to 8 membered heterocycloalkyl or 5 to 6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-4alkyl, fluorinated C1-2alkyl, and cyano; wherein Rcand REare each independently selected from the group consisting of hydrogen and C1-4alkyl ; and wherein RDis selected from the group consisting of hydrogen, C1-4alkyl, fluorinated C1-4alkyl, hydroxy substituted C1-4alkyl, cyano substituted C1-2alkyl, (hydroxy and fluoro substituted C1-4alkyl), -(C1-4alkyl)-O-(C1-4alkyl), -SO2-(C1-4alkyl), and -(C1-2alkyl)-SO2-N(C1-4alkyl)2; a is an integer from 0 to 1 ; L1is -CH2-;

[0022] R3is selected from the group consisting of phenyl, 4 to 6 membered heterocycloalkyl, 5 to 6 membered heteroaryl, and 4-(trifluoromethyl)- bicyclo[2.2.2]octan-1 -yl; wherein the phenyl, 4 to 6 membered heterocycloalkyl, 5 to 6 membered heteroaryl or 9 to 10 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-4alkyl, fluorinated C1-2alkyl, hydroxy substituted Ci 4alkyl, (C1-2alkyl)-CN, -(C2-4alkenyl)-CN, C1-4alkoxy, fluorinated C1-2alkoxy, -S-(fluorinated C1-2alkyl), -SFs, -NO2, -NRFRG, -(C1-2alkyl)-NRFRG, -NRF-C(O)-(C1-4alkyl), -NRF-C(O)-(hydroxy substituted C1-4alkyl), -NRF- C(O)-(C2-4alkenyl), -NRF-C(O)-(fluorinated C2-4alkenyl), -NRH-C(O)-(C2-4alkenyl)-NRFRG, -NRF-C(O)-(C2-4alkynyl), -NRF-C(O)-(C2-4alkenyl)-(4 to 6 membered heterocycloalkyl) and -NRF-C(O)-(C3-6cycloalkyl); and wherein RFand RGare each independently selected from the group consisting of hydrogen and C1-4alkyl;

[0023] R4is selected from wherein b is an integer from 0 to 3; each R5is independently selected from the group consisting of halogen, C1-4alkyl, fluorinated C1-4alkyl, hydroxy substituted C1-4alkyl, C1-4alkoxy, -NRJRK, -(C1-2alkyl)-NRJRM, -C(O)-NRJRM, -C(O)-NRL-(C1-2alkyl)-NRJRK, -(C1-2alkyl)-C(O)-NRJRK, and -(C1-2alkyl)-NRJ-C(O)-(C1-4alkyl); wherein RJ, RK, and RLare each independently selected from the group consisting of hydrogen and C1-4alkyl; and wherein RMis selected from the group consisting of hydrogen, C1-4alkyl, fluorinated C1-2alkyl, and -(C1-2alkyl)-O-(C1-2alkyl); wherein c is an integer from 0 to 2; each R6is independently selected from the group consisting of halogen, C1-4alkyl, fluorinated C1-4alkyl, hydroxy substituted C1-4alkyl, C1-4alkoxy, and -NRNRP; wherein RNand Rpare each independently selected from the group consisting of hydrogen, methyl and ethyl; d is an integer from 0 to 1 ;

[0024] L2is selected from the group consisting of -NH-C(O)-, -C(O)-NH-, -C(O)-NH-(C1-4alkyl)-, and -C(O)-NH-(fluorinated C1-4alkyl)-; provided that a terminal -C(O)- or -NH- portion of L1is bound directly to the phenyl;

[0025] R7is selected from the group consisting of 4 to 6 membered heterocycloalkyl and 5 to 6 membered heteroaryl; wherein the 4 to 6 membered heterocycloalkyl or 5 to 6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-4alkyl, fluorinated C1-2alkyl, C1-4alkoxy, fluorinated C1-2alkoxy, and -CN;

[0026] R8is selected from the group consisting of

[0027] (a) ; wherein is a nitrogen bound, 4 to 6 membered heterocycloalkyl; wherein the nitrogen bound, 4 to 6 membered heterocycloalkyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-4alkyl, fluorinated C1-2alkyl, hydroxy substituted C1-4alkyl, -(C1-2alkyl)-CN, -(C1-2alkyl)-O-(C1-4alkyl), -(C1-2alkyl)-O-(fluorinated C1-4alkyl), - O-(C1-2alkyl)-O-(C1-4alkyl), =NRQ, -NRQRS, -(C1-2alkyl)-NRQRs, -C(O)-NRQRS, -(C1-2alkyl)-C(O)-NRQRs, -NRQ-C(O)-C(O)-(C1-4alkyl), -NRT-C(O)-C(O)-NRQRS; -NRU-SO2- (C1-4alkyl), -(C1-2alkyl)-NRQ-SO2-(C1-4alkyl), -NRQ-SO2-(C3-5cycloalkyl), -SO2-NRQRS, - (C1-2alkyl)-SO2-(C1-4alkyl), and -(C1-2alkyl)-SO(NH2)-(C1-4alkyl); wherein RQ, Rsand RTare each independently selected from the group consisting of hydrogen and C1-4alkyl; and wherein Ruis selected from the group consisting of hydrogen, C1-4alkyl and cyclopropyl; is a nitrogen bound, 4 to

[0028] 6 membered heterocycloalkyl; wherein the nitrogen bound 4 to 6 membered heterocycloalkyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-2alkyl, fluorinated C1-2alkyl, hydroxy substituted C1-2alkyl, C1-4alkoxy, fluorinated C1-2alkoxy, cyano, and -C(O)-NRVRW; wherein Rvand Rware each independently selected from the group consisting of hydrogen and C1-4alkyl; wherein is selected from the group consisting of C3-6cycloalkyl, phenyl, 4 to 8 membered heterocycloalkyl, 5 to 6 membered heteroaryl, and 5 to 8 membered bicyclic, bridged or spirocyclic heterocycloalkyl; wherein the C3-6cycloalkyl, phenyl, 4 to 8 membered heterocycloalkyl, 5 to 6 membered heteroaryl, or 5 to 8 membered bicyclic, bridged or spirocyclic heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-4alkyl, fluorinated C1-2alkyl, C1-4alkoxy, fluorinated C1-2alkoxy, -SO2-(C1-2alkyl), -SO2-(fluorinated C1-2alkyl), - SO2-NRXRY, -SO(NH2)-CH3, cyano, =NRX, -NRXRY, -NRx-SO2-(C1-2alkyl), -C(O)-(C1-4alkyl), -C(O)OH, -C(O)O-(C1-4alkyl), and -C(O)-NRXRY; wherein Rxand RYare each independently selected from the group consisting of hydrogen, C1-4alkyl, fluorinated C1-2alkyl and hydroxy substituted C1-4alkyl; f is an integer from 0 to 1 ;

[0029] R9is selected from the group consisting of C3-5cycloalkyl, 4 to 6 membered heterocycloalkyl, -C(O)-(4 to 6 membered heterocycloalkyl), and -SO2-(4 to 6 membered heterocycloalkyl); wherein the C3-5cycloalkyl or 4 to 6 membered heterocycloalkyl, whether alone or as part of the R9substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-4alkyl, fluorinated C1-2alkyl, -SO2-(C1-2alkyl), and -SO2-(fluorinated C1-2alkyl); provided that when f is 1 , then is selected from the group consisting of phenyl, 4 to 8 membered heterocycloalkyl, and 5 to 6 membered heteroaryl;

[0030] (c) ; wherein is a nitrogen bound, 4 to 6 membered heterocycloalkyl; wherein the 4 to 6 membered heterocycloalkyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-2alkyl, fluorinated C1-2alkyl, hydroxy substituted C1-2alkyl, C1-4alkoxy, fluorinated C1-2alkoxy, cyano, and -C(O)-NRZRAA; wherein Rzand RAAare each independently selected from the group consisting of hydrogen and C1-4alkyl;

[0031] L3is selected from the group consisting of -(CH2)-, -C(O)-(CH2)-, -NH-, and -O-; wherein the L3group is bound at the 3- or 4- position of

[0032] R10is selected from the group consisting of 4 to 6 membered heterocycloalkyl, and 5 to 6 membered heteroaryl; wherein the 5 to 6 membered heterocycloalkyl or 5 to 6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-4alkyl, fluorinated C1-2alkyl, C1-4alkoxy, fluorinated C1-2alkoxy, -SO2-(C1-2alkyl), -SO2-(fluorinated C1-2alkyl), -SO2-(hydroxy substituted C1-4alkyl), -SO2-NRBBRCC, -SO(NH2)-CH3, cyano, =NRBB, -NRBBRCC, -NRBB- SO2-(C1-2alkyl), -C(O)-(C1-4alkyl), C3-5cycloalkyl,-C(O)OH, -C(O)O-(C1-4alkyl), and -C(O)- NRBBRCC; wherein RBBis selected from the group consisting of hydrogen and C1 -4alkyl; and wherein Rccis selected from the group consisting of hydrogen, C1-4alkyl, fluorinated C1-2alkyl and hydroxy substituted C1-4alkyl; wherein is nitrogen bound 5 to 14 membered bicyclic, bridged or spirocyclic heterocyclyl; wherein the 5 to 14 membered bicyclic, bridged or spirocyclic heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-4alkyl, fluorinated C1-2alkyl, C1-4alkoxy, fluorinated C1-2alkoxy, -SO2-(C1-2alkyl), -SO2-(fluorinated C1-2alkyl), -SO2-(hydroxy substituted C1-4alkyl), -SO2-NRDDREE, -SO(NH2)-CH3, cyano, =NRDD, -NRDDREE, -NRDD- SO2-(C1-2alkyl), -C(O)-(C1-4alkyl), -C(O)OH, -C(O)O-(C1-4alkyl), and -C(O)-NRDDREE, C3-5cycloalkyl, phenyl and 5 to 6 membered heteroaryl; wherein the phenyl or 5 to 6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-4alkyl, fluorinated C1-2alkyl, C1-4alkoxy, fluorinated C1-2alkoxy, -SO2-(C1-2alkyl), and -SO2-(fluorinated C1-2alkyl); wherein RDDis selected from the group consisting of hydrogen and C1-4alkyl; and wherein REEis selected from the group consisting of hydrogen, C1-4alkyl, fluorinated C1-2alkyl and hydroxy substituted C1-4alkyl ; and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

[0033] The present invention is further directed to isoquinoline derivative compounds selected from the group consisting of also known as (R)-2-methyl-3-((4-(4-(4-(methylsulfonyl)phenyl)piperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-4-(4- (trifluoromethyl)phenyl)butan-2-yl dihydrogen phosphate; also known as (R)-2-((3-cyano-5-(4-((dimethylphosphoryl)methyl)piperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propenamide; also known as (R)-2-((5-(4-(2-(dimethylphosphoryl)morpholino)piperidine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof.

[0034] The present invention is further directed to processes for the preparation of compounds of formula (I), compounds of formula (P1 ), compounds of formula (P2), and compounds of formula (P3). The present invention is further directed to a product prepared according to the process described herein.

[0035] 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.

[0036] Exemplifying the invention are methods of treating a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is a leukemia (selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), (acute) T-cell leukemia, acute monocytic leukemia, acute promyelocytic leukemia (APL), bisphenotypic B myelomonocytic leukemia, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia, and myelodysplastic syndrome (MDS)) comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.

[0037] Exemplifying the invention are methods of treating a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is a lymphoma (selected from the group consisting of AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell DLBCL, double-hit lymphoma, double-expressor lymphoma, anaplastic large cell lymphoma, marginal B cell lymphoma, primary mediastinal B-cell lymphoma, immunoblastic large cell lymphoma, Burkitt lymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoplasmatic lymphoma, precursor B - lymphoblastic lymphoma, lymphoma of the central nervous system, small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia (CLL), precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma, sarcoma of the soft tissue, gliosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma, breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma) comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.

[0038] In an embodiment, the present invention is directed to a compound of formula (I), (P1 ), (P2), or (P3) for use as a medicament.

[0039] In another embodiment, the present invention is directed to a compound of formula (I), (P1 ), (P2), or (P3) for use in the treatment of a cancer mediated by the BFL- 1 receptor, wherein the cancer mediated by the BFL-1 receptor is a leukemia (selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), (acute) T-cell leukemia, acute monocytic leukemia, acute promyelocytic leukemia (APL), bisphenotypic B myelomonocytic leukemia, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia, and myelodysplastic syndrome (MDS)).

[0040] In another embodiment, the present invention is directed to a compound of formula (I), (P1 ), (P2), or (P3) for use in the treatment of a cancer mediated by the BFL- 1 receptor, wherein the cancer mediated by the BFL-1 receptor is a lymphoma (selected from the group consisting of AIDS-related lymphoma, Hodgkin lymphoma, nonHodgkin'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).

[0041] In another embodiment, the present invention is directed to a composition comprising a compound of formula (I) (P1 ), (P2) or (P3) for the treatment of a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is a leukemia (selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), (acute) T-cell leukemia, acute monocytic leukemia, acute promyelocytic leukemia (APL), bisphenotypic B myelomonocytic leukemia, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia, and myelodysplastic syndrome (MDS)).

[0042] In another embodiment, the present invention is directed to a composition comprising a compound of formula (I), (P1 ), (P2), or (P3) for the treatment of a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is a lymphoma (selected from the group consisting of AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell DLBCL, double-hit lymphoma, double-expressor lymphoma, anaplastic large cell lymphoma, marginal B cell lymphoma, primary mediastinal B-cell lymphoma, immunoblastic large cell lymphoma, Burkitt lymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoplasmatic lymphoma, precursor B - lymphoblastic lymphoma, lymphoma of the central nervous system, small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia (CLL), precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma; sarcoma of the soft tissue, gliosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma, breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma).

[0043] 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.

[0044] 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.

[0045] In another example, the present invention is directed to a compound as described herein for use in a method for treating a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is a leukemia selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), (acute) T-cell leukemia, acute monocytic leukemia, acute promyelocytic leukemia (APL), bisphenotypic B myelomonocytic leukemia, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia, and myelodysplastic syndrome (MDS), in a subject in need thereof.

[0046] In another example, the present invention is directed to a compound as described herein for use in a method for treating a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is a lymphoma selected from the group consisting of AIDS-related lymphoma, Hodgkin lymphoma, nonHodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), subtypes of NHL such as Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B- cell DLBCL, double-hit lymphoma and double-expressor lymphoma; anaplastic large cell lymphoma, marginal B cell lymphoma and primary mediastinal B-cell lymphoma, immunoblastic large cell lymphoma, Burkitt lymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoplasmatic lymphoma, precursor B -lymphoblastic lymphoma, lymphoma of the central nervous system, small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL); T- cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma; sarcomas including but not limited to sarcoma of the soft tissue, gliosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma; and other cancers, such as solid tumors, including but not limited to breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma, in a subject in need thereof.

[0047] Detailed Description of the Invention

[0048] The present invention is directed to compounds of formula (I) wherein R1, R2, a, L1, R3, R4and R8are as herein defined, and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. The compounds of formula (I) of the present invention are useful for the treatment of cancers mediated by the BFL-1 receptor, including, leukemias, lymphomas and related cancers.

[0049] The present invention is further directed to compounds of formula (P1 ), compounds of formula (P2) and compounds of formula (P3), as herein defined, and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. The compounds of formula (P1 ), compounds of formula (P2) and compounds of formula (P3) of the present invention are useful for the treatment of cancers mediated by the BFL-1 receptor, including, leukemias, lymphomas and related cancers.

[0050] In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of hydrogen, halogen, hydroxy, C1-4alkyl, fluorinated C1-2alkyl, hydroxy substituted C1-2alkyl, C1-2alkoxy, -(C1-2alkyl)-O-(C1-2alkyl), -O-(C1-2alkyl)-O-(C1-2alkyl), -SO2-(C1-2alkyl), -CN, -NRARB, -(C1-2alkyl)-NRARB, - C(O)-NRARB, C3-5cycloalkyl, -(C1-2alkyl)-(C3-5cycloalkyl), -SO2-(C3-5cycloalkyl), 4 to 6 membered heterocycloalkyl, -(C1-2alkyl)-(5 to 6 membered heterocycloalkyl), -C(O)-(5 to 6 membered heterocycloalkyl), and 5 to 6 membered heteroaryl; wherein the C3-5cyclalkyl, 4 to 6 membered heterocycloalkyl or 5 to 6 membered heterocycloalkyl, whether alone or as part of a substituent group, is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C1-2alkyl, and fluorinated C1-2alkyl; and wherein RAand RBare each independently selected from the group consisting of hydrogen, C1-2alkyl and fluorinated C1-2alkyl.

[0051] In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of hydrogen, hydroxy, chloro, methyl, isopropyl, difluoromethyl, trifluoromethyl, hydroxy-methyl, methoxy, ethoxy, methoxy-methyl-, methoxy-ethoxy-, methyl-sulfonyl-, cyclopropyl-sulfonyl-, cyano, methyl-amino-, methyl-amino-methyl-, dimethyl-amino-methyl-, 2,2,2-trifluoroethyl- amino-methyl-, amino-carbonyl-, 1 -(trifluoromethyl)-cycloprop-1 -yl, morpholin-4-yl, piperazin-1 -yl, 3-fluoro-azetidin-1 -yl, 3,3-difluoro-azetidin-1 -yl, oxazol-2-yl, isoxazol-4-yl, morpholin-4-yl-methyl-, morpholin-4-yl-carbonyl-, 3 ,3-d if luoro-pyrrolidi n-1 -yl-methyl-, 3,3-difluoro-piperidin-1 -yl-methyl-, 4, 4-difluoro-piperidin-1 -yl-methyl-, and 4-methyl- piperazin-1 -yl-methyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of hydrogen, chloro, cyano and amino-carbonyl-. I n some embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of hydrogen, chloro, cyano and methyl-sulfonyl-. In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of hydrogen, chloro and cyano.

[0052] In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of cyano, methyl-sulfonyl, H, morpholin-4-yl-methyl, amino-carbonyl, methyl, chloro, dimethyl-amino-methyl, methoxy-methyl, cyclopropyl-sulfonyl, morpholin-4-yl, hydroxy-methyl, -(CO)- (morpholin-4-yl), ethoxy, 2,2,2-trifluoro-ethyl-amino-methyl, methyl-amino-methyl, methoxy, piperazin-1 -yl, difluoro-methyl, trifluoro-methyl, 3, 3-difluoro-pyrrolidin-1 -yl- methyl, 3-fluoro-azetidin-1 -yl, and hydroxy.

[0053] In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of cyano, methyl-sulfonyl, H, morpholin-4-yl-methyl, amino-carbonyl, methyl, chloro, dimethyl-amino-methyl, methoxy-methyl, cyclopropyl-sulfonyl, morpholin-4-yl, hydroxy-methyl, and -(CO)- (morpholin-4-yl).

[0054] In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of cyano, methyl-sulfonyl, H, morpholin-4-yl-methyl, amino-carbonyl, methyl, chloro, dimethyl-amino-methyl, methoxy-methyl, cyclopropyl-sulfonyl, and morpholin-4-yl.

[0055] In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of cyano, methyl-sulfonyl, H, morpholin-4-yl-methyl, amino-carbonyl, methyl, and chloro.

[0056] In some embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of fluorinated C1-4alkyl, hydroxy substituted C1-4alkyl, -NRCRD, -(C1-2alkyl)-NRcRD, -CH(NRcRE)-(fluorinated C1-2alkyl), - C(O)-NRc-CN, -C(O)-NRCRD, -(C1-4alkyl)-C(O)-NRcRD, -C(O)-NRc-(C1-2alkyl)-NRDRE, C3-5cycloalkyl, -C(O)-NRc-(C3-5cycloalkyl), -(C1-2alkyl)-C(O)-NRc-( C3-5cycloalkyl), -C(O)- NRc-(C1-2alkyl)-(C3-5cycloalkyl), -(C1-2alkyl)-NRc-(C3-5cycloalkyl), -(C1-2alkyl)-NRc-(C1-2alkyl)-(C3-5cycloalkyl), 4 to 6 membered heterocycloalkyl, -(C1-2alkyl)-(4 to 6 membered heterocycloalkyl), -(hydroxy substituted C1-2alkyl)-(4 to 6 membered heterocycloalkyl), - C(O)-NRc-(4 to 6 membered heterocycloalkyl), -C(O)-(4 to 6 membered heterocycloalkyl), -(C1-2alkyl)-NRc-(4 to 6 membered heterocycloalkyl), 5 to 6 membered heteroaryl, and -(C1-2alkyl)-(5 to 6 membered heteroaryl); wherein the C3-5cycloalkyl, 4 to 6 membered heterocycloalkyl and 5 to 6 membered heteroaryl, whether alone or as part of a substituent group is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-4alkyl, fluorinated C1-2alkyl, and cyano; and wherein Rcand REare each independently selected from the group consisting of hydrogen and C1-4alkyl ; and wherein RDis selected from the group consisting of hydrogen, C1-4alkyl, fluorinated C1-4alkyl, hydroxy substituted C1-4alkyl, cyano substituted C1-2alkyl, (hydroxy and fluoro substituted C1-4alkyl), -(C1-4alkyl)-O-(C1-4alkyl), -SO2-(C1-2alkyl), and -(C1-2alkyl)-SO2-N(C1-2alkyl)2.

[0057] In some embodiments, the present invention is directed to compounds of formula (I) wherein R11is selected from the group consisting of C3-5cycloalkyl, 4 to 8 membered heterocycloalkyl and 5 to 6 membered heteroaryl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R11is selected from the group consisting of C3-5cycloalkyl, 4 to 6 membered heterocycloalkyl and 5 to 6 membered heteroaryl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R11is C3-5cycloalkyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R11is 4 to 6 membered heterocycloalkyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R11is 5 to 6 membered heteroaryl.

[0058] In some embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of R-(2-fluoro-isopropyl), R- (hydroxy-methyl), 1 R*-(hydroxy-ethyl), 1S*-(hydroxy-ethyl), R*-(1 R*-hydroxy-ethyl), R*- (1 S*-hydroxy-ethyl), S*-(1 R*-hydroxy-ethyl), S*-(1 S*-hydroxy-ethyl), 2-hydroxy- isopropyl, R*-(2-hydroxy-isopropyl), S*-(2-hydroxy-isopropyl), R-(2-hydroxy-isopropyl), R-(2-hydroxy-isobutyl), R-(1 ,3-dihydroxy-1 -methyl-n-propyl), R-(1 R*,3-dihydroxy-1 - methyl-n-propyl), R-(2-hydroxy-tert-butyl), R-(amino-methyl), R-(methyl-amino-methyl), R-(dimethyl-amino-methyl), R-(2,2-difluoro-ethyl)-amino-methyl), R-(2-hydroxy-isobutyl- amino-methyl), R-(2-hydroxy-3,3,3-trifluoro-n-propyl-amino-methyl), R-(2-cyano-ethyl- amino-methyl), R-(methyl-sulfonyl-amino-methyl), R-(dimethyl-amino sulfonyl-ethyl- amino-methyl), R-(1 R-amino-2,2,2-trifluoro-ethyl), R-(1 S-amino-2,2,2-trifluoro-ethyl), S- (1 S-amino-2,2,2-trifluoro-ethyl), amino-carbonyl, R*-(amino-carbonyl), S*-(amino- carbonyl), methyl-amino-carbonyl, R-(D3-methyl-amino-carbonyl), R*-(methyl-amino- carbonyl), S*-(methyl-amino-carbonyl), R-(methyl-amino-carbonyl), S-(methyl-amino- carbonyl), R-(dimethyl-amino-carbonyl), R-(isopropyl-amino-carbonyl), R-(t-butyl-amino- carbonyl), R-(2-isobutyl-amino-carbonyl), R-(cyano-amino-carbonyl), R-(2-hydroxy- isobutyl-amino-carbonyl), R-((2,2-difluoro-ethyl)-amino-carbonyl), R-((2,2,2-trifluoro- ethyl)-amino-carbonyl), R-(2,2,3,3,3-pentafluoro-n-propyl-amino-carbonyl), R-(2- hydroxy-3,3,3-trifluoro-n-propyl-amino-carbonyl), R-(2-methoxy-isobutyl-amino- carbonyl), S*-(methyl-amino-carbonyl-methyl), R*-(methyl-amino-carbonyl-methyl), R- (methyl-amino-carbonyl-methyl), S-(methyl-amino-carbonyl-methyl), S-(2-hydroxy- isobutyl-amino-carbonyl-methyl), S-(2,2-difluoro-ethyl-amino-carbonyl-methyl), S-(2,2,2- trifluoro-ethyl-amino-carbonyl-methyl), S*-(2-(methyl-amino-carbonyl)-isopropyl), R*-(2- (methyl-amino-carbonyl)-isopropyl), R-(dimethyl-amino-ethyl-amino-carbonyl), R*- (dimethyl-amino-ethyl-amino-carbonyl), S*-(dimethyl-amino-ethyl-amino-carbonyl), R*- (1 -hydroxy-cycloprop-1 -yl), S*-(1 -hydroxy-cycloprop-1 -yl), R*-(1 -hydroxy-cyclobut-1 -yl), S*-(1 -hydroxy-cyclobut-1 -yl), R*-(3-hydroxy-oxetan-3-yl), S*-(3-hydroxy-oxetan-3-yl), R*-(4-hydroxy-piperidin-4-yl), S*-(4-hydroxy-piperidin-4-yl), R*-(4-hydroxy-tetrahydro- pyran-4-yl), S*-(4-hydroxy-tetrahydro-pyran-4-yl), 1 -(pi peridin-4-y I) -1 S*-hydroxy-methyl, R*-(piperidin-4-yl-R*-hydroxy-methyl), R*-(piperidin-4-yl-S*-hydroxy-methyl), R- (morpholin-4-yl-methyl), R-(thiomorpholin-4-yl 1 ,1 -dioxide-methyl), R-(thiomorpholin-4-yl 1 ,1 -dioxide-methyl), 5-methyl-pyridazin-2-yl, R-(3-methyl-1 ,2,4-oxadiazol-5-yl), R-(5- methyl-1 ,2,4-oxadiazol-2-yl), R-(5-methyl-1 ,3,4-oxadiazol-2-yl), S-(5-methyl-1 ,3,4- oxadiazol-2-yl)-methyl, R-(2-methyl-1 ,3 ,4-thiadiazol-5-y I) , R-(1 -methyl-1 ,2 ,3-triazol-4-y I) , R-(3,3-difluoro-cyclobut-1 -yl-amino-carbonyl), R-(3,3-dimethyl-cyclobut-1 -yl-amino- carbonyl), 1 -(trifluoro-methyl)-cycloprop-l -yl-amino-carbonyl, R-(1 -(trifluoro-methyl)- cycloprop-1 -yl-amino-carbonyl), R-(trans-(2-(trifluoro-methyl)-cycloprop-1 -yl)-amino- carbonyl), R-(1 -cyano-cycloprop-1 -yl-amino-carbonyl), R-(cyclobutyl-amino-carbonyl), R-(cis-(3-hydroxy-3-methyl-cyclobut-1 -yl)-amino-carbonyl), R-(trans-(3-hydroxy-3- methyl-cyclobut-1 -yl)-amino-carbonyl), R-((3-cyano-bicyclo[1 .1.1]pentan-1 -yl)-amino- carbonyl), R-(thietan-3-yl 1 ,1 -dioxide-amino-carbonyl), R-(1 -methyl-pyrrolidin-2-yl- methyl-amino-carbonyl), R-(S-(1 -methyl-4,4-difluoro-pyrrolidin-2-yl)-methyl-amino- carbonyl), R-(1 -methyl-piperidin-2-yl-methyl-amino-carbonyl), R-(4-methyl-morpholin-2- yl-methyl-amino-carbonyl), morpholin-4-yl-ethyl-amino-carbonyl, R-(tetrahydro-furan-2- yl-methyl-amino-carbonyl), S-(1 -(trifluoro-methyl)-cycloprop-l -yl-amino-carbonyl- methyl), R-(1 -(trifluoro-methyl)-cycloprop-l -yl-amino-carbonyl-methyl), R-(1 -(trifluoro- methyl)-cycloprop-1 -yl-methyl-amino-carbonyl), R-trans-(1 -(trifluoro-methyl)-cycloprop- 1 -yl-methyl-amino-carbonyl), R-(1 -cyano-cycloprop-1 -yl-methyl-amino-carbonyl), R- (hexahydro-1 H-pyrrolizin-7a-yl-methyl-amino-carbonyl), R-(morpholin-4-yl-carbonyl), R- (3 , 3-difl uoro-pyrrolidi n-1 -yl-carbonyl), R-(trans-(2-trifluoro-methyl-cycloprop-1 -yl)-amino- methyl), R-(cis-(3-hydroxy-3-methyl-cyclobut-1 -yl)-amino-methyl), R-(3-(trifluoromethyl)- bicyclo[1 .1 .1]pentan-1 -yl)-amino-methyl), R-(oxetan-3-yl-amino-methyl), R-(thietan-3-yl 1 ,1 -dioxide-amino-methyl), and R-(1 -trifluoro-methyl-cycloprop-1 -yl-methyl-amino- methyl).

[0059] In some embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of R-(2-hydroxy-isopropyl), methylamino-carbonyl, R-(methyl-amino-carbonyl), R-(2-hydroxy-isobutyl-amino-carbonyl), R- (2,2-difluoro-ethyl-amino-carbonyl), R-(1 -cyano-cycloprop-1 -yl-amino-carbonyl), 1 - trifluoro-methyl-cycloprop-1 -yl-amino-carbonyl, R-(1 -trifluoro-methyl-cycloprop-1 -yl- amino-carbonyl), and S-(methyl-amino-carbonyl-methyl).

[0060] In some embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of R-(2-fluoro-isopropyl), R- (hydroxy-methyl), 1 R*-(hydroxy-ethyl), 1S*-(hydroxy-ethyl), R*-(1 R*-hydroxy-ethyl), R*- (1 S*-hydroxy-ethyl), S*-(1 R*-hydroxy-ethyl), S*-(1 S*-hydroxy-ethyl), 2-hydroxy- isopropyl, R*-(2-hydroxy-isopropyl), S*-(2-hydroxy-isopropyl), R-(2-hydroxy-isopropyl), R-(2-hydroxy-isobutyl), R-(1 ,3-dihydroxy-1 -methyl-n-propyl), R-(1 R*,3-dihydroxy-1 - methyl-n-propyl), R-(2-hydroxy-tert-butyl), R-(amino-methyl), R-(methyl-amino-methyl), R-(dimethyl-amino-methyl), R-(2,2-difluoro-ethyl)-amino-methyl), R-(2-hydroxy-isobutyl- amino-methyl), R-(2-hydroxy-3,3,3-trifluoro-n-propyl-amino-methyl), R-(2-cyano-ethyl- amino-methyl), R-(methyl-sulfonyl-amino-methyl), R-(dimethyl-amino sulfonyl-ethyl- amino-methyl), R-(1 R-amino-2,2,2-trifluoro-ethyl), R-(1 S-amino-2,2,2-trifluoro-ethyl), S- (1 S-amino-2,2,2-trifluoro-ethyl), amino-carbonyl, R*-(amino-carbonyl), S*-(amino- carbonyl), methyl-amino-carbonyl, R-(D3-methyl-amino-carbonyl), R*-(methyl-amino- carbonyl), S*-(methyl-amino-carbonyl), R-(methyl-amino-carbonyl), S-(methyl-amino- carbonyl), R-(dimethyl-amino-carbonyl), R-(isopropyl-amino-carbonyl), R-(t-butyl-amino- carbonyl), R-(2-isobutyl-amino-carbonyl), R-(cyano-amino-carbonyl), R-(2-hydroxy- isobutyl-amino-carbonyl), R-((2,2-difluoro-ethyl)-amino-carbonyl), R-((2,2,2-trifluoro- ethyl)-amino-carbonyl), R-(2,2,3,3,3-pentafluoro-n-propyl-amino-carbonyl), R-(2- hydroxy-3,3,3-trifluoro-n-propyl-amino-carbonyl), R-(2-methoxy-isobutyl-amino- carbonyl), S*-(methyl-amino-carbonyl-methyl), R*-(methyl-amino-carbonyl-methyl), R- (methyl-amino-carbonyl-methyl), S-(methyl-amino-carbonyl-methyl), S-(2-hydroxy- isobutyl-amino-carbonyl-methyl), S-(2,2-difluoro-ethyl-amino-carbonyl-methyl), S-(2,2,2- trifluoro-ethyl-amino-carbonyl-methyl), S*-(2-(methyl-amino-carbonyl)-isopropyl), R*-(2- (methyl-amino-carbonyl)-isopropyl), R-(dimethyl-amino-ethyl-amino-carbonyl), R*- (dimethyl-amino-ethyl-amino-carbonyl), S*-(dimethyl-amino-ethyl-amino-carbonyl), R*- (1 -hydroxy-cycloprop-1 -yl), S*-(1 -hydroxy-cycloprop-1 -yl), R*-(1 -hydroxy-cyclobut-1 -yl), S*-(1 -hydroxy-cyclobut-1 -yl), R*-(3-hydroxy-oxetan-3-yl), S*-(3-hydroxy-oxetan-3-yl), R*-(4-hydroxy-piperidin-4-yl), S*-(4-hydroxy-piperidin-4-yl), R*-(4-hydroxy-tetrahydro- pyran-4-yl), S*-(4-hydroxy-tetrahydro-pyran-4-yl), 1 -(pi peridin-4-y I) -1 S*-hydroxy-methyl, R*-(piperidin-4-yl-R*-hydroxy-methyl), R*-(piperidin-4-yl-S*-hydroxy-methyl), R- (morpholin-4-yl-methyl), R-(thiomorpholin-4-yl 1 ,1 -dioxide-methyl), 5-methyl-pyridazin-2- yl, R-(3-methyl-1 ,2,4-oxadiazol-5-yl), R-(5-methyl-1 ,2,4-oxadiazol-2-yl), R-(5-methyl- 1 ,3,4-oxadiazol-2-yl), S-(5-methyl-1 ,3,4-oxadiazol-2-yl)-methyl, R-(2-methyl-1 ,3,4- thiadiazol-5-yl), R-(1 -methyl-1 ,2,3-triazol-4-yl), R-(3,3-difluoro-cyclobut-1 -yl-amino- carbonyl), R-(3,3-dimethyl-cyclobut-1 -yl-amino-carbonyl), R-(1 -(trifluoro-methyl)- cycloprop-1 -yl-amino-carbonyl), , R-(1 -cyano-cycloprop-1 -yl-amino-carbonyl), R- (cyclobutyl-amino-carbonyl), R-(cis-(3-hydroxy-3-methyl-cyclobut-1 -yl)-amino-carbonyl), R-(trans-(3-hydroxy-3-methyl-cyclobut-1 -yl)-amino-carbonyl), R-((3-cyano- bicyclo[1 .1 .1]pentan-1 -yl)-amino-carbonyl), R-(thietan-3-yl 1 ,1 -dioxide-amino-carbonyl), R-(1 -methyl-pyrrolidin-2-yl-methyl-amino-carbonyl), R-(S-(1 -methyl-4,4-difluoro- pyrrolidin-2-yl)-methyl-amino-carbonyl), R-(1 -methyl-piperidin-2-yl-methyl-amino- carbonyl), R-(4-methyl-morpholin-2-yl-methyl-amino-carbonyl), morpholin-4-yl-ethyl- amino-carbonyl, R-(tetrahydro-furan-2-yl-methyl-amino-carbonyl), S-(1 -(trifluoro- methyl)-cycloprop-1 -yl-amino-carbonyl-methyl), R-(1 -(trifluoro-methyl)-cycloprop-l -yl- amino-carbonyl-methyl), R-(1 -(trifluoro-methyl)-cycloprop-l -yl-methyl-amino-carbonyl), R-trans-(1 -(trifluoro-methyl)-cycloprop-l -yl-methyl-amino-carbonyl), R-(1 -cyano- cycloprop-1 -yl-methyl-amino-carbonyl), R-(hexahydro-1 H-pyrrolizin-7a-yl-methyl-amino- carbonyl), R-(morpholin-4-yl-carbonyl), R-(3,3-difluoro-pyrrolidin-1 -yl-carbonyl), R- (trans-(2-trifluoro-methyl-cycloprop-1 -yl)-amino-methyl), R-(cis-(3-hydroxy-3-methyl- cyclobut-1 -yl)-amino-methyl), R-(3-(trifluoromethyl)-bicyclo[1 .1 .1]pentan-1 -yl)-amino- methyl), R-(oxetan-3-yl-amino-methyl), R-(thietan-3-yl 1 ,1 -dioxide-amino-methyl), and R-(1 -trifluoro-methyl-cycloprop-1 -yl-methyl-amino-methyl) /

[0061] In some embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of R-(2-hydroxy-isopropyl), R- (methyl-amino-carbonyl), S-(methyl-amino-carbonyl-methyl) and R-(thiomorpholin-4-yl 1 ,1 -dioxide-methyl). In some embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of 2-hydroxy- isopropyl, R-(2-hydroxy-isopropyl), R-(methyl-amino-carbonyl), R*-(methyl-amino- carbonyl), S*-(methyl-amino-carbonyl) and R-(2-hydroxy-isobutyl-amino-carbonyl).

[0062] In some embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of R-(1 -methyl-piperidin-2-yl-methyl- amino-carbonyl), R-(2-hydroxy-isobutyl-amino-carbonyl), R-(dimethyl-amino-ethyl- amino-carbonyl), R-(methyl-amino-carbonyl), R-(2-hydroxy-isopropyl), R-(hexahydro- 1 H-pyrrolizin-7a-yl-methyl-amino-carbonyl), R-(2,2-difluoro-ethyl)-amino-carbonyl), R-(1 - cyano-cycloprop-1 -yl-methyl-amino-carbonyl), R-(cis-(3-hydroxy-3-methyl-cyclobut-1 - yl)-amino-carbonyl), R-(2,2,2-trifluoro-ethyl-amino-carbonyl), R*-(methyl-amino- carbonyl), R-(1 -methyl-pyrrolidin-2-yl-methyl-amino-carbonyl), S*-(methyl-amino- carbonyl), R-(1 -cyano-cycloprop-1 -yl-amino-carbonyl), R-(2,2-difluoro-ethyl-amino- carbonyl), R-(2-methoxy-isobutyl-amino-carbonyl), R-(trans-(2-trifluoro-methyl- cycloprop-1 -yl)-amino-carbonyl), R-(1 -trifluoro-methyl-cycloprop-1 -yl-amino-carbonyl), S*-(methyl-amino-carbonyl-methyl), R-(4-methyl-morpholin-2-yl-methyl-amino-carbonyl), R-(2-hydroxy-isobutyl-amino-methyl), R-(dimethyl-amino-carbonyl), R-(1 -methyl-1 ,2,3- triazol-4-yl), R-(2-isobutyl-amino-carbonyl), R-(cis-(3-hydroxy-3-methyl-cyclobut-1 -yl)- amino-methyl), R-(methyl-amino-methyl), R-(trans-(3-hydroxy-3-methyl-cyclobut-1 -yl)- amino-carbonyl), R-(dimethyl-amino-methyl), R-(tetrahydro-furan-2-yl-methyl-amino- carbonyl), R*-(methyl-amino-carbonyl-methyl), methyl-amino-carbonyl, S-(methyl- amino-carbonyl-methyl), S-(2-hydroxy-isobutyl-amino-carbonyl-methyl), morpholin-4-yl- ethyl-amino-carbonyl, R-(S-(1 -methyl-4,4-difluoro-pyrrolidin-2-yl)-methyl-amino- carbonyl), R-(1 S-amino-2,2,2-trifluoro-ethyl), R-(D3-methyl-amino-carbonyl), R*-(3- hydroxy-oxetan-3-yl), R-(2,2-difluoro-ethyl)-amino-methyl), R-(isopropyl-amino- carbonyl), R-(oxetan-3-yl-amino-methyl), R-(morpholin-4-yl-methyl), S*-(4-hydroxy- piperidin-4-yl), R-(5-methyl-1 ,2,4-oxadiazol-2-yl), R-(2-cyano-ethyl-amino-methyl), R-(2- methyl-1 ,3,4-thiadiazol-5-yl), R*-(amino-carbonyl), R-(methyl-amino-carbonyl-methyl), R-(thietan-3-yl 1 ,1 -dioxide-amino-carbonyl), R-(thietan-3-yl 1 ,1 -dioxide-amino-methyl), S*-(1 S*-hydroxy-ethyl), S-(2,2-difluoro-ethyl-amino-carbonyl-methyl), R-(5-methyl-1 ,3,4- oxadiazol-2-yl), 1 -(pi peridi n-4-yl)- 1 S*-hydroxy-methyl, R-(1 -trifluoro-methyl-cycloprop-1 - yl-methyl-amino-carbonyl), R-(hydroxy-methyl), 1 S*-(hydroxy-ethyl), R-(3,3-difluoro- pyrrolidin-1 -yl-carbonyl), R-(thiomorpholin-4-yl 1 ,1 -dioxide-methyl), R-((3-cyano- bicyclo[1 .1 .1]pentan-1 -yl)-amino-carbonyl), R-(2-hydroxy-3,3,3-trifluoro-n-propyl-amino- carbonyl), R-(1 R*,3-dihydroxy-1 -methyl-n-propyl), R-trans((1 -trifluoro-methyl-cycloprop- 1 -yl)-methyl-amino-carbonyl), R-(cyclobutyl-amino-carbonyl), R-(3,3-difluoro-cyclobut-1 - yl-amino-carbonyl), R-(2-hydroxy-isobutyl), R-(amino-methyl), and S*-(dimethyl-amino- ethyl-amino-carbonyl).

[0063] In some embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of R-(1 -methyl-piperidin-2-yl-methyl- amino-carbonyl), R-(2-hydroxy-isobutyl-amino-carbonyl), R-(dimethyl-amino-ethyl- amino-carbonyl), R-(methyl-amino-carbonyl), R-(2-hydroxy-isopropyl), R-(hexahydro- 1 H-pyrrolizin-7a-yl-methyl-amino-carbonyl), R-(2,2-difluoro-ethyl)-amino-carbonyl), R-(1 - cyano-cycloprop-1 -yl-methyl-amino-carbonyl), R-(cis-(3-hydroxy-3-methyl-cyclobut-1 - yl)-amino-carbonyl), R-(2,2,2-trifluoro-ethyl-amino-carbonyl), R*-(methyl-amino- carbonyl), R-(1 -methyl-pyrrolidin-2-yl-methyl-amino-carbonyl), S*-(methyl-amino- carbonyl), R-(1 -cyano-cycloprop-1 -yl-amino-carbonyl), R-(2,2-difluoro-ethyl-amino- carbonyl), R-(2-methoxy-isobutyl-amino-carbonyl), R-(trans-(2-trifluoro-methyl- cycloprop-1 -yl)-amino-carbonyl), R-(1 -trifluoro-methyl-cycloprop-1 -yl-amino-carbonyl), S*-(methyl-amino-carbonyl-methyl), R-(4-methyl-morpholin-2-yl-methyl-amino-carbonyl), R-(2-hydroxy-isobutyl-amino-methyl), R-(dimethyl-amino-carbonyl), R-(1 -methyl-1 ,2,3- triazol-4-yl), R-(2-isobutyl-amino-carbonyl), R-(cis-(3-hydroxy-3-methyl-cyclobut-1 -yl)- amino-methyl), R-(methyl-amino-methyl), R-(trans-(3-hydroxy-3-methyl-cyclobut-1 -yl)- amino-carbonyl), R-(dimethyl-amino-methyl), R-(tetrahydro-furan-2-yl-methyl-amino- carbonyl), R*-(methyl-amino-carbonyl-methyl), and S*-(dimethyl-amino-ethyl-amino- carbonyl).

[0064] In some embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected form the group consisting of R-(1 -methyl-piperidin-2-yl-methyl- amino-carbonyl), R-(2-hydroxy-isobutyl-amino-carbonyl), R-(dimethyl-amino-ethyl- amino-carbonyl), R-(methyl-amino-carbonyl), R-(2-hydroxy-isopropyl), R-(hexahydro- 1 H-pyrrolizin-7a-yl-methyl-amino-carbonyl), R-(2,2-difluoro-ethyl)-amino-carbonyl), R-(1 - cyano-cycloprop-1 -yl-methyl-amino-carbonyl), R-(cis-(3-hydroxy-3-methyl-cyclobut-1 - yl)-amino-carbonyl), R-(2,2,2-trifluoro-ethyl-amino-carbonyl), R*-(methyl-amino- carbonyl), R-(1 -methyl-pyrrolidin-2-yl-methyl-amino-carbonyl), S*-(methyl-amino- carbonyl), R-(1 -cyano-cycloprop-1 -yl-amino-carbonyl), R-(2,2-difluoro-ethyl-amino- carbonyl), R-(2-methoxy-isobutyl-amino-carbonyl), R-(trans-(2-trifluoro-methyl- cycloprop-1 -yl)-amino-carbonyl), R-(1 -trifluoro-methyl-cycloprop-1 -yl-amino-carbonyl), S*-(methyl-amino-carbonyl-methyl), R-(4-methyl-morpholin-2-yl-methyl-amino-carbonyl), R-(2-hydroxy-isobutyl-amino-methyl), R-(dimethyl-amino-carbonyl), and S*-(dimethyl- amino-ethyl-amino-carbonyl).

[0065] In some embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of R-(1 -methyl-piperidin-2-yl-methyl- amino-carbonyl), R-(2-hydroxy-isobutyl-amino-carbonyl), R-(dimethyl-amino-ethyl- amino-carbonyl), R-(methyl-amino-carbonyl), R-(2-hydroxy-isopropyl), R-(hexahydro- 1 H-pyrrolizin-7a-yl-methyl-amino-carbonyl), R-(2,2-difluoro-ethyl)-amino-carbonyl), R-(1 - cyano-cycloprop-1 -yl-methyl-amino-carbonyl), R-(cis-(3-hydroxy-3-methyl-cyclobut-1 - yl)-amino-carbonyl), R-(2,2,2-trifluoro-ethyl-amino-carbonyl), R*-(methyl-amino- carbonyl), R-(1 -methyl-pyrrolidin-2-yl-methyl-amino-carbonyl), S*-(methyl-amino- carbonyl), R-(1 -cyano-cycloprop-1 -yl-amino-carbonyl), R-(2,2-difluoro-ethyl-amino- carbonyl), and S*-(dimethyl-amino-ethyl-amino-carbonyl).

[0066] In some embodiments, the present invention is directed to compounds of formula (I) wherein a is 0. In some embodiments, the present invention is directed to compounds of formula (I) wherein a is 1 ; and L1is -CH2-.

[0067] In some embodiments, the present invention is directed to compounds of formula (I) wherein R3is selected from the group consisting of phenyl, 4 to 6 membered heterocycloalkyl, 5 to 6 membered heteroaryl, and 4-(trifluoromethyl)- bicyclo[2.2.2]octan-1 -yl; wherein the phenyl, 4 to 6 membered heterocycloalkyl, 5 to 6 membered heteroaryl or 9 to 10 membered heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C1-2alkyl, fluorinated C1-2alkyl, hydroxy substituted C1-4alkyl, (C1-2alkyl)-CN, -(C2-4alkenyl)- CN, C1-4alkoxy, fluorinated C1-2alkoxy, -S-(fluorinated C1-2alkyl), -SF5, -NO2, -NRFRG, - (C1-2alkyl)-NRFRG, -NRF-C(O)-(C1-4alkyl), -NRF-C(O)-(hydroxy substituted C1-4alkyl), - NRF-C(O)-(C2-4alkenyl), -NRF-C(O)-(fluorinated C2-4alkenyl), -NRH-C(O)-(C2-4alkenyl)- NRFRG, -NRF-C(O)-(C2-4alkynyl), -NRF-C(O)-(C2-4alkenyl)-(4 to 6 membered heterocycloalkyl) and -NRF-C(O)-(C3-6cycloalkyl); and wherein RF, RGand RHare each independently selected from the group consisting of hydrogen and C1-2alkyl.

[0068] In some embodiments, the present invention is directed to compounds of formula (I) wherein R3is selected from the group consisting of phenyl, 4-ethyl-phenyl, 4- (trifluoro-methyl)-phenyl, 4-(2,2,2-trifluoro-ethyl)-phenyl, 4-(pentafluoro-ethyl)-phenyl, 2- chloro-4-trifluoro-methyl-phenyl, 4-(1 -hydroxy-isopropyl)-phenyl, 3-(hydroxy-methyl)-4- trifluoro-methyl-phenyl, 4-(trifluoro-methoxy)-phenyl, 4-(trifluoro-methyl-thio)-phenyl, 4- (pentafluoro-thio)-phenyl, 4-(cyano-methyl)-phenyl, 4-(1 -cyano-vinyl)-phenyl, 2-(1 - cyano-vinyl-4-trifluoro-methyl-phenyl), 3-(cyano-methyl)-4-trifluoro-methyl-phenyl, 2- nitro-4-trifluoro-methyl-phenyl, 2-amino-4-trifluoro-methyl-phenyl, 3-amino-4-trifluoro- methyl-phenyl, 2-methyl-amino-4-trifluoro-methyl-phenyl, 2-(amino-methyl)-4-trifluoro- methyl-phenyl, 3-(amino-methyl)-4-trifluoro-methyl-phenyl, 3-(methyl-carbonyl-amino)-4- trifluoro-methyl-phenyl, 3-(hydroxy-methyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 4- (vinyl-carbonyl-amino)-phenyl, 2-(vinyl-carbonyl-amino)-4-trifluoro-methyl-phenyl), 3- (vinyl-carbonyl-amino)-4-(trifluoro-methyl)-phenyl, 2-(vinyl-carbonyl-amino)-4- (pentafluoro-ethyl)-phenyl, 2-(vinyl-carbonyl-amino)-4-trifluoro-methoxy-phenyl, 2-(N- methyl, N-vinyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(prope-1 -nyl-carbonyl- amino)-4-trifluoro-methyl-phenyl, 2-(3-dimethyl-amino-prope-1 -nyl-carbonyl-amino)-4- trifluoro-methyl-phenyl, 2-(1 -fluoro-vinyl-carbonyl-amino)-4-(trifluoro-methyl)-phenyl, 2- (propa-1 ,2-dienyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(propy-1 -nyl-carbonyl- amino)-4-trifluoro-methyl-phenyl, 3-(propy-2-nyl-carbonyl-amino)-4-(trifluoro-methyl)- phenyl, 2-(morpholin-4-yl-prope-1 -yl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2- (bicyclo[1 .1 .0]butan-1 -yl-carbonyl-amino)-4-(trifluoro-methyl)-phenyl, 1 -(2,2,2-trifluoro- ethyl)-piperidin-4-yl, 6-(trifluoro-methyl)-pyridin-3-yl, 6-(trifluoro-methoxy)-pyridin-3-yl, 2- (trifluoro-methyl)-pyrimidin-5-yl, 2-(trifluoro-methyl)-thiazol-4-yl, and 4-(trifluoromethyl)- bicyclo[2.2.2]octan-1 -yl.

[0069] In some embodiments, the present invention is directed to compounds of formula (I) wherein R3is selected from the group consisting of 4-trifluoro-methyl-phenyl, 4- (2,2,2-trifluoro-ethyl)-phenyl and 6-(trifluoro-methyl)-pyridin-3-yl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R3is selected from the group consisting of 4-trifluoro-methyl-phenyl and 6-(trif luoro-methyl)-pyridin-3- yi-

[0070] In some embodiments, the present invention is directed to compounds of formula (I) wherein R3is selected from the group consisting of 4-trifluoro-methyl-phenyl, 6- (trifluoro-methyl)-pyridin-3-yl, 2-(vinyl-carbonyl-amino)-4-trifluoro-methyl)-phenyl, 2- (propa-1 ,2-dienyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(1 -cyano-vinyl-4-trifluoro- methyl-phenyl), 2-(trif I uoro-methyl)-th iazol-4-yl , 2-(prope-1 -nyl-carbonyl-amino)-4- trifluoro-methyl-phenyl, 2-(trifluoro-methyl)-pyrimidin-5-yl, 4-(2,2,2-trifluoro-ethyl)-phenyl, 2-nitro-4-trifluoro-methyl-phenyl, 2-amino-4-trifluoro-methyl-phenyl, 4-(trifluoro- methoxy)-phenyl, 2-(vinyl-carbonyl-amino)-4-(pentafluoro-ethyl)-phenyl, 3-(amino- methyl)-4-trifluoro-methyl-phenyl, 2-chloro-4-trifluoro-methyl-phenyl, 2- (bicyclo[1 .1 .0]butan-1 -yl-carbonyl-amino)-4-(trifluoro-methyl)-phenyl, 3-(propy-2-nyl- carbonyl-amino)-4-(trifluoro-methyl)-phenyl, 2-(1 -fluoro-vinyl-carbonyl-amino)-4- (trifluoro-methyl)-phenyl, 4-(trifluoro-methyl)-bicyclo[2.2.2]octan-1 -yl , 3-(hydroxy- methyl)-4-trifluoro-methyl-phenyl, 4-(cyano-methyl)-phenyl, 3-(vinyl-carbonyl-amino)-4- trifluoro-methyl-phenyl, 4-(1 -cyano-vinyl)-phenyl, 2-(vinyl-carbonyl-amino)-4-trifluoro- methyl-phenyl), 3-(vinyl-carbonyl-amino-(4-trifluoro-methyl)-phenyl, 2-(N-methyl, N- vinyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(3-dimethyl-amino-prope-1 -nyl- carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(propy-1 -nyl-carbonyl-amino)-4-trifluoro- methyl-phenyl, 2-(morpholin-4-yl-propen-1 -yl-carbonyl-amino)-4-trifluoro-methyl-phenyl, and 2-(vinyl-carbonyl-amino)-4-trifluoro-methoxy-phenyl).

[0071] In some embodiments, the present invention is directed to compounds of formula (I) wherein R3is selected from the group consisting of 4-trifluoro-methyl-phenyl, 6- (trifluoro-methyl)-pyridin-3-yl, 2-(vinyl-carbonyl-amino)-4-trifluoro-methyl)-phenyl, 2- (propa-1 ,2-dienyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(1 -cyano-vinyl-4-trifluoro- methyl-phenyl), 2-(trif I uoro-methyl)-th iazol-4-yl , 2-(prope-1 -nyl-carbonyl-amino)-4- trifluoro-methyl-phenyl, 2-(trifluoro-methyl)-pyrimidin-5-yl, 4-(2,2,2-trifluoro-ethyl)-phenyl, 2-nitro-4-trifluoro-methyl-phenyl, 2-amino-4-trifluoro-methyl-phenyl, 4-(trifluoro- methoxy)-phenyl, 3-(vinyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 4-(1 -cyano-vinyl)- phenyl, 2-(vinyl-carbonyl-amino)-4-trifluoro-methyl-phenyl), 3-(vinyl-carbonyl-amino-(4- trifluoro-methyl)-phenyl, 2-(N-methyl, N-vinyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(3-dimethyl-amino-prope-1 -nyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(propy-1 - nyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(morpholin-4-yl-propen-1 -yl-carbonyl- amino)-4-trifluoro-methyl-phenyl, and 2-(vinyl-carbonyl-amino)-4-trifluoro-methoxy- phenyl).

[0072] In some embodiments, the present invention is directed to compounds of formula (I) wherein R3is selected form the group consisting of 4-trifluoro-methyl-phenyl, 6- (trifluoro-methyl)-pyridin-3-yl, 2-(vinyl-carbonyl-amino)-4-trifluoro-methyl)-phenyl, 2- (propa-1 ,2-dienyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(1 -cyano-vinyl-4-trifluoro- methyl-phenyl), 2-(trif I uoro-methyl)-th iazol-4-yl , 2-(prope-1 -nyl-carbonyl-amino)-4- trifluoro-methyl-phenyl, 2-(trifluoro-methyl)-pyrimidin-5-yl, 3-(vinyl-carbonyl-amino)-4- trifluoro-methyl-phenyl, 4-(1 -cyano-vinyl)-phenyl, 2-(vinyl-carbonyl-amino)-4-trifluoro- methyl-phenyl), 3-(vinyl-carbonyl-amino-(4-trifluoro-methyl)-phenyl, 2-(N-methyl,N-vinyl- carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(3-dimethyl-amino-prope-1 -nyl-carbonyl- amino)-4-trifluoro-methyl-phenyl, 2-(propy-1 -nyl-carbonyl-amino)-4-trifluoro-methyl- phenyl, 2-(morpholin-4-yl-propen-1 -yl-carbonyl-amino)-4-trifluoro-methyl-phenyl, and 2- (vinyl-carbonyl-amino)-4-trifluoro-methoxy-phenyl).

[0073] In some embodiments, the present invention is directed to compounds of formula (I) wherein R3is selected from the group consisting of 4-trifluoro-methyl-phenyl, 6- (trifluoro-methyl)-pyridin-3-yl, 2-(vinyl-carbonyl-amino)-4-trifluoro-methyl)-phenyl, 2- (propa-1 ,2-dienyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(1 -cyano-vinyl-4-trifluoro- methyl-phenyl), 2-(trifluoro-methyl)-thiazol-4-yl, 3-(vinyl-carbonyl-amino)-4-trifluoro- methyl-phenyl, 4-(1 -cyano-vinyl)-phenyl, 2-(vinyl-carbonyl-amino)-4-trifluoro-methyl- phenyl), 3-(vinyl-carbonyl-amino-(4-trifluoro-methyl)-phenyl, 2-(N-methyl,N-vinyl- carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(3-dimethyl-amino-prope-1 -nyl-carbonyl- amino)-4-trifluoro-methyl-phenyl, 2-(propy-1 -nyl-carbonyl-amino)-4-trifluoro-methyl- phenyl, 2-(morpholin-4-yl-propen-1 -yl-carbonyl-amino)-4-trifluoro-methyl-phenyl, and 2- (vinyl-carbonyl-amino)-4-trifluoro-methoxy-phenyl).

[0074] In some embodiments, the present invention is directed to compounds of formula

[0075] (I) wherein R4is selected from wherein b is an integer from 0 to 3; each R5is independently selected from the group consisting of halogen, C1-2alkyl, fluorinated C1-2alkyl, hydroxy substituted C1-3alkyl, C1-2alkoxy, -NRJRK, -(C1-2alkyl)- NRJRM, -C(O)-NRJRM, -C(O)-NRL-(C1-2alkyl)-NRJRK, -(C1-2alkyl)-C(O)-NRJRK, and -(C1-2alkyl)-NRJ-C(O)-(C1-4alkyl); and wherein RJ, RK, and RLare each independently selected from the group consisting of hydrogen and C1-3alkyl; and wherein RMis selected from the group consisting of hydrogen, C1-3alkyl, fluorinated C1-2alkyl, and -(C1-2alkyl)-O-(C1-2alkyl); or (b) ; wherein c is an integer from 0 to 2; each R6is C1-2alkyl; d is an integer from 0 to 1 ; L2is selected from the group consisting of -NH- C(O)-, -C(O)-NH-, -C(O)-NH-(C1-4alkyl)-, and -C(O)-NH-(fluorinated C1-4alkyl)-; provided that a terminal -C(O)- or -NH- portion of L1is bound directly to the phenyl; R7is selected from the group consisting of 4 to 6 membered heterocycloalkyl and 5 to 6 membered heteroaryl; wherein the 4 to 6 membered heterocycloalkyl or 5 to 6 membered heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of C1-2alkyl, fluorinated C1-2alkyl, and C1-2alkoxy.

[0076] In some embodiments, the present invention is directed to compounds of formula

[0077] (I), wherein In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is (a) ; wherein a is an integer from 0 to 3; each R5is independently selected from the group consisting of halogen, C1-2alkyl, fluorinated C1-2alkyl, hydroxy substituted C1-3alkyl, C1-2alkoxy, - NRJRK, -(C1-2alkyl)-NRJRM, -C(O)-NRJRM, -C(O)-NRL-(C1-2alkyl)-NRJRK, -(C1-2alkyl)- C(O)-NRJRK, and -(C1-2alkyl)-NRJ-C(O)-(C1-4alkyl); wherein RJ, RK, and RLare each independently selected from the group consisting of hydrogen and C1-3alkyl; and wherein RMis selected from the group consisting of hydrogen, C1-3alkyl, fluorinated C1-2alkyl, and -(C1-2alkyl)-O-(C1-2alkyl).

[0078] In some embodiments, the present invention is directed to compounds of formula

[0079] (I) wherein R4is . in some embodiments, the present invention is directed to compounds of formula (I) wherein R4is (b) ; wherein c is an integer from 0 to 2; each R6is independently selected from the group consisting of fluoro, chloro, C1-2alkyl, fluorinated C1-2alkyl, hydroxy substituted C1-2alkyl, and -NRNRP; wherein RNand Rpare each independently selected from the group consisting of hydrogen, methyl and ethyl; d is an integer from 0 to 1 ; L2is selected from the group consisting of -NH-C(O)-, -C(O)-NH-, - C(O)-NH-(C1-4alkyl)-, and -C(O)-NH-(fluorinated C1-4alkyl)-; provided that a terminal - C(O)- or -NH- portion of L1is bound directly to the phenyl; R7is selected from the group consisting of 4 to 6 membered heterocycloalkyl and 5 to 6 membered heteroaryl; and wherein the 4 to 6 membered heterocycloalkyl or 5 to 6 membered heteroaryl is optionally substituted with one to two substituents independently selected from the group consisting of fluoro, chloro, C1-3alkyl, fluorinated C1-2alkyl, C1-2alkoxy, fluorinated C1-2alkoxy, and -CN.

[0080] In some embodiments, the present invention is directed to compounds of formula

[0081] (I) wherein R4is (b) ; wherein c is an integer from 0 to 2; each R6is C1-2alkyl; d is an integer from 0 to 1 ; L2is selected from the group consisting of -NH-C(O)-, -C(O)-NH-, -C(O)-NH-(C1-4alkyl)-, and -C(O)-NH-(fluorinated C1-4alkyl)-; provided that a terminal -C(O)- or -NH- portion of L1is bound directly to the phenyl; R7is selected from the group consisting of 4 to 6 membered heterocycloalkyl and 5 to 6 membered heteroaryl; wherein the 4 to 6 membered heterocycloalkyl or 5 to 6 membered heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of C1-2alkyl, fluorinated C1-2alkyl, and C1-2alkoxy.

[0082] In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of 2,6-dimethyl-3-chloro-phenyl, 2,5- dimethyl-phenyl, 2,3,6-trimethyl-phenyl, 2,6-dimethyl-3-D3-methyl-phenyl, 2-(2,2- difluoroethyl)-3,6-dimethyl-phenyl, 2-(hydroxy-methyl)-3,6-dimethyl-phenyl, 2,6- dimethyl-3-hydroxy-methyl-phenyl, 2-(1 -hydroxy-isopropyl)-3,6-dimethyl-phenyl, 2- methoxy-3,6-dimethyl-phenyl, 3-methoxy-2,6-dimethyl-phenyl, 2,6-dimethyl-3-methoxy- phenyl, 2-amino-3,6-dimethyl-phenyl, 2-(methyl-amino)-3,6-dimethyl-phenyl, 2- (dimethyl-amino)-3,6-dimethyl-phenyl, 2-(amino-methyl)-3,6-dimethyl-phenyl, 2-(2,2- difluoroethyl-amino-methyl)-3,6-dimethyl-phenyl, 2-(methyl-amino-carbonyl)-3,6- dimethyl-phenyl, 2-(isopropyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(2,2,2- trifluoroethyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(methoxy-ethyl-amino-carbonyl)- 3,6-dimethyl-phenyl, 2-(2-(dimethyl-amino)-ethyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(methyl-amino-carbonyl-methyl)-3,6-dimethyl-phenyl, 2-(methyl-carbonyl-amino- methyl)-3,6-dimethyl-phenyl, 2-pyrazol-5-yl-3,6-dimethyl-phenyl, 2-(1 ,2,3-triazol-5-yl)- 3,6-dimethyl-phenyl, 2-(4-trifluoromethyl-1 ,2,3-triazol-5-yl)-3,6-dimethyl-phenyl, 2- (tetrahydropyran-4-yl-carbonyl-amino)-3,6-dimethyl-phenyl, 2-(1 -azetidin-3-yl-amino- carbonyl)-3,6-dimethyl-phenyl, 2-(1 -methyl-azetidin-3-yl-amino-carbonyl)-3,6-dimethyl- phenyl, 2-(1 -piperidin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(1 -methyl- piperidin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(pyridin-3-yl-methyl-amino- carbonyl)-3,6-dimethyl-phenyl, 2-(pyridin-4-yl-methyl-amino-carbonyl)-3,6-dimethyl- phenyl, 2-(2-pyridin-2-yl-isopropyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(3-(methoxy- pyridin-2-yl)-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(2-pyridin-2-yl-2,2-difluoro- ethyl-amino-carbonyl)-3,6-dimethyl-phenyl and 2-(pyrimidin-2-yl-methyl-amino- carbonyl)-3,6-dimethyl-phenyl.

[0083] In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of 2,5-dimethyl-phenyl, 2,3,6- trimethyl-phenyl, 2-(hydroxy-methyl)-3,6-dimethyl-phenyl, 2-(2-pyridin-2-yl-isopropyl- amino-carbonyl)-3,6-dimethyl-phenyl and 2-(3-methoxy-pyridin-2-yl-methyl-amino- carbonyl)-3,6-dimethyl-phenyl.

[0084] In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of 2,3,6-trimethyl-phenyl, 2,6- dimethyl-3-chloro-phenyl, 2-(4-(trifluoro-methyl)-1 ,2, 3-triazol- 1 -yl)-3,6-dimethyl-phenyl and 2-(1 -methyl-azetidin-3-yl-amino-carbonyl)-3,6-dimethyl-phenyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of 2,5-dimethyl-phenyl and 2,3,6-trimethyl-phenyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of 2,3,6-trimethyl-phenyl, 2- (hydroxy-methyl)-3,6-dimethyl-phenyl, 2-(1 ,2,3-triazol-5-yl)-3,6-dimethyl-phenyl, 2-(2- pyridin-2-yl-2,2-difluoro-ethyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(methoxy-ethyl- amino-carbonyl)-3,6-dimethyl-phenyl, 2,6-dimethyl-3-chloro-phenyl, 2,6-dimethyl-3-D3- methyl-phenyl, 2-(1 -methyl-piperidin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(3-methoxy-pyridin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(methyl- amino)-3,6-dimethyl-phenyl, 2,6-dimethyl-3-methoxy-phenyl, 2-(1 -methyl-azetidin-3-yl- amino-carbonyl)-3,6-dimethyl-phenyl, 2-(2,2,2-trifluoro-ethyl-amino-carbonyl)-3,6- dimethyl-phenyl, 2,5-dimethyl-phenyl, 2-amino-3,6-dimethyl-phenyl, 2-methoxy-3,6- dimethyl-phenyl, 2-(amino-methyl)-3,6-dimethyl-phenyl, 2-(2,2-difluoro-ethyl-amino- methyl)-3,6-dimethyl-phenyl, 2-(methyl-carbonyl-amino-methyl)-3,6-dimethyl-phenyl, 2- pyrazol-5-yl-3,6-dimethyl-phenyl, 2-(4-(trifluoro-methyl)-1 ,2,3-triazol-5-yl)-3,6-dimethyl- phenyl, 2-(1 -piperidin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(4-trif luoro- methyl-1 ,2,3-triazol-5-yl)-3,6-dimethyl-phenyl, 2-(isopropyl-amino-carbonyl)-3,6- dimethyl-phenyl, 2-(tetrahydropyran-4-yl-carbonyl-amino)-3,6-dimethyl-phenyl, 2,6- dimethyl-3-hydroxy-methyl-phenyl, 2-(dimethyl-amino)-3,6-dimethyl-phenyl, 3-methoxy- 2,6-dimethyl-phenyl, 2-(methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(pyrimidin-2-yl- methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-((3-methoxy-pyridin-2-yl)-methyl-amino- carbonyl)-3,6-dimethyl-phenyl, 2-(pyridin-4-yl-methyl-amino-carbonyl)-3,6-dimethyl- phenyl, 2-(pyridin-3-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(2-(dimethyl- amino)-ethyl-amino-carbonyl)-3,6-dimethyl-phenyl, and 2-(1 -azetidin-3-yl-amino- carbonyl)-3,6-dimethyl-phenyl.

[0085] In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of 2,3,6-trimethyl-phenyl, 2- (hydroxy-methyl)-3,6-dimethyl-phenyl, 2-(1 ,2,3-triazol-5-yl)-3,6-dimethyl-phenyl, 2-(2- pyridin-2-yl-2,2-difluoro-ethyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(methoxy-ethyl- amino-carbonyl)-3,6-dimethyl-phenyl, 2,6-dimethyl-3-chloro-phenyl, 2,6-dimethyl-3-D3- methyl-phenyl, 2-(1 -methyl-piperidin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(3-methoxy-pyridin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(methyl- amino)-3,6-dimethyl-phenyl, 2,6-dimethyl-3-methoxy-phenyl, 2-(1 -methyl-azetidin-3-yl- amino-carbonyl)-3,6-dimethyl-phenyl, 2-(2,2,2-trifluoro-ethyl-amino-carbonyl)-3,6- dimethyl-phenyl, 2,5-dimethyl-phenyl, 2-amino-3,6-dimethyl-phenyl, 2-methoxy-3,6- dimethyl-phenyl, 2-(amino-methyl)-3,6-dimethyl-phenyl, 2-(2,2-difluoro-ethyl-amino- methyl)-3,6-dimethyl-phenyl, 2-(methyl-carbonyl-amino-methyl)-3,6-dimethyl-phenyl, 2- pyrazol-5-yl-3,6-dimethyl-phenyl, 2-(methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2- (pyrimidin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-((3-methoxy-pyridin-2-yl)- methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(pyridin-4-yl-methyl-amino-carbonyl)- 3,6-dimethyl-phenyl, 2-(pyridin-3-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(2- (dimethyl-amino)-ethyl-amino-carbonyl)-3,6-dimethyl-phenyl, and 2-(1 -azetidin-3-yl- amino-carbonyl)-3,6-dimethyl-phenyl.

[0086] In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected form the group consisting of 2,3,6-trimethyl-phenyl, 2- (hydroxy-methyl)-3,6-dimethyl-phenyl, 2-(1 ,2,3-triazol-5-yl)-3,6-dimethyl-phenyl, 2-(2- pyridin-2-yl-2,2-difluoro-ethyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(methoxy-ethyl- amino-carbonyl)-3,6-dimethyl-phenyl, 2,6-dimethyl-3-chloro-phenyl, 2,6-dimethyl-3-D3- methyl-phenyl, 2-(1 -methyl-piperidin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(3-methoxy-pyridin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(methyl- amino)-3,6-dimethyl-phenyl, 2,6-dimethyl-3-methoxy-phenyl, 2-(1 -methyl-azetidin-3-yl- amino-carbonyl)-3,6-dimethyl-phenyl, 2-(2,2,2-trifluoro-ethyl-amino-carbonyl)-3,6- dimethyl-phenyl, 2,5-dimethyl-phenyl, 2-(methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-pyrazol-5-yl-3,6-dimethyl-phenyl, 2-(pyrimidin-2-yl-methyl-amino-carbonyl)-3,6- dimethyl-phenyl, 2-((3-methoxy-pyridin-2-yl)-methyl-amino-carbonyl)-3,6-dimethyl- phenyl, 2-(pyridin-4-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(pyridin-3-yl- methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(2,2-difluoro-ethyl-amino-methyl)-3,6- dimethyl-phenyl, 2-(2-(dimethyl-amino)-ethyl-amino-carbonyl)-3,6-dimethyl-phenyl, and 2-(1 -azetidin-3-yl-amino-carbonyl)-3,6-dimethyl-phenyl.

[0087] In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of 2,3,6-trimethyl-phenyl, 2- (hydroxy-methyl)-3,6-dimethyl-phenyl, 2-(1 ,2,3-triazol-5-yl)-3,6-dimethyl-phenyl, 2-(2- pyridin-2-yl-2,2-difluoro-ethyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(methoxy-ethyl- amino-carbonyl)-3,6-dimethyl-phenyl, 2,6-dimethyl-3-chloro-phenyl, 2-(1 -methyl- piperidin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(3-methoxy-pyridin-2-yl- methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(methyl-amino-carbonyl)-3,6-dimethyl- phenyl, 2-pyrazol-5-yl-3,6-dimethyl-phenyl, 2-(pyrimidin-2-yl-methyl-amino-carbonyl)- 3,6-dimethyl-phenyl, 2-((3-methoxy-pyridin-2-yl)-methyl-amino-carbonyl)-3,6-dimethyl- phenyl, 2-(pyridin-4-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(pyridin-3-yl- methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(2,2-difluoro-ethyl-amino-methyl)-3,6- dimethyl-phenyl, 2-(2-(dimethyl-amino)-ethyl-amino-carbonyl)-3,6-dimethyl-phenyl, and 2-(1 -azetidin-3-yl-amino-carbonyl)-3,6-dimethyl-phenyl.

[0088] In some embodiments, the present invention is directed to compounds of formula

[0089] (I) wherein is selected from the group consisting of azetidin-1 -yl, pyrrolidin-

[0090] 1 -yl, piperidin-1 -yl, piperazin-1 -yl, morpholin-4-yl, thiomorpholin-4-yl and thiomorpholin- 4-yl-1 , 1 -dioxide (preferably piperidin-1 -yl or piperazin-1 -yl); wherein the is further optionally substituted as described herein.

[0091] In some embodiments, the present invention is directed to compounds of formula

[0092] (I) wherein is selected from the group consisting of azetidin-1 -yl, pyrrolidin-

[0093] 1 -yl, piperidin-1 -yl, piperazin-1 -yl, morpholin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-yl-

[0094] 1 ,1 -dioxide (preferably piperidi n-1 -yl or piperazin-1 -yl); wherein the is further optionally substituted as described herein.

[0095] In some embodiments, the present invention is directed to compounds of formula

[0096] (I) wherein is selected from the group consisting of azetidin-1 -yl, pyrrolidin-

[0097] 1 -yl, piperidin-1 -yl, piperazin-1 -yl, morpholin-4-yl, thiomorpholin-4-yl and thiomorpholin- 4-yl-1 , 1 -dioxide (preferably piperidin-1 -yl or piperazin-1 -yl); wherein the is further optionally substituted as described herein. In some embodiments, the present invention is directed to compounds of formula (I) wherein R8is selected from the group consisting of wherein is selected from the group consisting of 3-

[0098] (methyl-sulfonyl-amino)-pyrrolidin-1 -yl,3-(methoxy-methyl)-piperidin-1 -yl, 4-(methoxy- methyl)-pi peridin- 1 -yl, 4-(difluoro-methoxy-methyl)-piperidin-1 -yl, 3,3-difluoro-4-hydroxy- piperidi n-1 -yl, 4-(2-hydroxy-isoprop-2-yl)-piperidin-1 -yl, 3,3-difluoro-4-(methyl-sulfonyl- methyl)-pi peridin- 1 -yl, 3-(methyl-sulfonyl-methyl)-piperidin-1 -yl, 4-(methyl-sulfonyl- methyl)-pi peridin- 1 -yl, 4-(isopropyl-sulfonyl-methyl)-piperidin-1 -yl, 4-(isobutyl-sulfonyl- methyl)-pi peridin- 1 -yl, 4-methyl-4-(methyl-sulfonyl-methyl)-piperidin-1 -yl, 4-(methyl- sulfonyl-amino-methyl)-piperidin-1 -yl, 4-(methyl-sulfonyl-amino)-piperidin-1 -yl, 4-(ethylsulfonyl-amino)-piperidin-1 -yl, 4-(cyclopropyl-sulfonyl-amino)-piperidin-1 -yl, 4-(N- methyl,N-(methyl-sulfonyl)-amino)-piperidin-1 -yl, 4-(methyl-SO(NH2)-methyl)-piperidin-1 - yl, 4-(N-methyl, N-(ethyl-sulfonyl)-amino)-piperidin-1 -yl, 4-(N-ethyl, N-(methyl-sulfonyl)- amino)-piperidin-1 -yl, 4-(N-cyclopropyl, N-(methyl-sulfonyl)-amino)-piperidin-1 -yl, 4- (cyano-methyl)-piperidin-1 -yl, 4-(amino-carbonyl-methyl)-piperidin-1 -yl, 4-(methyl- amino-carbonyl-methyl)-piperidin-1 -yl, 4-(dimethyl-amino-carbonyl-methyl)-piperidin-1 - yl, 4-(methyl-dicarbonyl-amino)-piperidin-1 -yl, 4-(dimethyl-amino-dicarbonyl-amino)- piperidin-1 -yl, piperazin-1 -yl, piperazin-1 -yl-3-one, 3-(hydroxy-methyl)-4-methyl- piperazin-1 -yl, 4-(2,2-difluoroethyl)-piperazin-1 -yl, 4-methyl-piperazin-1 -yl, 4-(methoxy- ethyl)-piperazin-1 -yl, 4-(dimethyl-amino-ethyl)-piperazin-1 -yl, 4-(dimethyl-amino- sulfonyl)-piperazin-1 -yl, 3-(4-butyl-amino-carbonyl)-piperazin-1 -yl, morpholin-4-yl, and thiomorpholin-4-yl-1 , 1 -dioxide; (b) wherein is selected from the group consisting of azetidine-1 -yl, piperidin-1-yl, 3-fluoro-piperidin-1 -yl, 4-fluoro- piperidin-1 -yl, piperidin-1 -yl-3-one, 4-hydroxy-piperidin-1 -yl, 4-(hydroxy-methyl)- piperidin-1 -yl, 3,3-difluoro-piperidin-1 -yl, 4,4-difluoro-piperidin-1 -yl, 3,3-difluoro-4R*- hydroxy-piperidin-1 -yl, 3,3-difluoro-4S*-hydroxy-piperidin-1 -yl, 3 ,3-di methyl-piperid in- 1 - yl, 4-cyano-piperidin-1 -yl, piperazin-1 -yl, piperazin-1 -yl-3-one, 3S-(hydroxy-methyl)- piperazin-1 -yl, 2R-methyl-piperazin-1 -yl, 2-(amino-carbonyl)-piperazin-1 -yl, and morpholin-4-yl; wherein is selected from the group consisting of 4-(1 - hydroxy-cycloprop-1 -yl), 4-(1 -(methyl-sulfonyl)-cycloprop-l -yl), 4-cis-(4-(methyl- sulfonyl)-cyclohex-1 -yl), 4-trans-(4-(methyl-sulfonyl)-cyclohex-1 -yl), 4-cis-(4-(methyl- sulfonyl-amino)-cyclohex-1 -yl), 4-trans-(4-(methyl-sulfonyl-amino)-cyclohex-1 -yl), 4-(3- (methyl-sulfonyl)-azetidin-1 -yl), 4-((1 -methy l-su If onyl)-py rrol id in-3-yl) , 2-(tetrahydro- furan-3-yl), 4-(1 -methyl-2-oxo-tetrahydro-pyrimidin-3-yl), 4-(tetrahydro-thiophen-3R*-yl), 4-(tetrahydro-thiophen-3S*-yl), 4-(tetrahydro-thiophen-3-yl-1 ,1 -dioxide), 4-(tetrahydro- pyran-4-yl-1 ,1 -dioxide), 4-(tetrahydro-thiopyran-4-yl-1 ,1 -dioxide), 3-(thiomorpholin-4-yl- 1 ,1 -dioxide), 4-(thiomorpholin-4-yl-1 ,1 -dioxide), (1 -methyl-carbonyl)-azepan-4-yl, 4-(4- (methyl-sulfonyl)-l ,4-diazepan-1 -yl), 4-(2-oxo-piperidin-1 -yl), 4-(6-oxo-piperidin-3-yl), 4- (1 -methyl-pi perid in-4-yl) , 4-(1 -methyl-2-oxo-piperidin-4-yl), 4-(4-(methyl-sulfonyl)- piperidi n-1 -yl), 4-(1 -(methyl-sulfony l)-piperid in-4-yl) , 4-(1 -(methyl-sulfonyl)-3,3-difluoro- piperidin-4-yl), 4-(4-(methyl-sulfonyl-amino)-piperidin-1 -yl), 4-(1 -(methyl-carbonyl)- piperidin-4-yl), 4-(1 -(methyl-carbonyl)-4-hydroxy-piperidin-4-yl), (1 -cyclopropyl-2-oxo- piperidin-4-yl), 4R*-(4-methyl-piperazin-4-yl), 4S*-(4-methyl-piperazin-4-yl), 4-(3-oxo-4- methyl-piperazin-1 -yl), 4R*-(3-oxo-4-methyl-piperazin-1 -yl), 4S*-(3-oxo-4-methyl- piperazin-1 -yl), 4-(3-oxo-4-isopropyl-piperazin-1 -yl), 4-(3-oxo-4-cyclopropyl-piperazin-1 - yl), 3-(4-(methyl-sulfonyl)-piperazin-1 -yl), 4-(4-(methyl-sulfonyl)-piperazin-1 -yl), 4R*-(4- (methyl-sulfonyl)-piperazin-1 -yl), 4S*-(4-(methyl-sulfonyl)-piperazin-1 -yl), 4-(2-oxo-4- (methyl-sulfonyl)-piperazin-1 -yl), 3-(4-oxetan-3-yl-piperazin-1 -yl), 4-(4-(trif luoro- methoxy)-phenyl), 4-(4-(azetidin-1 -yl-carbonyl)-phenyl, 4-(4-(methyl-sulfonyl)-phenyl), 4- (4-(trifluoro-methyl-sulfonyl)-phenyl), 4-(4-(methyl-amino-carbonyl)-phenyl), 4-(4- (dimethyl-amino-carbonyl)-phenyl), 4-(4-(amino-sulfonyl)-phenyl), 4-(4-carboxy-phenyl), 4-(4-(ethoxy-carbonyl)-phenyl), 3-(pyrazol-4-yl), 4-(pyrazol-4-yl), 3-(1 -(methyl-sulfonyl)- pyrazol-4-yl), 4-(1 -(methyl-sulfonyl)-pyrazol-4-yl), 4-(pyridin-3-yl), 4-(2-chloro-6-(methyl- sulfonyl)-pyridin-3-yl), 4-(6-hydroxy-pyridin-2-yl), 4-(2-methyl-pyridin-4-yl), 4-(2- isopropyl-6-(methyl-sulfonyl)-pyridin-3-yl), 4-(2-(difluoro-methyl)-6-(methyl-sulfonyl)- pyridin-3yl), 4-(2-(trifluoro-methyl)-6-methyl-sulfonyl)-pyridin-3-yl), 4-(6-(2,2,2-trifluoro- ethyl)-pyridin-3-yl), 4-(4-methoxy-6-(methyl-sulfonyl)-pyridin-3-yl), 4-(6-(trifluoro- methoxy)-pyridin-3-yl), 4-(6-methoxy-pyridin-2-yl), 4-(6-(methyl-sulfonyl)-pyridin-2-yl), 4- (4-(methyl-sulfonyl)-pyridin-3-yl), 4-(6-(methyl-sulfonyl)-pyridin-3-yl), 4R*-(6-(methyl- sulfonyl)-pyridin-3-yl), 4S*-(6-(methyl-sulfonyl)-pyridin-3-yl), 4-(2-methyl-6-(methyl- sulfonyl)-pyridin-3-yl), 4-(2-ethyl-6-(methyl-sulfonyl)-pyridin-3-yl), 4-(6-(2-hydroxy- isobutyl-amino-sulfonyl)-pyridin-3-yl), 4-(6-(2,2,2-trifluoro-ethyl-amino-sulfonyl)-pyridin-

[0099] 3-yl), 4-(6-(methyl-sulfonimidoyl)-pyridin-3-yl), 4-(5-cyano-pyridin-2-yl), 4-(6-(dimethyl- amino)-pyridin-3-yl), 4-(6-(amino-carbonyl)-pyridin-3-yl), 4-(1 -cyclopropyl)-2-oxo-pyridin-

[0100] 4-yl), 4-(2-cyclopropyl-6-(methyl-sulfonyl)-pyridin-3-yl),-(6-(3-hydroxy-3-methyl-azetidin- 1 -yl-su If ony l)-pyridin-3-yl) , 4-(6-(piperazin-1 -yl-su If ony l)-pyridi n-3-yl , 4-(6-(morpholin-4- yl-sulfonyl)-pyridin-3-yl), 4-(6-(2,2,2-trifluoro-ethyl)-piperazin-1 -yl-sulfonyl)-pyridin-3-yl), (6-(4-methyl-piperazin-1 -yl-sulfonyl)-pyridin-3-y I) , 4-(6-((thiomorpholin-4-yl-1 ,1 -dioxide)- sulfonyl)-pyridin-3-yl, 4-(5-(methyl-sulfonyl)-pyrimidin-2-yl), 4-(5-(methyl-sulfonyl)- pyrazin-2-yl), 4-(6-(methyl-sulfonyl)-pyridazin-3-yl), 3-(methyl-sulfonyl-amino)- bicyclo[1 .1 .1 ]pentan-1 -yl, (1 ,4)-2-(methyl-sulfonyl)-2-azabicyclo[2.2.1]heptan-5-yl, and (1 R,4R)-5-methyl-2-(methylsulfonyl)-2-azabicyclo[2.2.1]heptan-5-yl; (

[0101] (c) ; wherein is selected from the group consisting of piperidin-1 -yl, 3,3-difluoro-piperidin-1 -yl, 4,4-difluoro-piperidin-1 -yl, and piperazin-1 -yl; wherein L3is selected from the group consisting of 4-(-CH2-), 4-(-C(O)- (CH2)-), 3-(-NH-), 4-(-NH-), 3R*-(-NH-), 3S*-(-NH-), 4R*-(-NH-), 4S*-(-NH-), and 3-(-O-); wherein R10is selected from the group consisting of 3-(methyl-sulfonyl)-azetidin-1 -yl, 4- (methyl-sulfonyl)-piperidin-1 -yl, 1 -(methyl-sulfony l)-piperid in-4-yl , tetrahydro-thiophen-3- yl-1 ,1 -dioxide, 1 ,4-dioxan-3-yl, pyridin-4-yl, and 6-(methyl-sulfonyl)-pyridin-3-yl; is selected from the group consisting of 6-cyclopropyl-2,6-diazaspiro[3.3]heptan-2-yl, 2,3-dihydroxy-(1 S,4S)-2- azabicyclo[2.2.1 ]heptan-2-yl, 2,6-diazaspiro[3.4]octan-2-yl, 2-(methyl-sulfonyl)-2,6- diazaspiro[3.4]octan-2-yl, 2-(methyl-carbonyl)-2,6-diazaspiro[3.4]octan-2-yl, 2-thia-6- azaspiro[3.4]octan-6-yl 2,2-dioxide, 2,7-diazaspiro[3.5]nonan-7-yl-3-one, 2-oxa-6- azaspiro[3.5]nonan-6-yl, 2-oxa-5,8-diazaspiro[3.5]nonan-8-yl, 2-oxa-7- azaspiro[3.5]nonan-7-yl, 2-thia-7-azaspiro[3.5]nonan-7-yl 2,2-dioxide, 2-hydroxy-7- azaspiro[3.5]nonan-7-yl, 2-hydroxy-2-methyl-7-azaspiro[3.5]nonan-7-yl, 2-oxa-8- azaspiro[4.5]decan-8-yl, 2-thia-8-azaspiro[4.5]decan-8-yl 2,2-dioxide, 8-thia-2- azaspiro[4.5]decan-2-yl 8,8-dioxide, 3-azaspiro[5.5]undecan-3-yl; 3-oxa-9- azaspiro[5.5]undecan-9-yl, 3-(methyl-sulfonyl)-3,9-diazaspiro[5.5]undecan-3-yl, 6-oxa-2- thia-9-azaspiro[4.6]undecan-9-yl 2,2-dioxide, 3-thia-9-azaspiro[5.5]undecan-9-yl 3,3- dioxide, 1 -oxa-9-thia-4-azaspiro[5.5]undecan-4-yl 9,9-dioxide, 7-oxa-3-thia-10- azaspiro[5.6]dodecan-10-yl 3,3-dioxide, octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2- dioxide, (R*)-octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2-dioxide, (S*)- octahydropyrazino[2,1 -c] [ 1 ,4]thiazin-8-y I 2,2-dioxide, 7,7-dimethyl- octahydropyrazino[2,1 -c] [ 1 ,4]thiazin-8-y I 2,2-dioxide, 7,7-dimethyl-(R*)- octahydropyrazino[2,1 -c] [ 1 ,4]thiazin-8-y I 2,2-dioxide, 7,7-dimethyl-(S*)- octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2-dioxide, (4aR,8aR)-octahydro-1 H- pyrano[3,4-c]pyridin-7-yl, (4aR,8aS)-octahydro-1 H-pyrano[3,4-c]pyridin-7-yl, (4aS,8aR)- octahydro-1 H-pyrano[3,4-c]pyridin-7-yl, (4aS,8aS)-octahydro-1 H-pyrano[3,4-c]pyridin-7- yl, hexahydro-pyrazino[2,1 -c][1 ,4]oxazin-8-yl-4-one, octahydropyrazino[2,1 - c][1 ,4]oxazin-8-yl, (S)-octahydropyrazino[2,1 -c][1 ,4]oxazin-8-yl, octahydropyrazino[2,1 - c][1 ,4]oxazin-8-yl-6,6-d2, (S)-hexahydro-pyrazino[2,1 -c][1 ,4]oxazin-8-yl-4-one, (S*)- hexahydro-pyrazino[2,1 -c] [ 1 ,4]oxazin-8-yl-6-one, (R*)-hexahydro-pyrazino[2,1 - c][1 ,4]oxazin-8-yl-6-one, 8-methyl-(R*)-hexahydro-1 H-pyrazino[1 ,2-a]pyrazin-2-yl, 8- methyl-(S*)-hexahydro-1 H-pyrazino[1 ,2-a]pyrazin-2-yl, 8-(2,2,2-trifluoro-ethyl)-(R*)- octahydro-2H-pyrazino[1 ,2-a]pyrazin-2-yl, 8-(2,2,2-trifluoro-ethyl)-(S*)-octahydro-2H- pyrazino[1 ,2-a]pyrazin-2-yl, 2-(methyl-sulfonyl)-3,4,6,7,9,9aR*-hexahydro-1 H- pyrazino[1 ,2-a]pyrazin-8-yl, 2-(methyl-sulfonyl)-3,4,6,7,9,9aS*-hexahydro-1 H- pyrazino[1 ,2-a]pyrazin-8-yl, 2-imino-2-oxo-3,4,6,7,9,9a-hexahydro-1 H-pyrazino[2,1 - c][1 ,4]thiazin-8-yl , 7-(methyl-sulfonyl)-3,4-dihydro-1 H-isoqu inolin-2-yl, 6-chloro- spiro[isobenzofuran-1 ,4'-piperid in- 1 -yl], 6-(methyl-sulfonyl)-(1 R*)-spiro[isobenzofuran- 1 ,4'-pi peridin]- 1 '-yl, 6-(methyl-sulfonyl)-(1 S*)-spiro[isobenzofuran-1 ,4'-pi peridin]- 1 '-yl, 3- fluoro-6-(methyl-sulfonyl)-spiro[isobenzofuran-1 ,4'-pi peridin- 1 -yl], 5-(methyl-sulfonyl)- octahydropyrrolo[3,4-b]pyrrol-1 -yl, hexahydro-1 H-thieno[3,4-b]pyrrol-1 -yl 5,5-dioxide, 3- (trifluoro-methyl)-5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3-c]pyrimidin-6-yl, and 5-(4-(methyl- sulfonyl)-phenyl)-2,5-diazabicyclo[2.2.2]octan-2-yl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R8is selected from the group consisting of selected from the group consisting of 4-(methyl-SO(NH2)-methyl)-piperidin-1 -yl, 4-(methyl-sulfonyl-methyl)-piperidin-1 -yl, 4- (methyl-sulfonyl-amino)-piperidin-1 -yl, 4-(dimethyl-amino-carbonyl-methyl)-piperidin-1 - yl, 4-(ethyl-sulfonyl-amino)-piperidin-1 -yl, 4-(isopropyl-sulfonyl-methyl)-piperidin-1 -yl, 4- (cyclopropyl-sulfonyl-amino)-piperidin-1 -yl, 4-(methoxy-methyl)-piperidin-1 -yl, 4-(cyano- methyl)-pi peridin- 1 -yl, 4-(methyl-dicarbonyl-amino)-piperidin-1 -yl, 4-(amino-carbonyl- methyl)-piperidin-1 -yl, 4-(methoxy-ethyl)-piperazin-1 -yl, and 3-(hydroxy-methyl)-4- methyl-piperazin-1 -yl;

[0102] (b) ; wherein is selected from the group consisting of piperazin-1 -yl, piperidin-1 -yl, 3,3,-difluoro-piperidin-1 -yl, piperazin-1 - yl-3-one, 3,3-difluoro-4S*-hydroxy-piperidin-1 -yl, 3,3-difluoro-piperidin-1 -yl, , piperidin- 1 -yl-3-one, 3-fluoro-piperidin-1 -yl, 3,3-difluoro-4R*-hydroxy-piperidin-1 -yl, 2R-methyl- piperazin-1 -yl, 4-hydroxy-piperidin-1 -yl, and 4-cyano-piperidin-1 -yl; and wherein is selected from the group consisting of 4-(4-(methyl-sulfonyl)- phenyl), 4-(6-(methyl-sulfonyl)-pyridin-3-yl), 4-(4-(methyl-sulfonyl)-pyridin-3-yl), 4S*-(6- (methyl-sulfonyl)-pyridin-3-yl), 4R-(6-(methyl-sulfonyl)-pyridin-3-yl), 4R*-(6-(methyl- sulfonyl)-pyridin-3-yl), 4-(6-(methyl-sulfonyl)-pyridin-2-yl), (6-(methyl-sulfonyl)-pyridin-3- yl), (1 -cyclopropyl-2-oxo-piperidin-4-yl), 4-(1 -cyclopropyl-2-oxo-pyridin-4-yl), 4-(4- methyl-sulfonyl-phenyl), (4-(methyl-sulfonyl)-piperazin-1 -yl), (6-(3-oxo-4-methyl- piperazin-1 -yl-su If onyl)-pyridi n-3-yl) , 4-(4-(methyl-sulfonyl)-piperazin-1 -yl), (4-(methyl- sulfonyl)-piperidi n-1 -yl), 4-(4-(amino-sulfonyl)-phenyl), (6-(4-methyl-piperazin-1 -yl- sulfonyl)-pyridin-3-yl), 4-trans-(4-(methyl-sulfonyl)-cyclohex-1 -yl), 4-(6-(3-hydroxy-3- methyl-azetidin-1 -yl-su If ony l)-pyridi n-3-yl) , 4-(6-(piperazin-1 -yl-sulf onyl)-py rid in-3-yl , 4- (6-(2,2, 2-trif I uoro-ethyl)-pyridi n-3-yl) , 4-(1 -methyl-2-oxo-piperidin-4-yl), 4-(6-(2-hydroxy- isobutyl-amino-sulfonyl)-pyridin-3-yl), 4-(4-methyl-sulfonyl)-phenyl), 4-(1 -(methyl- sulfonyl)-piperidin-4-yl), 4-(thiomorpholin-4-yl-1 ,1 -dioxide), 4-(6-(methyl-sulfonimidoyl))- pyridin-3-y I) , 4S*-(3-oxo-4-methyl-piperazin-1 -yl) , 4-(2-methyl-6-(methyl-sulfonyl)- pyridin-3-yl), 4-(5-(methyl-sulfonyl)-pyrimidin-2-yl), 4-(6-(methyl-sulfonyl)-pyridazin-3-yl), 4-(4-(dimethyl-amino-carbonyl)-phenyl), 4R*-(3-oxo-4-methyl-piperazin-1 -yl), 4-(6- (morpholin-4-yl-sulfonyl)-pyridin-3-yl), 4-(4-(trifluoro-methoxy)-phenyl), 4-(4-(azetidin-1 - yl-carbonyl)-phenyl, 4-(6-((thiomorpholin-4-yl-1 ,1 ,-dioxide)-sulfonyl)-pyridin-3-yl), 4-(4- (methyl-amino-carbonyl)-phenyl), 4-(1 -(methyl-sulfonyl)-cyclopropyl), 4-(6-(trif luoro- methoxy)-pyridin-3-yl), 4-(tetrahydro-thiopyran-4-yl 1 ,1 -dioxide), 4-(4-(methyl-sulfonyl- amino)-piperidin-1 -yl), 4-(2-methyl-pyridin-4-yl), 4-(2-chloro-6-(methyl-sulfonyl)-pyridin- 3-yl), 4-(tetrahydro-thiophen-3R*-yl), 4-(6-(dimethyl-amino)-pyridin-3-yl), 4S-(6-(methyl- sulfonyl)-pyridin-3-yl), 4-(tetrahydro-thiophen-3-yl-1 ,1 -dioxide), 4-(tetrahydro-thiophen- 3S*-yl), 4-(4-(methyl-sulfonyl)-piperidin-1 -yl), 4-(2-cyclopropyl-6-(methyl-sulfonyl)- pyridin-3-yl), and 4-(2-isopropyl-6-(methyl-sulfonyl)-pyridin-3-yl);

[0103] (c) wherein is selected from the group consisting of 3,3-difluoro-piperidin-1 -yl, piperidin-1 -yl, and piperazin-1 -yl; wherein L3is selected from the group consisting of 4-(NH), 4S*-(NH), 3R*-(NH), 3-(NH), 4-(CH2), and 4R*-(NH); and wherein R10is selected from the group consisting of 1 -(methyl-sulfonyl- piperidin-4-yl), 1 -(methyl-sulfonyl)-piperidin-4-yl, 4-(methyl-sulfonyl)-piperidin-1 -yl, and 1 ,4-dioxan-3-yl; wherein is selected from the group consisting of (S*)-octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2-dioxide, octahydropyrazino[2,1 - c][1 ,4]thiazin-8-yl 2,2-dioxide, 7,7-dimethyl-octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2- dioxide, (S)-octahydropyrazino[2,1 -c][1 ,4]oxazin-8-yl, 2-thia-8-azaspiro[4.5]decan-8-yl

[0104] 2.2-dioxide, 1 -oxa-9-thia-4-azaspiro[5.5]undecan-4-yl 9,9-dioxide, 3-thia-9- azaspiro[5.5]undecan-9-yl 3,3-dioxide, 3-oxa-9-azaspiro[5.5]undecan-9-yl, 2-oxa-7- azaspiro[3.5]nonan-7-yl, 7-oxa-3-thia-10-azaspiro[5.6]dodecan-10-yl 3,3-dioxide, and

[0105] 2.3-dihydroxy-(1 S,4S)-2-azabicyclo[2.2.1]heptan-2-yl.

[0106] In some embodiments, the present invention is directed to compounds of formula (I) wherein R8is selected from the group consisting of (a) ; and wherein is selected from the group consisting of 4-(methyl-SO(NH2)-methyl)-piperidin-1 -yl and 4-(methyl-sulfonyl-methyl)-piperidin-1 -

[0107] (b) wherein is selected from the group consisting of piperazin-1 -yl, piperidin-1 -yl, 3,3,-difluoro-piperidin-1 -yl, piperazin-1 - yl-3-one, 3,3-difluoro-4S*-hydroxy-piperidin-1 -yl, 3,3-difluoro-piperidin-1 -yl, , piperidin- 1 -yl-3-one, 3-fluoro-piperidin-1 -yl, 3,3-difluoro-4R*-hydroxy-piperidin-1 -yl, and 2R- methyl-piperazin-1 -yl; and wherein is selected from the group consisting of 4-(4-(methyl-sulfonyl)-phenyl), 4-(6-(methyl-sulfonyl)-pyridin-3-yl), 4-(4- (methyl-sulfonyl)-pyridin-3-yl), 4S*-(6-(methyl-sulfonyl)-pyridin-3-yl), 4R-(6-(methyl- sulfonyl)-pyridin-3-yl), 4R*-(6-(methyl-sulfonyl)-pyridin-3-yl), 4-(6-(methyl-sulfonyl)- pyridin-2-yl), (6-(methyl-sulfonyl)-pyridin-3-yl), (1 -cyclopropyl-2-oxo-piperidin-4-yl), 4-(1 - cyclopropyl-2-oxo-pyridin-4-yl), 4-(4-methyl-sulfonyl-phenyl), (4-(methyl-sulfonyl)- piperazin- 1 -yl) , (6-(3-oxo-4-methyl-piperazin-1 -yl-sulfonyl)-pyridin-3-y I) , 4-(4-(methyl- sulfonyl)-piperazin-1 -yl), (4-(methyl-sulfonyl)-piperidin-1 -yl), 4-(4-(amino-sulfonyl)- phenyl), (6-(4-methyl-piperazin-1 -yl-sulfonyl)-pyridin-3-yl), 4-trans-(4-(methyl-sulfonyl)- cyclohex-1 -yl), 4-(6-(3-hydroxy-3-methyl-azetidin-1 -yl-su If ony l)-pyridi n-3-yl) , 4-(6- (piperazin-1 -yl-su If onyl)-pyridi n-3-yl , 4-(6-(2,2,2-trif lu oro-ethyl)-py ridin-3-yl) , 4-(1 -methyl- 2-oxo-piperidin-4-yl), 4-(6-(2-hydroxy-isobutyl-amino-sulfonyl)-pyridin-3-yl), 4-(4-methyl- sulfonyl)-phenyl), 4-(1 -(methyl-sulfonyl)-piperidin-4-yl), and 4-(thiomorpholin-4-yl-1 ,1 - dioxide); (c) wherein is 3,3-difluoro-piperidin-1 -yl; wherein L3is 4-(NH); and wherein R10is 1 -(methyl-sulfonyl-piperidin-4-yl); and (d) ; wherein is selected from the group consisting of octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2-dioxide, and (S*)-octahydropyrazino[2,1 - c][1 ,4]thiazin-8-yl 2,2-dioxide.

[0108] In some embodiments, the present invention is directed to compounds of formula (I) wherein R8is selected from the group consisting of

[0109] (b) ; wherein is selected from the group consisting ofpiperazin-1 -yl, piperidin-1 -yl, 3,3,-difluoro-piperidin-1 -yl, piperazin-1 - yl-3-one, 3,3-difluoro-4S*-hydroxy-piperidin-1 -yl, 3,3-difluoro-piperidin-1 -yl, piperidin-1 - yl-3-one, 3-fluoro-piperidin-1 -yl, and 3,3-difluoro-4R*-hydroxy-piperidin-1 -yl; and wherein is selected from the group consisting of 4-(4-(methyl- sulfonyl)-phenyl), 4-(6-(methyl-sulfonyl)-pyridin-3-yl), 4-(4-(methyl-sulfonyl)-pyridin-3-yl), 4S*-(6-(methyl-sulfonyl)-pyridin-3-yl), 4R-(6-(methyl-sulfonyl)-pyridin-3-yl), 4R*-(6- (methyl-sulfonyl)-pyridin-3-yl), 4-(6-(methyl-sulfonyl)-pyridin-2-yl), (6-(methyl-sulfonyl)- pyridin-3-yl), (1 -cyclopropyl-2-oxo-piperidin-4-yl), 4-(1 -cyclopropyl-2-oxo-pyridin-4-yl), 4- (4-methyl-sulfonyl-phenyl), (4-(methyl-sulfonyl)-piperazin-1 -yl), (6-(3-oxo-4-methyl- piperazin- 1 -yl-su If onyl)-pyridi n-3-yl) , 4-(4-(methyl-sulfonyl)-piperazin-1 -yl), (4-(methyl- sulfonyl)-piperidi n-1 -yl), 4-(4-(amino-sulfonyl)-phenyl), (6-(4-methyl-piperazin-1 -yl- sulfonyl)-pyridin-3-yl), and 4-trans-(4-(methyl-sulfonyl)-cyclohex-1 -yl);

[0110] (c) ; wherein is 3,3-difluoro-piperidin-1 -yl; wherein L3is 4-(NH); and wherein R10is 1 -(methyl-sulfonyl-piperidin-4-yl); is selected from the group consisting of octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2-dioxide, and (S*)-octahydropyrazino[2,1 - c][1 ,4]thiazin-8-yl 2,2-dioxide.

[0111] In some embodiments, the present invention is directed to compounds of formula (I) wherein R8is selected from the group consisting of group consisting of piperazin-1 -yl, piperidin-1 -yl, 3,3,-difluoro-piperidin-1 -yl, piperazin-1 - yl-3-one, 3,3-difluoro-4S*-hydroxy-piperidin-1 -yl, 3,3-difluoro-piperidin-1 -yl; and wherein is selected from the group consisting of 4-(4-(methyl-sulfonyl)- phenyl), 4-(6-(methyl-sulfonyl)-pyridin-3-yl), 4-(4-(methyl-sulfonyl)-pyridin-3-yl), 4S*-(6- (methyl-sulfonyl)-pyridin-3-yl), 4R-(6-(methyl-sulfonyl)-pyridin-3-yl), 4R*-(6-(methyl- sulfonyl)-pyridin-3-yl), 4-(6-(methyl-sulfonyl)-pyridin-2-yl), (6-(methyl-sulfonyl)-pyridin-3- yl), and (1 -cyclopropyl-2-oxo-piperidin-4-yl); and (c) wherein is 3,3-difluoro-piperidin-1 -yl; wherein L3is 4-(NH); and wherein R10is 1 -(methyl-sulfonyl-piperidin-4-yl).

[0112] In some embodiments, the present invention is directed to compounds of formula

[0113] (I) wherein R8is . In some embodiments, the present invention is directed to compounds of formula (I) wherein R8is ; wherein is a nitrogen bound, 5 to 6 membered heterocycloalkyl; wherein the nitrogen bound, 4 to 6 membered heterocycloalkyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-2alkyl, fluorinated C1-2alkyl, hydroxy substituted C1-3alkyl, -(C1-2alkyl)-CN, -(C1-2alkyl)-O-(C1-2alkyl), -(C1-2alkyl)-O-(fluorinated C1-2alkyl), -NRQRS, -(C1-2alkyl)-NRQRs, -C(O)-NRQRS, - (C1-2alkyl)-C(O)-NRQRs, -NRQ-C(O)-C(O)-(C1-2alkyl), -NRT-C(O)-C(O)-NRQRS; -NRU- SO2-(C1-3alkyl), -(C1-2alkyl)-NRQ-SO2-(C1-2alkyl), -NRQ-SO2-(C3-5cycloalkyl), -SO2- NRQRS, -(C1-2alkyl)-SO2-(C1-4alkyl), and -(C1-2alkyl)-SO(NH2)-(C1-2alkyl); wherein RQ, Rsand RTare each independently selected from the group consisting of hydrogen and C1-4alkyl; and wherein Ruis selected from the group consisting of hydrogen, C1-2alkyl and cyclopropyl.

[0114] In some embodiments, the present invention is directed to compounds of formula

[0115] (I) wherein R8is ; and wherein is selected from the group consisting of 3-(methyl-sulfonyl-amino)-pyrrolidin-1 -yl,3-(methoxy-methyl)-piperidin-1 -yl, 4-(methoxy-methyl)-piperidin-1 -yl , 4-(difluoro-methoxy-methyl)-piperidin-1 -yl , 3,3- difluoro-4-hydroxy-piperidin-1 -yl, 4-(2-hydroxy-isoprop-2-yl)-piperidin-1 -yl, 3,3-difluoro-4- (methyl-sulfonyl-methyl)-piperidin-1 -yl, 3-(methyl-sulfonyl-methyl)-piperidin-1 -yl, 4- (methyl-sulfonyl-methyl)-piperidin-1 -yl, 4-(isopropyl-sulfonyl-methyl)-piperidin-1 -yl, 4- (isobutyl-su If ony l-methyl)-pi peridi n-1 -yl, 4-methyl-4-(methyl-sulfonyl-methyl)-piperidin-1 - yl, 4-(methyl-sulfonyl-amino-methyl)-piperidin-1 -yl, 4-(methyl-sulfonyl-amino)-piperidin- 1 -yl, 4-(ethyl-sulfonyl-amino)-piperidin-1 -yl, 4-(cyclopropyl-sulfonyl-amino)-piperidin-1 -yl, 4-(N-methyl, N-(methyl-sulfonyl)-amino)-piperidin-1 -yl, 4-(methyl-SO(NH2)-methyl)- piperidin-1 -yl, 4-(N-methyl, N-(ethyl-sulfonyl)-amino)-piperidin-1 -yl, 4-(N-ethyl, N- (methyl-sulfonyl)-amino)-piperidin-1 -yl, 4-(N-cyclopropyl, N-(methyl-sulfonyl)-amino)- piperidi n-1 -yl, 4-(cyano-methyl)-piperidin-1 -yl, 4-(amino-carbonyl-methyl)-piperidin-1 -yl, 4-(methyl-amino-carbonyl-methyl)-piperidin-1 -yl, 4-(dimethyl-amino-carbonyl-methyl)- piperidi n-1 -yl, 4-(methyl-dicarbonyl-amino)-piperidin-1 -yl, 4-(dimethyl-amino-dicarbonyl- amino)-piperidin-1 -yl, piperazin-1 -yl, piperazin-1 -yl-3-one, 3-(hydroxy-methyl)-4-methyl- piperazin-1 -yl, 4-(2,2-difluoroethyl)-piperazin-1 -yl, 4-methyl-piperazin-1 -yl, 4-(methoxy- ethyl)-piperazin-1 -yl, 4-(dimethyl-amino-ethyl)-piperazin-1 -yl, 4-(dimethyl-amino- sulfonyl)-piperazin-1 -yl, 3-(4-butyl-amino-carbonyl)-piperazin-1 -yl, morpholin-4-yl, and thiomorpholin-4-yl-1 , 1 -dioxide.

[0116] In some embodiments, the present invention is directed to compounds of formula

[0117] (I) wherein R8is (a) and wherein is selected from the group consisting of 4-(methyl-SO(NH2)-methyl)-piperidin-1 -yl, 4-(methyl-sulfonyl-methyl)- piperidi n-1 -yl, 4-(methyl-sulfonyl-amino)-piperidin-1 -yl, 4-(dimethyl-amino-carbonyl- methyl)-pi peridin- 1 -yl, 4-(ethyl-sulfonyl-amino)-piperidin-1 -yl, 4-(isopropyl-sulfonyl- methyl)-pi peridin- 1 -yl, 4-(cyclopropyl-sulfonyl-amino)-piperidin-1 -yl, 4-(methoxy-methyl)- piperidi n-1 -yl, 4-(cyano-methyl)-piperidin-1 -yl, 4-(methyl-dicarbonyl-amino)-piperidin-1 - yl, 4-(amino-carbonyl-methyl)-piperidin-1 -yl, 4-(methoxy-ethyl)-piperazin-1 -yl, and 3- (hydroxy-methyl)-4-methyl-piperazin-1 -yl.

[0118] In some embodiments, the present invention is directed to compounds of formula

[0119] (I) wherein R8is (a) and wherein is selected from the group consisting of 4-(methyl-SO(NH2)-methyl)-piperidin-1 -yl and 4-(methyl-sulfonyl-methyl)- piperidin-1 -yl.

[0120] In some embodiments, the present invention is directed to compounds of formula

[0121] (I) wherein R8is In some embodiments, the present invention is directed to compounds of formula (I) wherein R8is ; wherein is a nitrogen bound, 4 to 6 membered heterocycloalkyl; wherein the nitrogen bound 4 to 6 membered heterocycloalkyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-2alkyl, hydroxy substituted C1-2alkyl, cyano, and -C(O)-NRVRW; wherein Rvand Rware each independently selected from the group consisting of hydrogen and C1-2alkyl; wherein is selected from the group consisting of C3-6cycloalkyl, phenyl, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, and 5 to 7 membered bicyclic, bridged or spirocyclic heterocycloalkyl; wherein the C3-6cycloalkyl, phenyl, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, or 5 to 7 membered bicyclic, bridged or spirocyclic heterocycloalkyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-3alkyl, fluorinated C1-2alkyl, C1-2alkoxy, fluorinated C1-2alkoxy, -SO2-(C1-2alkyl), -SO2-(fluorinated C1-2alkyl), -SO2-NRVRW, -SO(NH2)-CH3, cyano, =NRV, -NRVRW, -NRv-SO2-(C1-2alkyl), -C(O)-(C1-2alkyl), -C(O)OH, -C(O)O-(C1-2alkyl), and -C(O)-NRVRW; wherein Rvand Rware each independently selected from the group consisting of hydrogen, C1-2alkyl, fluorinated C1-2alkyl and hydroxy substituted C1-4alkyl; wherein f is an integer from 0 to 1 ; wherein R9is selected from the group consisting of C3-5cycloalkyl, 4 to 6 membered heterocycloalkyl, -C(O)-(4 to 6 membered heterocycloalkyl), and -SO2-(4 to 6 membered heterocycloalkyl); wherein the C3-5cycloalkyl or 4 to 6 membered heterocycloalkyl, whether alone or as part of the R9substituent is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-2alkyl, and fluorinatedC1-2alkyl ; provided that when f is 1 , then is selected from the group consisting of phenyl, 4 to 7 membered heterocycloalkyl, and 5 to 6 membered heteroaryl.

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

[0123] (I) wherein R8is ; wherein is selected from the group consisting of azetidine-1 -yl, piperidin-1 -yl, 3-fluoro-piperidin-1 -yl, 4-fluoro- piperidin-1 -yl, piperidin-1 -yl-3-one, 4-hydroxy-piperidin-1 -yl, 4-(hydroxy-methyl)- piperidin-1 -yl, 3,3-difluoro-piperidin-1 -yl, 4,4-difluoro-piperidin-1 -yl, 3,3-difluoro-4R*- hydroxy-piperidin-1 -yl, 3,3-difluoro-4S*-hydroxy-piperidin-1 -yl, 3 ,3-di methyl-piperid in- 1 - yl, 4-cyano-piperidin-1 -yl, piperazin-1 -yl, piperazin-1 -yl-3-one, 3S-(hydroxy-methyl)- piperazin-1 -yl, 2R-methyl-piperazin-1 -yl, 2-(amino-carbonyl)-piperazin-1 -yl, and morpholin-4-yl; wherein is selected from the group consisting of 4-(1 - hydroxy-cycloprop-1 -yl), 4-(1 -(methyl-sulfonyl)-cycloprop-l -yl), 4-cis-(4-(methyl- sulfonyl)-cyclohex-1 -yl), 4-trans-(4-(methyl-sulfonyl)-cyclohex-1 -yl), 4-cis-(4-(methyl- sulfonyl-amino)-cyclohex-1 -yl), 4-trans-(4-(methyl-sulfonyl-amino)-cyclohex-1 -yl), 4-(3- (methyl-sulfonyl)-azetidin-1 -yl), 4-((1 -methy l-su If onyl)-py rrol id in-3-yl) , 2-(tetrahydro- furan-3-yl), 4-(1 -methyl-2-oxo-tetrahydro-pyrimidin-3-yl), 4-(tetrahydro-thiophen-3R*-yl), 4-(tetrahydro-thiophen-3S*-yl), 4-(tetrahydro-thiophen-3-yl-1 ,1 -dioxide), 4-(tetrahydro- pyran-4-yl-1 ,1 -dioxide), 4-(tetrahydro-thiopyran-4-yl-1 ,1 -dioxide), 3-(thiomorpholin-4-yl- 1 ,1 -dioxide), 4-(thiomorpholin-4-yl-1 ,1 -dioxide), (1 -methyl-carbonyl)-azepan-4-yl, 4-(4- (methyl-sulfonyl)-1 ,4-diazepan-1 -yl), 4-(2-oxo-piperidin-1 -yl), 4-(6-oxo-piperidin-3-yl), 4- (1 -methyl-pi perid in-4-yl) , 4-(1 -methyl-2-oxo-piperidin-4-yl), 4-(4-(methyl-sulfonyl)- piperidi n-1 -yl), 4-(1 -(methyl-sulfony l)-piperid in-4-yl) , 4-(1 -(methyl-sulfonyl)-3,3-difluoro- piperidin-4-yl), 4-(4-(methyl-sulfonyl-amino)-piperidin-1 -yl), 4-(1 -(methyl-carbonyl)- piperidin-4-yl), 4-(1 -(methyl-carbonyl)-4-hydroxy-piperidin-4-yl), (1 -cyclopropyl-2-oxo- piperidin-4-yl), 4R*-(4-methyl-piperazin-4-yl), 4S*-(4-methyl-piperazin-4-yl), 4-(3-oxo-4- methyl-pi perazin- 1 -yl) , 4R*-(3-oxo-4-methyl-piperazin-1 -yl) , 4S*-(3-oxo-4-methyl- piperazin- 1 -yl) , 4-(3-oxo-4-isopropyl-piperazin-1 -yl), 4-(3-oxo-4-cyclopropyl-piperazin-1 - yl), 3-(4-(methyl-sulfonyl)-piperazin-1 -yl), 4-(4-(methyl-sulfonyl)-piperazin-1 -yl), 4R*-(4- (methyl-sulfonyl)-piperazin-1 -yl), 4S*-(4-(methyl-sulfonyl)-piperazin-1 -yl), 4-(2-oxo-4- (methyl-sulfonyl)-piperazin-1 -yl), 3-(4-oxetan-3-yl-piperazin-1 -yl), 4-(4-(trif luoro- methoxy)-phenyl), 4-(4-(azetidin-1 -yl-carbonyl)-phenyl, 4-(4-(methyl-sulfonyl)-phenyl), 4- (4-(trifluoro-methyl-sulfonyl)-phenyl), 4-(4-(methyl-amino-carbonyl)-phenyl), 4-(4- (dimethyl-amino-carbonyl)-phenyl), 4-(4-(amino-sulfonyl)-phenyl), 4-(4-carboxy-phenyl), 4-(4-(ethoxy-carbonyl)-phenyl), 3-(pyrazol-4-yl), 4-(pyrazol-4-yl), 3-(1 -(methyl-sulfonyl)- pyrazol-4-yl), 4-(1 -(methyl-sulfonyl)-pyrazol-4-yl), 4-(pyridin-3-yl), 4-(2-chloro-6-(methyl- sulfonyl)-pyridin-3-yl), 4-(6-hydroxy-pyridin-2-yl), 4-(2-methyl-pyridin-4-yl), 4-(2- isopropyl-6-(methyl-sulfonyl)-pyridin-3-yl), 4-(2-(difluoro-methyl)-6-(methyl-sulfonyl)- pyridin-3yl), 4-(2-(trifluoro-methyl)-6-methyl-sulfonyl)-pyridin-3-yl), 4-(6-(2,2,2-trifluoro- ethyl)-pyridin-3-yl), 4-(4-methoxy-6-(methyl-sulfonyl)-pyridin-3-yl), 4-(6-(trifluoro- methoxy)-pyridin-3-yl), 4-(6-methoxy-pyridin-2-yl), 4-(6-(methyl-sulfonyl)-pyridin-2-yl), 4- (4-(methyl-sulfonyl)-pyridin-3-yl), 4-(6-(methyl-sulfonyl)-pyridin-3-yl), 4R*-(6-(methyl- sulfonyl)-pyridin-3-yl), 4S*-(6-(methyl-sulfonyl)-pyridin-3-yl), 4-(2-methyl-6-(methyl- sulfonyl)-pyridin-3-yl), 4-(2-ethyl-6-(methyl-sulfonyl)-pyridin-3-yl), 4-(6-(2-hydroxy- isobutyl-amino-sulfonyl)-pyridin-3-yl), 4-(6-(2,2,2-trifluoro-ethyl-amino-sulfonyl)-pyridin-

[0124] 3-yl), 4-(6-(methyl-sulfonimidoyl)-pyridin-3-yl), 4-(5-cyano-pyridin-2-yl), 4-(6-(dimethyl- amino)-pyridin-3-yl), 4-(6-(amino-carbonyl)-pyridin-3-yl), 4-(1 -cyclopropyl)-2-oxo-pyridin-

[0125] 4-yl), 4-(2-cyclopropyl-6-(methyl-sulfonyl)-pyridin-3-yl),-(6-(3-hydroxy-3-methyl-azetidin- 1 -yl-su If ony l)-pyridin-3-yl) , 4-(6-(piperazin-1 -yl-su If ony l)-pyridi n-3-yl , 4-(6-(morpholin-4- yl-sulfonyl)-pyridin-3-yl), 4-(6-(2,2,2-trifluoro-ethyl)-piperazin-1 -yl-sulfonyl)-pyridin-3-yl), (6-(4-methyl-piperazin-1 -yl-sulfonyl)-pyridin-3-y I) , 4-(6-((thiomorpholin-4-yl-1 ,1 -dioxide)- sulfonyl)-pyridin-3-yl, 4-(5-(methyl-sulfonyl)-pyrimidin-2-yl), 4-(5-(methyl-sulfonyl)- pyrazin-2-yl), 4-(6-(methyl-sulfonyl)-pyridazin-3-yl), 3-(methyl-sulfonyl-amino)- bicyclo[1 .1 .1 ]pentan-1 -yl, (1 ,4)-2-(methyl-sulfonyl)-2-azabicyclo[2.2.1]heptan-5-yl, and (1 R,4R)-5-methyl-2-(methylsulfonyl)-2-azabicyclo[2.2.1]heptan-5-yl.

[0126] In some embodiments, the present invention is directed to compounds of formula (I) wherein R8is (b) ; wherein is selected from the group consisting of piperazin-1 -yl , piperidi n-1 -yl , 3 ,3,-difl uoro-pi peridi n-1 -yl , piperazin-1 -yl-3-one, 3,3-difluoro-4S*-hydroxy-piperidin-1 -yl, 3 ,3-difl uoro-piperid in- 1 - yl, , piperidin-1 -yl-3-one, 3-fluoro-piperidin-1 -yl, 3,3-difluoro-4R*-hydroxy-piperidin-1 -yl, 2R-methyl-piperazin-1 -yl, 4-hydroxy-piperidin-1 -yl, and 4-cyano-piperidin-1 -yl; and wherein is selected from the group consisting of 4-(4-(methyl- sulfonyl)-phenyl), 4-(6-(methyl-sulfonyl)-pyridin-3-yl), 4-(4-(methyl-sulfonyl)-pyridin-3-yl), 4S*-(6-(methyl-sulfonyl)-pyridin-3-yl), 4R-(6-(methyl-sulfonyl)-pyridin-3-yl), 4R*-(6- (methyl-sulfonyl)-pyridin-3-yl), 4-(6-(methyl-sulfonyl)-pyridin-2-yl), (6-(methyl-sulfonyl)- pyridin-3-yl), (1 -cyclopropyl-2-oxo-piperidin-4-yl), 4-(1 -cyclopropyl-2-oxo-pyridin-4-yl), 4-(4-methyl-sulfonyl-phenyl), (4-(methyl-sulfonyl)-piperazin-1 -yl), (6-(3-oxo-4-methyl- piperazin-1 -yl-su If onyl)-pyridi n-3-yl) , 4-(4-(methyl-sulfonyl)-piperazin-1 -yl), (4-(methyl- sulfonyl)-piperidi n-1 -yl), 4-(4-(amino-sulfonyl)-phenyl), (6-(4-methyl-piperazin-1 -yl- sulfonyl)-pyridin-3-yl), 4-trans-(4-(methyl-sulfonyl)-cyclohex-1 -yl), 4-(6-(3-hydroxy-3- methyl-azetidin-1 -yl-su If ony l)-pyridi n-3-yl) , 4-(6-(piperazin-1 -yl-sulf onyl)-py rid in-3-yl , 4- (6-(2,2, 2-trif I uoro-ethyl)-pyridi n-3-yl) , 4-(1 -methyl-2-oxo-piperidin-4-yl), 4-(6-(2-hydroxy- isobutyl-amino-sulfonyl)-pyridin-3-yl), 4-(4-methyl-sulfonyl)-phenyl), 4-(1 -(methyl- sulfonyl)-piperidin-4-yl), 4-(thiomorpholin-4-yl-1 ,1 -dioxide), 4-(6-(methyl-sulfonimidoyl))- pyridin-3-yl), 4S*-(3-oxo-4-methyl-piperazin-1 -yl), 4-(2-methyl-6-(methyl-sulfonyl)- pyridin-3-yl), 4-(5-(methyl-sulfonyl)-pyrimidin-2-yl), 4-(6-(methyl-sulfonyl)-pyridazin-3-yl), 4-(4-(dimethyl-amino-carbonyl)-phenyl), 4R*-(3-oxo-4-methyl-piperazin-1 -yl), 4-(6- (morpholin-4-yl-sulfonyl)-pyridin-3-yl), 4-(4-(trifluoro-methoxy)-phenyl), 4-(4-(azetidin-1 - yl-carbonyl)-phenyl, 4-(6-((thiomorpholin-4-yl-1 ,1 ,-dioxide)-sulfonyl)-pyridin-3-yl), 4-(4- (methyl-amino-carbonyl)-phenyl), 4-(1 -(methyl-sulfonyl)-cyclopropyl), 4-(6-(trif luoro- methoxy)-pyridin-3-yl), 4-(tetrahydro-thiopyran-4-yl 1 ,1 -dioxide), 4-(4-(methyl-sulfonyl- amino)-piperidin-1 -yl), 4-(2-methyl-pyridin-4-yl), 4-(2-chloro-6-(methyl-sulfonyl)-pyridin- 3-yl), 4-(tetrahydro-thiophen-3R*-yl), 4-(6-(dimethyl-amino)-pyridin-3-yl), 4S-(6-(methyl- sulfonyl)-pyridin-3-yl), 4-(tetrahydro-thiophen-3-yl-1 ,1 -dioxide), 4-(tetrahydro-thiophen- 3S*-yl), 4-(4-(methyl-sulfonyl)-piperidin-1 -yl), 4-(2-cyclopropyl-6-(methyl-sulfonyl)- pyridin-3-yl), and 4-(2-isopropyl-6-(methyl-sulfonyl)-pyridin-3-yl).

[0127] In some embodiments, the present invention is directed to compounds of formula

[0128] (I) wherein R8is (b ) ; wherein is selected from the group consisting of piperazin-1 -yl, piperidi n-1 -yl, 3 ,3,-difl uoro-pi peridi n-1 -yl, piperazin-1 -yl-3-one, 3,3-difluoro-4S*-hydroxy-piperidin-1 -yl, 3 ,3-difl uoro-piperid in- 1 -yl, piperidin-1 -yl-3-one, 3-fluoro-piperidin-1 -yl, 3,3-difluoro-4R*-hydroxy-piperidin-1 -yl, and

[0129] 2R-methyl-piperazin-1 -yl; and wherein is selected from the group consisting of 4-(4-(methyl-sulfonyl)-phenyl), 4-(6-(methyl-sulfonyl)-pyridin-3-yl), 4-(4- (methyl-sulfonyl)-pyridin-3-yl), 4S*-(6-(methyl-sulfonyl)-pyridin-3-yl), 4R-(6-(methyl- sulfonyl)-pyridin-3-yl), 4R*-(6-(methyl-sulfonyl)-pyridin-3-yl), 4-(6-(methyl-sulfonyl)- pyridin-2-yl), (6-(methyl-sulfonyl)-pyridin-3-yl), (1 -cyclopropyl-2-oxo-piperidin-4-yl), 4-(1 - cyclopropyl-2-oxo-pyridin-4-yl), 4-(4-methyl-sulfonyl-phenyl), (4-(methyl-sulfonyl)- piperazin-1 -yl), (6-(3-oxo-4-methyl-piperazin-1 -yl-sulfonyl)-pyridin-3-y I) , 4-(4-(methyl- sulfonyl)-piperazin-1 -yl), (4-(methyl-sulfonyl)-piperidin-1 -yl), 4-(4-(amino-sulfonyl)- phenyl), (6-(4-methyl-piperazin-1 -yl-sulfonyl)-pyridin-3-yl), 4-trans-(4-(methyl-sulfonyl)- cyclohex-1 -yl), 4-(6-(3-hydroxy-3-methyl-azetidin-1 -yl-su If ony l)-pyridi n-3-yl) , 4-(6- (piperazin-1 -yl-su If onyl)-pyridi n-3-yl , 4-(6-(2,2,2-trif lu oro-ethyl)-py ridin-3-yl) , 4-(1 -methyl- 2-oxo-piperidin-4-yl), 4-(6-(2-hydroxy-isobutyl-amino-sulfonyl)-pyridin-3-yl), 4-(4-methyl- sulfonyl)-phenyl), 4-(1 -(methyl-sulfonyl)-piperidin-4-yl), and 4-(thiomorpholin-4-yl-1 ,1 - dioxide).

[0130] In some embodiments, the present invention is directed to compounds of formula

[0131] (I) wherein R8is (b) wherein is selected from the group consisting ofpiperazin-1 -yl, piperidin-1 -yl, 3 , 3, -dif luoro-piperidi n-1 -yl, piperazin-1 -yl-3-one, 3,3-difluoro-4S*-hydroxy-piperidin-1 -yl, 3 ,3-difl uoro-piperid in- 1 -yl, piperidin-1 -yl-3-one, 3-fluoro-piperidin-1 -yl, and 3,3-difluoro-4R*-hydroxy-piperidin-1 -yl; and wherein is selected from the group consisting of 4-(4-(methyl- sulfonyl)-phenyl), 4-(6-(methyl-sulfonyl)-pyridin-3-yl), 4-(4-(methyl-sulfonyl)-pyridin-3-yl), 4S*-(6-(methyl-sulfonyl)-pyridin-3-yl), 4R-(6-(methyl-sulfonyl)-pyridin-3-yl), 4R*-(6- (methyl-sulfonyl)-pyridin-3-yl), 4-(6-(methyl-sulfonyl)-pyridin-2-yl), (6-(methyl-sulfonyl)- pyridin-3-yl), (1 -cyclopropyl-2-oxo-piperidin-4-yl), 4-(1 -cyclopropyl-2-oxo-pyridin-4-yl), 4- (4-methyl-sulfonyl-phenyl), (4-(methyl-sulfonyl)-piperazin-1 -yl) , (6-(3-oxo-4-methyl- piperazin- 1 -yl-su If onyl)-pyridi n-3-yl) , 4-(4-(methyl-sulfonyl)-piperazin-1 -yl), (4-(methyl- sulfonyl)-piperidi n-1 -yl), 4-(4-(amino-sulfonyl)-phenyl), (6-(4-methyl-piperazin-1 -yl- sulfonyl)-pyridin-3-yl) , and 4-trans-(4-(methyl-sulfonyl)-cyclohex-1 -yl).

[0132] In some embodiments, the present invention is directed to compounds of formula

[0133] (I) wherein R8is (b) wherein is selected from the group consisting of piperazin-1 -yl, piperidi n-1 -yl, 3 ,3,-difl uoro-pi peridi n-1 -yl, piperazin-1 -yl-3-one, 3,3-difluoro-4S*-hydroxy-piperidin-1 -yl, 3 ,3-difl uoro-piperid in- 1 -yl; and wherein is selected from the group consisting of 4-(4-(methyl- sulfonyl)-phenyl), 4-(6-(methyl-sulfonyl)-pyridin-3-yl), 4-(4-(methyl-sulfonyl)-pyridin-3-yl), 4S*-(6-(methyl-sulfonyl)-pyridin-3-yl), 4R-(6-(methyl-sulfonyl)-pyridin-3-yl), 4R*-(6- (methyl-sulfonyl)-pyridin-3-yl), 4-(6-(methyl-sulfonyl)-pyridin-2-yl), (6-(methyl-sulfonyl)- pyridin-3-yl), and (1 -cyclopropyl-2-oxo-piperidin-4-yl).

[0134] In some embodiments, the present invention is directed to compounds of formula

[0135] (I) wherein R8is In some embodiments, the present invention is directed to compounds of formula (I) wherein R8is ; wherein is a nitrogen bound, 5 to 6 membered heterocycloalkyl; wherein the 5 to 6 membered heterocycloalkyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, C1-3alkyl, fluorinated C1-2alkyl, and hydroxy substituted C1-3alkyl; wherein L3is selected from the group consisting of -(CH2)-, -C(O)-(CH2)-, -NH-, and -O-; wherein the L3group is bound at the 3- or 4- position of ; wherein R10is selected from the group consisting of 4 to 6 membered heterocycloalkyl, and 5 to 6 membered heteroaryl; wherein the 4 to 6 membered heterocycloalkyl or 5 to 6 membered heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-2alkyl, fluorinated C1-2alkyl, -SO2-(C1-2alkyl), -SO2-(hydroxy substituted C1-4alkyl), -SO2-NRZRAA, and -NRz-SO2-(C1-2alkyl) and -C(O)-NRZRAA; wherein Rzis selected from the group consisting of hydrogen and C1-2alkyl; and wherein RAAis selected from the group consisting of hydrogen, and C1-2alkyl.

[0136] In some embodiments, the present invention is directed to compounds of formula

[0137] (I) wherein R8is ; wherein is selected from the group consisting of piperidin-1 -yl, 3,3-difluoro-piperidin-1 -yl, 4,4-difluoro-piperidin-1 -yl, and piperazin-1 -yl; wherein L3is selected from the group consisting of 4-(-CH2-), 4-(- C(O)-(CH2)-), 3-(-NH-), 4-(-NH-), 3R*-(-NH-), 3S*-(-NH-), 4R*-(-NH-), 4S*-(-NH-), and 3- (-O-); and wherein R10is selected from the group consisting of 3-(methyl-sulfonyl)- azetidin-1 -yl, 4-(methyl-sulfonyl)-piperidin-1 -yl, 1 -(methyl-sulfonyl)-piperidin-4-yl, tetrahydro-thiophen-3-yl-1 ,1 -dioxide, 1 ,4-dioxan-3-yl, pyridin-4-yl, and 6-(methyl- sulfonyl)-pyridin-3-yl.

[0138] In some embodiments, the present invention is directed to compounds of formula —

[0139] (I) wherein R8is (c) ; wherein is selected from the group consisting of 3,3-difluoro-piperidin-1 -yl, piperidin-1 -yl, and piperazin-1 -yl; wherein L3is selected from the group consisting of 4-(NH), 4S*-(NH), 3R*-(NH), 3-(NH), 4-(CH2), and 4R*-(NH); and wherein R10is selected from the group consisting of 1 -(methyl- sulfonyl-piperidin-4-yl) , 1 - (methyl-su If ony l)-piperidi n-4-yl , 4-(methyl-sulfonyl)-piperidin-1 - yl, and 1 ,4-dioxan-3-yl.

[0140] In some embodiments, the present invention is directed to compounds of formula (I) wherein R8is (c) is 3,3-difluoro- piperidin-1 -yl; wherein L3is 4-(NH); and wherein R10is 1 -(methyl-sulfonyl-piperidin-4-

[0141] In some embodiments, the present invention is directed to compounds of formula

[0142] (I) wherein R8is In some embodiments, the present invention is directed to compounds of formula (I) wherein R8is is nitrogen bound 7 to 14 membered bicyclic, bridged or spirocyclic heterocyclyl; wherein the 5 to

[0143] 12 membered bicyclic, bridged or spirocyclic heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-2alkyl, fluorinated C1-2alkyl, -SO2-(C1-2alkyl), -SO2-NRABRAC, =NRAB, - NRABRAC, -NRAB-SO2-(C1-2alkyl), -C(O)-(C1-2alkyl), -C(O)-NRABRAC, cyclopropyl, phenyl and 5 to 6 membered heteroaryl; wherein the phenyl or 5 to 6 membered heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-2alkyl, fluorinated C1-2alkyl, and -SO2-(C1-2alkyl); wherein RABis selected from the group consisting of hydrogen and C1-2alkyl; and wherein RACis selected from the group consisting of hydrogen, and C1-2alkyl.

[0144] In some embodiments, the present invention is directed to compounds of formula

[0145] (I) wherein R8is ; wherein is selected from the group consisting of 6-cyclopropyl-2,6-diazaspiro[3.3]heptan-2-yl, 2,3-dihydroxy-(1 S,4S)-2- azabicyclo[2.2.1 ]heptan-2-yl, 2,6-diazaspiro[3.4]octan-2-yl, 2-(methyl-sulfonyl)-2,6- diazaspiro[3.4]octan-2-yl, 2-(methyl-carbonyl)-2,6-diazaspiro[3.4]octan-2-yl, 2-thia-6- azaspiro[3.4]octan-6-yl 2,2-dioxide, 2,7-diazaspiro[3.5]nonan-7-yl-3-one, 2-oxa-6- azaspiro[3.5]nonan-6-yl, 2-oxa-5,8-diazaspiro[3.5]nonan-8-yl, 2-oxa-7- azaspiro[3.5]nonan-7-yl, 2-thia-7-azaspiro[3.5]nonan-7-yl 2,2-dioxide, 2-hydroxy-7- azaspiro[3.5]nonan-7-yl, 2-hydroxy-2-methyl-7-azaspiro[3.5]nonan-7-yl, 2-oxa-8- azaspiro[4.5]decan-8-yl, 2-thia-8-azaspiro[4.5]decan-8-yl 2,2-dioxide, 8-thia-2- azaspiro[4.5]decan-2-yl 8,8-dioxide, 3-azaspiro[5.5]undecan-3-yl; 3-oxa-9- azaspiro[5.5]undecan-9-yl, 3-(methyl-sulfonyl)-3,9-diazaspiro[5.5]undecan-3-yl, 6-oxa-2- thia-9-azaspiro[4.6]undecan-9-yl 2,2-dioxide, 3-thia-9-azaspiro[5.5]undecan-9-yl 3,3- dioxide, 1 -oxa-9-thia-4-azaspiro[5.5]undecan-4-yl 9,9-dioxide, 7-oxa-3-thia-10- azaspiro[5.6]dodecan-10-yl 3,3-dioxide, octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2- dioxide, (R*)-octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2-dioxide, (S*)- octahydropyrazino[2,1 -c] [ 1 ,4]thiazin-8-y I 2,2-dioxide, 7,7-dimethyl- octahydropyrazino[2,1 -c] [ 1 ,4]thiazin-8-y I 2,2-dioxide, 7,7-dimethyl-(R*)- octahydropyrazino[2,1 -c] [ 1 ,4]thiazin-8-y I 2,2-dioxide, 7,7-dimethyl-(S*)- octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2-dioxide, (4aR,8aR)-octahydro-1 H- pyrano[3,4-c]pyridin-7-yl, (4aR,8aS)-octahydro-1 H-pyrano[3,4-c]pyridin-7-yl, (4aS,8aR)- octahydro-1 H-pyrano[3,4-c]pyridin-7-yl, (4aS,8aS)-octahydro-1 H-pyrano[3,4-c]pyridin-7- yl, hexahydro-pyrazino[2,1 -c][1 ,4]oxazin-8-yl-4-one, octahydropyrazino[2,1 - c][1 ,4]oxazin-8-yl, (S)-octahydropyrazino[2,1 -c][1 ,4]oxazin-8-yl, octahydropyrazino[2,1 - c][1 ,4]oxazin-8-yl-6,6-d2, (S)-hexahydro-pyrazino[2,1 -c][1 ,4]oxazin-8-yl-4-one, (S*)- hexahydro-pyrazino[2,1 -c] [ 1 ,4]oxazin-8-yl-6-one, (R*)-hexahydro-pyrazino[2,1 - c][1 ,4]oxazin-8-yl-6-one, 8-methyl-(R*)-hexahydro-1 H-pyrazino[1 ,2-a]pyrazin-2-yl, 8- methyl-(S*)-hexahydro-1 H-pyrazino[1 ,2-a]pyrazin-2-yl, 8-(2,2,2-trifluoro-ethyl)-(R*)- octahydro-2H-pyrazino[1 ,2-a]pyrazin-2-yl, 8-(2,2,2-trifluoro-ethyl)-(S*)-octahydro-2H- pyrazino[1 ,2-a]pyrazin-2-yl, 2-(methyl-sulfonyl)-3,4,6,7,9,9aR*-hexahydro-1 H- pyrazino[1 ,2-a]pyrazin-8-yl, 2-(methyl-sulfonyl)-3,4,6,7,9,9aS*-hexahydro-1 H- pyrazino[1 ,2-a]pyrazin-8-yl, 2-imino-2-oxo-3,4,6,7,9,9a-hexahydro-1 H-pyrazino[2,1 - c][1 ,4]thiazin-8-yl , 7-(methyl-sulfonyl)-3,4-dihydro-1 H-isoqu inolin-2-yl, 6-chloro- spiro[isobenzofuran-1 ,4'-piperid in- 1 -yl], 6-(methyl-sulfonyl)-(1 R*)-spiro[isobenzofuran- 1 ,4'-pi peridin]- 1 '-yl, 6-(methyl-sulfonyl)-(1 S*)-spiro[isobenzofuran-1 ,4'-pi peridin]- 1 '-yl, 3- fluoro-6-(methyl-sulfonyl)-spiro[isobenzofuran-1 ,4'-pi peridin- 1 -yl], 5-(methyl-sulfonyl)- octahydropyrrolo[3,4-b]pyrrol-1 -yl, hexahydro-1 H-thieno[3,4-b]pyrrol-1 -yl 5,5-dioxide, 3- (trifluoro-methyl)-5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3-c]pyrimidin-6-yl, and 5-(4-(methyl- sulfonyl)-phenyl)-2,5-diazabicyclo[2.2.2]octan-2-yl.

[0146] In some embodiments, the present invention is directed to compounds of formula (I) wherein R8is (d) wherein is selected from the group consisting of (S*)-octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2-dioxide, octahydropyrazino[2,1 -c] [ 1 ,4]thiazin-8-yl 2,2-dioxide, 7,7-dimethyl- octahydropyrazino[2,1 -c] [ 1 ,4]thiazin-8-y I 2,2-dioxide, (S)-octahydropyrazino[2,1 - c][1 ,4]oxazin-8-yl, 2-thia-8-azaspiro[4.5]decan-8-yl 2,2-dioxide, 1 -oxa-9-thia-4- azaspiro[5.5]undecan-4-yl 9,9-dioxide, 3-thia-9-azaspiro[5.5]undecan-9-yl 3,3-dioxide, 3-oxa-9-azaspiro[5.5]undecan-9-yl, 2-oxa-7-azaspiro[3.5]nonan-7-yl, 7-oxa-3-thia-10- azaspiro[5.6]dodecan-10-yl 3,3-dioxide, and 2,3-dihydroxy-(1 S,4S)-2- azabicyclo[2.2.1 ]heptan-2-yl.

[0147] In some embodiments, the present invention is directed to compounds of formula

[0148] (I) wherein R8is (d) ; wherein is selected from the group consisting of octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2-dioxide, and (S*)- octahydropyrazino[2,1 -c] [ 1 ,4]thiazin-8-y I 2,2-dioxide.

[0149] 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, a, L1, R3, R4, R8, etc.) are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein. In additional embodiments, the present invention is any single compound or subset of compounds selected from the representative compounds listed in Tables 1 -4 below.

[0150] In additional embodiments, the present invention is directed to methods of treating a leukemia or lymphoma comprising administering a therapeutically effective amount of any single compound or subset of compounds independently selected from the representative compounds listed in Tables 1 -3, below. In additional embodiments, the present invention is directed to methods of treating a leukemia or lymphoma comprising administering a therapeutically effective amount of a compound of formula (P1 ), compound of formula (P2) or compound of formula (P3). In certain embodiments, the present invention is directed to one or more compounds of Formula (I) independently selected from the group consisting of the compounds listed in Tables 1 -4, below.

[0151] Representative compounds of formula (I) of the present invention are as listed in Table 1 to 4 below. Unless otherwise noted, wherein a stereogenic center is present in the listed compound, the compound was prepared as a mixture of stereo-configurations. 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 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 are intended to indicate that measured stereo-configuration of the center.

[0152] In certain embodiments, the present invention is directed to one or more compounds of Formula (I) independently selected from the group consisting of the compounds listed in Tablei , below.

[0153] Table 1 : Representative Compounds for Formula (l-A)

[0154] In certain embodiments, the present invention is directed to one or more compounds of Formula (I) independently selected from the group consisting of the compounds listed in Table 2, below.

[0155] Table 2: Representative Compound of Formula (l-B)

[0156]

[0157] In certain embodiments, the present invention is directed to one or more compounds of Formula (I) independently selected from the group consisting of the compounds listed in Table 3, below.

[0158] Table 3: Representative Compound of Formula (l-C)

[0159] In certain embodiments, the present invention is directed to one or more compounds of Formula (I) independently selected from the group consisting of the compounds listed in Table 4, below.

[0160] In certain embodiments, the present invention is directed to one or more compounds of formula (I) independently selected from the group consisting of (2R)-N-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6- trimethylphenyl)-1 -isoquinolyl]amino]-3-[6-(trifluoromethyl)-3-pyridyl]propenamide;

[0161] N-[2-[(2R)-3-hydroxy-3-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 - carbonyl]-7-(2,3,6-trimethylphenyl)-1 -isoquinolyl]amino]butyl]-5- (trifluoromethyl)phenyl]prop-2-enamide; (2R)-N-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6- trimethylphenyl)-1 -isoquinolyl]amino]-3-[2-(prop-2-enoylamino)-4- (trifluoromethyl)phenyl]propenamide;

[0162] [1 -[[(1 R)-2-hydroxy-2-methyl-1 -[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]-7- (2,3,6-trimethylphenyl)-5-isoquinolyl]-[4-(6-methylsulfonyl-3-pyridyl)-1 - piperidyl]methanone;

[0163] [3,3-difluoro-4S-[(1 -methylsulfonyl-4-piperidyl)amino]-1 -piperidy l]-[ 1 -[[2-hydroxy- 2-methyl-1 R-[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]-7-(2,3,6-trimethylphenyl)- 5-isoquinolyl]methanone;

[0164] [(4S*)-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)-5- isoquinolyl]methanone;

[0165] [(4RS)-3,3-difluoro-4-(6-methylsulfonyl-3-pyridyl)-1 -piperidyl]-[ 1 -[[(1 R)-2-hydroxy- 2-methyl-1 -[[6-(trifluoromethyl)-3-pyridyl]methyl]propyl]amino]-7-(2,3,6-trimethylphenyl)- 5-isoquinolyl]methanone;

[0166] 1 -[[(1 R)-2-hydroxy-2-methyl-1 -[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]-5- [4-(6-methylsulfonyl-3-pyridyl)piperidine-1 -carbonyl]-7-(2,3,6- trimethylphenyl)isoquinoline-3-carbonitrile;

[0167] [1 -[[(1 R)-2-hydroxy-2-methyl-1 -[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]-3- methylsulfonyl-7-(2,3,6-trimethylphenyl)-5-isoquinolyl]-[4-(6-methylsulfonyl-3-pyridyl)-1 - piperidyl]methanone;

[0168] [1 -[[(1 R)-2-hydroxy-2-methyl-1 -[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]-3- (morpholinomethyl)-7-(2,3,6-trimethylphenyl)-5-isoquinolyl]-[4-(6-methylsulfonyl-3- pyridyl)- 1 -piperidyl]methanone;

[0169] [3-chloro-1 -[[(1 R)-2-hydroxy-2-methyl-1 -[[6-(trifluoromethyl)-3- pyridyl]methyl]propyl]amino]-7-(2,3,6-trimethylphenyl)-5-isoquinolyl]-[4-(6- methylsulfonyl-3-pyridyl)-1 -piperidyl]methanone;

[0170] [3-chloro-1 -[[(1 R)-2-hydroxy-2-methyl-1 -[[4- (trifluoromethyl)phenyl]methyl]propyl]amino]-7-(2,3,6-trimethylphenyl)-5-isoquinolyl]-[4- (4-methylsulfonylcyclohexyl)piperazin-1 -yl]methanone; (2R)-2-[[5-[(4S*)-3,3-difluoro-4-(6-methylsulfonyl-3-pyridyl)piperidine-1 -carbonyl]- 3-methylsulfonyl-7-(2,3,6-trimethylphenyl)-1 -isoquinolyl]amino]-N-methyl-3-[6- (trifluoromethyl)-3-pyridyl]propenamide;

[0171] (2R)-2-[[3-cyano-5-[(4S*)-3,3-difluoro-4-(6-methylsulfonyl-3-pyridyl)piperidine-1 - carbonyl]-7-(2,3,6-trimethylphenyl)-1 -isoquinolyl]amino]-N-methyl-3-[4- (trifluoromethyl)phenyl]propenamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof.

[0172] In some embodiments, the present invention is directed to the compound of formula (P1 ) also known as (R)-2-methyl-3-((4-(4-(4-(methylsulfonyl)phenyl)piperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-4-(4- (trifluoromethyl)phenyl)butan-2-yl dihydrogen phosphate; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof.

[0173] In certain embodiments, the present invention is directed to compounds of formula (I) which, when tested for BFL-1 receptor inhibition according to the procedure as described in Biological Example 1 or 2, which follows hereinafter, exhibit a Ki of less than or equal to about 1 pM, preferably less than or equal to about 500 nM, more preferably less than or equal to about 250 nM, more preferably less than or equal to about 100 nM, more preferably less than or equal to about 50 nM, more preferably less than or equal to about 10 nM, more preferably less than or equal to about 5 nM, more preferably less than or equal to about 1 nM, more preferably less than or equal to about 0.5 nM, more preferably less than or equal to about 0.2 nM, more preferably less than or equal to about 0.1 nM, more preferably less than or equal to about 0.05 nM, more preferably less than or equal to about 0.03 nM, more preferably less than or equal to about 0.02 nM.

[0174] In certain embodiments, the present invention is directed to compounds of formula (I) wherein the substituents selected for one or more of the variables defined herein (i.e. R1, R2, a, L1, R3, R4, R8, etc.) are independently selected to be one or more of the substituents present in compounds of formula (I) which, when tested for BFL-1 receptor inhibition according to the procedure as described in Biological Example 1 or 2, which follows hereinafter, exhibit a Ki of less than or equal to about 1 pM, preferably less than or equal to about 500 nM, more preferably less than or equal to about 250 nM, more preferably less than or equal to about 100 nM, more preferably less than or equal to about 50 nM, more preferably less than or equal to about 10 nM, more preferably less than or equal to about 5 nM, more preferably less than or equal to about 1 nM, more preferably less than or equal to about 0.5 nM, more preferably less than or equal to about 0.2 nM, more preferably less than or equal to about 0.1 nM, more preferably less than or equal to about 0.05 nM, more preferably less than or equal to about 0.03 nM, more preferably less than or equal to about 0.02 nM.

[0175] Abbreviations and Definitions

[0176] Abbreviations used in the specification, for example in the Schemes, Synthesis Examples and Biological Examples, are as listed in the Table A, below:

[0177] Table A: Abbreviations

[0178]

[0179]

[0180]

[0181] As used herein, unless otherwise noted, “halogen” shall mean chloro, bromo, fluoro and iodo, preferably bromo, fluoro or chloro, more preferably fluoro or chloro. As used herein, unless otherwise noted, the term “oxo” shall mean a functional group of the structure =0 (i.e. a substituent oxygen atom connected to another atom by a double bond). One skilled in the art will recognize that wherein the oxo group is bound to a ring nitrogen or a nitrogen substituted with two non-hydrogen substituent groups, the result will be a N-oxide bond (i.e. >N+-O .

[0182] As used herein, unless otherwise noted, the term “Cx-Yalkyl” wherein X and Y are integers, whether used alone or as part of a substituent group, include straight and branched chains containing between X and Y carbon atoms. For example, Ci 4alkyl radicals include straight and branched chains of between 1 and 4 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl.

[0183] As used herein, unless otherwise noted, the terms “-(Cx-Yalkyl)-, -(Cx-Yalkylene)-, Cx-Yalkyl- and -Cx-Yalkylene-” wherein X and Y are integers, shall denote any Cx-Yalkyl carbon chain as herein defined, wherein said Cx-Yalkyl chain is divalent and is further bound through two points of attachment, preferably through two terminal carbon atoms.

[0184] 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. Suitable examples include, but are not limited to - CH2F, CHF2, -CF3J-CH2-CF3, -CF2-CH3, -CH2-CH2-CH2F, -CH2-CH2-CF3, -C(CH3)2CF3, -C(CF3)3, and the like.

[0185] As used herein, unless otherwise noted, the term “hydroxy substituted Cx-Yalkyl” shall mean any Cx-Yalkyl group as defined above substituted with one or more hydroxy (-0H) groups, preferably one to three, more preferably one to two hydroxy groups. Suitable examples include but are not limited to -CH2OH, -CH2CH2OH, -CH(OH)CH3, - CH(OH)CH2OH, -CH2CH2CH2OH, -C(CH2OH)3, and the like.

[0186] As used herein, unless otherwise noted, the term “hydroxy and fluoro substituted Cx-Yalkyl” shall mean any Cx-Yalkyl group as defined above substituted with one or more hydroxy (-0H) groups, preferably one to three, more preferably one to two hydroxy groups; further substituted with one of more, preferably one to three fluoro groups. Suitable examples include but are not limited to -CF2OH, -CFHCH2OH, -CH(OH)-CF3, - CH2-CH(OH)-CF3, -CF(CH2OH)2, -CF2-CH2(OH), and the like. As used herein, unless otherwise noted, the term “cyano substituted Cx-Yalkyl” shall mean any Cx-Yalkyl group as defined above substituted with one or more cyano (- CN) groups, preferably one to three, more preferably one to two hydroxy groups. Suitable examples include but are not limited to -CH2-CN, -CH2CH2-CN, -CH(CN)CH3, -CH(CN)CH2-CN, -CH2CH2CH2-CN, and the like.

[0187] As used herein, unless otherwise noted, the term “Cx-Yalkenyl” wherein X and Y are integers, whether used alone or as part of a substituent group, include straight and branched chains containing between X and Y carbon atoms, further containing at least one unsaturated double bond. “C2-4alkenyl” shall include straight and branched chain composition of between 2 and 4 carbon atoms containing at least one double bong, including for example, -CH=CH2, -CH2-CH-CH2, -CH=CH-CH3, -CH2-CH2-CH-CH2, - CH2-CH-CH-CH3, -CH-CH-CH2-CH3, and the like.

[0188] As used herein, unless otherwise noted, the term “fluorinated Cx-Yalkenyl” shall mean any Cx-Yalkenyl 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 -CH=CF2, -CH2-CH-CF2, -CH=CH-CF3, -CF2-CF2-CH-CH2, -CF2-CH=CH- CF3, -CH-CH-CF2-CF3, and the like.

[0189] As used herein, unless otherwise noted, the term “cyano substituted Cx-Yalkenyl” shall mean any Cx-Yalkenyl group as defined above substituted with one or more cyano (-CN) groups, preferably one to three, more preferably one to two hydroxy groups. Suitable examples include but are not limited to -CH=CH-CN, -CH2-CH=CH-CN, - CH=CH-CH2-CN, -CH(CN)-CH2-CH=CH2, -CH2-CH-CH-CH2-CN, -CH-CH-CH2-CH2- CN, and the like.

[0190] As used herein, unless otherwise noted, the term “Cx-Yalkynyl” wherein X and Y are integers, whether used alone or as part of a substituent group, include straight and branched chains containing between X and Y carbon atoms, further containing at least one unsaturated double bond. For example, “C2-4alkynyl” shall include straight and branched chain composition of between 2 and 4 carbon atoms containing at least one double bond, including for example, -CCH2, -CH2-CCH2, -CC-CH3, -CH2-CH2-CCH, - CH2-CC-CH3, -CC-CH2-CH3, and the like. As used herein, unless otherwise noted, “Cx-yalkoxy” wherein X and Y are integers, shall mean an oxygen ether radical of the above described straight or branched chain Cx-yalkyl groups containing between X and Y carbon atoms. For example, C1-4alkoxy shall include methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy, iso-butyloxy, sec-butyloxy and tert-butyloxy.

[0191] As used herein, unless otherwise noted, the term “fluorinated Cx-yalkoxy” shall mean any Cx-yalkoxy oxygen ether radical as defined above, substituted with one or more fluoro groups, preferably one to three fluoro groups. Suitably examples include, but are not limited to -CH2F, CHF2, -CF3, -CH2-CF3, -CF2-CH3, -CH2-CH2-CH2F, -CH2- CH2-CF3, -C(CH3)2CF3, -C(CF3)3, and the like.

[0192] As used herein, unless otherwise noted, the term “Cx-ycycloalkyl”, wherein X and Y are integers, shall mean any stable X- to Y-membered monocyclic, bicyclic, polycyclic, bridged or spirocyclic saturated carbon ring structure, preferably a monocyclic, bicyclic, bridged or spirocyclic saturated carbon ring structure. For example, the term “C3-8cycloalkyl” includes, but is not limited to, cyclopropyl, cyclobutyl, bicyclo[1 .1 .0]butan-1 -yl, cyclopentyl, bicyclo[1 .1 .1 ]pentan-1 -yl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl, cyclooctyl, bicyclo[2.2.2]octan-2-yl, and the like.

[0193] As used herein, unless otherwise noted, the term “5 to 6 membered heteroaryl” shall denote any five or six membered, monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S. Unless otherwise noted, the 5 to 6 membered heteroaryl (regardless of the number of ring atoms, the number and identity of ring heteroatoms, etc.) may be bound through any ring atom which results in a stable structure. Suitably examples include, but are not limited to furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thidiazolyl, tetrazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, dioxinyl, oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl, and the like.

[0194] As used herein, unless otherwise noted, the term “heterocycloalkyl” shall denoted any saturated, monocyclic ring containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; or any saturated bicyclic, fused, bridged or spirocyclic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S. Unless otherwise noted, the heterocycloalkyl (regardless of the number of ring atoms, the number and identity of ring heteroatoms, etc.) may be bound through any ring atom which results in a stable structure. Suitable examples include, but are not limited to, pyrrolidinyl, 1 ,3- dioxolanyl, pyrazolidinyl, tetrahydrofuranyl, peterahydrothiophenyl, piperidiyl, piperazinyl, 1 ,-dioxanyl, morpholinyl, 1 ,4-dithianyl, thiomorpholinyl, 1 ,3,5-trithianyl, norbornnanyl, adamtanyl, quinuclidinyl, azabicyclo[2.2.1]heptan-5-yl, and the like.

[0195] As used herein, unless otherwise noted, the term “X to Y membered heterocycloalkyl” wherein X and Y are integers shall denote any heterocycloalkyl ring structure as described herein, wherein said heterocycloalkyl ring structure contains between X and Y ring atoms (e.g., 4 to 12 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, 4 to 7 membered heterocycloalkyl, 4 to 6 membered heterocycloalkyl, 5 to 12 membered heterocycloalkyl, 5 to 8 membered heterocycloalkyl, 5 to 7 membered heterocycloalkyl, 5 to 6 membered heterocycloalkyl, and the like).

[0196] As used herein, unless otherwise noted, the term “X to Y membered bicyclic, bridged or spirocyclic heterocycloalkyl”, wherein X and Y are integers (e.g. 5 to 8 membered bicyclic, bridged or spirocyclic heterocycloalkyl, 5 to 8 membered bicyclic, bridged or spirocyclic heterocycloalkyl, 5 to 7 membered bicyclic, bridged or spirocyclic heterocycloalkyl, and the like) shall denote any saturated bicyclic, bridged or spirocyclic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S. Unless otherwise noted, the X to Y membered bicyclic, bridged or spirocyclic heterocycloalkyl (regardless of the number of ring atoms, the number and identity of ring heteroatoms, etc.) may be bound through any ring atom which results in a stable structure.

[0197] As used herein, unless otherwise noted, the term “heterocyclyl” shall denote any monocyclic, saturated, partially unsaturated or aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; or any saturated, partially unsaturated, partially aromatic or aromatic bicyclic, fused, bridged or spirocyclic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S. Unless otherwise noted, the heterocyclyl (regardless of the number of ring atoms, the number and identity of ring heteroatoms, degree of saturation or unsaturation, etc.) may be bound through any ring atom which results in a stable structure. Suitable examples include, but are not limited to, pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, purazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, indolinyl, chromenyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo[b][1 ,4]dioxinyl, benzo[d][1 ,3]dioxolyl, 2H- benzo[d][1 ,2,3]triazol-5-yl , and the like.

[0198] As used herein, unless otherwise noted, the term “X to Y membered heterocyclyl” wherein X and Y are integers (e.g. 5 to 8 membered heterocyclyl) shall denote any heterocyclyl ring structure as described herein, wherein said heterocyclyl ring structure contains between X and Y ring atoms.

[0199] As used herein, unless otherwise noted, the term “X to Y membered bicyclic, bridged or spirocyclic heterocyclyl”, wherein X and Y are integers (e.g. 5 to 14 membered bicyclic, bridged or spirocyclic heterocyclyl, 7 to 14 membered bicyclic, bridged or spirocyclic heterocyclyl, 8 to 12 membered bicyclic, bridged or spirocyclic heterocyclyl, 8 to 11 membered bicyclic, bridged or spirocyclic heterocyclyl, 5 to 12 membered bicyclic, bridged or spirocyclic heterocycloalkyl, 5 to 8 membered bicyclic, bridged or spirocyclic heterocycloalkyl, and the like) shall denote any saturated, partially unsaturated, partially aromatic or aromatic bicyclic, bridged or spirocyclic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S. Unless otherwise noted, the X to Y membered bicyclic, bridged or spirocyclic heterocyclyl (regardless of the number of ring atoms, the number and identity of ring heteroatoms, degree of saturation or unsaturation, etc.) may be bound through any ring atom which results in a stable structure. Suitable examples include, but are not limited to 2,6-diazaspiro[3.3]heptan-2-yl, 2-azabicyclo[2.2.1]heptan-2-yl, 2,6-diazaspiro[3.4]octan-

[0200] 2-yl, 2,7-diazaspiro[3.5]nonan-7-yl-3, 2-oxa-6-azaspiro[3.5]nonan-6-yl, 2-oxa-5,8- diazaspiro[3.5]nonan-8-yl, 7-azaspiro[3.5]nonan-7-yl, 2-oxa-7-azaspiro[3.5]nonan-7-yl,

[0201] 2-thia-7-azaspiro[3.5]nonan-7-yl, 2-oxa-8-azaspiro[4.5]decan-8-yl, 2-thia-8- azaspiro[4.5]decan-8-yl, 8-thia-2-azaspiro[4.5]decan-2-yl, 3-azaspiro[5.5]undecan-3-yl;

[0202] 3-oxa-9-azaspiro[5.5]undecan-9-yl, 3,9-diazaspiro[5.5]undecan-3-yl, 6-oxa-2-thia-9- azaspiro[4.6]undecan-9-yl 2,2-dioxide, 3-thia-9-azaspiro[5.5]undecan-9-yl, 1 -oxa-9-thia-

[0203] 4-azaspiro[5.5]undecan-4-yl, 7-oxa-3-thia-10-azaspiro[5.6]dodecan-10-yl, octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl, octahydro-1 H-pyrano[3,4-c]pyridin-7-yl, hexahydro-pyrazino[2,1 -c][1 ,4]oxazin-8-yl-4-one, octahydropyrazino[2,1 -c][1 ,4]oxazin-8- yl, hexahydro-1 H-pyrazino[1 ,2-a]pyrazin-2-yl, octahydro-2H-pyrazino[1 ,2-a]pyrazin-2-yl, hexahydro-1 H-pyrazino[1 ,2-a]pyrazin-8-yl, hexahydro-1 H-pyrazino[1 ,2-a]pyrazin-8-yl, 3,4-dihydro-1 H-isoqu inoli n-2-yl , spiro[isobenzofuran-1 ,4'-pi perid in-1 -yl], octahydropyrrolo[3,4-b]pyrrol-1 -yl, hexahydro-1 H-thieno[3,4-b]pyrrol-1 -yl, tetrahydro-

[0204] [1 ,2,4]triazolo[4,3-c]pyrimidin-6-yl, 2,5-diazabicyclo[2.2.2]octan-2-yl, and the like.

[0205] As used herein, unless otherwise noted, the term “nitrogen bound” when used to modify a heteroaryl, heterocycloalkyl or heterocyclyl group, shall denote that said heteroaryl, heterocycloalkyl or heterocyclyl group contains at least one ring nitrogen atom, and further that said heteroaryl, heterocycloalkyl or heterocyclyl group is bound through a ring nitrogen atom.

[0206] When a particular group is "substituted" (e.g. Cx-yalkyl, Cx-ycycloalkyl, heterocyclyl, heterocycloalkyl, 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. 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) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.

[0207] In some embodiments, the present invention is directed to pharmaceutically acceptable salts of the compounds of formula (I).

[0208] 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.

[0209] 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.

[0210] Representative acids which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: acids including acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L- aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)- camphoric acid, camphorsulfonic acid, (+)-(1 S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1 ,2-disu Ifonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D- glucoronic acid, L-glutamic acid, oc-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (±)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1 ,5-disulfonic acid, 1 -hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid.

[0211] 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.

[0212] 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).

[0213] As used herein, the symbol or notation shall denote the presence of a stereogenic center.

[0214] 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.

[0215] 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%.

[0216] Throughout the specification and claims, wherein a compound or substituent group is drawn or named, the “*S” and “*R” or “S*” and “R*” designations associated with a given stereo-center indicate that although the compound or substituent group is present in an excess of one stereo-orientation at said stereo-center, the exact stereoconfiguration has not been determined. Further, wherein a compound or substituent group is drawn or named, the “S” and “R” designations indicate that the stereoorientation at said stereo-center was measured / determined and that the compound or group is present in an excess of the corresponding “S” or “R” stereo-orientation.

[0217] Wherein a compound or substituent group contains two stereo-centers which are drawn using “ and I or > "HI “ bond symbols, and which are the further denoted as “RS”, it is intended to indicate that the compound is present in an excess of either the “cis” or “trans” orientation of said two stereo-centers, although the exact stereo-configuration has not been determined.

[0218] In some embodiments, the present invention is directed to compounds of formula (I) wherein the stereocenter denoted with a “*” is present in the R- stereo-orientation. In some embodiments, the present invention is directed to compounds of formula (I) wherein the stereocenter denoted with a is present in an S- stereo-orientation. In some embodiments, the present invention is directed to compounds of formula (II) wherein the stereocenter denoted with a is present in the R- stereo-orientation. In some embodiments, the present invention is directed to compounds of formula (II) wherein the stereocenter denoted with a is present in an S- stereo-orientation. In some embodiments, the present invention is directed to compounds of formula (III) wherein the stereocenter denoted with a is present in the R- stereo-orientation. In some embodiments, the present invention is directed to compounds of formula (III) wherein the stereocenter denoted with a is present in an S- stereo-orientation.

[0219] As used herein, unless otherwise noted, the term “isotopologues” shall mean molecules that differ only in their isotopic composition. More particularly, an isotopologue of a molecule differs from the parent molecule in that it contains at least one atom which is an isotope (i.e. has a different number of neutrons from its parent atom). For example, isotopologues of water include, but are not limited to, "light water" (HOH or H2O), "semi-heavy water" with the deuterium isotope in equal proportion to protium (HDO or1H2HO), “heavy water” with two deuterium isotopes of hydrogen per molecule (c / 2O or2H2O), "super-heavy water" or tritiated water (T2O or3H2O), where the hydrogen atoms are replaced with tritium (3H) isotopes, two heavy-oxygen water isotopologues (H218O and H217O) and isotopologues where the hydrogen and oxygen atoms may each independently be replaced by isotopes, for example the doubly labeled water isotopologue d218O.

[0220] As used herein, unless otherwise noted, the term “isotopomer” shall mean isomers with isotopic atoms, having the same number of each isotope of each element but differing in their position. Isotopomers include both constitutional isomers and stereoisomers solely based on isotopic location. For example, CH3CHDCH3and CH3CH2CH2D are a pair of constitutional isotopomers of n-propane; whereas (R)-CH3CHDOH and (S)-CH3CHDOH or (Z)-CH3CH=CHD and (E)-CH3CH=CHD are examples of isotopic stereoisomers of ethanol and n-propene, respectively.

[0221] 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 isotopically enriched form. For example, a reference to hydrogen includes within its scope1H,2H (D), and3H (T). Similarly, references to carbon and oxygen include within their scope respectively12C,13C and14C and16O and18O. The isotopes may be radioactive or non-radioactive. Radiolabelled compounds of formula (I) may comprise one or more radioactive isotope(s) selected from the group of3H,11C,18F, 1221,123|,125|,1311,75Br,76Br,77Br and82Br. Preferably, the radioactive isotope is selected from the group of3H,11C and18F.

[0222] Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a “phenyl-(C1-C6alkylene)-amino-carbonyl- (C1-Cealkylene)-” substituent refers to a group of the formula

[0223] One skilled in the art will further recognize that in the chemical structures provided herein, a methyl substituent group may be denoted or as “ . For example, a 4-methyl-pyridin-2-yl substituent may be drawn as , respectively.

[0224] 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.

[0225] 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.

[0226] 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).

[0227] General Synthesis Schemes

[0228] Compounds of formula (I) of the present invention may be prepared by coupling suitably selected substituent groups onto a central 5-C(O)-isoquinoline scaffold of the following structure (A)

[0229] wherein the numbering denotes the ring atoms around the 5-C(O)-isoquinoline scaffold. More specifically, the compounds of the present invention may be prepared by coupling one or more of the following substituent groups, at the noted positions:

[0230] (a) an R1group (herein referred to as the “top" substituent) to the carbon ring atom at the 3-position of the 5-C(O)-isoquinoline scaffold (for example, as described in Scheme 9, below);

[0231] (b) an R4group (herein referred to as the “bottom" substituent) to the carbon ring atom at the 7-position of the 5-C(O)-isoquinoline scaffold (for example, as described in Schemes 5 and 6, below);

[0232] (c) an -NH-C(R2)-(L1)a-(R3) group (herein referred to as the “right hand side” or “RHS” substituent) to the carbon ring atom at the 1 -position of the 5-C(O)- isoquinoline scaffold (for example, as described in Scheme 7, below); and

[0233] (d) an R8group (herein referred to as the “left hand side” or “LHS” substituent), to the -C(O)- at the 5-position of the 5-C(O)-isoquinoline scaffold (for example, as described in Scheme 8, below).

[0234] One skilled in the art will recognize that the “top”, “bottom”, “right hand side” and “left hand side” substituent groups may be introduced I coupled onto the 5-C(O)- isoquinoline scaffold in any order, and in either a single coupling step or in multiple steps (as for example, described in more detail in the Schemes which follow herein). One skilled in the art will further recognize that depending on the order in which the “top”, “bottom”, “right hand side” and “left hand side” substituent groups are introduced I coupled onto the 5-C(O)-isoquinoline scaffold, reactive terminal groups and I or substituents may be protected at a suitable or desired step prior to said coupling step, and de-protected at any suitable subsequent step, according to known methods.

[0235] Preferably, compounds of formula (I) are prepared by coupling the substituent groups in the following order: (1 ) “bottom” substituent, (2) “right hand side” substituent, (3) “left hand side” substituent, and (4) “top” substituent.

[0236] Compounds of formula (I) of the present invention may be prepared by coupling the “bottom”, “right hand side”, “left hand side” and “top” substituents onto the 5-C(O)- isoquinoline scaffold, starting from a suitably substituted compound of formula (V) wherein R1is hydrogen, or chloro, PG1is -OH or a suitably selected oxygen protecting group such as, -O-C1-4alkyl (preferably methoxy, ethoxy, or tert-butoxy), -O- benzyl, and the like; and wherein LG1and LG2are each an independently selected suitable leaving group such as Cl, Br, I, and the like. Preferably, LG1and LG2are not the same and are chosen to allow for selective coupling at either the 1 - or 7-position of the 5-C(O)-isoquinoline scaffold. Preferably, when coupling the “bottom”, LG1and LG2are selected to direct or favor coupling at the 7-position of the 5-C(O)-isoquinoline scaffold (for example, where LG1is Cl and LG2is I). Further, one skilled in the art will recognize that when coupling the “right hand substituent”, LG1and LG2may be selected to direct or favor coupling at the 1 -position of the 5-C(O)-isoquinoline scaffold (for example where LG1is Cl and LG2is Br or Cl).

[0237] Compounds of formula (V) are known compounds, or compound which may be prepared as described herein, for example as described in Scheme 1 -3, below.

[0238] Compounds of formula (I) may alternatively be prepared by coupling the “bottom”, “right hand side”, “left hand side” and “top” substituents onto the 5-C(O)- isoquinoline scaffold, starting from a suitably substituted compound of formula (XV) wherein R1is -CH3, PG1is -OH or a suitably selected oxygen protecting group such as -O-C1-4alkyl (preferably methoxy, ethoxy, or tert-butoxy), -O-benzyl, and the like; and wherein LG2is a suitably selected group, such as -OH, -OCH3, Cl, Br, I, and the like.

[0239] Compounds of formula (XV) are known compounds, or compound which may be prepared as described herein, for example as described in Scheme 4, below.

[0240] Compounds of formula (V) wherein R1is hydrogen, PG1is -O-(C1-4alkyl), LG1is

[0241] Cl and LG2is Br may be prepared as described in Scheme 1 , below.

[0242] Scheme 1

[0243] Accordingly, 5-bromo-2-fluoro-1 ,3-dimethylbenzene, a known compound, is reacted with a suitably selected oxidizing agent such as KMnO4, O3, O2, H2O2, and the like; in a suitably selected solvent or mixture of solvents, such as a mixture of water and tert-BuOH, water, AcOH, a mixture of ACN and H2O, and the like; at a temperature in the range of from about 55°C to about 80°C; to yield 5-bromo-2-fluoroisophthalic acid.

[0244] 5-Bromo-2-fluoroisophthalic acid is then reacted with a suitably selected acid such as H2SO4, HCI, MsOH, H3PO4, and the like; in a suitably selected alcohol of the formula A1OH, wherein A1is C1-4alkyl, preferably methyl, ethyl, isopropyl or tert-butyl; at an elevated temperature, for example at about 70°C or reflux temperature; to yield the corresponding compound of formula (VI), wherein both A1groups are the same and correspond to the A1alkyl of the alcohol.

[0245] The compound of formula (VI) is reacted with tert-butyl 2-cyanoacetate, a known compound; in the presence of a suitably selected base such as K2CO3, NaOtBu, NaH, Na3PO4, and the like; in the presence of a suitably selected additive such as TBAB, Pd(dppf)Cl2, Pd(tBu3P)2, and the like; in a suitably selected solvent such as DMSO, DMF, 1 ,4-dioxane, and the like; at a temperature in the range of from about room temperature to about 100°C, preferably at about 100°C; to yield the corresponding compound of formula (VII).

[0246] The compound of formula (VII) is reacted with a suitably selected salt such as NaCI, LiCI, KOH, and the like; in a suitably selected solvent such as DMSO, a mixture of DMSO and H2O, a mixture of MeOH and H2O, and the like; at a temperature in the range of from about 75°C to about 165°C, preferably at about 100°C; to yield the corresponding compound of formula (VIII).

[0247] The compound of formula (VIII) is reacted with a suitably selected Lewis acid such as CoCl2·6H2O, AICI3, and the like; in the presence of a suitably selected reducing agent such as NaBH4, UAIH4, Pt O2 / H2, and the like; in a suitably selected solvent or mixture of solvents such as methanol, a mixture of 2-methyl-THF and methanol, diethyl ether and THF, and the like; at a temperature in the range of from about -20°C to about 60°C, preferably at about 0°C; to yield the corresponding compound of formula (IX).

[0248] The compound of formula (IX) is reacted with a suitably selected oxidizing agent such as Mn02, Pd, 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone, and the like; in a suitably selected solvent such as toluene, 1 ,4-dioxane, DCE, and the like; at a temperature in the range of from about 50°C to about 130°C, preferably at about 110°C; to yield the corresponding compound of formula (X).

[0249] The compound of formula (X) is reacted with a suitably selected chlorinating agent (or source of chlorine) such as POCI3, SOCl2, PCI5, and the like; at a temperature in the range of from about 50°C to about 130°C, preferably at about 100°C; to yield the corresponding compound of formula (Va), a compound of formula (V) wherein R1is H, PG1is -O-(C1-4alkyl), LG1is -Cl and LG2is -Br.

[0250] Compounds of formula (V), wherein R1is hydrogen, PG1is -OH, LG1is Cl and LG2is I may be prepared as described in Scheme 2, below.

[0251] Scheme 2

[0252] Accordingly, dimethyl 5-iodoisophthalate, a known compound, is reacted with ammonia or a suitably selected amine source such as NH4OH, ammonia borane, and the like; in a suitably selected solvent such as methanol, THF, H2O, and the like; at a temperature in the range of from about room temperature to about 120°C, preferably at about 90°C; to yield 5-iodo-isophthalamide.

[0253] 5-lodo-isophthalamide is reacted with a suitably selected reducing agent such as (COCI)2, (chloromethylene)dimethyliminium chloride, and the like; in the presence of a suitably selected base such as pyridine, NaOAc, and the like; in a suitably selected solvent or mixture of solvents such as a mixture of acetonitrile and DMF, DCE, toluene, 1 ,4-dioxane and the like; at a temperature in the range of from about -20°C to about 40°C, preferably at about 0°C; to yield 5-iodo-isophthalonitrile.

[0254] 5-lodo-isophthalonitrile is reacted with a suitably selected methylating agent such as CH3I, trimethylsulfonium iodide and the like; in the presence of a suitably selected base such as LDA, n-BuLi, KOtBu, and the like; in a suitably selected solvent such as THF, hexanes, diethyl ether, and the like; at a temperature in the range of from about - 120°C to about 0°C, preferably at about -96°C; to yield 5-iodo-2-methylisophthalonitrile.

[0255] 5-lodo-2-methylisophthalonitrile is reacted with 1 , 1 -dimethoxy- N,N- dimethylmethanamine, a known compound; in a suitably selected solvent such as DMF, ACN, and the like; at an elevated temperature, for example at about 110°C; to yield (E)- 2-(2-(dimethylamino)vinyl)-5-iodoisophthalonitrile.

[0256] (E)-2-(2-(Dimethylamino)vinyl)-5-iodoisophthalonitrile is reacted with a suitably selected acid such as HCI, HBr, and the like; in a suitably selected solvent such as methanol, butanol, AcOH, and the like; at an elevated temperature, for example at about 95°C; to yield 7-iodo-1-oxo-1 ,2-dihydroisoquinoline-5-carbonitrile.

[0257] 7-lodo-1 -oxo-1 ,2-dihydroisoquinoline-5-carbonitrile is reacted with a suitably selected mixture of acids such as a mixture of H2SO4and AcOH, a mixture of MsOH and H2SO4, and the like; in a suitably selected solvent such as H2O, MeOH, EtOH, and the like; at an elevated temperature, for example at about 130°C; to yield 7-iodo-1 -oxo- 1 ,2-dihydroisoquinoline-5-carboxylic acid.

[0258] 7-iodo-1 -oxo-1 ,2-dihydroisoquinoline-5-carboxylic acid is reacted with a suitably selected chlorinating agent such as SOCl2, POCI3, PCI5, and the like; in a suitably selected solvent such as DMF, toluene, benzene, and the like; at a temperature in the range of from about 60°C to about 120°C, preferably at about 80°C; to yield the corresponding compound of formula (Vb), a compound of formula (V) wherein R1is H, PG1is -OH, LG1is -Cl and LG2is -I.

[0259] Compounds of formula (V), wherein R1is -Cl, PG1is -O-(C1-4alkyl), LG1is Cl and LG2is Br may be prepared as described in Scheme 3, below.

[0260]

[0261] Scheme 3

[0262] Accordingly, a suitably substituted compound of formula (VIII), prepared for example as described in Scheme 1 above, is reacted with a suitably selected base such as NaOCH3, NaH, K2CO3, and the like; in a suitably selected solvent such as methanol, and the like; at a temperature in the range of from about 40°C to about 100°C, preferably at about 70°C; to yield the corresponding compound of formula (XI).

[0263] The compound of formula (XI) is reacted with a suitably selected acid such as HCI, H2SO4, H3PO4, and the like; in a suitably selected solvent such as methanol, H2O, DCM, and the like; at a temperature in the range of from about room temperature to about 120°C, preferably at about 70°C; to yield the corresponding compound of formula (XII).

[0264] The compound of formula (XII) is reacted with a suitably selected chlorinating agent such as phenylphosphonic dichloride (PPDC), POCI3, SOCl2, PCI5, and the like; at a temperature in the range of from about 80°C to about 130°C, preferably at about 110°C; to yield the corresponding compound of formula (Vc), a compound of formula (V) wherein R1is -Cl, PG1is -O-(C1-4alkyl), LG1is -Cl and LG2is -Br.

[0265] Compounds of formula (XV) wherein R1is -CH3, PG1is -OH, and LG2is -OCH3may be prepared as described in Scheme 4, below.

[0266]

[0267] Scheme 4

[0268] Accordingly, 2-bromo-5-methoxy-1 ,3-dimethylbenzene, a known compound is reacted with a suitably selected oxidizing agent such as KMnO4, O3, O2, H2O2, and the like; in a suitably selected solvent or mixture of solvents such as a mixture of tert- butanol / water, water, AcOH, a mixture of ACN and H2O, and the like; at a temperature in the range of from about 50°C to about 120°C, preferably at about 100°C; to yield 2- bromo-5-methoxyisophthalic acid.

[0269] 2-Bromo-5-methoxyisophthalic acid is reacted with pentane-2, 4-dione, a known compound; in the presence of a suitably selected base such as K3PO4, K2CO3, KOtBu, and the like; in the presence of a suitably selected additive such as Cui, Pd(OAc)2, and the like; in a suitably selected solvent such as DMF, DMSO, DMA, and the like; at a temperature in the range of from about 80°C to about 130°C, preferably at about 105°C; to yield 7-methoxy-3-methyl-1 -oxo-1 H-isochromene-5-carboxylic acid.

[0270] 7-Methoxy-3-methyl-1 -oxo-1 H-isochromene-5-carboxylic acid is reacted with an ammonium salt such as NH4OAc, and the like; in the presence of ammonia; in a suitably selected solvent such as water, MeOH, DMSO, or THF; at a temperature in the range of from about 60°C to about 140°C, preferably at about 80°C; to yield the compound of formula (XVa), a compound of formula (XV) wherein R1is -CH3, PG1is -OH, and LG2is -OCH3.

[0271] The compound of formula (XVa) may be further optionally reacted with a suitably selected source of chlorine such as POCI3, SOCl2, PCI5, and the like; in a suitably selected solvent such as DMF, toluene, benzene, and the like; at an elevated temperature in the range of from about 60°C to about 130°C, for example at about 100°C; to yield the corresponding compound of formula (XVIa).

[0272] The following general synthesis schemes describe methods for individually coupling the “bottom”, “right hand side”, “left hand side” and “top” substituents onto the 5-C(O)-isoquinoline scaffold. Said schemes may be applied in any order or sequence which is suitable for preparing the compounds of formula (I) of the present invention, as would be readily recognized by those skilled in the art.

[0273] The “bottom” substituent may be coupled onto the 5-C(O)-isoquinoline scaffold as described in Scheme 5, below.

[0274] Scheme 5

[0275] Accordingly, a suitably substituted compound of formula (V), wherein R1is hydrogen or chloro, PG1is OH or a suitably selected oxygen protecting group such as methoxy, ethoxy, tert-butoxy, benzyl, and the like, and LG1and LG2are suitably selected leaving groups such as Cl, Br, I, and the like, wherein LG1and LG2are different and are selected to direct or favor coupling at the 7-position of the isoquinoline, is reacted with a suitably substituted compound of formula (XX), wherein LGAis a suitably selected reactive coupling group such as a group of the formula -B(R)2 (a boronic acid wherein each R is OH, a dialkyl boronic ester wherein each R is -O-C1-

[0276] 4alkyl, or a cyclic boronic ester of the formula (wherein the two R groups are taken together with the boron atom to which they are bound), a known compound or compound prepared by known methods; in the presence of a suitably selected palladium catalyst such as Pd(dppf)Cl2, CataCXium A Pd G3, Pd(PPh3)4, XPhos Pd G3and the like; in the presence of a suitably selected base such as K3PO4, Cs2CO3, Na2CO3, TEA, CsF, K2CO3, and the like; in a suitably selected solvent such as 1 ,4- dioxane, toluene, DMSO, THF, and the like; at a temperature in the range of from about room temperature to about 120°C, preferably at about 90°C; to yield the corresponding compound of formula (XXI).

[0277] Alternatively, a suitably substituted compound of formula (V), wherein R1is hydrogen or chloro, PG1is OH or a suitably selected oxygen protecting group such as methoxy, ethoxy, tert-butoxy, benzyl, and the like, and LG1and LG2are suitably selected leaving groups such as Cl, Br, I, and the like, wherein LG1and LG2are different and are selected to direct or favor coupling at the 7-position of the isoquinoline, is converted to the corresponding compounds of formula (XXII) wherein -B(R)2 is a boronic acid wherein each R is OH, a dialkyl boronic ester wherein each R is -O-C1-4alkyl, or a cyclic boronic ester of the formula (wherein the two R groups are taken together with the boron atom to which they are bound), according to known methods.

[0278] The compound of formula (XXII) is reacted with a suitably substituted compound of formula (XX) wherein LGAis a suitably selected leaving group such as a halogen (preferably Br or I), -OS(O)2CF3, and the like, a known compound or compound prepared by known methods; in the presence of a suitably selected palladium catalyst such as Pd(dppf)Cl2, CataCXium A Pd G3, Pd(PPh3)4, XPhos Pd G3and the like; in the presence of a suitably selected base such as K3PO4, Cs2CO3, Na2CO3, TEA, CsF, K2CO3, and the like; in a suitably selected solvent such as 1 ,4-dioxane, toluene, DMSO, THF, and the like; at a temperature in the range of from about room temperature to about 120°C, preferably at about 90°C; to yield the corresponding compound of formula (XXI).

[0279] The "bottom” substituent, particularly “bottom” substituents wherein R4is (b) may alternatively be coupled onto the 5-C(O)-isoquinoline scaffold as described in Scheme 6, below.

[0280] Scheme 6

[0281] Accordingly, a suitably substituted compound of formula (V), wherein R1is hydrogen or chloro, PG1is OH or a suitably selected oxygen protecting group such as methoxy, ethoxy, tert-butoxy, benzyl, and the like, and LG1and LG2are suitably selected leaving groups such as Cl, Br, I, and the like, wherein LG1and LG2are different and are selected to direct or favor coupling at the 7-position of the isoquinoline, is reacted with a suitably substituted compound of formula (XXIII), wherein WAis a suitably selected reactive group such as -C(O)H, -C(O)OH, C(O)CH3, -NO2, -NH2, CN, OCH3, -CH2OH, -CH2NHC(O)CH3, and the like, and wherein LG3is a suitably selected reactive coupling group, such as a group of the formula -B(R)2 (a boronic acid wherein each R is OH, a dialkyl boronic ester wherein each R is -O-C1-4alkyl, or a cyclic boronic ester of the formula (wherein the two R groups are taken together with the boron atom to which they are bound), a known compound or compound prepared by known methods; in the presence of a suitably selected palladium catalyst such as Pd(dppf)Cl2, Pd(PPh3)4, CataCXium A Pd G3, XPhos Pd G3, XantPhos Pd G4, and the like; in the presence of a suitably selected base such as K3PO4, Cs2CO3, TEA, CsF, Na2CO3, KOAc, and the like; in a suitably selected solvent such as 1 ,4-dioxane, toluene, DMSO, THF and the like; at a temperature in the range of from about room temperature to about 120°C, preferably at about 90°C; to yield the corresponding compound of formula (XXIV).

[0282] The compound of formula (XXIV) is then further reacted to functionalize and I or convert the WAgroup to the desired -(L2)d-R8substituent, to yield the corresponding compound of formula (XXV).

[0283] For example, wherein WAis -C(O)H, the compound of formula (XXIV) may be reacted with a suitably selected oxidizing agent, such as NaCIO2, PCC, H2O2, NaCIO, O2, and the like; in the presence of a suitably selected additive such as NaH2PO4, 2- methyl-2-butene, Na2HPO4, and the like; in a suitably selected solvent or mixture of solvents, such as DMSO, H2O, DMF, AON, a mixture of DMSO and water, a mixture of tBuOH and water, acetone and water, ACN and water, MeOH and water, and the like; at a temperature in the range of from about 0°C to about 80°C, preferably at about 50°C; to yield an intermediate wherein the WAaldehyde substituent group (i.e. -C(O)H) has been converted to an acid substituent group (i.e. -C(O)OH); and the resulting intermediate reacted with a suitably substituted compound of the formula NH2-R8, a suitably substituted compound of the formula NH2-(C1-4alkyl)-R8or a suitably substituted compound of the formula -NH-(fluorinated C1-4alkyl)-R8, a known compound or compound prepared by known methods; in the presence of a suitably selected amide coupling reagent such as HATU, T3P®, EDO, TCFH, DOC, PyBOP, Si-DCC, Si-HOBT, and the like; in the presence of a suitably selected base such as TEA, DIPEA, and the like; in a suitably selected solvent such as DMF, DCM, DMSO, THF, ACN, DMA, and the like; at a temperature in the range of from about room temperature to about 80°C, preferably at about room temperature; to yield the corresponding compound of formula (XXV) where R4is and -

[0284] (L2)d-R8is -C(O)-NH-R8, -C(O)-NH-(C1-4alkyl)-R8or -C(O)-NH-(fluorinated C1-4alkyl)-R8, respectively.

[0285] One skilled in the art will recognize that compounds of formula (XXIV) wherein WAis -CH2OH may be prepared from the corresponding compound of formula (XXIV) wherein WAis -C(O)H, by reacting with a suitably selected reducing agent, such as NaBFU, UAIH4, and the like; in a suitably selected solvent such as MeOH, EtOH, and the like; at a temperature in the range of from about -20°C to about room temperature, preferably at about 0°C.

[0286] One skilled in the art will further recognize that compounds of formula (XXIV) wherein WAis -NH2may be prepared from the corresponding compound of formula (XXIV) wherein WAis -NO2, by reacting with a suitably selected reducing agent, such as Fe, Zn, H2, and the like; in the presence of a suitably selected additive such as NH4CI, AcOH, Pd / C, and the like; in a suitably selected solvent or mixture of solvents, such as MeOH, EtOH, H2O, THF, a mixture of MeOH, THF and water, a mixture of EtOH, THF, and water, and the like; at a temperature in the range of from about 0°C to about 60°C, preferably at about 25 °C.

[0287] Preferably, the “bottom” substituent is coupled onto the 5-C(O)-isoquinoline scaffold prior to coupling of the “right hand side”, “left hand side” and “top” substituent groups; wherein the “right hand side”, “left hand side” and “top” substituents groups may be coupled in any order following coupling of the “bottom” substituent group.

[0288] The “right hand side” substituent may be coupled onto the 5-C(O)-isoquinoline scaffold as described in Scheme 7, below.

[0289]

[0290] Scheme 7

[0291] Accordingly, a suitably substituted compound of formula (V), wherein R1is hydrogen or chloro, PG1is OH or a suitably selected oxygen protecting group such as methoxy, ethoxy, tert-butoxy, benzyl, and the like, and LG1and LG2are suitably selected leaving groups such as Cl, Br, I, and the like, is reacted with a suitably substituted compound of formula (XXVI), a known compound or compound prepared by known methods; in the presence of a suitably selected palladium catalyst such as CataCXium A Pd G3, SPhos Pd G3, BrettPhos Pd G3, XantPhos Pd G4, rac-BINAP Pd G4, and the like; in the presence of a suitably selected base such as K3PO4, Cs2CO3, TEA, Na2CO3, and the like; in a suitably selected solvent such as 1 ,4-dioxane, toluene, DMSO, THF, 2- methyl-THF, and the like; at a temperature in the range of from about room temperature to about 120°C, preferably at about 90°C; to yield the corresponding compound of formula (XXVII).

[0292] The "left hand side” substituent may be coupled onto the 5-C(O)-isoquinoline scaffold as described in Scheme 8, below.

[0293] Scheme 8

[0294] Accordingly, a suitably substituted compound of formula (V), wherein PG1is OH is reacted with a suitably substituted compound of formula (XXVIII), a known compound or compound prepared by known methods; in the presence of a suitably selected amide coupling reagent such as HATU, T3P®, TCFH, EDC, DCC, PyBOP, and the like; in the presence of a suitably selected base such as TEA, DIPEA, and the like; in a suitably selected solvent such as DMF, THF, DMA, acetonitrile, and the like; at a temperature in the range of from about 0°C to about 60°C, preferably at about room temperature; to yield the corresponding compound of formula (XXIX).

[0295] One skilled in the art will recognize that a suitably substituted compound of formula (XVa) may be substituted for the compound of formula (V) in Scheme 8 above, and reacted as described therein, to couple the “left hand side” substituent onto the 5- C(O)-isoquinoline core and yield the corresponding compound of formula (XXX) which compound of formula (XXX) may then be further functionalized, as described herein, to yield the desired compound of formula (I).

[0296] The “top” substituent may be coupled onto the 5-C(O)-isoquinoline scaffold as described in Scheme 9, below. Preferably, the “top” substituent is coupled onto the 5- C(O)-isoquinoline scaffold, after coupling of the “bottom” and “right hand side” substituents.

[0297] Scheme 9

[0298] Accordingly, a suitably substituted compound of formula (XXXI), wherein WBis LG1or a “right hand side" substituent (i.e. a group of the formula -NH-CH(R2)-(L1)a-R3) and Wcis PG1or a “left-hand side” substituent (i.e. a group of the formula -R9), a known compound or compound prepared as described herein, preferably a compound of formula (XXXI) wherein WBis a “right hand side” substituent, is reacted with a suitably substituted compound of formula (XXXII), wherein LG4is H or is a suitably selected reactive coupling group such as a group of the formula -B(R)2(a boronic acid wherein each R is OH, a dialkyl boronic ester wherein each R is -O-C1-4alkyl, or a cyclic boronic ester of the formula (wherein the two R groups are taken together with the boron atom to which they are bound), a group of the formula -BF3K, a group of the formula -Sn(Bu)3, a group of the formula -Zn, or a group of the formula -N=CH-phenyl, a known compound or compound prepared by known methods; in the presence of a suitably selected palladium catalyst such as XantPhos Pd G3, PdCl2(dtbpf), CataCXium Pd G4, Pd(Ad-BGPhos), RockPhos Pd G3, XPhos Pd G3, tBu XPhos Pd G3, and the like; and when LG4is -Sn(Bu)3in the presence of a suitably selected base such as K3PO4, Cs2CO3, Na2CO3, NaOtBu, TEA, CsF, K2CO3, and the like; in a suitably selected solvent or mixture of solvents such as 1 ,4-dioxane, toluene, DMF, DMSO, THF, 1 ,4- dioxane / water, and the like; at a temperature in the range of from about room temperature to about 120°C, preferably at about 100°C; to yield the corresponding compound of formula (XXXIII).

[0299] One skilled in the art will recognize that compounds of formula (XXXIII) wherein R1is -C1-4alkyl may be prepared from the corresponding compound of formula (XXXIII) wherein R1is -C1-4alkenyl, by reacting with H2in the presence of a suitably selected catalyst such as Pd / C, PtO2, Raney Ni, [lr(cod)(PCy3)(py)]PF6, and the like; in a suitably selected solvent or mixture of solvents, such as MeOH, EtOH, H2O, THF, and the like; at a temperature in the range of from about 0°C to about 60°C, preferably at about 25°C.

[0300] One skilled in the art will further recognize that compounds of formula (XXXIII) wherein R1is -C(O)H may be prepared from the corresponding compound of formula (XXXIII) wherein R1is -CHCH2, by reacting with a suitable oxidant such as dipotassium osmate, OsO4, O3, and the like; in the presence of a suitably selected additive such as sodium periodate, dimethyl sulfide, and the like; in a suitably selected solvent or mixture of solvents such as 1 ,4-dioxane / water, ethyl acetate, MeOH, THF, THF / H2O, DCM / MeOH and the like; at a temperature in the range from about -78°C to room temperature, preferably at about room temperature; to yield an intermediate which is then further reacted according to known methods, to functionalize and I or convert the - C(O)H group to the desired R1substituent.

[0301] The “top” substituent may be coupled onto the 5-C(O)-isoquinoline scaffold either before or after coupling of the “left-hand side” substituent group.

[0302] One skilled in the art will recognize, that when desired or preferred, suitably selected leaving groups such as a halogen, such as Br, Cl, I and the like, preferably Br or I, may be converted to a reactive coupling group of the formula -B(R)2 (a boronic acid wherein each R is OH, a dialkyl boronic ester wherein each R is -O-C1-4alkyl, or a cyclic boronic ester of the formula by reacting with a suitably selected boron source such as bis(pinacolato)diboron, B2(OH)4, and the like; in the presence of a suitably selected palladium catalyst such as Pd(dppf)Cl2, PdCl2(PPh3)2, XPhos Pd G4, and the like; in the presence of a suitably selected base such as KOAc, TEA, K3PO4, NaOtBu, and the like; in a suitably selected solvent or mixture of solvents, such as 1 ,4- dioxane, DMSO, toluene, and the like; at a temperature greater than about 80°C, preferably at about 100°C.

[0303] 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.

[0304] 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. One skilled in the art will recognize that, where not otherwise specified, the reaction step(s) is performed under suitable conditions, according to known methods, to provide the desired product. One skilled in the art will further recognize that, in the specification and claims as presented herein, wherein a reagent or reagent class / tvoe (e.g. base, solvent, etc.) is recited in more than one step of a process, the individual reagents are independently selected for each reaction step and may be the same or 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. One skilled in the art will further 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.

[0305] 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.

[0306] 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.

[0307] 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.

[0308] 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.

[0309] As used herein, unless otherwise noted, the term “leaving group” shall mean a charged or uncharged atom or group which departs during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like.

[0310] 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.

[0311] 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 .

[0312] 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.

[0313] Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartaric acid and / or (+)-d i-p-tol uoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.

[0314] Additionally, chiral HPLC against a standard may be used to determine percent enantiomeric excess (%ee). The enantiomeric excess may be calculated as follows [ (Rmoles-Smoles) / (Rmoles+Smoles) ] X 100% where Rmoles and Smoles are the R and S mole fractions in the mixture such that Rmoles+Smoles = 1 . The enantiomeric excess may alternatively be calculated from the specific rotations of the desired enantiomer and the prepared mixture as follows: ee = ([oc-obs] I [oc-max]) X 100.

[0315] Methods of Treatment I Cancers Mediated by BFL-1 Receptor

[0316] Abbreviations used in the specification, more particularly abbreviations used to designate diseases or disorders (e.g. leukemias and lymphomas, cancers) which may be treated with the compounds of the present invention are as listed in Table B, below. Table B: Disease or Disorder Abbreviations

[0317] The present invention is further directed to methods of treating a cancer mediated by the BFL-1 receptor (including, but not limited to leukemias and lymphomas) comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I).

[0318] As used herein, unless otherwise noted the term “cancer mediated by the BFL-1 receptor” shall include leukemias and lymphomas. Leukemias include, but are not limited to, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), (acute) T-cell leukemia, acute monocytic leukemia, acute promyelocytic leukemia (APL), bisphenotypic B myelomonocytic leukemia, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia, myelodysplastic syndrome (MDS) (which can develop into an acute myeloid leukemia).

[0319] 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.

[0320] In certain embodiments, the cancer mediated by the BFL-1 receptor is a leukemia. In certain embodiments, the cancer mediate by the BFL-1 receptor is a leukemia selected from the group consisting of acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS). In certain embodiments, the cancer mediated by the BFL-1 receptor is a leukemia is acute myeloid leukemia (AML).

[0321] In certain embodiments, the cancer mediated by the BFL-1 receptor is a lymphoma. In certain embodiments, the cancer mediated by the BFL-1 receptor is a lymphoma selected from the group consisting of AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), subtypes of NHL such as Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell DLBCL, double-hit lymphoma and double-expressor lymphoma; anaplastic large cell lymphoma, marginal B cell lymphoma and primary mediastinal B-cell lymphoma, immunoblastic large cell lymphoma, Burkitt lymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoplasmatic lymphoma, precursor B -lymphoblastic lymphoma, lymphoma of the central nervous system, small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL). In certain embodiments, the cancer mediated by the BFL- 1 receptor is a lymphoma selected from the group consisting of T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma. In certain embodiments, the cancer mediated by the BFL-1 receptor is a sarcoma selected from the group consisting sarcoma of the soft tissue, gliosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma. In certain embodiments, the cancer mediated by the BFL-1 receptor is a solid tumor, selected from the group consisting of breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma. In certain embodiments, the cancer mediated by the BFL-1 receptor is a leukemia is Diffuse Large Cell Lymphoma (DLBCL).

[0322] As used herein, unless otherwise noted, the terms “treating”, “treatment” and the like, shall include the management and care of a subject or patient, preferably a mammal, more preferably a human, for the purpose of combating a disease, condition, or disorder and includes the administration of any of the compounds of the present invention to prevent the onset of symptoms or complications, alleviate symptoms or complications, slow the progression of the disease or disorder, or eliminate the disease, condition, or disorder. The terms "treating" or "treatment" further include: (a) inhibiting the disease-state, i.e. , arresting its development; and / or (b) relieving the disease-state, i.e. , causing regression of the disease state. As used herein, "risk reduction" includes treatment which lowers the incidence of development or progression of a disease, disorder or condition.

[0323] 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. 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.

[0324] Pharmaceutical Compositions

[0325] 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 (P1 ), a compound of formula (P2) and I or a compound of formula (P3) as described herein.

[0326] 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. The present invention is further directed to pharmaceutical compositions comprising, consisting of or consisting essentially of a compound of formula (P1 ), a compound of formula (P2) and I or a compound of formula (P3) as described herein and one or more pharmaceutically acceptable carriers or excipients.

[0327] 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.

[0328] 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.

[0329] The present invention further comprises pharmaceutical compositions containing a compound of formula (I) with a pharmaceutically acceptable carrier. The present invention further comprises pharmaceutical compositions containing a compound of formula (P1 ), a compound of formula (P2) or a compound of formula (P3) with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing one or more of the compounds of the present invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral). Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations may also be coated with substances such as sugars or be enteric coated so as to modulate major site of absorption. For parenteral administration, the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.

[0330] To prepare the pharmaceutical compositions of this invention, one or more compounds of the present invention as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules, caplets, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 0.01 mg to about 1000 mg or any amount or range therein, and may be given at a dosage of from about 0.05 mg / day to about 1000 mg / day, or any amount or range therein, about 0.1 mg / day to about 500 mg / day, or any amount or range therein, preferably from about 1 mg / day to about 300 mg / day, or any amount or range therein.

[0331] 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.

[0332] Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these pre-formulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from about 0.01 mg to about 1 ,000 mg, or any amount or range therein, of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form yielding the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

[0333] 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.

[0334] The methods 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 300 mg of the compound, or any amount or range therein, more preferably from about 0.1 mg to about 300 mg of the compound, or any amount or range therein, more preferably from about 10 mg to about 100 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.

[0335] 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.

[0336] For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders; lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

[0337] The liquid forms may include suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.

[0338] 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 of preparation desired for administration (e.g. oral or parenteral). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be measured in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain. Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1 -3, edited by Lieberman et al;

[0339] 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.

[0340] 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 or prophylaxis of thromboembolic disorders, inflammatory disorders or diseases or conditions in which plasma kallikrein activity is implicated is required.

[0341] 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.

[0342] Examples 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.

[0343] Unless otherwise indicated in the examples, all temperature is expressed in Centigrade (°C). All reactions were conducted under an inert atmosphere at ambient temperature unless otherwise noted. Unless otherwise specified, reaction solutions were stirred at room temperature under a N2(g) or Ar<g) atmosphere. Reagents employed without synthetic details are commercially available or made according to known methods, for example according to literature procedures. When solutions were “concentrated to dryness”, they were concentrated using a rotary evaporator under reduced pressure; when solutions were dried, they were typically dried over a drying agent such as MgSC or Na2SO4. Where a synthesis product is listed as having been isolated as a residue, it will be understood by those skilled in the art that the term “residue” does not limit the physical state in which the product was isolated and may include, for example, a solid, an oil, a foam, a gum, a syrup, and the like.

[0344] 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.

[0345] LC-MS: Unless otherwise indicated, the analytical LC-MS system used consisted of one of the following: 1 ) Shimadzu LCMS-2020 with electrospray ionization (ESI) in positive ion detection mode with a HALO C18 column, 30 x 5.0 mm, 2.7 pm. Mobile phase A was water containing 0.05% TFA and mobile phase B was acetonitrile containing 0.05% TFA with a flow rate of 1 .5 mL / min. 2) Agilent 1260 Inifinity II with electrospray ionization (ESI) in positive ion detection mode with an InfinityLab Poroshell 120 EC-C18 column, 50 x 2.1 mm, 2.7 pm. Mobile phase A was water containing 0.1% TFA and mobile phase B was acetonitrile containing 0.1% TFA with a flow rate of 1 .2 mL / min. Mobile phase gradients were optimized for the individual compounds. Calculated mass corresponds to the exact mass.

[0346] 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®). NMR: Unless otherwise noted,1H NMR and19F NMR spectra were acquired using 600 MHz spectrometers, 400 MHz spectrometers, 356 MHz spectrometers or 300 MHz spectrometers in a suitably selected deuterated solvent such as Dimethyl Sulfoxide-de, Chloroform-d, Methanol-d4, Deuterium Oxide, Acetic Acid-d4, Acetone-de, Acetonitrile-da, Benzene-de, Cyclohexane-di2, N, N-Dimethyl-formamide-d?, 1 ,4- Dioxane-ds, Ethanol-de, Methylene Chloride-d2, Pyridine-ds, 1 ,1 ,2,2-Tetrachloroethane- d2, Tetrahydrofuran-ds, Toluene-ds, Trifluoroacetic Acid-d, Trifluoroethanol-da, and the like. NMR data are reported in parts per million (5) and are referenced to the residual solvent signal of the deuterated solvent or TMS (Trimethylsilane). Coupling constants (J) are reported in hertz (Hz). The nature of the shifts as to multiplicity is reported as s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (double of triplets), td (triplet of doublets), dq (doublet of quartets), tt (triplet of triplets), tdd (triplet of doublet of doublets), dtd (doublet of triplet of doublets), ddt (doublet of doublet of triplets), qd (quartet of doublets), qt (quartet of triplets), m (multiplet), br (broad). It will be understood that for compounds comprising an exchangeable proton, said proton may or may not be visible on an NMR spectrum depending on the choice of solvent used for running the NMR spectrum and the concentration of the compound in the solution.

[0347] Unless otherwise noted, in the synthesis examples provided herein, wherein a mixture of solvents is presented as a ratio, said ratio shall be understood to be a volume:volume (or volume / volume) ratio.

[0348] Example 1 . (R)-N-(2-(3-(methylamino)-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-3-oxopropyl)-5- (trifluoromethyl)phenyl)acrylamide.

[0349]

[0350] Step A: N-(2-bromo-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroacetamide. 2-Bromo-5-(trifluoromethyl)aniline (12.0g, 0.050 mol), pyridine (9 mL, 0.113 mol), and DCM (250 mL) were added to a round bottom flask. 2,2,2-Trifluoroacetic anhydride (7.3 mL, 0.0525 mol) was then added dropwise at 0°C over 10 minutes. The reaction mixture was stirred for 30 minutes at 0°C, then warmed to room temperature overnight. Reaction was quenched with 2M aqueous HCI and extracted twice with DCM. The organic layers were combined and washed with addition 2M aqueous HCI, followed by NaHCO3, then brine. The organic layer was dried with Na2SO3, filtered, and concentrated. The resulting solid was washed with 9:1 pentane / Et2O to yield the title compound as a white solid.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.39 (dd, J=8.31 , 1.96 Hz, 1 H) 7.76 (d, J=8.31 Hz, 1 H) 8.52 (br s, 1 H) 8.66 (d, J=1.47 Hz, 1 H).

[0351] Step B: Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(2-(2,2,2-trifluoroacetamido)- 4-(trifluoromethyl)phenyl)propanoate.

[0352] N-(2-bromo-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroacetamide (4.0g, 0.0119 mol), methyl (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (3.56g, 0.0108 mol), manganese (1.78g, 0.0325 mol), and [4,4'-Bis(1 ,1 -dimethylethyl)-2,2'-bipyridine] nickel (II) dibromide (0.605g, 1 .08 mmol) were added into a flask. The flask was sealed, and atmosphere was exchanged with argon. The flask was then charged with DMA (32 mL), heated to 60°C, and stirred overnight. The reaction was cooled to room temperature, quenched with 2M aqueous HCI, and diluted with EtOAc. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with 2M aqueous HCI, deionized water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by normal phase chromatography with mobile phase gradient 0-100% EtOAc / heptane to yield the title compound.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42 - 1 .44 (m, 9 H) 3.18 (d, J=6.36 Hz, 2 H) 3.78 (s, 3 H) 4.44 (q, J=6.36 Hz, 1 H) 5.35 (br d, J=6.85 Hz, 1 H) 7.31 (d, J=7.83 Hz, 1 H) 7.46 (dd, J=8.07, 1.22 Hz, 1 H) 8.14 (s, 1 H) 9.75 (br s, 1 H).

[0353] Step C: Tert-butyl (R)-(1 -(methylamino)-1 -oxo-3-(2-(2,2,2-trifluoroacetamido)-4- (trifluoromethyl)phenyl)propan-2-yl)carbamate.

[0354] Monomethylamine 40% w / w aqueous (2 mL, 22.9 mmol) was added to methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(2-(2,2,2-trifluoroacetamido)-4- (trifluoromethyl)phenyl)propanoate (2.1 g, 4.58 mmol) dissolved in MeOH (10 mL). The reaction mixture was stirred at room temperature for 18h. The reaction mixture was concentrated and purified by normal phase chromatography with mobile phase gradient 0-100% EtOAc / heptane to yield the title compound. MS (ESI): mass calculated for C18H21F6N3O4was 457.1 and the m / z measured was 480.1 [M+Na]+.

[0355] Step D: (R)-2-amino-N-methyl-3-(2-(2,2,2-trifluoroacetamido)-4- (trifluoromethyl)phenyl)propenamide.

[0356] Trifluoroacetic acid (8 mL, 104 mmol) was added to tert-butyl (R)-(1 - (methylamino)-1 -oxo-3-(2-(2,2,2-trifluoroacetamido)-4-(trifluoromethyl)phenyl)propan-2- yl)carbamate (1.22g, 2.67 mmol) dissolved in DCM (8 mL). The reaction mixture was stirred at room temperature for 16h. The reaction mixture was then concentrated, diluted with NaHCO3, and extracted three times with EtOAc. The organic layer was combined, dried over Na2SO4, filtered, and concentrated to yield the title compound. MS (ESI): mass calculated for C13H13F6N3O2was 357.1 and the m / z measured was 358.1 [M+H]+.

[0357] Step E: (R)-N-methyl-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7- (2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-3-(2-(2,2,2-trifluoroacetamido)-4- (trifluoromethyl)phenyl)propenamide.

[0358] (1 -Chloro-7-(2,3,6-trimethylphenyl)isoquinolin-5-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone (400mg, 0.730 mmol), (R)-2-amino-N- methyl-3-(2-(2,2,2-trifluoroacetamido)-4-(trifluoromethyl)phenyl)propenamide (391 mg, 1.10 mmol), JosiPhos SL-J009-1 Pd G3 (135mg, 0.146 mmol), cesium carbonate (713mg, 2.19 mmol), and 1 ,4-dioxane (14.6 mL) were added into a vial in the glovebox. The reaction mixture was stirred at 80°C for 30 minutes. The reaction mixture was then filtered through CELITE® and concentrated. The resulting residue was purified by normal phase chromatography with gradient 0-100% EtOAc / heptane to yield the title compound. MS (ESI): mass calculated for C43H42F6N6O5S was 868.3 and the m / z measured was 867.3 [M-H]-.1H NMR (400 MHz, DMSO-d6) δ ppm 0.83 - 0.89 (m, 2 H) 1 .21 - 1 .29 (m, 4 H) 1 .95 (d, J=2.45 Hz, 4 H) 2.00 - 2.02 (m, 1 H) 2.27 (s, 3 H) 2.58 (d, J=4.65 Hz, 3 H) 3.08 (s, 3 H) 3.49 - 3.57 (m, 2 H) 3.74 - 3.98 (m, 2 H) 5.05 (br s, 1 H) 6.87 (d, J=5.87 Hz, 1 H) 7.02 - 7.16 (m, 4 H) 7.36 - 7.77 (m, 8 H) 7.91 (d, J=5.87 Hz, 1 H) 8.02 (br s, 1 H) 8.18 - 8.26 (m, 1 H) 11.33 (br s, 1 H).

[0359] Step F: (R)-3-(2-amino-4-(trifluoromethyl)phenyl)-N-methyl-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 - yl)amino)propenamide.

[0360] 7N Ammonia in MeOH (13 mL) was added to (R)-N-methyl-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 - yl)amino)-3-(2-(2,2,2-trifluoroacetamido)-4-(trifluoromethyl)phenyl)propenamide (600 mg, 0.691 mmol) in MeOH (13 mL). The reaction mixture was stirred for 18h at 50°C. The reaction mixture was concentrated and purified by preparative reverse-phase HPLC with a linear gradient of 20-100% B to A in 20 mins (A: 10 mM ammonium carbonate, 0.1 % ammonium hydroxide in water; B: 10 mM ammonium carbonate, 0.1% ammonium hydroxide in 90% ACN / water; column: Phenomenex Gemini NX-C18, 150x30 mm, 5uM, 110A) to yield the title compound. MS (ESI): mass calculated for C41H43F3N6O4S was 772.3 and the m / z measured was 771 .3 [M-H]-. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .90 (br s, 2 H) 1 .96 (s, 3 H) 2.01 (s, 2 H) 2.28 (d, J=4.40 Hz, 3 H) 2.60 (d, J=4.40 Hz, 3 H) 2.94 - 3.05 (m, 2 H) 3.08 (s, 3 H) 3.29 (m, J=6.40 Hz, 3 H) 3.44 - 3.63 (m, 2 H) 3.71 - 4.04 (m, 2 H) 4.89 (br s, 1 H) 5.67 (br d, J=13.21 Hz, 2 H) 6.67 (br t, J=6.1 1 Hz, 1 H) 6.84 (d, J=6.36 Hz, 1 H) 6.88 (s, 1 H) 7.00 - 7.17 (m, 4 H) 7.21 - 7.31 (m, 1 H) 7.35 - 7.42 (m, 1 H) 7.60 - 7.72 (m, 3 H) 7.86 (d, J=6.36 Hz, 1 H) 7.99 - 8.08 (m, 1 H) 8.24 - 8.33 (m, 1 H).

[0361] Step G: (R)-N-(2-(3-(methylamino)-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine- 1 -carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-3-oxopropyl)-5- (trifluoromethyl)phenyl)acrylamide. Acrylic anhydride (0.07 mL, 0.582 mmol) was added to (R)-3-(2-amino-4- (trifluoromethyl)phenyl)-N-methyl-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)propenamide (300mg, 0.388 mmol) and DIEA (0.4 mL, 2.33 mmol) in DCM (4 mL). The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated and purified by preparative reverse-phase HPLC with a linear gradient of 20-100% B to A in 20 mins (A: 10 mM ammonium carbonate, 0.1% ammonium hydroxide in water; B: 10 mM ammonium carbonate, 0.1% ammonium hydroxide in 90% ACN / water; column: Phenomenex Gemini NX-C18, 150x30 mm, 5uM, 110A) to yield the title compound. MS (ESI): mass calculated for C44H45F3N6O5S was 826.3 and the m / z measured was 825.3 [M-H]-. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .84 - 2.03 (m, 6 H) 2.09 (s, 1 H) 2.27 (s, 3 H) 2.60 (d, J=4.40 Hz, 4 H) 3.08 (s, 3 H) 3.16 - 3.25 (m, 3 H) 3.53 (br s, 2 H) 3.71 - 4.03 (m, 3 H) 4.91 - 5.10 (m, 1 H) 5.69 - 5.82 (m, 1 H) 6.18 - 6.32 (m, 1 H) 6.50 - 6.63 (m, 1 H) 6.85 (br d, J=5.87 Hz, 1 H) 7.00 - 7.17 (m, 4 H) 7.31 - 7.44 (m, 2 H) 7.50 - 7.63 (m, 1 H) 7.68 (br d, J=8.80 Hz, 3 H) 7.87 (br d, J=5.87 Hz, 1 H) 8.09 (br d, J=5.87 Hz, 2 H) 8.18 - 8.30 (m, 1 H) 9.86 (s, 1 H).

[0362] Example 2. (R)-N-(2-(3-(methylamino)-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)"7-(2,3,6"trimethylphenyl)isoquinolin-1~yl)amino)"3-oxopropyl)”5~ (trifluoromethoxy)phenyl)acrylamide

[0363] The title compound was similarly prepared according to the procedure described in Example 1 , above, substituting 2-bromo-5-(trifluoromethoxy)aniline for 2-bromo-5- (trifluoromethyl)aniline in Step A. Chemical Formula: C44H45F3N6O6S: Calculated Mass: 842.31 ; MS (ESI): m / z measured, 841.2 [M-H]-. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .85 - 2.05 (m, 6 H) 2.27 (s, 3 H) 2.60 (br d, J=4.40 Hz, 3 H) 3.08 (s, 3 H) 3.13 - 3.25 (m, 4 H) 3.54 (br s, 3 H) 3.72 - 4.00 (m, 3 H) 4.90 - 5.05 (m, 1 H) 5.70 - 5.79 (m, 1 H) 6.21 - 6.31 (m, 1 H) 6.50 - 6.62 (m, 1 H) 6.85 (br d, J=5.87 Hz, 1 H) 6.96 - 7.18 (m, 5 H) 7.36 - 7.52 (m, 2 H) 7.68 (br d, J=8.80 Hz, 3 H) 7.80 (br s, 1 H) 7.87 (br d, J=6.36 Hz, 1 H) 8.00 - 8.09 (m, 1 H) 8.19 - 8.32 (m, 1 H) 9.76 - 9.83 (m, 1 H)

[0364] Example 3. (R,E)-4-(dimethylamino)-N-(2-(3-(methylamino)-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 - yl)amino)-3-oxopropyl)-5-(trifluoromethyl)phenyl)but-2-enamide.

[0365] DIEA (0.08 mL, 0.453 mmol) followed by 1 -propanephosphonic anhydride solution (0.27 mL, 0.453 mmol) were added to trans-4-dimethylaminocrotonic acid hydrochloride (30 mg, 0.181 mmol) dissolved in DMF (0.9 mL, 0.0906 mmol). The mixture was stirred for 10 min before (R)-3-(2-amino-4-(trifluoromethyl)phenyl)-N- methyl-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6- trimethylphenyl)isoquinolin-1 -yl)amino)propanamide (70 mg, 0.0906 mmol) was added. The reaction mixture was stirred for 2h at room temperature. The reaction mixture was purified by preparative reverse-phase HPLC with a linear gradient of 20-100% B to A in 20 mins (A: 10 mM ammonium carbonate, 0.1% ammonium hydroxide in water; B: 10 mM ammonium carbonate, 0.1% ammonium hydroxide in 90% ACN / water; column: Phenomenex Gemini NX-C18, 150x30 mm, 5uM, 110A) to yield the title compound. MS (ESI): mass calculated for C47H52F3N7O5S was 883.4 and the m / z measured was 882.3 [M-H]-. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.85 - 2.03 (m, 6 H) 2.19 (s, 5 H) 2.27 (d, J=3.91 Hz, 3 H) 2.59 (d, J=4.40 Hz, 3 H) 3.04 - 3.11 (m, 5 H) 3.14 - 3.28 (m, 5 H) 3.45 - 3.60 (m, 3 H) 3.71 - 4.00 (m, 3 H) 4.95 - 5.10 (m, 1 H) 6.41 (br d, J=16.14 Hz, 1 H) 6.70 - 6.80 (m, 1 H) 6.85 (d, J=6.36 Hz, 1 H) 7.01 - 7.16 (m, 4 H) 7.32 - 7.44 (m, 2 H) 7.49 - 7.62 (m, 1 H) 7.65 - 7.75 (m, 3 H) 7.87 (s, 1 H) 8.02 - 8.12 (m, 2 H) 8.18 - 8.28 (m, 1 H) 9.74 (d, J=4.40 Hz, 1 H). Additional representative compounds of the present invention were similarly prepared according to the procedure described in Example 3 above, selecting and substituting a suitable acid reagent for the trans-4-dimethylaminocrotonic acid hydrochloride. In the table below, when a given compound is listed without specific stereo-orientation, the compound was prepared as a mixture of stereoisomers.

[0366]

[0367] Example 4. (R)-N-(5-(3-(methylamino)-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-3-oxopropyl)-2- (trifluoromethyl)benzyl)acrylamide.

[0368]

[0369] Step A: Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(3-cyano-4- (trifluoromethyl)phenyl) propanoate.

[0370] (S)-Methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (1 g, 3.04 mmol), 5- iodo-2-(trifluoromethyl)benzonitrile (752 mg, 2.532 mmol), [4,4'-Bis(1 , 1 -dimethylethyl)- 2,2'-bipyridine] nickel (II) dibromide (142 mg, 0.253 mmol), manganese (422 mg, 7.60 mmol), and DMA (13 mL) were added into a vial. The vial was evacuated and filled with argon three times. The reaction mixture was stirred for 24h at 50°C. The reaction was filtered through CELITE®, concentrated, and purified by normal phase chromatography with gradient 0-100% EtOAc / heptane to yield the title compound. MS (ESI): mass calculated for C17H19F3N2O4was 372.1 and the m / z measured was 395.0 [M+Na]+.

[0371] Step B: (R)-2-amino-3-(3-cyano-4-(trifluoromethyl)phenyl)-N-methylpropanamide. Monomethylamine 40% w / w aqueous (2 mL, 22.2 mmol) was added to methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(3-cyano-4-(trifluoromethyl)phenyl) propanoate (826 mg, 2.22 mmol) dissolved in MeOH (4.5 mL). The reaction mixture was stirred for 18h at room temperature. The reaction mixture was concentrated, the resulting residue was diluted with NaHCO3, and extracted three times with EtOAc. The organic layer was combined, dried over Na2SO4, filtered, and concentrated to yield the title compound. MS (ESI): mass calculated for C12H12F3N3O was 271 .1 and the m / z measured was 272.0 [M+H]+.

[0372] Step C: (R)-3-(3-cyano-4-(trifluoromethyl)phenyl)-N-methyl-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 - yl)amino)propenamide.

[0373] (1 -Chloro-7-(2,3,6-trimethylphenyl)isoquinolin-5-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone (750 mg, 1.37 mmol), (R)-2-amino-3- (3-cyano-4-(trifluoromethyl)phenyl)-N-methylpropanamide (445 mg, 1.64 mmol), #C# (2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino-1 ,1 '-biphenyl)]palladium(ll) methanesulfonate (107 mg, 0.137 mmol), cesium carbonate (1 .34 g, 4.11 mmol), and 1 ,4-dioxane (30 mL) were added into a vial. The reaction vial was filled and purged with argon three times. The reaction mixture was stirred at 90°C for 24h. The reaction mixture was filtered through CELITE® and concentrated. The resulting residue was purified by normal phase chromatography with gradient 0-50% MeOH / DCM to yield the title compound. MS (ESI): mass calculated for C42H41F3N6O4S was 782.3 and the m / z measured was 783.3 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .88 - 2.04 (m, 6 H) 2.29 (d, J=4.89 Hz, 3 H) 2.61 (d, J=4.40 Hz, 3 H) 3.08 (s, 3 H) 3.13 - 3.31 (m, 6 H) 3.45

[0374] - 3.59 (m, 2 H) 3.71 - 3.98 (m, 2 H) 4.91 - 5.01 (m, 1 H) 6.82 (br d, J=5.87 Hz, 1 H) 7.00

[0375] - 7.17 (m, 4 H) 7.36 - 7.44 (m, 1 H) 7.58 - 7.72 (m, 3 H) 7.78 - 7.93 (m, 3 H) 8.03 - 8.16 (m, 2 H) 8.23 - 8.36 (m, 1 H).

[0376] Step D: (R)-3-(3-(aminomethyl)-4-(trifluoromethyl)phenyl)-N-methyl-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 - yl)amino)propenamide.

[0377] Sodium borohydride (615 mg, 16.1 mmol) was added to (R)-3-(3-cyano-4- (trifluoromethyl)phenyl)-N-methyl-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)propenamide (630 mg, 0.805 mmol) and nickel(ll) chloride hexahydrate (383 mg, 1.61 mmol) in MeOH (6 mL) and THF (6 mL) at 0°C. The reaction mixture was allowed to warm to room temperature and then stirred for 16h. The reaction mixture was filtered, diluted with NaHCO3, and extracted three times with EtOAc. The organic layer was combined, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified with normal phase chromatography with gradient 0-100% 80%MeOH:DCM / DCM to yield the title compound. MS (ESI): mass calculated for C42H45F3N6O4S was 786.3 and the m / z measured was 787.3 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .84 - 2.08 (m, 6 H) 2.22 - 2.36 (m, 3 H) 2.59 (br s, 3 H) 2.98 - 3.27 (m, 8 H) 3.43 - 3.63 (m, 3 H) 3.68 - 4.02 (m, 5 H) 4.92 (br s, 1 H) 6.72 - 6.86 (m, 1 H) 6.94 - 7.21 (m, 5 H) 7.29 - 7.52 (m, 3 H) 7.54 - 7.88 (m, 5 H) 7.94 - 8.10 (m, 1 H) 8.20 - 8.37 (m, 1 H). Step E: (R)-N-(5-(3-(methylamino)-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine- 1 -carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-3-oxopropyl)-2- (trifluoromethyl)benzyl)acrylamide.

[0378] (R)-3-(3-(Aminomethyl)-4-(trifluoromethyl)phenyl)-N-methyl-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 - yl)amino)propenamide (136 mg, 0.173 mmol) and DIEA (0.2 mL, 1.04 mmol) were dissolved in DCM (2 mL). Acrylic anhydride (0.03 mL, 0.259 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 3h. The reaction was concentrated and purified by preparative reverse-phase HPLC with a linear gradient of 20-100% B to A in 20 mins (A: 10 mM ammonium carbonate, 0.1% ammonium hydroxide in water; B: 10 mM ammonium carbonate, 0.1% ammonium hydroxide in 90% ACN / water; column: Phenomenex Gemini NX-C18, 150x30 mm, 5uM, 110A) to yield the title compound. MS (ESI): mass calculated for C45H47F3N6O5S was 840.3 and the m / z measured was 841 .3 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .82 - 2.07 (m, 6 H) 2.28 (br d, J=4.40 Hz, 3 H) 2.58 (br d, J=3.91 Hz, 3 H) 3.08 (s, 3 H) 3.12 - 3.31 (m, 6 H) 3.53 (br s, 2 H) 3.71 - 4.00 (m, 2 H) 4.42 (br s, 2 H) 4.90 (br s, 1 H) 5.60 (br d, J=10.27 Hz, 1 H) 6.06 - 6.16 (m, 1 H) 6.20 - 6.34 (m, 1 H) 6.82 (br d, J=5.38 Hz, 1 H) 7.00 - 7.20 (m, 4 H) 7.34 - 7.74 (m, 7 H) 7.84 (br d, J=5.38 Hz, 1 H) 8.01 (br s, 1 H) 8.28 (br s, 1 H) 8.50 (br s, 1 H)

[0379] Additional representative compounds of the present invention were similarly prepared according to the procedure described in Example 1 -4 above, selecting and substituting a suitable reagent(s) as would be readily recognized by those skilled in the art. In the table below, when a given compound is listed without specific stereoorientation, the compound was prepared as a mixture of stereoisomers.

[0380]

[0381]

[0382] Example 5. (2R)-N-methyl-2-((5-(2-(tetrahydrofuran-3-yl)morpholine-4-carbonyl)-7- (2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-3-(4-(trifluoromethyl)phenyl)propenamide

[0383] To a vial containing 2-(tetrahydrofuran-3-yl)morpholine (15.7 mg, 0.1 mmol) was added (R)-1 -((1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-7- (2,3,6-trimethylphenyl)isoquinoline-5-carboxylic acid (40 mg, 75 μmol), followed by a solution of HATU (31 mg, 82 μmol) in DMA (373 μL). DIPEA (53μL, 306 μmol mmol) was added and the reaction mixture was stirred at 55°C for 5 hours. The reaction mixtures were cooled to room temperature, diluted with DMA (1 mL) and H2O (180 μL) and purified by reverse phase chromatography (Stationary phase: Waters XBridge Prep C18, 5um, 19 x 150mm ; Mobile phase : water (0.1% NH4OH) (A) - Acetonitrile (B), gradient elution: 35-70% B in A over 12 min, flow rate: 25 mL / min) to yield (2R)-N- methyl-2-((5-(2-(tetrahydrofuran-3-yl)morpholine-4-carbonyl)-7-(2,3,6- trimethylphenyl)isoquinolin-1 -yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide as a white powder.1H NMR (401 MHz, DMSO-d6) δ 8.28 - 8.20 (m, 1 H), 8.05 (br s, 1 H), 7.83 (br d, J = 6.8 Hz, 1 H), 7.59 - 7.49 (m, 5H), 7.44 - 7.34 (m, 1 H), 7.32 - 7.23 (m, 1 H), 7.16 - 7.12 (m, 1 H), 7.10 (br s, 1 H), 6.90 - 6.81 (m, 1 H), 6.73 - 6.63 (m, 1 H), 4.93 (br s, 1 H), 4.44 - 4.31 (m, 1 H), 4.00 - 3.84 (m, 1 H), 3.80 - 3.73 (m, 1 H), 3.53 (s, 3H), 3.37 (br d, J = 8.6 Hz, 1 H), 3.19 (br s, 2H), 3.04 (br d, J = 13.2 Hz, 2H), 2.90 - 2.69 (m, 1 H), 2.60 (br d, J = 3.4 Hz, 3H), 2.28 (br d, J = 4.4 Hz, 2H), 2.31 - 2.24 (m, 1 H), 2.04 - 1.78 (m, 8H) MS (ESI): mass calulated for C38H41F3N4O4, 674.3; m / z measured 675.3 [M+H]+.

[0384] Additional representative compounds of the present invention were similarly prepared according to the procedure described in Example 5 above, selecting and substituting a suitably substituted amine for the 2-(tetrahydrofuran-3-yl)morpholine, as noted in the Table below. In the table below, when a given compound is listed without specific stereo-orientation, the compound was prepared as a mixture of stereoisomers. Purifications were performed by preparative reverse phase HPLC, in different conditions depending on the reaction profile, as would be readily recognized by those skilled in the art.

[0385] Example 6. (R)-N-methyl-2-((5-(4-(4-(methylsulfonyl)phenyl)-3-oxopiperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide.

[0386] Step A: tert-butyl 4-(4-(methylsulfonyl)phenyl)-3-oxopiperazine-1 -carboxylate A mixture of tert-butyl 3-oxopiperazine-1 -carboxylate (500 mg, 2.5 mmol), 1 - bromo-4-(methylsulfonyl)benzene (704 mg, 3 mmol), Cui (48 mg, 0.25 mmol), potassium carbonate (1.0 g, 7.5 mmol) and (R,R)-N,N'-dimethyl-1 ,2- cyclohexanediamine (71 mg, 0.5 mmol) in 1 ,4-dioxane (10 mL) was stirred at 120 °C for 16 h. The reaction mixture was diluted with water (10 mL). The aqueous layer was extracted with ethyl acetate (25 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (40 g, gradient elution: 0 ~ 80% EtOAc in hexanes). The fractions were collected and concentrated under vacuum to yield tert-butyl 4-(4-(methylsulfonyl)phenyl)-3-oxopiperazine-1 -carboxylate. MS (ESI): mass calculated for C16H22N2O5S, 354.4; m / z measured 299.0 [M-tBu+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 1 .44 (s, 9 H) 3.23 (s, 3 H) 3.63 - 3.75 (m, 2 H) 3.75 - 3.87 (m, 2 H) 4.12 (s, 2 H) 7.62 - 7.71 (m, 2 H) 7.91 - 7.98 (m, 2 H)

[0387] Step B: 1 -(4-(methylsulfonyl)phenyl)piperazin-2-one

[0388] To a mixture of tert-butyl 4-(4-(methylsulfonyl)phenyl)-3-oxopiperazine-1 - carboxylate (766 mg, 2.1 mmol) in DCM (10 mL) was added 4M HCI in 1 ,4-dioxane (16.2 mL. 64.8 mmol). The mixture was stirred at room temperature for 16 h. The solvent was removed under vacuum to yield a white solid. The solid was suspended in hexanes (10 mL). The solid was collected and dried to yield 1 -(4- (methylsulfonyl)phenyl)piperazin-2-one hydrochloride as a white powder. MS (ESI): mass calculated for C41H14N2O3S, 254.3; m / z measured 255.1 [M+H]+. Step C: methyl (R)-1 -((1 -(methylamino)-1 -oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5- carboxylate

[0389] To a degassed mixture of methyl 1 -chloro-7-(2,3,6-trimethylphenyl)isoquinoline- 5-carboxylate (1.1 g, 3.2 mmol), (R)-2-amino-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide (956 mg, 3.9 mmol) and cesium carbonate (3.2 g, 9.7 mmol) in 1 ,4-dioxane (20 mL), SPhos Pd G4 (203 mg, 0.24 mmol) was added. The reaction was stirred at 90 °C for 12 h. The reaction mixture was filtered over CELITE®, rinsing with EtOAc. The filtrate was diluted with saturated sodium bicarbonate (20 mL) and EtOAc (20 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous MgSO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0-80% EtOAc / heptane) to yield methyl (R)-1 -((1 - (methylamino)-1 -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-7-(2,3,6- trimethylphenyl)isoquinoline-5-carboxylate. MS (ESI): mass calculated for C31H30F3N3O3, 549.6; m / z measured 550.2 [M+H]+.

[0390] Step D: (R)-1 -((1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2- yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5-carboxylic acid

[0391] To a solution of methyl (R)-1 -((1 -(methylamino)-1 -oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5- carboxylate (910 mg, 1.6 mmol) in THF (16 mL), and MeOH (16 mL), was added NaOH (16 mL, 1 M, 16 mmol). The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo and the mixture was diluted with water (10 mL). The solution was slowly acidified with 1 M aqueous HCI to pH = 5 while stirring vigorously. The aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with brine (30 mL), dried over anhydrous MgSO4, filtered, and concentrated to yield (R)-1 -((1 -(methylamino)-1 -oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5- carboxylic acid. MS (ESI): mass calculated for C30H28F3N3O3, 535.6; m / z measured 536.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 1.81 - 1.96 (m, 4 H) 2.28 (d, J=5.87 Hz, 4 H) 2.50 (br d, J=1 .47 Hz, 2 H) 2.60 (d, J=4.40 Hz, 3 H) 3.11 -3.26 (m, 3 H) 4.88 - 5.03 (m, 1 H) 7.05 - 7.18 (m, 2 H) 7.50 - 7.58 (m, 4 H) 7.61 (br d, J=8.31 Hz, 1 H) 7.79 - 7.95 (m, 3 H) 8.04 (br s, 1 H) 8.41 (br d, J=10.27 Hz, 1 H)

[0392] Step E: (R)-N-methyl-2-((5-(4-(4-(methylsulfonyl)phenyl)-3-oxopiperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide

[0393] HATU (26.0 mg, 67 μmol) was added to a mixture of (R)-1 -((1 -(methylamino)-1 - oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-7-(2,3,6- trimethylphenyl)isoquinoline-5-carboxylic acid (30 mg, 56 μmol), 1 -(4- (methylsulfonyl)phenyl)piperazin-2-one hydrochloride (14 mg, 56 μmol) and DIEA (16.0 mg, 1 18 μmol) in DMF (400 μL). The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with brine (2 mL) and extracted with EtOAc (2 mL x3). The combined extract was concentrated to dryness in vacuo. The resulting residue was purified by preparative reverse-phase HPLC (Stationary phase: Boston Prime C18, 5 μm, 150 x 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - Acetonitrile (B), gradient elution: 45 - 75% B in A over 7 min, flow rate: 25 mL / min) to yield (R)-N-methyl- 2-((5-(4-(4-(methylsulfonyl)phenyl)-3-oxopiperazine-1 -carbonyl)-7-(2,3,6- trimethylphenyl)isoquinolin-1 -yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide. MS (ESI): mass calculated for C41H40F3N5O5S, 771.9; m / z measured 772.2 [M+H]+. 1 H NMR (400 MHz, Chloroform-d) δ ppm 1 .86 - 1 .99 (m, 6 H) 2.30 (d, J=4.89 Hz, 3 H) 2.75 (br s, 3 H) 3.05 (s, 3 H) 3.33 (br s, 2 H) 3.61 - 3.79 (m, 2 H) 3.91 - 4.05 (m, 1 H) 4.05 - 4.15 (m, 1 H) 4.18 - 4.47 (m, 1 H) 4.72 (br s, 1 H) 5.00 - 5.14 (m, 1 H) 5.70 - 5.90 (m, 1 H) 6.14 - 6.42 (m, 1 H) 6.96 - 7.03 (m, 1 H) 7.03 - 7.09 (m, 2 H) 7.10 - 7.17 (m, 1 H) 7.38 (br d, J=6.85 Hz, 2 H) 7.41 - 7.45 (m, 1 H) 7.49 - 7.56 (m, 4 H) 7.58 (br s, 1 H) 7.94 - 8.01 (m, 2 H) 8.07 (dd, J=5.87, 0.98 Hz, 1 H).

[0394] Example 7. (R)-N-methyl-2-((5-(4-(6-(methylsulfonyl)pyridin-3-yl)-3-oxopiperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide.

[0395]

[0396] Step A: tert-butyl 4-(6-(methylsulfonyl)pyridin-3-yl)-3-oxopiperazine-1 -carboxylate A mixture of tert-butyl 3-oxopiperazine-1 -carboxylate (200 mg, 1 mmol), 5-bromo- 2-(methylsulfonyl)pyridine (283 mg, 1.2 mmol), Cui (19 mg, 0.1 mmol), K2CO3(414 mg, 3 mmol) and (R,R)-N,N'-dimethyl-1 ,2-cyclohexanediamine (28 mg, 0.2 mmol) in 1 ,4- dioxane (10 mL) was stirred at 120 °C for 16 h. The reaction mixture was diluted with water (10 mL). The aqueous layer was extracted with ethyl acetate (25 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (40 g, gradient elution: 0 ~ 80% EtOAc in hexanes). The fractions were collected and concentrated under vacuum to yield tert-butyl 4-(6-(methylsulfonyl)pyridin-3-yl)-3- oxopiperazine-1 -carboxylate. MS (ESI): mass calculated for C15H21 N3O5S, 355.4; m / z measured 356.1 [M-tBu+H]+.

[0397] Step B: 1 -(6-(methylsulfonyl)pyridin-3-yl)piperazin-2-one

[0398] To a mixture of tert-butyl 4-(6-(methylsulfonyl)pyridin-3-yl)-3-oxopiperazine-1 - carboxylate (133 mg, 0.37 mmol) in DCM (10 mL) was added 4M HCI in 1 ,4-dioxane (2.8 mL. 11 mmol). The mixture was stirred at room temperature for 16 h. The solvent was removed under vacuum to yield a white solid. The white solid was suspended in hexanes (10 mL). The solid was then collected and dried to yield 1 -(6- (methylsulfonyl)pyridin-3-yl)piperazin-2-one hydrochloride as a white powder. MS (ESI): mass calculated for C10H13N3O3S, 255.3; m / z measured 256.9 [M+H]+.

[0399] Step C: (R)-N-methyl-2-((5-(4-(6-(methylsulfonyl)pyridin-3-yl)-3-oxopiperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-3-(4- (trifluoromethyl)phenyl)propenamide

[0400] HATU (26.0 mg, 67 μmol) was added to a mixture of (R)-1 -((1 -(methylamino)-1 - oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-7-(2,3,6- trimethylphenyl)isoquinoline-5-carboxylic acid (30 mg, 56 μmol), 1 -(6- (methylsulfonyl)pyridin-3-yl)piperazin-2-one hydrochloride (16 mg, 56 μmol) and TEA (16.0 mg, 118 μmol) in DMF (400 μL). The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with brine (2 mL) and extracted with EtOAc (2 mL x3). The combined extract was concentrated to dryness in vacuo. The resulting residue was purified by preparative reverse-phase HPLC (Stationary phase: Boston Prime C18, 5 μm, 150 x 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - Acetonitrile (B), gradient elution: 45 - 75% B in A over 7 min, flow rate: 25 mL / min) to yield (R)-N-methyl- 2-((5-(4-(6-(methylsulfonyl)pyridin-3-yl)-3-oxopiperazine-1 -carbonyl)-7-(2,3,6- trimethylphenyl)isoquinolin-1 -yl)amino)-3-(4-(trifluoromethyl)phenyl)propenamide. MS (ESI): mass calculated for C40H39F3N6O5S, 772.8; m / z measured 773.2 [M+H]+. 1 H NMR (400 MHz, Chloroform-d) δ ppm 1 .83 - 2.06 (m, 5 H) 2.23 - 2.39 (m, 3 H) 2.69 - 2.82 (m, 3 H) 3.22 (s, 2 H) 3.26 - 3.37 (m, 2 H) 3.63 - 3.87 (m, 2 H) 3.96 - 4.08 (m, 1 H) 4.08 - 4.18 (m, 1 H) 4.22 - 4.49 (m, 1 H) 4.66 - 4.86 (m, 1 H) 4.98 - 5.15 (m, 1 H) 5.68 - 5.92 (m, 1 H) 6.10 - 6.32 (m, 1 H) 6.95 - 7.09 (m, 2 H) 7.10 - 7.17 (m, 1 H) 7.30 - 7.40 (m, 2 H) 7.41 - 7.45 (m, 1 H) 7.46 - 7.54 (m, 2 H) 7.59 (br d, J=3.42 Hz, 1 H) 7.96 (dd, J=8.80, 2.45 Hz, 1 H) 8.05 - 8.09 (m, 1 H) 8.12 (br d, J=8.31 Hz, 1 H) 8.76 (br s, 1 H)

[0401] Example 8. (R)-2-((3-cyano-5-(4-(6-(methylsulfonyl)pyridin-3-yl)-3-oxopiperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-N-(2-hydroxy-2- methylpropyl)-3-(4-(trifluoromethyl)phenyl)propanamide.

[0402] Step A: (R)-2-((3-chloro-5-(4-(6-(methylsulfonyl)pyridin-3-yl)-3-oxopiperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-N-(2-hydroxy-2- methylpropyl)-3-(4-(trifluoromethyl)phenyl)propanamide

[0403] To a solution of (R)-3-chloro-1 -((1 -((2-hydroxy-2-methylpropyl)amino)-1 -oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5- carboxylic acid (40 mg, 57 μmol), 1 -(6-(methylsulfonyl)pyridin-3-yl)piperazin-2-one hydrochloride (17 mg, 57 μmol) and HATU (26 mg, 69 μmol) in DMF (1 mL), was added TEA (17 μL, 120 μmol). The reaction was stirred at room temperature for 2 h. The solvent was evaporated, and The resulting residue was diluted with saturated sodium bicarbonate solution (1 mL). A solid formed and was collected and dried to yield (R)-2- ((3-chloro-5-(4-(6-(methylsulfonyl)pyridin-3-yl)-3-oxopiperazine-1 -carbonyl)-7-(2,3,6- trimethylphenyl)isoquinolin-1 -yl)amino)-N-(2-hydroxy-2-methylpropyl)-3-(4- (trifluoromethyl)phenyl)propanamide. MS (ESI): mass calculated for C44H43CIF3N6O6S, 865.3; m / z measured 865.2 [M]+.

[0404] Step B: (R)-2-((3-cyano-5-(4-(6-(methylsulfonyl)pyridin-3-yl)-3-oxopiperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-N-(2-hydroxy-2- methylpropyl)-3-(4-(trifluoromethyl)phenyl)propanamide

[0405] A suspension of (R)-2-((3-chloro-5-(4-(6-(methylsulfonyl)pyridin-3-yl)-3- oxopiperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-N-(2- hydroxy-2-methylpropyl)-3-(4-(trifluoromethyl)phenyl)propanamide (41 mg, 50 pmmol), zinc cyanide (4 mg, 40 pmmol), and tBuXPhos Pd G3 (6 mg, 0.70 pmmol) in 1 :1 H2O:THF (1 mL) was degassed with N2 for 15 min. The mixture was then stirred at 72°C for 16 h. The mixture was cooled to room temperature, filtered, concentrated and The resulting residue was purified by preparative reverse-phase HPLC (Stationary phase: Boston Prime C18, 5 μm, 150 x 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - Acetonitrile (B), gradient elution: 45 - 75% B in A over 7 min, flow rate: 25 mL / min) to yield (R)-2-((3-cyano-5-(4-(6-(methylsulfonyl)pyridin-3-yl)-3-oxopiperazine-1 -carbonyl)- 7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-N-(2-hydroxy-2-methylpropyl)-3-(4- (trifluoromethyl)phenyl)propanamide. MS (ESI): mass calculated for C44H44F3N7O6S, 855.9; m / z measured 856.2 [M+H]+. 1 H NMR (400 MHz, chloroform-d) δ ppm 1 .02 - 1.17 (m, 6 H) 1.71 (br s, 3 H) 1.89 - 1.99 (m, 5 H) 2.24 - 2.36 (m, 3 H) 3.08 - 3.17 (m, 1 H) 3.20 (s, 3 H) 3.26 - 3.37 (m, 2 H) 3.64 - 3.86 (m, 2 H) 3.97 - 4.08 (m, 1 H) 4.14 (br s, 1 H) 5.05 (br d, J=3.42 Hz, 1 H) 6.38 (br d, J=5.87 Hz, 1 H) 6.43 - 6.57 (m, 1 H) 7.03 - 7.10 (m, 1 H) 7.1 1 - 7.18 (m, 1 H) 7.34 - 7.46 (m, 2 H) 7.47 - 7.60 (m, 4 H) 7.69 - 7.78 (m, 1 H) 7.95 - 8.03 (m, 1 H) 8.06 - 8.18 (m, 1 H) 8.79 (br d, J=7.83 Hz, 1 H) Example 9. (R)-2-((3-cyano-5-(4-((methylsulfonyl)methyl)piperidine-1 -carbonyl)-7-(2,3,6- trimethylphenyl)isoquinolin-1 -yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide.

[0406] To a solution of (R)-3-cyano-1 -((1 -(methylamino)-1 -oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5- carboxylic acid (20 mg, 36 μmol), 4-((methylsulfonyl)methyl)piperidine hydrochloride (8 mg, 40 mmol) and HATU (16 mg, 43 μmol) in DMF (1 mL) was added TEA (10 μL, 75 μmol). The reaction was stirred at room temperature for 2 h. The solvent was evaporated and The resulting residue was purified by preparative reverse-phase HPLC (Stationary phase: Boston Prime C18, 5 μm, 150 x 30 mm; Mobile phase: water (formic acid) (A) - Acetonitrile (B), gradient elution: 45 - 75% B in A over 7 min, flow rate: 25 mL / min) to yield (R)-2-((3-cyano-5-(4-((methylsulfonyl)methyl)piperidine-1 -carbonyl)-7- (2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propenamide. MS (ESI): mass calculated for C38H40F3N5O4S, 719.8; m / z measured 720.3 [M+H]+.1H NMR (400 MHz, Chloroform-d) δ ppm 1.30 (d, J=6.85 Hz, 1 H) 1 .65 - 1 .78 (m, 1 H) 1 .81 - 1 .95 (m, 6 H) 1 .99 (br d, J=9.29 Hz, 1 H) 2.1 1 (br d, J=13.21 Hz, 1 H) 2.25 - 2.34 (m, 3 H) 2.37 - 2.48 (m, 1 H) 2.74 (d, J=4.89 Hz, 3 H) 2.93 - 2.97 (m, 3 H) 2.98 - 3.13 (m, 3 H) 3.17 - 3.27 (m, 1 H) 3.29 - 3.37 (m, 1 H) 3.40 - 3.53 (m, 1 H) 4.82 - 4.94 (m, 1 H) 4.95 - 5.07 (m, 1 H) 5.84 (br d, J=19.07 Hz, 1 H) 6.31 - 6.46 (m, 1 H) 7.02 - 7.08 (m, 1 H) 7.11 - 7.17 (m, 1 H) 7.30 - 7.49 (m, 4 H) 7.51 - 7.56 (m, 2 H) 7.61 - 7.70 (m, 1 H)

[0407] Example 10. (R)-1 -((1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2- yl)amino)-5-(4-((methylsulfonyl)methyl)piperidine-1 -carbonyl)-7-(2,3,6- trimethylphenyl)isoquinoline-3-carboxamide.

[0408]

[0409] A mixture of methyl (R)-3-cyano-1 -((1 -(methylamino)-1 -oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5- carboxylate (47 mg, 8.2 μmol) and LiOH (6 mg, 24.5 mmol) in 1 :1 Water:THF (1 mL) was stirred at 80 °C for 2 h. The reaction mixture was neutralized with HCI (1 M in H2O) (0.25 mL). The aqueous layer was extracted with 10% MeOH in dichloromethane. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. To the resulting residue, 4-((methylsulfonyl)methyl)piperidine hydrochloride (7 mg, 35 mmol), HATU (16 mg, 41 μmol), TEA (10 μL, 73 μmol) and DMF (1 mL) were added. The reaction was stirred at room temperature for 2 h. The solvent was evaporated and The resulting residue was purified by preparative reverse-phase HPLC (Stationary phase: Boston Prime C18, 5 μm, 150 x 30 mm; Mobile phase: water (formic acid) (A) - Acetonitrile (B), gradient elution: 45 - 75% B in A over 7 min, flow rate: 25 mL / min) to yield (R)-1 -((1 -(methylamino)-l -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-5- (4-((methylsulfonyl)methyl)piperidine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)isoquinoline- 3-carboxamide. MS (ESI): mass calculated for C38H42F3N5O5S, 737.8; m / z measured 738.3 [M+H]+.1H NMR (400 MHz, Chloroform-d) δ ppm 1.13 - 1.47 (m, 2 H) 1.77 - 1.98 (m, 6 H) 2.05 (br d, J=12.72 Hz, 1 H) 2.24 - 2.33 (m, 3 H) 2.35 - 2.50 (m, 1 H) 2.75 - 2.82 (m, 3 H) 2.93 (s, 3 H) 2.95 - 3.13 (m, 3 H) 3.22 - 3.33 (m, 1 H) 3.33 - 3.52 (m, 2 H) 4.62 - 4.80 (m, 1 H) 4.80 - 4.97 (m, 1 H) 5.62 - 5.74 (m, 2 H) 6.12 - 6.23 (m, 1 H) 7.04 - 7.10 (m, 1 H) 7.1 1 - 7.17 (m, 1 H) 7.30 - 7.38 (m, 2 H) 7.39 - 7.44 (m, 1 H) 7.44 - 7.49 (m, 1 H) 7.53 (br d, J=7.83 Hz, 2 H) 7.68 - 7.82 (m, 1 H) 7.96 - 8.12 (m, 1 H)

[0410] Example 11 . (R)-2-((3-cyano-5-(4-(6-(methylsulfonyl)pyridin-3-yl)-3-oxopiperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide.

[0411]

[0412] To a solution of (R)-3-cyano-1 -((1 -(methylamino)-1 -oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5- carboxylic acid (30 mg, 54 μmol), 1 -(6-(methylsulfonyl)pyridin-3-yl)piperazin-2-one hydrochloride (16 mg, 54 μmol) and HATU (24 mg, 64 μmol) in DMF (1 mL) was added TEA (16 μL, 112 μmol). The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated and The resulting residue was purified by preparative reverse-phase HPLC (Stationary phase: Boston Prime C18, 5 μm, 150 x 30 mm; Mobile phase: water (formic acid) (A) - Acetonitrile (B), gradient elution: 45 - 75% B in A over 7 min, flow rate: 25 mL / min) to yield (R)-2-((3-cyano-5-(4-(6-(methylsulfonyl)pyridin-3-yl)- 3-oxopiperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-N-methyl- 3-(4-(trifluoromethyl)phenyl)propanamide. MS (ESI): mass calculated for C41H38F3N7O5S, 737.8; m / z measured 738.3 [M+H]+.1H NMR (400 MHz, Chloroform-d) δ ppm 1 .91 (d, J=4.89 Hz, 3 H) 1 .93 - 1 .98 (m, 3 H) 2.27 - 2.34 (m, 3 H) 2.76 (d, J=4.89 Hz, 3 H) 3.16 - 3.26 (m, 4 H) 3.30 - 3.42 (m, 1 H) 3.66 - 3.76 (m, 1 H) 3.76 - 3.86 (m, 1 H) 4.06 (br s, 1 H) 4.14 (br s, 1 H) 4.67 - 4.86 (m, 1 H) 4.91 - 5.08 (m, 1 H) 5.71 - 5.81 (m, 1 H) 6.46 (br s, 1 H) 7.01 - 7.10 (m, 1 H) 7.12 - 7.19 (m, 1 H) 7.33 - 7.44 (m, 2 H) 7.49 - 7.59 (m, 4 H) 7.69 - 7.75 (m, 1 H) 7.92 - 8.07 (m, 3 H) 8.13 (br d, J=7.83 Hz, 2 H) 8.75 - 8.86 (m, 1 H)

[0413] Example 12. (R)-2-((3-cyano-5-((R)-2-methyl-4-(4-(methylsulfonyl)phenyl)piperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide.

[0414]

[0415] Step A: Tert-butyl (R)-2-methyl-4-(4-(methylsulfonyl)phenyl)piperazine-1 - carboxylate

[0416] A degassed mixture of 4-bromophenyl methyl sulfone (100 mg, 0.43 mmol)), (R)- 1 -N-boc-2-methylpiperazine (170 mg, 0.85 mmol), sodium tert-butoxide (49 mg, 0.51 mmol) and methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1 ,1 biphenyl)(2'-methylamino-1 ,1 '-biphenyl-2-yl)palladium(ll) (37 mg, 0.043 mmol) in toluene (2 mL) was heated in a microwave at 140 °C for 40 min. The mixture was filtered through CELITE® and washed with EtOAc (25 mL). The filtrate was concentrated and The resulting residue was purified by silica gel chromatography (0 - 75% EtOAc in Hex) to yield tert-butyl (R)-2-methyl-4-(4-(methylsulfonyl)phenyl)piperazine-1 - carboxylate. MS (ESI): mass calculated for C17H26N2O4S, 354.5; m / z measured 255.1 [M-Boc+H]+

[0417] Step B: (R)-3-methyl-1 -(4-(methylsulfonyl)phenyl)piperazine

[0418] To a solution of tert-butyl (R)-2-methyl-4-(4-(methylsulfonyl)phenyl)piperazine-1 - carboxylate (112 mg, 0.32 mmol) in DCM (3 mL) was added HCI (4M in 1 ,4-dioxane) (0.79 mL, 3.2 mmol) was added. The mixture was stirred at room temperature for 2 h. The solvent was evaporated, and The resulting residue was suspended in hexanes (10 mL). The solid was collected and dried to yield (R)-3-methyl-1 -(4- (methylsulfonyl)phenyl)piperazine as an hydrochloride salt. MS (ESI): mass calculated for C12H18N2O2S, 254.3; m / z measured 255.1 [M+H]+.

[0419] Step C: (R)-2-((3-cyano-5-((R)-2-methyl-4-(4-(methylsulfonyl)phenyl)piperazine- 1 -carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide

[0420] To a solution of (R)-3-cyano-1 -((1 -(methylamino)-1 -oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5- carboxylic acid (20 mg, 36 μmol), (R)-3-methyl-1 -(4-(methylsulfonyl)phenyl)piperazine hydrochloride (11 mg, 39 μmol) and HATU (16 mg, 43 μmol) in DMF (1 mL) was added TEA (15 μL, 111 μmol). The reaction was stirred at room temperature for 2 h. The solvent was evaporated and The resulting residue was purified by preparative reversephase HPLC (Stationary phase: Boston Prime C18, 5 μm, 150 x 30 mm; Mobile phase: water (formic acid) (A) - Acetonitrile (B), gradient elution: 45 - 75% B in A over 7 min, flow rate: 25 mL / min) to yield (R)-2-((3-cyano-5-((R)-2-methyl-4-(4- (methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 - yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide. MS (ESI): mass calculated for C43H43F3N6O4S, 796.9; m / z measured 797.3 [M+H]+.1H NMR (400 MHz, Chloroform-d) δ ppm 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .30 (br s, 2 H) 1 .93 (br d, J=19.56 Hz, 6 H) 2.23 - 2.38 (m, 3 H) 2.77 (d, J=4.89 Hz, 3 H) 3.01 (s, 3 H) 3.14 - 3.22 (m, 1 H) 3.29 - 3.40 (m, 2 H) 3.43 - 3.56 (m, 1 H) 3.57 - 3.80 (m, 2 H) 3.83 - 4.07 (m, 1 H) 4.68 - 4.88 (m, 1 H) 4.91 - 5.02 (m, 1 H) 5.58 - 5.79 (m, 1 H) 6.27 - 6.47 (m, 1 H) 6.92 (br d, J=8.80 Hz, 2 H) 7.04 - 7.10 (m, 1 H) 7.14 - 7.19 (m, 1 H) 7.33 - 7.53 (m, 4 H) 7.56 (d, J=7.83 Hz, 2 H) 7.68 (br s, 1 H) 7.79 (d, J=8.80 Hz, 2 H)

[0421] Example 13. (R)-2-((3-cyano-5-(4-(5-(methylsulfonyl)pyridin-2-yl)piperidine-1 -carbonyl)- 7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide.

[0422] Step A: Tert-butyl 5-(methylsulfonyl)-3',6'-dihydro-[2,4'-bipyridine]-1 '(2'H)- carboxylate

[0423] To a mixture of 2-bromo-5-(methylsulfonyl)pyridine (300 mg, 1.3 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1 (2H)-carboxylate (589 mg, 1 .9 mmol) and K2CO3(527 mg, 3.8 mmol) in 1 ,4-dioxane:H2O (v / v, 9 / 1 , 5 mL) was added Pd(dppf)Cl2(93 mg 127 μmol). The mixture was degassed, and the mixture was stirred at 80 °C for 16 h. The reaction mixture was filtered, and the filter cake was rinsed with ethyl acetate (20 mL). The filtrate was partitioned between ethyl acetate (20 mL) and H2O (18 mL). The aqueous layer was extracted with ethyl acetate (25 mL x 3). The combined extracts were washed with brine (25 mL), dried over anhydrous Na2SO4, filtered, andconcentrated. The resulting residue was subjected to column chromatography over silica gel (gradient elution: 0 - 60% EtOAc in heptane). The fractions were collected and concentrated to dryness in vacuo to yield tert-butyl 5- (methylsulfonyl)-3',6'-dihydro-[2,4'-bipyridine]-1 '(2'H)-carboxylate. mass calculated for C16H22N2O4S, 338.4; m / z measured 283 [M-tBu+H]+.

[0424] Step B: Tert-butyl 4-(5-(methylsulfonyl)pyridin-2-yl)piperidine-1 -carboxylate

[0425] A solution of tert-butyl 5-(methylsulfonyl)-3',6'-dihydro-[2,4'-bipyridine]-1 '(2'H)- carboxylate (244 mg, 0.7 mmol) in MeOH (8 mL) was treated with Pd / C (5% wet) (230 mg, 0.11 mmol) and hydrogenated at room temperature under H2atmosphere. The reaction mixture was filtered through CELITE®, and the pad washed with 10% NH3OH MeOH / DCM to extract the desired product. The filtrate was concentrated under vacuum to yield tert-butyl 4-(5-(methylsulfonyl)pyridin-2-yl)piperidine-1 -carboxylate, mass calculated for C16H24N2O4S, 340.4; m / z measured 241.1 [M-Boc+H]+.

[0426] Step C: 5-(Methylsulfonyl)-2-(piperidin-4-yl)pyridine

[0427] To a solution of tert-butyl 4-(5-(methylsulfonyl)pyridin-2-yl)piperidine-1 - carboxylate (231 mg, 679 μmol) in DCM (7 mL) was added 4 M HCI / 1 ,4-dioxane (0.9 mL). The suspension was stirred at room temperature for 3 h. The reaction mixture was then concentrated, and The resulting residue was suspended in heptane (25 mL). The precipitate was filtered to yield 5-(methylsulfonyl)-2-(piperidin-4-yl)pyridine as an hydrochloride salt. MS (ESI): mass calculated for C11H16O2N2S, 240.3; m / z measured 241.1 [M+H]+.

[0428] Step D: (R)-2-((3-cyano-5-(4-(5-(methylsulfonyl)pyridin-2-yl)piperidine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide To a solution of (R)-3-cyano-1 -((1 -(methylamino)- 1 -oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-7-(2,3,6- trimethylphenyl)isoquinoline-5-carboxylic acid (30 mg, 54 μmol), 5-(methylsulfonyl)-2- (piperidin-4-yl)pyridine hydrochloride (16 mg, 68 μmol) and HATU (28 mg, 74 μmol) in DMF (1 mL) was added TEA (26 μL, 191 nmol). The reaction mixture was then stirred at room temperature for 2 h. The solvent was evaporated and The resulting residue was purified by preparative reverse-phase HPLC (Stationary phase: Boston Prime C18, 5 μm, 150 x 30 mm; Mobile phase: water (formic acid) (A) - Acetonitrile (B), gradient elution: 45 - 75% B in A over 7 min, flow rate: 25 mL / min) to yield (R)-2-((3-cyano-5-(4- (5-(methylsulfonyl)pyridin-2-yl)piperidine-1 -carbonyl)-7-(2,3,6- trimethylphenyl)isoquinolin-1 -yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide. MS (ESI): mass calculated for C42H41F3N6O4S, 782.9; m / z measured 783.3 [M+H]+.1H NMR (400 MHz, Chloroform-d) δ ppm 1.72 - 1 .83 (m, 1 H) 1 .83 - 1 .99 (m, 7 H) 2.08 - 2.23 (m, 1 H) 2.25 - 2.36 (m, 3 H) 2.76 (d, J=4.89 Hz, 3 H) 2.98 - 3.08 (m, 1 H) 3.11 (br d, J=7.83 Hz, 3 H) 3.14 - 3.27 (m, 2 H) 3.28 - 3.44 (m, 1 H) 3.51 - 3.71 (m, 1 H) 4.96 (br s, 1 H) 4.99 - 5.13 (m, 1 H) 5.57 - 5.78 (m, 1 H) 6.19 - 6.40 (m, 1 H) 7.01 - 7.11 (m, 1 H) 7.13 - 7.19 (m, 1 H) 7.18 - 7.18 (m, 1 H) 7.31 - 7.47 (m, 3 H) 7.49 - 7.58 (m, 3 H) 7.63 (br d, J=3.91 Hz, 2 H) 8.09 - 8.24 (m, 1 H) 9.08 (br d, J=17.12 Hz, 1 H)

[0429] Example 14. (R)-N-methyl-2-((3-(methylsulfonyl)-5-((S)-octahydropyrazino[2,1 - c][1 ,4]oxazine-8-carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide.

[0430] Step A: (R)-2-((3-chloro-5-((S)-octahydropyrazino[2,1 -c][1 ,4]oxazine-8-carbonyl)- 7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide

[0431] To a solution of (R)-3-chloro-1 -((1 -(methylamino)-1 -oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5- carboxylic acid (30 mg, 53 μmol), (S)-octahydropyrazino[2,1 -c][1 ,4]oxazine dihydrochloride (12 mg, 58 μmol), HATU (24 mg, 63 μmol) in DMF (1 mL) was added TEA (15 μL, 110 μmol). The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated, and the resulting residue was suspended in saturated sodium bicarbonate solution. The precipitate was collected to yield (R)-2-((3-chloro-5- ((S)-octahydropyrazino[2,1 -c][1 ,4]oxazine-8-carbonyl)-7-(2,3,6- trimethylphenyl)isoquinolin-1 -yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide. MS (ESI): mass calculated for C37H39CIF3N5O3, 694.2; m / z measured 694.3 [M]+.

[0432] Step B: (R)-N-methyl-2-((3-(methylsulfonyl)-5-((S)-octahydropyrazino[2,1 - c][1 ,4]oxazine-8-carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide

[0433] A mixture of (R)-2-((3-chloro-5-((S)-octahydropyrazino[2,1 -c][1 ,4]oxazine-8- carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide (37 mg, 53 μmol), sodium methanesulfinate (11 mg, 103 μmol), Cui (4 mg, 18 μmol), L-proline (5 mg, 46 μmol) and Cs2CO3(6 mg, 19 μmol) in DMSO (2 mL) was degassed and the resulting yellow suspension was stirred at 135 °C for 24 h. Sodium methanesulfinate (11 mg, 103 μmol) and L-proline (5 mg, 46 μmol) were added and the heating continued for another 24 h. The mixture was filtered, andthe resulting residue was purified by preparative reverse-phase HPLC (Stationary phase: Boston Prime C18, 5 μm, 150 x 30 mm; Mobile phase: water (formic acid) (A) - Acetonitrile (B), gradient elution: 45 - 75% B in A over 7 min, flow rate: 25 mL / min) to yield (R)-N-methyl-2-((3-(methylsulfonyl)-5-((S)-octahydropyrazino[2,1 -c][1 ,4]oxazine-8- carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide. MS (ESI): mass calculated for C38H42F3N5O5S, 737.8; m / z measured 738.3 [M+H]+.1H NMR (400 MHz, Chloroform-d) δ ppm1H NMR (400 MHz, Chloroform-d) δ ppm 1 .86 - 1 .99 (m, 6 H) 2.09 - 2.22 (m, 1 H) 2.31 (br s, 3 H) 2.34 - 2.45 (m, 1 H) 2.46 - 2.57 (m, 1 H) 2.58 - 2.72 (m, 2 H) 2.74 (br d, J=1 .96 Hz, 3 H)

[0434] 2.79 - 2.95 (m, 1 H) 3.04 - 3.17 (m, 4 H) 3.23 - 3.35 (m, 3 H) 3.58 - 3.75 (m, 1 H) 3.80 -

[0435] 3.90 (m, 1 H) 4.59 - 4.89 (m, 1 H) 4.92 - 5.05 (m, 1 H) 5.97 - 6.31 (m, 1 H) 5.98 - 6.10

[0436] (m, 1 H) 6.33 - 6.46 (m, 1 H) 7.02 - 7.11 (m, 1 H) 7.16 (br t, J=6.60 Hz, 1 H) 7.36 - 7.52

[0437] (m, 3 H) 7.53 - 7.61 (m, 2 H) 7.66 (br s, 1 H) 7.73 - 7.84 (m, 1 H). Example 15. (R)-(3-chloro-1 -((3-hydroxy-3-methyl-1 -(2-(trifluoromethyl)pyrimidin-5- yl)butan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinolin-5-yl)(4-(6- (methylsulfonyl)pyridin-3-yl)piperidin-1 -yl)methanone.

[0438] Step A: Methyl-(R)-3-chloro-1 -((3-hydroxy-3-methyl-1 -(2- (trifluoromethyl)pyrimidin-5-yl)butan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5- carboxylate

[0439] A mixture of (R)-3-amino-2-methyl-4-(2-(trifluoromethyl)pyrimidin-5-yl)butan-2-ol (90 mg, 0.32 mmol), potassium phosphate (201 mg, 0.95 mmol) and methyl 1 ,3- dichloro-7-(2,3,6-trimethylphenyl)isoquinoline-5-carboxylate (118 mg, 0.32 mmol) in THF (2 mL) was degassed, followed by addition of rac-binap PD G4 (32 mg, 0.032 mmol) and 2, 2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl (10 mg, 0.016 mmol). The resulting mixture was then heated at 80 °C for 24 h. The reaction mixture was concentrated and The resulting residue was purified by silica gel chromatography (0- 100% EtOAc in Hex) to yield methyl-(R)-3-chloro-1 -((3-hydroxy-3-methyl-1 -(2- (trifluoromethyl)pyrimidin-5-yl)butan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5- carboxylate. MS (ESI): mass calculated for C30H30CIF3N4O3, 587.0; m / z measured 587.3 [M]+.

[0440] Step B: (R)-3-chloro-1 -((3-hydroxy-3-methyl-1 -(2-(trifluoromethyl)pyrimidin-5- yl)butan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5-carboxylic acid

[0441] A solution of methyl-(R)-3-chloro-1 -((3-hydroxy-3-methyl-1 -(2- (trifluoromethyl)pyrimidin-5-yl)butan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5- carboxylate (106 mg, 0.181 mmol) and NaOH (1.8 mL, 1 M, 1.8 mmol) in THF (2 mL) and MeOH (2 mL) was stirred at room temperature for 12 h. The solvent was evaporated in vacuo and the resulting mixture was purified by reverse phase HPLC (water:acetonitrile:formic acid) to yield (R)-3-chloro-1 -((3-hydroxy-3-methyl-1 -(2- (trifluoromethyl)pyrimidin-5-yl)butan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5- carboxylic acid. MS (ESI): mass calculated for C29H28CIF3N4O3, 573.0; m / z measured 573.2 [M]+.

[0442] Step C: (R)-(3-chloro-1 -((3-hydroxy-3-methyl-1 -(2-(trifluoromethyl)pyrimidin-5- yl)butan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinolin-5-yl)(4-(6- (methylsulfonyl)pyridin-3-yl)piperidin-1 -yl)methanone

[0443] To a solution of (R)-3-chloro-1 -((3-hydroxy-3-methyl-1 -(2- (trifluoromethyl)pyrimidin-5-yl)butan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5- carboxylic acid (38 mg, 66 μmol), 2-(methylsulfonyl)-5-(piperidin-4-yl)pyridine (23 mg, 73 μmol), and HATU (30 mg, 80 μmol) in DMF (1 mL) was added TEA (28 μL, 206 μmol). The reaction was stirred at room temperature for 2 h. The solvent was evaporated and The resulting residue was purified by preparative reverse-phase HPLC (Stationary phase: Boston Prime C18, 5 μm, 150 x 30 mm; Mobile phase: water (formic acid) (A) - Acetonitrile (B), gradient elution: 45 - 75% B in A over 7 min, flow rate: 25 mL / min) to yield (R)-(3-chloro-1 -((3-hydroxy-3-methyl-1 -(2-(trifluoromethyl)pyrimidin-5- yl)butan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinolin-5-yl)(4-(6- (methylsulfonyl)pyridin-3-yl)piperidin-1 -yl)methanone. MS (ESI): mass calculated for C340H42CIF3N6O4S, 795.3; m / z measured 795.2 [M]+.1H NMR (400 MHz, Chloroform-d) δ ppm1H NMR (400 MHz, Chloroform-d) δ ppm 1 .23 - 1 .34 (m, 3 H) 1 .38 - 1 .48 (m, 3 H) 1.73 - 1.87 (m, 2 H) 1.88 - 2.01 (m, 6 H) 2.02 - 2.12 (m, 1 H) 2.27 - 2.34 (m, 4 H) 2.83 - 3.03 (m, 3 H) 3.16 (br d, J=13.21 Hz, 1 H) 3.21 (br d, J=4.89 Hz, 3 H) 3.24 - 3.33 (m, 1 H) 3.60 (br d, J=10.27 Hz, 1 H) 4.65 (br s, 1 H) 5.04 (br t, J=13.69 Hz, 1 H) 5.84 - 6.00 (m, 1 H) 6.77 - 7.00 (m, 1 H) 7.04 - 7.09 (m, 1 H) 7.11 - 7.17 (m, 1 H) 7.30 - 7.41 (m, 1 H) 7.48 (s, 1 H) 7.69 - 7.87 (m, 1 H) 8.05 (br dd, J=19.32, 8.07 Hz, 1 H) 8.60 (br d, J=11 .25 Hz, 1 H) 8.69 - 8.80 (m, 2 H).

[0444] Example 16. (R)-2-((3-cyano-5-(4-(4-sulfamoylphenyl)piperidine-1 -carbonyl)-7-(2,3,6- trimethylphenyl)isoquinolin-1 -yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide.

[0445] To a solution of (R)-3-cyano-1 -((1 -(methylamino)-1 -oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5- carboxylic acid (30 mg, 54 μmol), 4-(piperidin-4-yl)benzenesulfonamide (14 mg, 59 μmol), HATU (24 mg, 64 μmol) in DMF (1 mL) was added TEA (16 μL, 112 μmol). The reaction was stirred at room temperature for 2 h. The solvent was evaporated and The resulting residue was purified by preparative reverse-phase HPLC (Stationary phase: Boston Prime C18, 5 μm, 150 x 30 mm; Mobile phase: water (formic acid) (A) - Acetonitrile (B), gradient elution: 45 - 75% B in A over 7 min, flow rate: 25 mL / min) to yield (R)-2-((3-cyano-5-(4-(4-sulfamoylphenyl)piperidine-1 -carbonyl)-7-(2,3,6- trimethylphenyl)isoquinolin-1 -yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide. MS (ESI): mass calculated for C42H41F3N6O4S, 782.9; m / z measured 783.3 [M+H]+.1H NMR (400 MHz, Chloroform-d) δ ppm 1.75 -

[0446] 1.82 (m, 1 H) 1.84 - 1.88 (m, 1 H) 1.88 - 1.93 (m, 3 H) 1.96 (br s, 2 H) 2.03 - 2.15 (m, 1 H) 2.27 - 2.36 (m, 3 H) 2.77 (d, J=4.89 Hz, 3 H) 2.83 - 2.92 (m, 1 H) 2.95 - 3.07 (m, 1 H) 3.10 - 3.27 (m, 2 H) 3.31 - 3.40 (m, 1 H) 3.48 - 3.65 (m, 1 H) 4.72 - 4.86 (m, 2 H) 4.91 - 5.00 (m, 1 H) 5.02 - 5.14 (m, 1 H) 5.58 - 5.74 (m, 1 H) 6.20 - 6.39 (m, 1 H) 7.02 - 7.11 (m, 1 H) 7.13 - 7.19 (m, 1 H) 7.32- 7.47 (m, 4 H) 7.48 - 7.59 (m, 3 H) 7.64 (br s, 1 H)

[0447] 7.83 - 7.94 (m, 2 H)

[0448] Additional representative compounds of the present invention were similarly prepared according to the procedure described in the Examples described above (e.g. Example s, 7, 9, 11 , 12, 13, 15, 16), selecting and substituting a suitable reagent(s) as would be readily recognized by those skilled in the art. In the table below, when a given compound is listed without specific stereo-orientation, the compound was prepared as a mixture of stereoisomers.

[0449]

[0450]

[0451]

[0452] _

[0453]

[0454]

[0455]

[0456]

[0457]

[0458] ( tr

[0459] (t

[0460] M1H 3. H 7. (

[0461] ( tr (t

[0462] M

[0463] 12. ( H 7. 7.

[0464]

[0465]

[0466]

[0467] Example 17. (R)-N-methyl-2-((3-methyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide

[0468] Step A: 2-Bromo-5-methoxyisophthalic acid

[0469] Into a solution of 2-bromo-5-methoxy-1 ,3-dimethylbenzene (30.0 g, 139.48 mmol) was dissolved in tBuOH (1200 mL) / H2O (1200 mL), and the reaction mixture was heated to 100 °C with stirring. KMnO4(264.51 g, 1 .67 mol) was added to the solution in batches and the resulting mixture was stirred at 100 °C for 12 h. Ten identical reactions were set up in parallel. The reaction mixture was diluted with ethyl acetate (2000 mL). The mixture was filtered through a pad of CELITE®, and the resulting solid was rinsed with ethyl acetate (1000 mL x 2). 2 M aq. HCI was added to the filtrate to adjust the pH of aqueous layer to ~ 3, and the mixture was extracted with ethyl acetate (1000 mL x 3). The combined organic layer was dried with Na2SO4, filtered, and concentrated under vacuum to yield 2-bromo-5-methoxyisophthalic acid as a white solid.1H NMR (400 MHz, DMSO-d6) 7.25 (s, 2H), 3.81 (s, 3H)

[0470] Step B: 7-Methoxy-3-methyl-1 -oxo-1 H-isochromene-5-carboxylic acid

[0471] Cui (9.07 g, 47.63 mmol) was added to a mixture of 2-bromo-5- methoxyisophthalic acid (131 g, 476.27 mmol), 2,4-pentanedione (71.52 g, 714.41 mmol) and K3PO4(202.19 g, 952.55 mmol) in NMP (1300 mL) under N2. The yellow mixture was stirred at 105 °C for 24 h. The mixture was diluted with H2O (2000 mL), then 1 M aq. HCI was added to adjust the pH to ~4. The mixture was then extracted with ethyl acetate (1000 mL x 2). The organic phase was washed with brine (1000 mL x 2), dried with Na2SO4, filtered, and concentrated under vacuum. The resulting residue was triturated with EtOAc (1 L) at 25 °C for 1 hr to yield 7-methoxy-3-methyl-1 -oxo-1 H- isochromene-5-carboxylic acid as a yellow solid.1H NMR (400 MHz, DMSO-d6) 11 .41 (br s, 1 H), 7.88 - 7.74 (m, 2H), 7.16 (s, 1 H), 3.92 - 3.82 (m, 3H), 2.21 (s, 3H)

[0472] Step C: 7-Methoxy-3-methyl-1 -oxo-1 ,2-dihydroisoquinoline-5-carboxylic acid NH4OAC (55.29 g, 717.32 mmol) was added to a mixture of 7-methoxy-3-methyl- 1 -oxo-1 H-isochromene-5-carboxylic acid (56 g, 239.11 mmol) in NH3*H2O (560 mL). The reaction mixture was heated at 80 °C for 2 h. The mixture was washed with ethyl acetate (200 mL x 2), and the organic phase was discarded. Then 1 M aq. HCI was added to the aqueous phase to adjust the pH to ~1 , and the mixture was filtered. The solid was rinsed with H2O (200 mL), collected and dried under vacuum to yield 7- methoxy-3-methyl-1 -oxo-1 ,2-dihydroisoquinoline-5-carboxylic acid as a yellow solid.

[0473] Step D: 7-Methoxy-3-methyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 - carbonyl)isoquinolin-1 (2H)-one

[0474] To a solution of 7-methoxy-3-methyl-1 -oxo-1 ,2-dihydroisoquinoline-5-carboxylic acid 50 g, 214.39 mmol) in DMF (800 mL), HATU (105.97 g, 278.71 mmol) and DIEA (166.25 g, 1 .29 mol, 224.06 mL) was added, and the resulting yellow solution stirred at 25 °C for 30 min. 1 -(4-(Methylsulfonyl)phenyl)piperazine (56.67 g, 235.83 mmol) was added, and the yellow mixture was stirred at 25 °C for 4 hrs. The reaction mixture was diluted with H2O (2000 mL), then filtered. The filter cake was rinsed with H2O (1000 mL), dried to yield 7-methoxy-3-methyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 - carbonyl)isoquinolin-1 (2H)-one as a yellow solid.1H NMR (400 MHz, DMSO-d6) 1 1 .39 (s, 1 H), 7.78 - 7.57 (m, 3H), 7.27 (d, J = 2.6 Hz, 1 H), 7.07 (d, J = 9.0 Hz, 2H), 6.10 (s, 1 H), 3.92 - 3.77 (m, 5H), 3.64 - 3.48 (m, 2H), 3.40 - 3.34 (m, 3H), 3.09 (s, 3H), 2.18 (s, 3H).

[0475] Step E: 7-Hydroxy-3-methyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 - carbonyl)isoquinolin-1 (2H)-one

[0476] BBr3(2.65 kg, 10.59 mol) was dropwise to a solution of 7-methoxy-3-methyl-5-(4- (4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)isoquinolin-1 (2H)-one (91 g, 199.77 mmol,) in DCM (2000 mL) at -65 °C for 1 h. The mixture was warmed to 25 °C slowly and stirred at 25 °C for 12 hrs. The reaction was quenched with MeOH (2500 mL) at 0 °C, then stirred at 25 °C for 30 min, and then concentrated under vacuum. The resulting residue was co-evaporated with ethyl acetate (1000 mL x 2). The resulting residue was triturated with ethyl acetate (1000 mL) at 25 °C for 2 hours, then filtered. The filter cake was rinsed with ethyl acetate (500 mL), collected and dried under vacuum to yield 7- hydroxy-3-methyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)isoquinolin- 1 (2H)-one as a yellow solid.1H NMR (400 MHz, DMSO-d6) 11 .20 (br s, 1 H), 7.68 (d, J = 9.0 Hz, 2H), 7.55 (d, J = 2.5 Hz, 1 H), 7.07 (dd, J = 3.1 , 5.9 Hz, 3H), 6.04 (s, 1 H), 3.91 - 3.77 (m, 2H), 3.53 (br d, J = 1.5 Hz, 2H), 3.38 - 3.15 (m, 4H), 3.08 (s, 3H), 2.14 (s, 3H).

[0477] Step F: 3-Methyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-1 -oxo- 1 ,2-dihydroisoquinolin-7-yl 1 ,1 ,2,2,3,3,4,4,4-nonafluorobutane-1 -sulfonate

[0478] To a mixture of 1 ,1 ,2,2,3,3,4,4,4-nonafluorobutane-1 -sulfonyl fluoride (128.64 g, 425.82 mmol, 74.79 mL) and 7-hydroxy-3-methyl-5-(4-(4- (methylsulfonyl)phenyl)piperazine-1 -carbonyl)isoquinolin-1 (2H)-one (94 g, 212.91 mmol) and DMAP (1 .82 g, 14.90 mmol) in DCM (1200 mL) and MeOH (300 mL), was added DIEA (110.07 g, 851.64 mmol, 148.34 mL) at 0 °C. The mixture was then stirred at 25 °C for 12 hrs. The reaction was quenched with sat. aq. NH4CI (2000 mL) and extracted with DCM (2000 mL x 3). The organic layer was dried with Na2SO4, filtered, andconcentrated under vacuum. The resulting residue was triturated with EtOAc (500 mL) at 25 °C for 1 h to yield 3-methyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 - carbonyl)-1 -oxo-1 ,2-dihydroisoquinolin-7-yl 1 ,1 ,2,2,3,3,4,4,4-nonafluorobutane-1 - sulfonate as a white solid after filtration.1H NMR (400 MHz, DMSO-d6) 11 .79 (s, 1 H), 8.12 (d, J = 2.6 Hz, 1 H), 7.91 (d, J = 2.8 Hz, 1 H), 7.70 (d, J = 9.0 Hz, 2H), 7.08 (d, J = 9.0 Hz, 2H), 6.24 (s, 1 H), 3.86 (br t, J = 5.1 Hz, 2H), 3.67 - 3.50 (m, 2H), 3.26 (br s, 4H), 3.09 (s, 3H), 2.25 (s, 3H)

[0479] Step G: (1 -Hydroxy-3-methyl-7-(2,3,6-trimethylphenyl)isoquinolin-5-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone

[0480] CataCXium® A Pd G3 (6.24 g, 8.57 mmol) was added to a mixture of 3-methyl-5- (4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-1 -oxo-1 ,2-dihydroisoquinolin-7-yl 1 ,1 ,2, 2,3, 3,4,4, 4-nonafluorobutane-1 -sulfonate (31 g, 42.84 mmol), (2,3,6- trimethylphenyl)boronic acid (10.54 g, 64.26 mmol) and K3PO4(36.38 g, 171 .37 mmol) in DMF (300 mL) and H2O (33 mL). Three identical reactions of this type were set up and were stirred at 80 °C for 16 h. The mixtures were cooled to 25 °C, combined and filtered. The filtrate was diluted with water (2000 mL) resulting in the formation of a solid which was isolated by filtration. The solid was dissolved in DOM and diluted with water (2000 mL). The layers were separated and the aq. layer was extracted with DOM (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, and concentrated under reduced pressure to yield a residue. The resulting residue was triturated with EtOAc (200 mL) 25 °C for 1 h to yield (1 -hydroxy-3-methyl-7- (2,3,6-trimethylphenyl)isoquinolin-5-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1 - yl)methanone as a yellow solid after filtration.1H NMR (400 MHz, DMSO-d6) 11 .47 (s, 1 H), 7.89 (d, J = 1 .1 Hz, 1 H), 7.74 - 7.63 (m, 2H), 7.39 (d, J = 1 .8 Hz, 1 H), 7.13 - 7.02 (m, 4H), 6.23 (s, 1 H), 3.92 - 3.80 (m, 2H), 3.66 - 3.47 (m, 2H), 3.32 - 3.27 (m, 4H), 3.08 (s, 3H), 2.24 (d, J = 2.4 Hz, 6H), 1.92 (d, J = 16.8 Hz, 6H)Step H: (1 -Chloro-3-methyl-7- (2,3,6-trimethylphenyl)isoquinolin-5-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1 - yl)methanone

[0481] A solution of (1 -hydroxy-3-methyl-7-(2,3,6-trimethylphenyl)isoquinolin-5-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone (42.0 g, 77.2 mmol) in POCI3(300 mL), a yellow solution, was stirred at 90 °C for 1 hr. After this time, the reaction mixture was concentrated under reduced pressure, then adjust the pH to ~8 with sat. aq. NaHCO3and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield (1 -chloro-3-methyl-7-(2,3,6-trimethylphenyl)isoquinolin-5- yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1 -yl)methanone as a yellow solid. Step I: (R)-N- methyl-2-((3-methyl-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6- trimethylphenyl)isoquinolin-1 -yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide

[0482] To a solution of (1 -chloro-3-methyl-7-(2,3,6-trimethylphenyl)isoquinolin-5-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone (45 g, 80.0 mmol,) and (R)-2-amino-N- methyl-3-(4-(trifluoromethyl)phenyl)propanamide (25.6 g, 104 mmol) in 1 ,4-dioxane (400 mL), was added Cs2CO3(78.2 g, 240 mmol) and SPhos Pd G3 (6.25 g, 8.01 mmol), and the resulting solution was stirred at N2 at 100°C for 16 h. The reaction mixture was cooled to 25 °C, filtered, diluted with water (1000 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (1 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a residue. The resulting residue was purified by flash silica gel chromatography (ISCO®; 660 g SepaFlash® Silica Flash Column, Eluent of 0-85% Ethyl acetate / Petroleum ether gradient @ 100 mL / min), then further purified by reverse phase column chromatography: Phenomenex luna C18 250 x 80 mm x 10 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 40%-80%, 20 min to yield (R)-N-methyl-2-((3-methyl-5-(4-(4- (methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 - yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide as a yellow solid.1H NMR (400 MHz, DMSO-d6) 8.29 - 8.12 (m, 1 H), 8.01 (br s, 1 H), 7.67 (br d, J = 8.6 Hz, 2H), 7.56 (s, 5H), 7.30 (br s, 1 H), 7.19 - 6.97 (m, 4H), 6.64 (s, 1 H), 4.92 (br s, 1 H), 3.86 (br d, J = 4.5 Hz, 2H), 3.52 (br s, 2H), 3.29 - 3.14 (m, 6H), 3.08 (s, 3H), 2.61 (br d, J = 4.1 Hz, 3H), 2.36 - 2.22 (m, 6H), 2.05 - 1 .83 (m, 6H)

[0483] Example 18. (R)-N-methyl-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7- (2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-3-(6-(trifluoromethyl)pyridin-3- yl)propenamide

[0484]

[0485] Step A: (R)-N-methyl-2-((5-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7- (2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-3-(6-(trifluoromethyl)pyridin-3- yl)propanamide

[0486] To a solution of (1 -chloro-7-(2,3,6-trimethylphenyl)isoquinolin-5-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone (12.5 g, 22.81 mmol) and (R)-2- amino-N-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propanamide (7.33 g, 29.65 mmol) in 1 ,4-dioxane (128 mL), was added Cs2CO3(22.29 g, 68.42 mmol) and SPhos Pd G3 (1 .78 g, 2.28 mmol), and the resulting solution stirred at N2 at 100 °C for 16 h. The reaction mixture was cooled to 25 °C, filtered, diluted with water (100 mL) and extracted with EtOAc (100 mL x 6). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to yield a residue. The resulting residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0-95% ethyl acetate / Petroleum ether gradient @120 mL / min). The resulting residue was dissolved in ethyl acetate (100 ml) and the SPhos Pd G3 removed with supported metal remover SMA-905, which was repeated in triplicate. The resulting residue was lyophilized with deionized water (50 ml) to remove ethyl acetate in duplicate to yield (R)-N-methyl-2-((5-(4-(4- (methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 - yl)amino)-3-(6-(trifluoromethyl)pyridin-3-yl)propanamide as a light yellow solid. MS (ESI): mass calculated for C40H41F3N6O4S, 758.3; m / z measured - 759.4 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 8.73 (br s, 1 H), 8.35 - 8.21 (m, 1 H), 8.14 - 7.96 (m, 2H), 7.84 (d, J = 6.0 Hz, 1 H), 7.75 (br s, 1 H), 7.68 (br d, J = 8.8 Hz, 3H), 7.44 - 7.36 (m, 1 H), 7.17 - 7.01 (m, 4H), 6.82 (d, J= 6.0 Hz, 1 H), 4.97 (br s, 1 H), 4.00 - 3.71 (m, 2H), 3.60 - 3.44 (m, 2H), 3.29 - 3.14 (m, 5H), 3.08 (s, 3H), 2.61 (d, J = 4.3 Hz, 3H), 2.28 (d, J= 5.1 Hz, 3H), 2.05 - 1.87 (m, 6H) Example 19. ((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)isoquinolin-5-yl)methanone and ((S*)-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)isoquinolin-5-yl)methanone

[0487] Step A: Methyl 1 -chloro-7-(2,3,6-trimethylphenyl)isoquinoline-5-carboxylate

[0488] A mixture of methyl 7-bromo-1 -chloroisoquinoline-5-carboxylate (10.0 g, 33.3 mmol), (2,3,6-trimethylphenyl)boronic acid (7.09 g, 43.3 mmol), Cs2CO3(32.5 g, 99.8 mmol), Pd(dppf)Cl2(4.87 g, 6.65 mmol) in 1 ,4-dioxane (150 mL) and H2O (16.6 mL) was degassed at 25°C and purged with N2 for 3 times, and the mixture was then stirred at 85°C for 16 hrs under N2 atmosphere to yield a yellow solution. After cooling to room temperature, the reaction mixture was filtered to remove the solid material. The filtrate was poured into water (1 .20 L) at 25°C and extracted with ethyl acetate (800 mL x 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, andconcentrated under reduced pressure to yield a residue. The resulting residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0~ 5% Ethyl acetate / Petroleum ether gradient @ 120 mL / min) to yield methyl 1 -chloro-7-(2,3,6-trimethylphenyl)isoquinoline-5-carboxylate as a white solid. MS (ESI): mass calculated for C20H18CINO2, 339.1 ; m / z measured = 339.9 [M+H]+.1H NMR: (400 MHz CDCI3) δ 8.83 (d, J = 6.00 Hz, 1 H) 8.40 - 8.45 (m, 2 H) 8.33 (d, J= 1.50 Hz, 1 H) 7.15 - 7.21 (m, 1 H) 7.07 - 7.14 (m, 1 H) 4.01 (s, 3 H) 2.34 (s, 3 H) 2.01 (s, 3 H) 1.96 (s, 3 H)

[0489] Step B: (R)-Methyl 1 -((3-hydroxy-3-methyl-1 -(4-(trifluoromethyl)phenyl)butan-2- yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5-carboxylate

[0490] A mixture of methyl 1 -chloro-7-(2,3,6-trimethylphenyl)isoquinoline-5-carboxylate (6.80 g, 20.0 mmol), (R)-3-amino-2-methyl-4-(4-(trifluoromethyl)phenyl)butan-2-ol (5.94 g, 24.0 mmol), Cs2CO3(16.3 g, 50.0 mmol), racemic BINAP Pd G4 (1 .61 g, 1 .60 mmol) in 2-MeTHF (136 mL) was degassed and purged with N2 for 3 times at 25 °C, then stirred at 90 °C for 24 hrs under N2 atmosphere to yield a yellow solution. After cooling to 25 °C, the solids were removed by filtration. The reaction mixture was concentrated under reduced pressure to yield a residue. The resulting residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0-15% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to yield (R)-methyl 1 - ((3-hydroxy-3-methyl-1 -(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-7-(2,3,6- trimethylphenyl)isoquinoline-5-carboxylate as a yellow-orange solid. MS (ESI): mass calculated for C32H33F3N2O3, 550.2; m / z measured = 551.3 [M+H]+.1H NMR: (400 MHz DMSO-d6) δ 8.48 (s, 1 H) 7.88 - 7.92 (m, 1 H) 7.80 (d, J = 6.13 Hz, 1 H) 7.58 (dd, J = 6.13, 1.38 Hz, 1 H) 7.43 - 7.48 (m, 2 H) 7.35 - 7.42 (m, 2 H) 7.13 - 7.18 (m, 2 H) 4.90 (br s, 1 H) 4.68 (br s, 1 H) 3.86 (s, 3 H) 3.20 (br d, J = 12.88 Hz, 1 H) 2.98 (br t, J = 12.63 Hz, 1 H) 2.28 (d, J = 10.88 Hz, 3 H) 1 .94 (d, J = 3.50 Hz, 3 H) 1 .90 (s, 3 H) 1 .22 (s, 3 H) 1.18 (s, 3 H).

[0491] Step C: (R)-1 -((3-Hydroxy-3-methyl-1 -(4-(trifluoromethyl)phenyl)butan-2- yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5-carboxylic acid

[0492] In a 500 mL round-bottom flask, (R)-methyl 1 -((3-hydroxy-3-methyl-1-(4- (trifluoromethyl)phenyl)butan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5- carboxylate (9.00 g, 16.3 mmol) was dissolved in 2-MeTHF (190 mL), and MeOH (190 mL) before dropwise addition of NaOH (1 M, 159 mL) at 25 °C. The flask was degassed and purged with N2, then stirred at 25 °C for 10 h to yield a yellow solution. The reaction mixture was concentrated under reduced pressure to remove the solvent. The resulting residue was slowly acidified with 1 M aq. HCI to pH ~ 4 while stirring vigorously, at which point a significant amount of precipitate was observed to form, and the reaction was opaque light orange and thick. The mixture was extracted with ethyl acetate (600 mL x 2). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, and concentrated under reduced pressure to yield a yellow-orange solid. The yellow-orange solid was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~ 15% Dichloromethane / Methanol gradient @ 150 mL / min) to yield (R)-1 -((3-hydroxy-3-methyl-1 -(4- (trifluoromethyl)phenyl)butan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5- carboxylic acid as a yellow-orange solid. MS (ESI): mass calculated for C31H31F3N2O3, 536.2; m / z measured = 537.2 [M+H]+.1H NMR: (400 MHz DMSO-d6) δ 8.57 (br s, 1 H) 7.96 (br s, 1 H) 7.75 (br s, 2 H) 7.45 - 7.50 (m, 2 H) 7.39 - 7.44 (m, 2 H) 7.07 - 7.17 (m, 2 H) 4.66 (br s, 1 H) 4.12 (br d, J = 2.00 Hz, 1 H) 3.25 - 3.49 (m, 1 H) 2.98 - 3.10 (m, 1 H) 2.28 (d, J = 11 .38 Hz, 3 H) 1 .94 (d, J = 8.25 Hz, 3 H) 1 .90 (d, J = 2.63 Hz, 3 H) 1 .24 (s, 6 H).

[0493] Step D: (R)-(3 ,3-Dif I uoro-4-(6-(methylsulfonyl) pyridin-3-yl) pi peridin- 1 -yl) (1 -((3- hydroxy-3-methyl-1 -(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-7-(2,3,6- trimethylphenyl)isoquinolin-5-yl)methanone

[0494] A mixture of (R)-1 -((3-hydroxy-3-methyl-1 -(4-(trifluoromethyl)phenyl)butan-2- yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5-carboxylic acid (12.3 g, 22.8 mmol), 5- (3,3-difluoropiperidin-4-yl)-2-(methylsulfonyl)pyridine (7.32 g, 26.5 mmol), HATU (13.0 g, 34.2 mmol) and DIEA (8.85 g, 68.5 mmol, 1 1 .9 mL) in DMF (245 mL) was degassed and purged with N2 for 3 times, then stirred at 20 °C for 12 h under N2 to yield a yellow solution. The resulting mixture was filtered, andthe filtrate concentrated to yield a residue which was washed with H2O (100mL). The resulting residue, (R)-(3,3-difluoro- 4-(6-(methylsu Ifonyl) pyridi n-3-yl) pi perid in-1 -yl) (1 -((3-hydroxy-3-methyl-1 -(4- (trifluoromethyl)phenyl)butan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinolin-5- yl)methanone as a light yellow solid, was used directly in Step E (SFC-separation) without further purification.. MS (ESI): mass calculated for C42H43F5N4O4S, 794.3: m / z measured = 795.2 [M+H]+.1H NMR: (400 MHz DMSO-d6) δ 8.68 - 8.80 (m, 1 H) 8.00 - 8.32 (m, 3 H) 7.71 - 7.87 (m, 1 H) 7.29 - 7.50 (m, 5 H) 7.00 - 7.19 (m, 3 H) 6.53 - 6.75 (m, 1 H) 4.51 - 5.11 (m, 3 H) 3.39 - 3.89 (m, 3 H) 3.27 - 3.31 (m, 3 H) 3.17 - 3.25 (m, 1 H) 2.94 - 3.05 (m, 1 H) 2.20 - 2.34 (m, 4 H) 1.89 - 2.03 (m, 6 H) 1.21 (br d, J = 10.76 Hz, 6 H).

[0495] Step E: ((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)isoquinolin-5-yl)methanone and ((S*)-3,3-difluoro-4-(6- (methylsu If ony I) pyridin-3-yl) pi peridin- 1 -yl) (1 -(((R)-3-hydroxy-3-methyl-1 -(4- (trifluoromethyl)phenyl)butan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinolin-5- yl)methanone (R)-(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)isoquinolin-5-yl)methanone was separated by SFC (column: DAICEL CHIRALCEL OD (250mm*50mm, 10um); mobile phase: [CO2- / PrOH (0.1 %NH3H2O)]; B%: 40%, isocratic elution mode Peak 1 : 2.416 min; Peak 2: 2.648 min). After SFC separation, each diastereomer was diluted with MTBE (20.0 mL) and n-heptane (140 mL), then stirred for 2 h at 25 °C, filtered, and washed with n-heptane (50.0 mL). The resulting filter cake was diluted with H2O (100 mL) and the resulting mixture was stirred for 4 hrs at 50 °C, then filtered, washed with H2O (20.0 mL) and concentrated under reduced pressure.

[0496] ((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)isoquinolin-5-yl)methanone, isolated as the first eluted product, a yellow solid: MS (ESI): mass calculated for C42H43F5N4O4S, 794.3; m / z measured - 795.2

[0497] 1H NMR: (400 MHz DMSO-d6) δ 8.70 - 8.80 (m, 1 H) 8.29 (br d, J = 18.26 Hz, 1 H) 8.00 - 8.22 (m, 2 H) 7.72 - 7.86 (m, 1 H) 7.33 - 7.49 (m, 5 H) 7.00 - 7.22 (m, 3 H) 6.58 - 6.77 (m, 1 H) 4.55 - 5.09 (m, 3 H) 3.40 - 3.89 (m, 3 H) 3.29 (br d, J = 4.50 Hz, 3 H) 3.21 (br d, J = 13.76 Hz, 1 H) 2.94 - 3.05 (m, 1 H) 2.18 - 2.34 (m, 4 H) 1.71 - 2.11 (m, 8 H) 1.23 (br s, 6 H)

[0498] ((S*)-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)isoquinolin-5-yl)methanone, isolated as the second eluted product, a yellow solid: MS (ESI): mass calculated for C42H 3F5N4O4S, 794.3; m / z measured - 795.21H NMR: (400 MHz DMSO-d6) δ 8.68 - 8.82 (m, 1 H) 7.98 - 8.40 (m, 3 H) 7.68 - 7.88 (m, 1 H) 7.30 - 7.49 (m, 4 H) 7.02 - 7.26 (m, 3 H) 6.50 - 6.81 (m, 1 H) 4.48 - 5.39 (m, 3 H) 3.39 - 3.89 (m, 3 H) 3.27 - 3.31 (m, 3 H) 3.21 (br d, J = 13.01 Hz, 1 H) 2.93 - 3.06 (m, 1 H) 2.16 - 2.35 (m, 4 H) 1.73 - 2.11 (m, 7 H) 1.22 (br d, J = 5.88 Hz, 6 H).

[0499] Example 20. (R)-2-((3-cyano-5-((R)-3,3-difluoro-4-(6-(methylsulfonyl)pyridin-3- yl)piperidine-1 -carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propenamide and (R)-2-((3-cyano-5-((S)-3,3-difluoro-4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1 - carbonyl)-7-(2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propenamide

[0500] Step A: methyl 1 ,3-dichloro-7-(2,3,6-trimethylphenyl)isoquinoline-5-carboxylate

[0501] A mixture of methyl 7-bromo-1 ,3-dichloroisoquinoline-5-carboxylate (5.00 g, 14.9 mmol), (2,3,6-trimethylphenyl)boronic acid (2.69 g, 16.4 mmol), Pd(dppf)Cl2(2.18 g, 2.99 mmol), and Cs2CO3(14.6 g, 44.8 mmol) in 1 ,4-dioxane (67.5 mL) and H2O (7.5 mL) was degassed and purged with N2. The yellow mixture was then stirred at 85 °C for 12 h under N2. Six identical parallel reactions were set up in this manner. After this time, the six batches were combined and the reaction was quenched with H2O (500 mL) at 25 °C, and the resulting mixture extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, and concentrated under reduced pressure to yield a residue. The resulting residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate / Petroleum ether gradient @ 150 mL / min) to yield methyl 1 ,3- dichloro-7-(2,3,6-trimethylphenyl)isoquinoline-5-carboxylate as a white solid. MS (ESI): mass calculated for C20H17Cl2NO2, 373.1 ; m / z measured - 374.2 [M+H]+.1H NMR: (400 MHz CDCI3) δ 8.97 (d, J = 0.75 Hz, 1 H) 8.31 - 8.39 (m, 2 H) 7.15 - 7.21 (m, 1 H) 7.07 - 7.13 (m, 1 H) 4.01 (s, 3 H) 2.34 (s, 3 H) 1 .98 - 2.01 (m, 3 H) 1 .94 - 1 .97 (m, 3 H)

[0502] Step B: (R)-Methyl 3-chloro-1 -((1 -(methylamino)-1 -oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5- carboxylate

[0503] To a solution of methyl 1 ,3-dichloro-7-(2,3,6-trimethylphenyl)isoquinoline-5- carboxylate (6.00 g, 16.0 mmol) and (R)-2-amino-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide (4.34 g, 17.6 mmol) in 2-MeTHF (120 mL) was added Cs2CO3(13.1 g, 40.0 mmol) and racemic BINAP Pd G4 (1.29 g, 1.28 mmol). The yellow mixture was stirred at 90 °C for 24 h. Four identical reactions were setup in parallel and, once complete, were combined, then cooled to room temperature. The combined reaction mixtures were filtered to remove the solid materials. The reaction mixture was concentrated under reduced pressure to yield a residue. The resulting residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0-15% Ethyl acetate I Petroleum ether gradient @ 120 mL / min) to yield (R)-methyl 3-chloro-1 -((1 -(methylamino)-1 -oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-7-(2,3,6-trimethylphenyl)isoquinoline-5- carboxylate as a yellow solid. MS (ESI): mass calculated for C31H29CIF3N3O3, 583.2; m / z measured = 584.1 [M+H]+.1H NMR: (400 MHz CDCI3) δ 8.18 (d, J = 12.8 Hz, 2 H) 7.69 (br s, 1 H) 7.55 (d, J = 8.00 Hz, 2 H) 7.42 (d, J = 7.88 Hz, 2 H) 7.00 - 7.20 (m, 2 H) 6.09 (br s, 1 H) 5.89 (br s, 1 H) 4.90 - 5.06 (m, 1 H) 3.97 (s, 3 H) 3.37 (dt, J = 13.60, 4.28 Hz, 1 H) 3.16 - 3.28 (m, 1 H) 2.77 (d, J = 4.88 Hz, 3 H) 2.32 (d, J = 4.00 Hz, 3 H) 1 .93 - 1 .99 (m, 3 H) 1 .91 (d, J = 4.24 Hz, 3 H)

[0504] Step C: (R)-methyl 3-cyano-1 -((1 -(methylamino)-1 -oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-7-(2,3,6-trimethylphenyl)i...

Claims

What is claimed:

1. A compound of formula (I)whereinR1is selected from the group consisting of hydrogen, halogen, hydroxy, C1-4alkyl, fluorinated C1-4alkyl, hydroxy substituted Ci 4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, - (C1-2alkyl)-O-(C1-4alkyl), -O-(C1-2alkyl)-O-(C1-4alkyl), -SO2-(C1-4alkyl), -CN, -NRARB, -(C1-2alkyl)-NRARB, -C(O)-NRARB, C3-5cycloalkyl, -(C1-2alkyl)-(C3-5cycloalkyl), -SO2-(C3-5cycloalkyl), 4 to 6 membered heterocycloalkyl, -(C1-2alkyl)-(4 to 6 membered heterocycloalkyl), -C(O)-(5 to 6 membered heterocycloalkyl), 5 to 6 membered heteroaryl, and -(C1-2alkyl)-(5 to 6 membered heteroaryl); wherein the C3-5cycl alkyl, 4 to 6 membered heterocycloalkyl or 5 to 6 membered heterocycloalkyl, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-2alkyl, and fluorinated C1-2alkyl; and wherein RAand RBare each independently selected from the group consisting of hydrogen, C1-4alkyl and fluorinated C1-2alkyl;R2is selected from the group consisting of fluorinated C1-4alkyl, hydroxy substituted C1-4alkyl, -NRCRD, -(C1-2alkyl)-NRcRD, -CH(NRcRE)-(fluorinated C1-3alkyl), - C(O)-NRc-CN, -C(O)-NRcRD, -(C1-4alkyl)-C(O)-NRcRD, -C(O)-NRc-(C1-2alkyl)-NRDRE, - R11, -(C1-2alkyl)-R11, -(hydroxy substituted C1-2alkyl)-R11, -C(O)-NRC-R11, -(C1-2alkyl)- C(O)-NRC-R11, -C(O)-NRc-(C1-2alkyl)-R11, -C(O)-R11, -(C1-2alkyl)-NRc-R11, and -(C1-2alkyl)-NRc-(C1-2alkyl)-R11; wherein R11is C3-5cycloalkyl, 4 to 8 membered heterocycloalkyl and 5 to 6 membered heteroaryl; and wherein the C3-5cycloalkyl, 4 to 8 membered heterocycloalkylor 5 to 6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-4alkyl, fluorinated C1-2alkyl, and cyano; wherein Rcand REare each independently selected from the group consisting of hydrogen and C1-4alkyl ; and wherein RDis selected from the group consisting of hydrogen, C1-4alkyl, fluorinated C1-4alkyl, hydroxy substituted C1-4alkyl, cyano substituted C1-2alkyl, (hydroxy and fluoro substituted C1-4alkyl), -(C1-4alkyl)-O-(C1-4alkyl), -SO2-(C1-4alkyl), and -(C1-2alkyl)-SO2-N(C1-4alkyl)2; a is an integer from 0 to 1 ; and L1is -CH2-;R3is selected from the group consisting of phenyl, 4 to 6 membered heterocycloalkyl, 5 to 6 membered heteroaryl, and 4-(trifluoromethyl)- bicyclo[2.2.2]octan-1 -yl; wherein the phenyl, 4 to 6 membered heterocycloalkyl, 5 to 6 membered heteroaryl or 9 to 10 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-4alkyl, fluorinated C1-2alkyl, hydroxy substituted Ci 4alkyl, (C1-2alkyl)-CN, -(C2-4alkenyl)-CN, C1-4alkoxy, fluorinated C1-2alkoxy, -S-(fluorinated C1-2alkyl), -SF5, -NO2, -NRFRG, -(C1-2alkyl)-NRFRG, -NRF-C(O)-(C1-4alkyl), -NRF-C(O)-(hydroxy substituted C1-4alkyl), -NRF- C(O)-(C2-4alkenyl), -NRF-C(O)-(fluorinated C2-4alkenyl), -NRH-C(O)-(C2-4alkenyl)-NRFRG, -NRF-C(O)-(C2-4alkynyl), -NRF-C(O)-(C2-4alkenyl)-(4 to 6 membered heterocycloalkyl) and -NRF-C(O)-(C3-6cycloalkyl); and wherein RFand RGare each independently selected from the group consisting of hydrogen and C1-4alkyl;R4is selected fromwherein b is an integer from 0 to 3; each R5is independently selected from the group consisting of halogen, C1-4alkyl, fluorinated C1-4alkyl, hydroxy substituted C1-4alkyl, C1-4alkoxy, -NRJRK, -(C1-2alkyl)-NRJRM, -C(O)-NRJRM, -C(O)-NRL-(C1-2alkyl)-NRJRK, -(C1-2alkyl)-C(O)-NRJRK, and -(C1-2alkyl)-NRJ-C(O)-(C1-4alkyl); wherein RJ, RK, and RLare each independentlyselected from the group consisting of hydrogen and C1-4alkyl; and wherein RMis selected from the group consisting of hydrogen, C1-4alkyl, fluorinated C1-2alkyl, and -(C1-wherein c is an integer from 0 to 2; each R6is independently selected from the group consisting of halogen, C1-4alkyl, fluorinated C1-4alkyl, hydroxy substituted C1-4alkyl, C1-4alkoxy, and -NRNRP; wherein RNand Rpare each independently selected from the group consisting of hydrogen, methyl and ethyl; d is an integer from 0 to 1 ;L2is selected from the group consisting of -NH-C(O)-, -C(O)-NH-, -C(O)-NH-(C1-4alkyl)-, and -C(O)-NH-(fluorinated C1-4alkyl)-; provided that a terminal -C(O)- or -NH- portion of L1is bound directly to the phenyl;R7is selected from the group consisting of 4 to 6 membered heterocycloalkyl and 5 to 6 membered heteroaryl; wherein the 4 to 6 membered heterocycloalkyl or 5 to 6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-4alkyl, fluorinated C1-2alkyl, C1-4alkoxy, fluorinated C1-2alkoxy, and -CN;R8is selected from the group consisting ofis a nitrogen bound, 4 to 6 membered heterocycloalkyl; wherein the nitrogen bound, 4 to 6 membered heterocycloalkyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-4alkyl, fluorinated C1-2alkyl, hydroxy substituted C1-4alkyl, -(C1-2alkyl)-CN, -(C1-2alkyl)-O-(C1-4alkyl), -(C1-2alkyl)-O-(fluorinated C1-4alkyl), - O-(C1-2alkyl)-O-(C1-4alkyl), =NRQ, -NRQRS, -(C1-2alkyl)-NRQRs, -C(O)-NRQRS, -(C1-2alkyl)-C(O)-NRQRs, -NRQ-C(O)-C(O)-(C1-4alkyl), -NRT-C(O)-C(O)-NRQRS; -NRU-SO2- (C1-4alkyl), -(C1-2alkyl)-NRQ-SO2-(C1-4alkyl), -NRQ-SO2-(C3-5cycloalkyl), -SO2-NRQRS, - (C1-2alkyl)-SO2-(C1-4alkyl), and -(C1-2alkyl)-SO(NH2)-(C1-4alkyl); wherein RQ, Rsand RTare each independently selected from the group consisting of hydrogen and C1-4alkyl; and wherein Ruis selected from the group consisting of hydrogen, C1-4alkyl and cyclopropyl;(b)whereinis a nitrogen bound, 4 to6 membered heterocycloalkyl; wherein the nitrogen bound 4 to 6 membered heterocycloalkyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-2alkyl, fluorinated C1-2alkyl, hydroxy substituted C1-2alkyl, C1-4alkoxy, fluorinated C1-2alkoxy, cyano, and -C(O)-NRVRW; wherein Rvand Rware each independently selected from the group consisting of hydrogen and C1-4alkyl;- — (■ C )— - wherein « is selected from the group consisting of C3-6cycloalkyl, phenyl, 4 to 8 membered heterocycloalkyl, 5 to 6 membered heteroaryl, and 5 to 8 membered bicyclic, bridged or spirocyclic heterocycloalkyl; wherein the C3-6cycloalkyl, phenyl, 4 to 8 membered heterocycloalkyl, 5 to 6 membered heteroaryl, or 5 to 8 membered bicyclic, bridged or spirocyclic heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-4alkyl, fluorinated C1-2alkyl, C1-4alkoxy, fluorinated C1-2alkoxy, -SO2-(C1-2alkyl), -SO2-(fluorinated C1-2alkyl), - SO2-NRXRY, -SO(NH2)-CH3, cyano, =NRX, -NRXRY, -NRx-SO2-(C1-2alkyl), -C(O)-(C1-4alkyl), -C(O)OH, -C(O)O-(C1-4alkyl), and -C(O)-NRXRY; wherein Rxand RYare each independently selected from the group consisting of hydrogen, C1-4alkyl, fluorinated C1-2alkyl and hydroxy substituted C1-4alkyl ; f is an integer from 0 to 1 ;R9is selected from the group consisting of C3-5cycloalkyl, 4 to 6 membered heterocycloalkyl, -C(O)-(4 to 6 membered heterocycloalkyl), and -SO2-(4 to 6 membered heterocycloalkyl); wherein the C3-5cycloalkyl or 4 to 6 membered heterocycloalkyl, whether alone or as part of the R9substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-4alkyl, fluorinated C1-2alkyl, -SO2-(C1-2alkyl), and -SO2-(fluorinated C1-2alkyl); provided that when f is 1 , thenis selected from the group consisting of phenyl, 4 to 8 membered heterocycloalkyl, and 5 to 6 membered heteroaryl;(c)whereinis a nitrogen bound, 4 to 6 membered heterocycloalkyl; wherein the 4 to 6 membered heterocycloalkyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-2alkyl, fluorinated C1-2alkyl, hydroxy substituted C1-2alkyl, C1-4alkoxy, fluorinated C1-2alkoxy, cyano, and -C(O)-NRZRAA; wherein Rzand RAAare each independently selected from the group consisting of hydrogen and C1-4alkyl ;L3is selected from the group consisting of -(CH2wherein the L3group is bound at the 3- or 4- positionR10is selected from the group consisting of 4 to 6 membered heterocycloalkyl, and 5 to 6 membered heteroaryl; wherein the 5 to 6 membered heterocycloalkyl or 5 to 6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-4alkyl, fluorinated C1-2alkyl, C1-4alkoxy, fluorinated C1-2alkoxy, -SO2-(C1-2alkyl), -SO2-(fluorinated C1-2alkyl), -SO2-(hydroxy substituted C1-4alkyl), -SO2-NRBBRCC, -SO(NH2)-CH3, cyano, =NRBB, -NRBBRCC, -NRBB- SO2-(C1-2alkyl), -C(O)-(C1-4alkyl), C3-5cycloalkyl,-C(O)OH, -C(O)O-(C1-4alkyl), and -C(O)-NRBBRCG; wherein RBBis selected from the group consisting of hydrogen and C1 -4alkyl; and wherein Rccis selected from the group consisting of hydrogen, C1-4alkyl, fluorinated C1-2alkyl and hydroxy substituted C1-4alkyl; and (d); whereinis nitrogen bound 5 to 14 membered bicyclic, bridged or spirocyclic heterocyclyl; wherein the 5 to 14 membered bicyclic, bridged or spirocyclic heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-4alkyl, fluorinated C1-3alkyl, C1-4alkoxy, fluorinated C1-2alkoxy, -SO2-(C1-2alkyl), -SO2-(fluorinated C1-2alkyl), -SO2-(hydroxy substituted C1-4alkyl), -SO2-NRDDREE, -SO(NH2)-CH3, cyano, =NRDD, -NRDDREE, -NRDD- SO2-(C1-2alkyl), -C(O)-(C1-4alkyl), -C(O)OH, -C(O)O-(C1-4alkyl), and -C(O)-NRDDREE, C3-5cycloalkyl, phenyl and 5 to 6 membered heteroaryl; wherein the phenyl or 5 to 6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-4alkyl, fluorinated C1-2alkyl, C1-4alkoxy, fluorinated C1-2alkoxy, -SO2-(C1-2alkyl), and -SO2-(fluorinated C1-2alkyl); wherein RDDis selected from the group consisting of hydrogen and C1-4alkyl; and wherein REEis selected from the group consisting of hydrogen, C1-4alkyl, fluorinated C1-2alkyl and hydroxy substituted C1-4alkyl; or a stereoisomer or pharmaceutically acceptable salt thereof.

2. A compound as in Claim 1 , whereinR1is selected from the group consisting of hydrogen, halogen, hydroxy, C1-4alkyl, fluorinated C1-2alkyl, hydroxy substituted C1-2alkyl, C1-2alkoxy, -(C1-2alkyl)-O-(C1-2alkyl), - O-(C1-2alkyl)-O-(C1-2alkyl), -SO2-(C1-2alkyl), -CN, -NRARB, -(C1-2alkyl)-NRARB, -C(O)- NRARB, C3-5cycloalkyl, -(C1-2alkyl)-(C3-5cycloalkyl), -SO2-(C3-5cycloalkyl), 4 to 6 membered heterocycloalkyl, -(C1-2alkyl)-(5 to 6 membered heterocycloalkyl), -C(O)-(5 to 6 membered heterocycloalkyl), and 5 to 6 membered heteroaryl; wherein the C3-5cycl alkyl, 4 to 6 membered heterocycloalkyl or 5 to 6 memberedheterocycloalkyl, whether alone or as part of a substituent group, is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C1-2alkyl, and fluorinated C1-2alkyl; wherein RAand RBare each independently selected from the group consisting of hydrogen, C1-2alkyl and fluorinated C1-2alkyl;R2is selected from the group consisting of fluorinated C1-4alkyl, hydroxy substituted C1-4alkyl, -NRCRD, -(C1-2alkyl)-NRcRD, -CH(NRcRE)-(fluorinated C1-2alkyl), - C(O)-NRc-CN, -C(O)-NRCRD, -(C1-4alkyl)-C(O)-NRcRD, -C(O)-NRc-(C1-2alkyl)-NRDRE, C3-5cycloalkyl, -C(O)-NRc-(C3-5cycloalkyl), -(C1-2alkyl)-C(O)-NRc-(C3-5cycloalkyl), -C(O)- NRc-(C1-2alkyl)-(C3-5cycloalkyl), -(C1-2alkyl)-NRc-(C3-5cycloalkyl), -(C1-2alkyl)-NRc-(C1-2alkyl)-(C3-5cycloalkyl), 4 to 6 membered heterocycloalkyl, -(C1-2alkyl)-(4 to 6 membered heterocycloalkyl), -(hydroxy substituted C1-2alkyl)-(4 to 6 membered heterocycloalkyl), - C(O)-NRc-(4 to 6 membered heterocycloalkyl), -C(O)-(4 to 6 membered heterocycloalkyl), -(C1-2alkyl)-NRc-(4 to 6 membered heterocycloalkyl), 5 to 6 membered heteroaryl, and -(C1-2alkyl)-(5 to 6 membered heteroaryl); wherein the C3-5cycloalkyl, 4 to 6 membered heterocycloalkyl and 5 to 6 membered heteroaryl, whether alone or as part of a substituent group is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-4alkyl, fluorinated C1-2alkyl, and cyano; wherein Rcand REare each independently selected from the group consisting of hydrogen and C1-4alkyl; wherein RDis selected from the group consisting of hydrogen, C1-4alkyl, fluorinated C1-4alkyl, hydroxy substituted C1-4alkyl, cyano substituted C1-2alkyl, (hydroxy and fluoro substituted C1-4alkyl), -(C1-4alkyl)-O-(C1-4alkyl), -SO2-(C1-2alkyl), and -(C1-2alkyl)-SO2-N(C1-2alkyl)2; a is an integer from 0 to 1 ; and L1is -CH2-;R3is selected from the group consisting of phenyl, 4 to 6 membered heterocycloalkyl, 5 to 6 membered heteroaryl, and 4-(trifluoromethyl)- bicyclo[2.2.2]octan-1 -yl; wherein the phenyl, 4 to 6 membered heterocycloalkyl, 5 to 6 membered heteroaryl or 9 to 10 membered heteroaryl is optionally substituted with one to threesubstituents independently selected from the group consisting of halogen, C1-2alkyl, fluorinated C1-2alkyl, hydroxy substituted Ci 4alkyl, (C1-2alkyl)-CN, -(C2-4alkenyl)-CN, C1-4alkoxy, fluorinated C1-2alkoxy, -S-(fluorinated Ciaalkyl), -SF5, -NO2, -NRFRG, -(C1-2alkyl)-NRFRG, -NRF-C(O)-(C1-4alkyl), -NRF-C(O)-(hydroxy substituted C alkyl), -NRF- C(O)-(C2-4alkenyl), -NRF-C(O)-(fluorinated C2-4alkenyl), -NRH-C(O)-(C2-4alkenyl)-NRFRG, -NRF-C(O)-(C2-4alkynyl), -NRF-C(O)-(C2-4alkenyl)-(4 to 6 membered heterocycloalkyl) and -NRF-C(O)-(C3-6cycloalkyl); wherein RFand RGare each independently selected from the group consisting of hydrogen and C1-2alkyl;R4is selected fromwherein b is an integer from 0 to 3; each R5is independently selected from the group consisting of halogen, C1-2alkyl, fluorinated Ciaalkyl, hydroxy substituted C-i-salkyl, C1-2alkoxy, -NRJRK, -(C1-2alkyl)-NRJRM, -C(O)-NRJRM, -C(O)-NRL-(C1-2alkyl)-NRJRK, -(C1-2alkyl)-C(O)-NRJRK, and -(C1-2alkyl)-NRJ-C(O)-(C1-4alkyl); wherein RJ, RK, and RLare each independently selected from the group consisting of hydrogen and Ci salkyl; and wherein RMis selected from the group consisting of hydrogen, C1-3alkyl, fluorinated Ciaalkyl, and -(C1-2alkyl)-O-(C1-2alkyl);wherein c is an integer from 0 to 2; each R6is C1-2alkyl; d is an integer from 0 to 1 ;L2is selected from the group consisting of -NH-C(O)-, -C(O)-NH-, -C(O)-NH-(C1-4alkyl)-, and -C(O)-NH-(fluorinated Ciaalkyl)-; provided that a terminal -C(O)- or -NH- portion of L1is bound directly to the phenyl;R7is selected from the group consisting of 4 to 6 membered heterocycloalkyl and 5 to 6 membered heteroaryl; wherein the 4 to 6 membered heterocycloalkyl or 5 to 6 membered heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of C1-2alkyl, fluorinated C1-2alkyl, and C1-2alkoxy;R8is selected from the group consisting ofis a nitrogen bound, 5 to 6 membered heterocycloalkyl; wherein the nitrogen bound, 4 to 6 membered heterocycloalkyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-2alkyl, fluorinated C1-2alkyl, hydroxy substituted C1-3alkyl, -(C1-2alkyl)-CN, -(C1-2alkyl)-O-(C1-2alkyl), -(C1-2alkyl)-O-(fluorinated C1-2alkyl), - NRQRS, -(C1-2alkyl)-NRQRs, -C(O)-NRQRS, -(C1-2alkyl)-C(O)-NRQRs, -NRQ-C(O)-C(O)- (C1-2alkyl), -NRT-C(O)-C(O)-NRQRS; -NRu-SO2-(C1-3alkyl), -(C1-2alkyl)-NRQ-SO2-(C1-2alkyl), -NRQ-SO2-(C3-5cycloalkyl), -SO2-NRQRS, -(C1-2alkyl)-SO2-(C1-4alkyl), and -(C1-2alkyl)-SO(NH2)-(C1-2alkyl); wherein RQ, Rsand RTare each independently selected from the group consisting of hydrogen and C1-4alkyl; and wherein Ruis selected from the group consisting of hydrogen, C1-2alkyl and cyclopropyl;nitrogen bound, 4 to6 membered heterocycloalkyl; wherein the nitrogen bound 4 to 6 membered heterocycloalkyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-2alkyl, hydroxy substituted C1-2alkyl, cyano, and -C(O)-NRVRW; wherein Rvand Rware each independently selected from the group consisting of hydrogen and C1-2alkyl;whereinis selected from the group consisting of Ca ecycloalkyl, phenyl, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, and 5 to 7 membered bicyclic, bridged or spirocyclic heterocycloalkyl; wherein the Ca ecycloalkyl, phenyl, 4 to 7 membered heterocycloalkyl, 5 to 6 membered heteroaryl, or 5 to 7 membered bicyclic, bridged or spirocyclic heterocycloalkyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-3alkyl, fluorinated C1-2alkyl, C1-2alkoxy, fluorinated C1-2alkoxy, -SO2-(C1-2alkyl), -SO2-(fluorinated C1-2alkyl), - SO2-NRVRW, -SO(NH2)-CH3, cyano, =NRX, -NRXRY, -NRx-SO2-(C1-2alkyl), -C(O)-(C1-2alkyl), -C(O)OH, -C(O)O-(C1-2alkyl), and -C(O)-NRXRY; wherein Rxand RYare each independently selected from the group consisting of hydrogen, C1-2alkyl, fluorinated C1-2alkyl and hydroxy substituted C1-4alkyl; f is an integer from 0 to 1 ;R9is selected from the group consisting of C3-5cycloalkyl, 4 to 6 membered heterocycloalkyl, -C(O)-(4 to 6 membered heterocycloalkyl), and -SO2-(4 to 6 membered heterocycloalkyl); wherein the C3-5cycloalkyl or 4 to 6 membered heterocycloalkyl, whether alone or as part of the R9substituent is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-2alkyl, and fluorinated C1-2alkyl; provided that when f is 1 , thenis selected from the group consisting of phenyl, 4 to 7 membered heterocycloalkyl, and 5 to 6 membered heteroaryl;is a nitrogen bound, 5 to 6 membered heterocycloalkyl;wherein the 5 to 6 membered heterocycloalkyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, C1-2alkyl, fluorinated C1-2alkyl, and hydroxy substituted C1-2alkyl;L3is selected from the group consisting of -(CH2)-, -C(O)-(CH2)-, -NH-, and -O-; wherein the L3group is bound at the 3- or 4- position of;R10is selected from the group consisting of 4 to 6 membered heterocycloalkyl, and 5 to 6 membered heteroaryl; wherein the 4 to 6 membered heterocycloalkyl or 5 to 6 membered heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-2alkyl, fluorinated C1-2alkyl, -SO2-(C1-2alkyl), -SO2-(hydroxy substituted C1-4alkyl), -SO2-NRBBRCC, and -NRBB-SO2-(C1-2alkyl) and -C(O)-NRBBRcc; wherein RBBis selected from the group consisting of hydrogen and C1-2alkyl ; wherein Rccis selected from the group consisting of hydrogen, and C1-2alkyl; and (d); whereinis nitrogen bound 7 to 14 membered bicyclic, bridged or spirocyclic heterocyclyl; wherein the 5 to 12 membered bicyclic, bridged or spirocyclic heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-2alkyl, fluorinated C1-2alkyl, -SO2-(C1-2alkyl), -SO2-NRDDREE, =NRDD, -NRDDREE, -NRDD-SO2-(C1-2alkyl), -C(O)-(C1-2alkyl), - C(O)-NRDDREE, cyclopropyl, phenyl and 5 to 6 membered heteroaryl; wherein the phenyl or 5 to 6 membered heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-2alkyl, fluorinated C1-2alkyl, and -SO2-(C1-2alkyl); wherein RDDis selected from the group consisting of hydrogen and C1-2alkyl; wherein REEis selected from the group consisting of hydrogen, and C1-2alkyl; or a stereoisomer or pharmaceutically acceptable salt thereof.

3. A compound as in Claim 1 , whereinR1is selected from the group consisting of hydrogen, hydroxy, chloro, methyl, isopropyl, difluoromethyl, trifluoromethyl, hydroxy-methyl, methoxy, ethoxy, methoxy- methyl-, methoxy-ethoxy-, methyl-sulfonyl-, cyclopropyl-sulfonyl-, cyano, methyl-amino-, methyl-amino-methyl-, dimethyl-amino-methyl-, 2,2,2-trifluoroethyl-amino-methyl-, amino-carbonyl-, 1 -(trifluoromethyl)-cycloprop-1 -yl, morpholin-4-yl, piperazin-1 -yl, 3- fluoro-azetidin-1 -yl, 3,3-difluoro-azetidin-1 -yl, oxazol-2-yl, isoxazol-4-yl, morpholin-4-yl- methyl-, morpholin-4-yl-carbonyl-, 3,3-difluoro-pyrrolidin-1 -yl-methyl-, 3,3-difluoro- piperidin-1 -yl-methyl-, 4, 4-difluoro-piperidin-1 -yl-methyl-, and 4-methyl-piperazin-1 -yl- methyl;R2is selected from the group consisting of R-(2-fluoro-isopropyl), R-(hydroxy- methyl), 1 R*-(hydroxy-ethyl), 1 S*-(hydroxy-ethyl), R*-(1 R*-hydroxy-ethyl), R*-(1S*- hydroxy-ethyl), S*-(1 R*-hydroxy-ethyl), S*-(1S*-hydroxy-ethyl), 2-hydroxy-isopropyl, R*- (2-hydroxy-isopropyl), S*-(2-hydroxy-isopropyl), R-(2-hydroxy-isopropyl), R-(2-hydroxy- isobutyl), R-(1 ,3-dihydroxy-1 -methyl-n-propyl), R-(1 R*,3-dihydroxy-1 -methyl-n-propyl), R-(2-hydroxy-tert-butyl), R-(amino-methyl), R-(methyl-amino-methyl), R-(dimethyl- amino-methyl), R-(2,2-difluoro-ethyl)-amino-methyl), R-(2-hydroxy-isobutyl-amino- methyl), R-(2-hydroxy-3,3,3-trifluoro-n-propyl-amino-methyl), R-(2-cyano-ethyl-amino- methyl), R-(methyl-sulfonyl-amino-methyl), R-(dimethyl-amino sulfonyl-ethyl-amino- methyl), R-(1 R-amino-2,2,2-trifluoro-ethyl), R-(1 S-amino-2,2,2-trifluoro-ethyl), S-(1 S- amino-2,2,2-trifluoro-ethyl), amino-carbonyl, R*-(amino-carbonyl), S*-(amino-carbonyl), methyl-amino-carbonyl, R-(D3-methyl-amino-carbonyl), R*-(methyl-amino-carbonyl), S*- (methyl-amino-carbonyl), R-(methyl-amino-carbonyl), S-(methyl-amino-carbonyl), R- (dimethyl-amino-carbonyl), R-(isopropyl-amino-carbonyl), R-(t-butyl-amino-carbonyl), R- (2-isobutyl-amino-carbonyl), R-(cyano-amino-carbonyl), R-(2-hydroxy-isobutyl-amino- carbonyl), R-((2,2-difluoro-ethyl)-amino-carbonyl), R-((2,2,2-trifluoro-ethyl)-amino- carbonyl), R-(2,2,3,3,3-pentafluoro-n-propyl-amino-carbonyl), R-(2-hydroxy-3,3,3- trifluoro-n-propyl-amino-carbonyl), R-(2-methoxy-isobutyl-amino-carbonyl), S*-(methyl- amino-carbonyl-methyl), R*-(methyl-amino-carbonyl-methyl), R-(methyl-amino-carbonyl- methyl), S-(methyl-amino-carbonyl-methyl), S-(2-hydroxy-isobutyl-amino-carbonyl- methyl), S-(2,2-difluoro-ethyl-amino-carbonyl-methyl), S-(2,2,2-trifluoro-ethyl-amino- carbonyl-methyl), S*-(2-(methyl-amino-carbonyl)-isopropyl), R*-(2-(methyl-amino-carbonyl)-isopropyl), R-(dimethyl-amino-ethyl-amino-carbonyl), R*-(dimethyl-amino- ethyl-amino-carbonyl), S*-(dimethyl-amino-ethyl-amino-carbonyl), R*-(1 -hydroxy- cycloprop-1 -yl), S*-(1 -hydroxy-cycloprop-1 -yl), R*-(1 -hydroxy-cyclobut-1 -yl), S*-(1- hydroxy-cyclobut-1 -yl), R*-(3-hydroxy-oxetan-3-yl), S*-(3-hydroxy-oxetan-3-yl), R*-(4- hydroxy-piperidin-4-yl), S*-(4-hydroxy-piperidin-4-yl), R*-(4-hydroxy-tetrahydro-pyran-4- yl), S*-(4-hydroxy-tetrahydro-pyran-4-yl), 1 -(piperidin-4-yl)-1 S*-hydroxy-methyl, R*- (piperidin-4-yl-R*-hydroxy-methyl), R*-(piperidin-4-yl-S*-hydroxy-methyl), R-(morpholin- 4-yl-methyl), R-(thiomorpholin-4-yl 1 ,1 -dioxide-methyl), R-(thiomorpholin-4-yl 1 ,1- dioxide-methyl), 5-methyl-pyridazin-2-yl, R-(3-methyl-1 ,2,4-oxadiazol-5-yl), R-(5-methyl- 1 ,2,4-oxadiazol-2-yl), R-(5-methyl-1 ,3,4-oxadiazol-2-yl), S-(5-methyl-1 ,3,4-oxadiazol-2- yl)-methyl, R-(2-methyl-1 ,3,4-thiadiazol-5-yl), R-(1 -methyl-1 ,2,3-triazol-4-yl), R-(3,3- difluoro-cyclobut-1 -yl-amino-carbonyl), R-(3,3-dimethyl-cyclobut-1 -yl-amino-carbonyl), 1 -(trifluoro-methyl)-cycloprop-l -yl-amino-carbonyl, R-(1 -(trifluoro-methyl)-cycloprop-l -yl- amino-carbonyl), R-(trans-(2-(trifluoro-methyl)-cycloprop-1 -yl)-amino-carbonyl), R-(1 - cyano-cycloprop-1 -yl-amino-carbonyl), R-(cyclobutyl-amino-carbonyl), R-(cis-(3- hydroxy-3-methyl-cyclobut-1 -yl)-amino-carbonyl), R-(trans-(3-hydroxy-3-methyl- cyclobut-1 -yl)-amino-carbonyl), R-((3-cyano-bicyclo[1 .1 .1]pentan-1 -yl)-amino-carbonyl), R-(thietan-3-yl 1 ,1 -dioxide-amino-carbonyl), R-(1 -methyl-pyrrolidin-2-yl-methyl-amino- carbonyl), R-(S-(1 -methyl-4,4-difluoro-pyrrolidin-2-yl)-methyl-amino-carbonyl), R-(1 - methyl-piperidin-2-yl-methyl-amino-carbonyl), R-(4-methyl-morpholin-2-yl-methyl-amino- carbonyl), morpholin-4-yl-ethyl-amino-carbonyl, R-(tetrahydro-furan-2-yl-methyl-amino- carbonyl), S-(1 -(trifluoro-methyl)-cycloprop-l -yl-amino-carbonyl-methyl), R-(1 -(trifluoro- methyl)-cycloprop-1 -yl-amino-carbonyl-methyl), R-(1 -(trifluoro-methyl)-cycloprop-l -yl- methyl-amino-carbonyl), R-trans-(1 -(trifluoro-methyl)-cycloprop-l -yl-methyl-amino- carbonyl), R-(1 -cyano-cycloprop-1 -yl-methyl-amino-carbonyl), R-(hexahydro-1 H- pyrrolizin-7a-yl-methyl-amino-carbonyl), R-(morpholin-4-yl-carbonyl), R-(3,3-difluoro- pyrrol idin- 1 -yl-carbonyl), R-(trans-(2-trifluoro-methyl-cycloprop-1 -yl)-amino-methyl), R- (cis-(3-hydroxy-3-methyl-cyclobut-1 -yl)-amino-methyl), R-(3-(trifluoromethyl)- bicyclo[1 .1 .1]pentan-1 -yl)-amino-methyl), R-(oxetan-3-yl-amino-methyl), R-(thietan-3-yl 1 ,1 -dioxide-amino-methyl), and R-(1 -trifluoro-methyl-cycloprop-1 -yl-methyl-amino- methyl);a is an integer from 0 to 1 ; and L1is -CH2-;R3is selected from the group consisting of phenyl, 4-ethyl-phenyl, 4-(trifluoro- methyl)-phenyl, 4-(2,2,2-trifluoro-ethyl)-phenyl, 4-(pentafluoro-ethyl)-phenyl, 2-chloro-4- trifluoro-methyl-phenyl, 4-(1 -hydroxy-isopropyl)-phenyl, 3-(hydroxy-methyl)-4-trifluoro- methyl-phenyl, 4-(trifluoro-methoxy)-phenyl, 4-(trifluoro-methyl-thio)-phenyl, 4- (pentafluoro-thio)-phenyl, 4-(cyano-methyl)-phenyl, 4-(1 -cyano-vinyl)-phenyl, 2-(1 - cyano-vinyl-4-trifluoro-methyl-phenyl), 3-(cyano-methyl)-4-trifluoro-methyl-phenyl, 2- nitro-4-trifluoro-methyl-phenyl, 2-amino-4-trifluoro-methyl-phenyl, 3-amino-4-trifluoro- methyl-phenyl, 2-methyl-amino-4-trifluoro-methyl-phenyl, 2-(amino-methyl)-4-trifluoro- methyl-phenyl, 3-(amino-methyl)-4-trifluoro-methyl-phenyl, 3-(methyl-carbonyl-amino)-4- trifluoro-methyl-phenyl, 3-(hydroxy-methyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 4- (vinyl-carbonyl-amino)-phenyl, 2-(vinyl-carbonyl-amino)-4-trifluoro-methyl-phenyl), 3- (vinyl-carbonyl-amino)-4-(trifluoro-methyl)-phenyl, 2-(vinyl-carbonyl-amino)-4- (pentafluoro-ethyl)-phenyl, 2-(vinyl-carbonyl-amino)-4-trifluoro-methoxy-phenyl, 2-(N- methyl,N-vinyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(prope-1 -nyl-carbonyl- amino)-4-trifluoro-methyl-phenyl, 2-(3-dimethyl-amino-prope-1 -nyl-carbonyl-amino)-4- trifluoro-methyl-phenyl, 2-(1 -fluoro-vinyl-carbonyl-amino)-4-(trifluoro-methyl)-phenyl, 2- (propa-1 ,2-dienyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(propy-1 -nyl-carbonyl- amino)-4-trifluoro-methyl-phenyl, 3-(propy-2-nyl-carbonyl-amino)-4-(trifluoro-methyl)- phenyl, 2-(morpholin-4-yl-prope-1 -yl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2- (bicyclo[1 .1 .0]butan-1 -yl-carbonyl-amino)-4-(trifluoro-methyl)-phenyl, 1 -(2,2,2-trifluoro- ethyl)-piperidin-4-yl, 6-(trifluoro-methyl)-pyridin-3-yl, 6-(trifluoro-methoxy)-pyridin-3-yl, 2- (trifluoro-methyl)-pyrimidin-5-yl, 2-(trifluoro-methyl)-thiazol-4-yl, and 4-(trifluoromethyl)- bicyclo[2.2.2]octan-1 -yl;R4is selected from the group consisting of 2,6-dimethyl-3-chloro-phenyl, 2,5- dimethyl-phenyl, 2,3,6-trimethyl-phenyl, 2,6-dimethyl-3-D3-methyl-phenyl, 2-(2,2- difluoroethyl)-3,6-dimethyl-phenyl, 2-(hydroxy-methyl)-3,6-dimethyl-phenyl, 2,6- dimethyl-3-hydroxy-methyl-phenyl, 2-(1 -hydroxy-isopropyl)-3,6-dimethyl-phenyl, 2- methoxy-3,6-dimethyl-phenyl, 3-methoxy-2,6-dimethyl-phenyl, 2,6-dimethyl-3-methoxy- phenyl, 2-amino-3,6-dimethyl-phenyl, 2-(methyl-amino)-3,6-dimethyl-phenyl, 2-(dimethyl-amino)-3,6-dimethyl-phenyl, 2-(amino-methyl)-3,6-dimethyl-phenyl, 2-(2,2- difluoroethyl-amino-methyl)-3,6-dimethyl-phenyl, 2-(methyl-amino-carbonyl)-3,6- dimethyl-phenyl, 2-(isopropyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(2,2,2- trifluoroethyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(methoxy-ethyl-amino-carbonyl)- 3,6-dimethyl-phenyl, 2-(2-(dimethyl-amino)-ethyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(methyl-amino-carbonyl-methyl)-3,6-dimethyl-phenyl, 2-(methyl-carbonyl-amino- methyl)-3,6-dimethyl-phenyl, 2-pyrazol-5-yl-3,6-dimethyl-phenyl, 2-(1 ,2,3-triazol-5-yl)- 3,6-dimethyl-phenyl, 2-(4-trifluoromethyl-1 ,2,3-triazol-5-yl)-3,6-dimethyl-phenyl, 2- (tetrahydropyran-4-yl-carbonyl-amino)-3,6-dimethyl-phenyl, 2-(1 -azetidin-3-yl-amino- carbonyl)-3,6-dimethyl-phenyl, 2-(1 -methyl-azetidin-3-yl-amino-carbonyl)-3,6-dimethyl- phenyl, 2-(1 -piperidin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(1 -methyl- piperidin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(pyridin-3-yl-methyl-amino- carbonyl)-3,6-dimethyl-phenyl, 2-(pyridin-4-yl-methyl-amino-carbonyl)-3,6-dimethyl- phenyl, 2-(2-pyridin-2-yl-isopropyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(3-(methoxy- pyridin-2-yl)-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(2-pyridin-2-yl-2,2-difluoro- ethyl-amino-carbonyl)-3,6-dimethyl-phenyl and 2-(pyrimidin-2-yl-methyl-amino- carbonyl)-3,6-dimethyl-phenyl;R8is selected from the group consisting ofis selected from the group consisting of 3-(methyl-sulfonyl-amino)-pyrrolidin-1 -yl,3-(methoxy-methyl)-piperidin-1 -yl , 4-(methoxy- methyl)-pi peridin- 1 -yl, 4-(difluoro-methoxy-methyl)-piperidin-1 -yl, 3,3-difluoro-4-hydroxy- piperidi n-1 -yl, 4-(2-hydroxy-isoprop-2-yl)-piperidin-1 -yl, 3,3-difluoro-4-(methyl-sulfonyl- methyl)-pi peridin- 1 -yl, 3-(methyl-sulfonyl-methyl)-piperidin-1 -yl, 4-(methyl-sulfonyl- methyl)-pi peridin- 1 -yl, 4-(isopropyl-sulfonyl-methyl)-piperidin-1 -yl, 4-(isobutyl-sulfonyl- methyl)-pi peridin- 1 -yl, 4-methyl-4-(methyl-sulfonyl-methyl)-piperidin-1 -yl, 4-(methyl- sulfonyl-amino-methyl)-piperidin-1 -yl, 4-(methyl-sulfonyl-amino)-piperidin-1 -yl, 4-(ethyl- sulfonyl-amino)-piperidin-1 -yl, 4-(cyclopropyl-sulfonyl-amino)-piperidin-1 -yl, 4-(N- methyl,N-(methyl-sulfonyl)-amino)-piperidin-1 -yl, 4-(methyl-SO(NH2)-methyl)-piperidin-1 - yl, 4-(N-methyl, N-(ethyl-sulfonyl)-amino)-piperidin-1 -yl, 4-(N-ethyl, N-(methyl-sulfonyl)-amino)-piperidin-1 -yl, 4-(N-cyclopropyl, N-(methyl-sulfonyl)-amino)-piperidin-1 -yl, 4- (cyano-methyl)-piperidin-1 -yl, 4-(amino-carbonyl-methyl)-piperidin-1 -yl, 4-(methyl- amino-carbonyl-methyl)-piperidin-1 -yl, 4-(dimethyl-amino-carbonyl-methyl)-piperidin-1 - yl, 4-(methyl-dicarbonyl-amino)-piperidin-1 -yl, 4-(dimethyl-amino-dicarbonyl-amino)- piperidin-1 -yl, piperazin-1 -yl, piperazin-1 -yl-3-one, 3-(hydroxy-methyl)-4-methyl- piperazin-1 -yl, 4-(2,2-difluoroethyl)-piperazin-1 -yl, 4-methyl-piperazin-1 -yl, 4-(methoxy- ethyl)-piperazin-1 -yl, 4-(dimethyl-amino-ethyl)-piperazin-1 -yl, 4-(dimethyl-amino- sulfonyl)-piperazin-1 -yl, 3-(4-butyl-amino-carbonyl)-piperazin-1 -yl, morpholin-4-yl, and thiomorpholin-4-yl-1 , 1 -dioxide;(b); whereinis selected from the group consisting of azetidine-1 -yl, piperidin-1-yl, 3-fluoro-piperidin-1 -yl, 4-fluoro- piperidin-1 -yl, piperidin-1 -yl-3-one, 4-hydroxy-piperidin-1 -yl, 4-(hydroxy-methyl)- piperidin-1 -yl, 3,3-difluoro-piperidin-1 -yl, 4,4-difluoro-piperidin-1 -yl, 3,3-difluoro-4R*- hydroxy-piperidin-1 -yl, 3,3-difluoro-4S*-hydroxy-piperidin-1 -yl, 3 ,3-di methyl-piperid in- 1 - yl, 4-cyano-piperidin-1 -yl, piperazin-1 -yl, piperazin-1 -yl-3-one, 3S-(hydroxy-methyl)- piperazin-1 -yl, 2R-methyl-piperazin-1 -yl, 2-(amino-carbonyl)-piperazin-1 -yl, and morpholin-4-yl; whereinis selected from the group consisting of 4-(1 -hydroxy- cycloprop-1 -yl), 4-(1 -(methyl-sulfonyl)-cycloprop-l -yl), 4-cis-(4-(methyl-sulfonyl)- cyclohex-1 -yl), 4-trans-(4-(methyl-sulfonyl)-cyclohex-1 -yl), 4-cis-(4-(methyl-sulfonyl- amino)-cyclohex-1 -yl), 4-trans-(4-(methyl-sulfonyl-amino)-cyclohex-1 -yl), 4-(3-(methyl- sulfonyl)-azetidin-1 -yl), 4-((1 -methyl-sulfonyl)-pyrrolidin-3-y I) , 2-(tetrahydro-furan-3-yl), 4-(1 -methyl-2-oxo-tetrahydro-pyrimidin-3-yl), 4-(tetrahydro-thiophen-3R*-yl), 4- (tetrahydro-thiophen-3S*-yl), 4-(tetrahydro-thiophen-3-yl-1 ,1 -dioxide), 4-(tetrahydro- pyran-4-yl-1 ,1 -dioxide), 4-(tetrahydro-thiopyran-4-yl-1 ,1 -dioxide), 3-(thiomorpholin-4-yl- 1 ,1 -dioxide), 4-(thiomorpholin-4-yl-1 ,1 -dioxide), (1 -methyl-carbonyl)-azepan-4-yl, 4-(4- (methyl-sulfonyl)-l ,4-diazepan-1 -yl), 4-(2-oxo-piperidin-1 -yl), 4-(6-oxo-piperidin-3-yl), 4- (1 -methyl-pi perid in-4-yl) , 4-(1 -methyl-2-oxo-piperidin-4-yl), 4-(4-(methyl-sulfonyl)- piperidi n-1 -yl), 4-(1 -(methyl-sulfony l)-piperid in-4-yl) , 4-(1 -(methyl-sulfonyl)-3,3-difluoro-piperidi n-4-yl) , 4-(4-(methyl-sulfonyl-amino)-piperidin-1 -yl) , 4-(1 -(methyl-carbonyl)- piperidi n-4-yl) , 4-(1 -(methyl-carbonyl)-4-hydroxy-piperidin-4-yl), (1 -cyclopropyl-2-oxo- piperidin-4-yl), 4R*-(4-methyl-piperazin-4-yl), 4S*-(4-methyl-piperazin-4-yl), 4-(3-oxo-4- methyl-piperazin-1 -yl), 4R*-(3-oxo-4-methyl-piperazin-1 -yl), 4S*-(3-oxo-4-methyl- piperazin-1 -yl), 4-(3-oxo-4-isopropyl-piperazin-1 -yl), 4-(3-oxo-4-cyclopropyl-piperazin-1 - yl), 3-(4-(methyl-sulfonyl)-piperazin-1 -yl), 4-(4-(methyl-sulfonyl)-piperazin-1 -yl), 4R*-(4- (methyl-sulfonyl)-piperazin-1 -yl), 4S*-(4-(methyl-sulfonyl)-piperazin-1 -yl), 4-(2-oxo-4- (methyl-sulfonyl)-piperazin-1 -yl), 3-(4-oxetan-3-yl-piperazin-1 -yl), 4-(4-(trif luoro- methoxy)-phenyl), 4-(4-(azetidin-1 -yl-carbonyl)-phenyl, 4-(4-(methyl-sulfonyl)-phenyl), 4- (4-(trifluoro-methyl-sulfonyl)-phenyl), 4-(4-(methyl-amino-carbonyl)-phenyl), 4-(4- (dimethyl-amino-carbonyl)-phenyl), 4-(4-(amino-sulfonyl)-phenyl), 4-(4-carboxy-phenyl), 4-(4-(ethoxy-carbonyl)-phenyl), 3-(pyrazol-4-yl), 4-(pyrazol-4-yl), 3-(1 -(methyl-sulfonyl)- pyrazol-4-yl), 4-(1 -(methyl-sulfonyl)-pyrazol-4-yl), 4-(pyridin-3-yl), 4-(2-chloro-6-(methyl- sulfonyl)-pyridin-3-yl), 4-(6-hydroxy-pyridin-2-yl), 4-(2-methyl-pyridin-4-yl), 4-(2- isopropyl-6-(methyl-sulfonyl)-pyridin-3-yl), 4-(2-(difluoro-methyl)-6-(methyl-sulfonyl)- pyridin-3yl), 4-(2-(trifluoro-methyl)-6-methyl-sulfonyl)-pyridin-3-yl), 4-(6-(2,2,2-trifluoro- ethyl)-pyridin-3-yl), 4-(4-methoxy-6-(methyl-sulfonyl)-pyridin-3-yl), 4-(6-(trifluoro- methoxy)-pyridin-3-yl), 4-(6-methoxy-pyridin-2-yl), 4-(6-(methyl-sulfonyl)-pyridin-2-yl), 4- (4-(methyl-sulfonyl)-pyridin-3-yl), 4-(6-(methyl-sulfonyl)-pyridin-3-yl), 4R*-(6-(methyl- sulfonyl)-pyridin-3-yl), 4S*-(6-(methyl-sulfonyl)-pyridin-3-yl), 4-(2-methyl-6-(methyl- sulfonyl)-pyridin-3-yl), 4-(2-ethyl-6-(methyl-sulfonyl)-pyridin-3-yl), 4-(6-(2-hydroxy- isobutyl-amino-sulfonyl)-pyridin-3-yl), 4-(6-(2,2,2-trifluoro-ethyl-amino-sulfonyl)-pyridin-3-yl), 4-(6-(methyl-sulfonimidoyl)-pyridin-3-yl), 4-(5-cyano-pyridin-2-yl), 4-(6-(dimethyl- amino)-pyridin-3-yl), 4-(6-(amino-carbonyl)-pyridin-3-yl), 4-(1 -cyclopropyl)-2-oxo-pyridin-4-yl), 4-(2-cyclopropyl-6-(methyl-sulfonyl)-pyridin-3-yl),-(6-(3-hydroxy-3-methyl-azetidin- 1 -yl-su If ony l)-pyridin-3-yl) , 4-(6-(piperazin-1 -yl-su If ony l)-pyridi n-3-yl , 4-(6-(morpholin-4- yl-sulfonyl)-pyridin-3-yl), 4-(6-(2,2,2-trifluoro-ethyl)-piperazin-1 -yl-sulfonyl)-pyridin-3-yl), (6-(4-methyl-piperazin-1 -yl-sulfonyl)-pyridin-3-y I) , 4-(6-((thiomorpholin-4-yl-1 ,1 -dioxide)- sulfonyl)-pyridin-3-yl, 4-(5-(methyl-sulfonyl)-pyrimidin-2-yl), 4-(5-(methyl-sulfonyl)- pyrazin-2-yl), 4-(6-(methyl-sulfonyl)-pyridazin-3-yl), 3-(methyl-sulfonyl-amino)-bicyclo[1 .1 .1 ]pentan-1 -yl, (1 ,4)-2-(methyl-sulfonyl)-2-azabicyclo[2.2.1]heptan-5-yl, and (1 R,4R)-5-methyl-2-(methylsulfonyl)-2-azabicyclo[2.2.1]heptan-5-yl;(c)whereinis selected from the group consisting of piperidin-1 -yl, 3,3-difluoro-piperidin-1 -yl, 4,4-difluoro-piperidin-1 -yl, and piperazin-1 -yl;L3is selected from the group consisting of 4-(-CH2-), 4-(-C(O)-(CH2)-), 3-(-NH-), 4-(-NH-), 3R*-(-NH-), 3S*-(-NH-), 4R*-(-NH-), 4S*-(-NH-), and 3-(-O-);R10is selected from the group consisting of 3-(methyl-sulfonyl)-azetidin-1 -yl, 4- (methyl-sulfonyl)-piperidin-1 -yl, 1 -(methyl-sulfony l)-piperid in-4-yl , tetrahydro-thiophen-3- yl-1 ,1 -dioxide, 1 ,4-dioxan-3-yl, pyridin-4-yl, and 6-(methyl-sulfonyl)-pyridin-3-yl;is selected from the group consisting of 6-cyclopropyl-2,6-diazaspiro[3.3]heptan-2-yl, 2,3-dihydroxy-(1 S,4S)-2- azabicyclo[2.2.1 ]heptan-2-yl, 2,6-diazaspiro[3.4]octan-2-yl, 2-(methyl-sulfonyl)-2,6- diazaspiro[3.4]octan-2-yl, 2-(methyl-carbonyl)-2,6-diazaspiro[3.4]octan-2-yl, 2-thia-6- azaspiro[3.4]octan-6-yl 2,2-dioxide, 2,7-diazaspiro[3.5]nonan-7-yl-3-one, 2-oxa-6- azaspiro[3.5]nonan-6-yl, 2-oxa-5,8-diazaspiro[3.5]nonan-8-yl, 2-oxa-7- azaspiro[3.5]nonan-7-yl, 2-thia-7-azaspiro[3.5]nonan-7-yl 2,2-dioxide, 2-hydroxy-7- azaspiro[3.5]nonan-7-yl, 2-hydroxy-2-methyl-7-azaspiro[3.5]nonan-7-yl, 2-oxa-8- azaspiro[4.5]decan-8-yl, 2-thia-8-azaspiro[4.5]decan-8-yl 2,2-dioxide, 8-thia-2- azaspiro[4.5]decan-2-yl 8,8-dioxide, 3-azaspiro[5.5]undecan-3-yl; 3-oxa-9- azaspiro[5.5]undecan-9-yl, 3-(methyl-sulfonyl)-3,9-diazaspiro[5.5]undecan-3-yl, 6-oxa-2- thia-9-azaspiro[4.6]undecan-9-yl 2,2-dioxide, 3-thia-9-azaspiro[5.5]undecan-9-yl 3,3- dioxide, 1 -oxa-9-thia-4-azaspiro[5.5]undecan-4-yl 9,9-dioxide, 7-oxa-3-thia-10- azaspiro[5.6]dodecan-10-yl 3,3-dioxide, octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2- dioxide, (R*)-octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2-dioxide, (S*)- octahydropyrazino[2,1 -c] [ 1 ,4]thiazin-8-y I 2,2-dioxide, 7,7-dimethyl- octahydropyrazino[2,1 -c] [ 1 ,4]thiazin-8-y I 2,2-dioxide, 7,7-dimethyl-(R*)- octahydropyrazino[2,1 -c] [ 1 ,4]thiazin-8-y I 2,2-dioxide, 7,7-dimethyl-(S*)- octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2-dioxide, (4aR,8aR)-octahydro-1 H-pyrano[3,4-c]pyridin-7-yl, (4aR,8aS)-octahydro-1 H-pyrano[3,4-c]pyridin-7-yl, (4aS,8aR)- octahydro-1 H-pyrano[3,4-c]pyridin-7-yl, (4aS,8aS)-octahydro-1 H-pyrano[3,4-c]pyridin-7- yl, hexahydro-pyrazino[2,1 -c][1 ,4]oxazin-8-yl-4-one, octahydropyrazino[2,1 - c][1 ,4]oxazin-8-yl, (S)-octahydropyrazino[2,1 -c][1 ,4]oxazin-8-yl, octahydropyrazino[2,1 - c][1 ,4]oxazin-8-yl-6,6-d2, (S)-hexahydro-pyrazino[2,1 -c][1 ,4]oxazin-8-yl-4-one, (S*)- hexahydro-pyrazino[2,1 -c] [ 1 ,4]oxazin-8-yl-6-one, (R*)-hexahydro-pyrazino[2,1 - c][1 ,4]oxazin-8-yl-6-one, 8-methyl-(R*)-hexahydro-1 H-pyrazino[1 ,2-a]pyrazin-2-yl, 8- methyl-(S*)-hexahydro-1 H-pyrazino[1 ,2-a]pyrazin-2-yl, 8-(2,2,2-trifluoro-ethyl)-(R*)- octahydro-2H-pyrazino[1 ,2-a]pyrazin-2-yl, 8-(2,2,2-trifluoro-ethyl)-(S*)-octahydro-2H- pyrazino[1 ,2-a]pyrazin-2-yl, 2-(methyl-sulfonyl)-3,4,6,7,9,9aR*-hexahydro-1 H- pyrazino[1 ,2-a]pyrazin-8-yl, 2-(methyl-sulfonyl)-3,4,6,7,9,9aS*-hexahydro-1 H- pyrazino[1 ,2-a]pyrazin-8-yl, 2-imino-2-oxo-3,4,6,7,9,9a-hexahydro-1 H-pyrazino[2,1 - c][1 ,4]thiazin-8-yl, 7-(methyl-sulfonyl)-3,4-dihydro-1 H-isoqu inolin-2-yl, 6-chloro- spiro[isobenzofuran-1 ,4'-piperid in- 1 -yl], 6-(methyl-sulfonyl)-(1 R*)-spiro[isobenzofuran- 1 ,4'-pi peridin]- 1 '-yl, 6-(methyl-sulfonyl)-(1 S*)-spiro[isobenzofuran-1 ,4'-pi peridin]- 1 '-yl, 3- fluoro-6-(methyl-sulfonyl)-spiro[isobenzofuran-1 ,4'-pi peridin- 1 -yl], 5-(methyl-sulfonyl)- octahydropyrrolo[3,4-b]pyrrol-1 -yl, hexahydro-1 H-thieno[3,4-b]pyrrol-1 -yl 5,5-dioxide, 3- (trifluoro-methyl)-5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3-c]pyrimidin-6-yl, and 5-(4-(methyl- sulfonyl)-phenyl)-2,5-diazabicyclo[2.2.2]octan-2-yl; or a stereoisomer or pharmaceutically acceptable salt thereof.

4. A compound as in Claim 3, whereinR1is selected from the group consisting of hydrogen, chloro, cyano and aminocarbonyl-;R2is selected from the group consisting of R-(2-hydroxy-isopropyl), methylamino-carbonyl, R-(methyl-amino-carbonyl), R-(2-hydroxy-isobutyl-amino-carbonyl), R- (2,2-difluoro-ethyl-amino-carbonyl), R-(1 -cyano-cycloprop-1 -yl-amino-carbonyl), 1 - trifluoro-methyl-cycloprop-1 -yl-amino-carbonyl, R-(1 -trifluoro-methyl-cycloprop-1 -yl- amino-carbonyl), and S-(methyl-amino-carbonyl-methyl). a is 1 ; and L1is -CH2-;R3is selected from the group consisting of 4-trifluoro-metyl-phenyl and 6-(trifluoro-methyl)-pyridin-3-yl;R4is selected from the group consisting of 2,5-dimethyl-phenyl, 2,3,6-trimethyl- phenyl, 2-(hydroxy-methyl)-3,6-dimethyl-phenyl, 2-(2-pyridin-2-yl-isopropyl-amino- carbonyl)-3,6-dimethyl-phenyl and 2-(3-methoxy-pyridin-2-yl-methyl-amino-carbonyl)- 3,6-dimethyl-phenyl;R8is; whereinis selected from the group consisting of3-(methyl-sulfonyl-amino)-pyrrolidin-1 -yl,3-(methoxy-methyl)-piperidin-1 -yl , 4-(methoxy- methyl)-pi peridin- 1 -yl, 4-(difluoro-methoxy-methyl)-piperidin-1 -yl, 3,3-difluoro-4-hydroxy- piperidi n-1 -yl, 4-(2-hydroxy-isoprop-2-yl)-piperidin-1 -yl, 3,3-difluoro-4-(methyl-sulfonyl- methyl)-pi peridin- 1 -yl, 3-(methyl-sulfonyl-methyl)-piperidin-1 -yl, 4-(methyl-sulfonyl- methyl)-pi peridin- 1 -yl, 4-(isopropyl-sulfonyl-methyl)-piperidin-1 -yl, 4-(isobutyl-sulfonyl- methyl)-pi peridin- 1 -yl, 4-methyl-4-(methyl-sulfonyl-methyl)-piperidin-1 -yl, 4-(methyl- sulfonyl-amino-methyl)-piperidin-1 -yl, 4-(methyl-sulfonyl-amino)-piperidin-1 -yl, 4-(ethyl- sulfonyl-amino)-piperidin-1 -yl, 4-(cyclopropyl-sulfonyl-amino)-piperidin-1 -yl, 4-(N- methyl,N-(methyl-sulfonyl)-amino)-piperidin-1 -yl, 4-(methyl-SO(NH2)-methyl)-piperidin-1 - yl, 4-(N-methyl, N-(ethyl-sulfonyl)-amino)-piperidin-1 -yl, 4-(N-ethyl, N-(methyl-sulfonyl)- amino)-piperidin-1 -yl, 4-(N-cyclopropyl, N-(methyl-sulfonyl)-amino)-piperidin-1 -yl, 4- (cyano-methyl)-piperidin-1 -yl, 4-(amino-carbonyl-methyl)-piperidin-1 -yl, 4-(methyl- amino-carbonyl-methyl)-piperidin-1 -yl, 4-(dimethyl-amino-carbonyl-methyl)-piperidin-1 - yl, 4-(methyl-dicarbonyl-amino)-piperidin-1 -yl, 4-(dimethyl-amino-dicarbonyl-amino)- piperidin-1 -yl, piperazin-1 -yl, piperazin-1 -yl-3-one, 3-(hydroxy-methyl)-4-methyl- piperazin-1 -yl, 4-(2,2-difluoroethyl)-piperazin-1 -yl, 4-methyl-piperazin-1 -yl, 4-(methoxy- ethyl)-piperazin-1 -yl, 4-(dimethyl-amino-ethyl)-piperazin-1 -yl, 4-(dimethyl-amino- sulfonyl)-piperazin-1 -yl, 3-(4-butyl-amino-carbonyl)-piperazin-1 -yl, morpholin-4-yl, and thiomorpholin-4-yl-1 , 1 -dioxide; or a stereoisomer or pharmaceutically acceptable salt thereof.

5. A compound as in Claim 3, whereinR1is selected from the group consisting of hydrogen, hydroxy, chloro, methyl, isopropyl, difluoromethyl, trifluoromethyl, hydroxy-methyl, methoxy, ethoxy, methoxy-methyl-, methoxy-ethoxy-, methyl-sulfonyl-, cyclopropyl-sulfonyl-, cyano, methyl-amino-, methyl-amino-methyl-, dimethyl-amino-methyl-, 2,2,2-trifluoroethyl-amino-methyl-, amino-carbonyl-, 1 -(trifluoromethyl)-cycloprop-1 -yl, morpholin-4-yl, piperazin-1 -yl, 3- fluoro-azetidin-1 -yl, 3,3-difluoro-azetidin-1 -yl, oxazol-2-yl, isoxazol-4-yl, morpholin-4-yl- methyl-, morpholin-4-yl-carbonyl-, 3,3-difluoro-pyrrolidin-1 -yl-methyl-, 3,3-difluoro- piperidin-1 -yl-methyl-, 4, 4-difluoro-piperidin-1 -yl-methyl-, and 4-methyl-piperazin-1 -yl- methyl;R2is selected from the group consisting of R-(2-fluoro-isopropyl), R-(hydroxy- methyl), 1 R*-(hydroxy-ethyl), 1 S*-(hydroxy-ethyl), R*-(1 R*-hydroxy-ethyl), R*-(1S*- hydroxy-ethyl), S*-(1 R*-hydroxy-ethyl), S*-(1S*-hydroxy-ethyl), 2-hydroxy-isopropyl, R*- (2-hydroxy-isopropyl), S*-(2-hydroxy-isopropyl), R-(2-hydroxy-isopropyl), R-(2-hydroxy- isobutyl), R-(1 ,3-dihydroxy-1 -methyl-n-propyl), R-(1 R*,3-dihydroxy-1 -methyl-n-propyl), R-(2-hydroxy-tert-butyl), R-(amino-methyl), R-(methyl-amino-methyl), R-(dimethyl- amino-methyl), R-(2,2-difluoro-ethyl)-amino-methyl), R-(2-hydroxy-isobutyl-amino- methyl), R-(2-hydroxy-3,3,3-trifluoro-n-propyl-amino-methyl), R-(2-cyano-ethyl-amino- methyl), R-(methyl-sulfonyl-amino-methyl), R-(dimethyl-amino sulfonyl-ethyl-amino- methyl), R-(1 R-amino-2,2,2-trifluoro-ethyl), R-(1 S-amino-2,2,2-trifluoro-ethyl), S-(1 S- amino-2,2,2-trifluoro-ethyl), amino-carbonyl, R*-(amino-carbonyl), S*-(amino-carbonyl), methyl-amino-carbonyl, R-(D3-methyl-amino-carbonyl), R*-(methyl-amino-carbonyl), S*- (methyl-amino-carbonyl), R-(methyl-amino-carbonyl), S-(methyl-amino-carbonyl), R- (dimethyl-amino-carbonyl), R-(isopropyl-amino-carbonyl), R-(t-butyl-amino-carbonyl), R- (2-isobutyl-amino-carbonyl), R-(cyano-amino-carbonyl), R-(2-hydroxy-isobutyl-amino- carbonyl), R-((2,2-difluoro-ethyl)-amino-carbonyl), R-((2,2,2-trifluoro-ethyl)-amino- carbonyl), R-(2,2,3,3,3-pentafluoro-n-propyl-amino-carbonyl), R-(2-hydroxy-3,3,3- trifluoro-n-propyl-amino-carbonyl), R-(2-methoxy-isobutyl-amino-carbonyl), S*-(methyl- amino-carbonyl-methyl), R*-(methyl-amino-carbonyl-methyl), R-(methyl-amino-carbonyl- methyl), S-(methyl-amino-carbonyl-methyl), S-(2-hydroxy-isobutyl-amino-carbonyl- methyl), S-(2,2-difluoro-ethyl-amino-carbonyl-methyl), S-(2,2,2-trifluoro-ethyl-amino- carbonyl-methyl), S*-(2-(methyl-amino-carbonyl)-isopropyl), R*-(2-(methyl-amino- carbonyl)-isopropyl), R-(dimethyl-amino-ethyl-amino-carbonyl), R*-(dimethyl-amino- ethyl-amino-carbonyl), S*-(dimethyl-amino-ethyl-amino-carbonyl), R*-(1 -hydroxy-cycloprop-1 -yl), S*-(1 -hydroxy-cycloprop-1 -yl), R*-(1 -hydroxy-cyclobut-1 -yl), S*-(1- hydroxy-cyclobut-1 -yl), R*-(3-hydroxy-oxetan-3-yl), S*-(3-hydroxy-oxetan-3-yl), R*-(4- hydroxy-piperidin-4-yl), S*-(4-hydroxy-piperidin-4-yl), R*-(4-hydroxy-tetrahydro-pyran-4- yl), S*-(4-hydroxy-tetrahydro-pyran-4-yl), 1 -(piperidin-4-yl)-1 S*-hydroxy-methyl, R*- (piperidin-4-yl-R*-hydroxy-methyl), R*-(piperidin-4-yl-S*-hydroxy-methyl), R-(morpholin-4-yl-methyl), R-(thiomorpholin-4-yl 1 ,1 -dioxide-methyl), 5-methyl-pyridazin-2-yl, R-(3- methyl-1 ,2,4-oxadiazol-5-yl), R-(5-methyl-1 ,2,4-oxadiazol-2-yl), R-(5-methyl-1 ,3,4- oxadiazol-2-yl), S-(5-methyl-1 ,3,4-oxadiazol-2-yl)-methyl, R-(2-methyl-1 ,3,4-thiadiazol-5-yl), R-(1 -methyl-1 ,2,3-triazol-4-yl), R-(3,3-difluoro-cyclobut-1 -yl-amino-carbonyl), R- (3,3-dimethyl-cyclobut-1 -yl-amino-carbonyl), R-(1 -(trifluoro-methyl)-cycloprop-l -yl- amino-carbonyl), , R-(1 -cyano-cycloprop-1 -yl-amino-carbonyl), R-(cyclobutyl-amino- carbonyl), R-(cis-(3-hydroxy-3-methyl-cyclobut-1 -yl)-amino-carbonyl), R-(trans-(3- hydroxy-3-methyl-cyclobut-1 -yl)-amino-carbonyl), R-((3-cyano-bicyclo[1 .1 .1]pentan-1 - yl)-amino-carbonyl), R-(thietan-3-yl 1 ,1 -dioxide-amino-carbonyl), R-(1 -methyl-pyrrolidin- 2-yl-methyl-amino-carbonyl), R-(S-(1 -methyl-4,4-difluoro-pyrrolidin-2-yl)-methyl-amino- carbonyl), R-(1 -methyl-piperidin-2-yl-methyl-amino-carbonyl), R-(4-methyl-morpholin-2- yl-methyl-amino-carbonyl), morpholin-4-yl-ethyl-amino-carbonyl, R-(tetrahydro-furan-2- yl-methyl-amino-carbonyl), S-(1 -(trifluoro-methyl)-cycloprop-l -yl-amino-carbonyl- methyl), R-(1 -(trifluoro-methyl)-cycloprop-l -yl-amino-carbonyl-methyl), R-(1 -(trifluoro- methyl)-cycloprop-1 -yl-methyl-amino-carbonyl), R-trans-(1 -(trifluoro-methyl)-cycloprop-1 -yl-methyl-amino-carbonyl), R-(1 -cyano-cycloprop-1 -yl-methyl-amino-carbonyl), R- (hexahydro-1 H-pyrrolizin-7a-yl-methyl-amino-carbonyl), R-(morpholin-4-yl-carbonyl), R- (3 , 3-difl uoro-pyrrolidi n-1 -yl-carbonyl), R-(trans-(2-trifluoro-methyl-cycloprop-1 -yl)-amino- methyl), R-(cis-(3-hydroxy-3-methyl-cyclobut-1 -yl)-amino-methyl), R-(3-(trifluoromethyl)- bicyclo[1 .1 .1]pentan-1 -yl)-amino-methyl), R-(oxetan-3-yl-amino-methyl), R-(thietan-3-yl 1 ,1 -dioxide-amino-methyl), and R-(1 -trifluoro-methyl-cycloprop-1 -yl-methyl-amino- methyl); a is an integer from 0 to 1 ; and L1is -CH2-;R3is selected from the group consisting of phenyl, 4-ethyl-phenyl, 4-(trifluoro- methyl)-phenyl, 4-(2,2,2-trifluoro-ethyl)-phenyl, 4-(pentafluoro-ethyl)-phenyl, 2-chloro-4- trifluoro-methyl-phenyl, 4-(1 -hydroxy-isopropyl)-phenyl, 3-(hydroxy-methyl)-4-trifluoro-methyl-phenyl, 4-(trifluoro-methoxy)-phenyl, 4-(trifluoro-methyl-thio)-phenyl, 4- (pentafluoro-thio)-phenyl, 4-(cyano-methyl)-phenyl, 4-(1 -cyano-vinyl)-phenyl, 2-(1 - cyano-vinyl-4-trifluoro-methyl-phenyl), 3-(cyano-methyl)-4-trifluoro-methyl-phenyl, 2- nitro-4-trifluoro-methyl-phenyl, 2-amino-4-trifluoro-methyl-phenyl, 3-amino-4-trifluoro- methyl-phenyl, 2-methyl-amino-4-trifluoro-methyl-phenyl, 2-(amino-methyl)-4-trifluoro- methyl-phenyl, 3-(amino-methyl)-4-trifluoro-methyl-phenyl, 3-(methyl-carbonyl-amino)-4- trifluoro-methyl-phenyl, 3-(hydroxy-methyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 4- (vinyl-carbonyl-amino)-phenyl, 2-(vinyl-carbonyl-amino)-4-trifluoro-methyl-phenyl), 3- (vinyl-carbonyl-amino)-4-(trifluoro-methyl)-phenyl, 2-(vinyl-carbonyl-amino)-4- (pentafluoro-ethyl)-phenyl, 2-(vinyl-carbonyl-amino)-4-trifluoro-methoxy-phenyl, 2-(N- methyl,N-vinyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(prope-1 -nyl-carbonyl- amino)-4-trifluoro-methyl-phenyl, 2-(3-dimethyl-amino-prope-1 -nyl-carbonyl-amino)-4- trifluoro-methyl-phenyl, 2-(1 -fluoro-vinyl-carbonyl-amino)-4-(trifluoro-methyl)-phenyl, 2- (propa-1 ,2-dienyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(propy-1 -nyl-carbonyl- amino)-4-trifluoro-methyl-phenyl, 3-(propy-2-nyl-carbonyl-amino)-4-(trifluoro-methyl)- phenyl, 2-(morpholin-4-yl-prope-1 -yl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2- (bicyclo[1 .1 .0]butan-1 -yl-carbonyl-amino)-4-(trifluoro-methyl)-phenyl, 1 -(2,2,2-trifluoro- ethyl)-piperidin-4-yl, 6-(trifluoro-methyl)-pyridin-3-yl, 6-(trifluoro-methoxy)-pyridin-3-yl, 2- (trifluoro-methyl)-pyrimidin-5-yl, 2-(trifluoro-methyl)-thiazol-4-yl, and 4-(trifluoromethyl)- bicyclo[2.2.2]octan-1 -yl;R4is selected from the group consisting of 2,6-dimethyl-3-chloro-phenyl, 2,5- dimethyl-phenyl, 2,3,6-trimethyl-phenyl, 2,6-dimethyl-3-D3-methyl-phenyl, 2-(2,2- difluoroethyl)-3,6-dimethyl-phenyl, 2-(hydroxy-methyl)-3,6-dimethyl-phenyl, 2,6- dimethyl-3-hydroxy-methyl-phenyl, 2-(1 -hydroxy-isopropyl)-3,6-dimethyl-phenyl, 2- methoxy-3,6-dimethyl-phenyl, 3-methoxy-2,6-dimethyl-phenyl, 2,6-dimethyl-3-methoxy- phenyl, 2-amino-3,6-dimethyl-phenyl, 2-(methyl-amino)-3,6-dimethyl-phenyl, 2- (dimethyl-amino)-3,6-dimethyl-phenyl, 2-(amino-methyl)-3,6-dimethyl-phenyl, 2-(2,2- difluoroethyl-amino-methyl)-3,6-dimethyl-phenyl, 2-(methyl-amino-carbonyl)-3,6- dimethyl-phenyl, 2-(isopropyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(2,2,2- trifluoroethyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(methoxy-ethyl-amino-carbonyl)- 3,6-dimethyl-phenyl, 2-(2-(dimethyl-amino)-ethyl-amino-carbonyl)-3,6-dimethyl-phenyl,2-(methyl-amino-carbonyl-methyl)-3,6-dimethyl-phenyl, 2-(methyl-carbonyl-amino- methyl)-3,6-dimethyl-phenyl, 2-pyrazol-5-yl-3,6-dimethyl-phenyl, 2-(1 ,2,3-triazol-5-yl)- 3,6-dimethyl-phenyl, 2-(4-trifluoromethyl-1 ,2,3-triazol-5-yl)-3,6-dimethyl-phenyl, 2- (tetrahydropyran-4-yl-carbonyl-amino)-3,6-dimethyl-phenyl, 2-(1 -azetidin-3-yl-amino- carbonyl)-3,6-dimethyl-phenyl, 2-(1 -methyl-azetidin-3-yl-amino-carbonyl)-3,6-dimethyl- phenyl, 2-(1 -piperidin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(1 -methyl- piperidin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(pyridin-3-yl-methyl-amino- carbonyl)-3,6-dimethyl-phenyl, 2-(pyridin-4-yl-methyl-amino-carbonyl)-3,6-dimethyl- phenyl, 2-(2-pyridin-2-yl-isopropyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(3-(methoxy- pyridin-2-yl)-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(2-pyridin-2-yl-2,2-difluoro- ethyl-amino-carbonyl)-3,6-dimethyl-phenyl and 2-(pyrimidin-2-yl-methyl-amino- carbonyl)-3,6-dimethyl-phenyl;group consisting of azetidine-1 -yl, piperidin-1 -yl, 3-fluoro-piperidin-1 -yl, 4-fluoro- piperidin-1 -yl, piperidin-1 -yl-3-one, 4-hydroxy-piperidin-1 -yl, 4-(hydroxy-methyl)- piperidin-1 -yl, 3,3-difluoro-piperidin-1 -yl, 4,4-difluoro-piperidin-1 -yl, 3,3-difluoro-4R*- hydroxy-piperidin-1 -yl, 3,3-difluoro-4S*-hydroxy-piperidin-1 -yl, 3 ,3-di methyl-piperid in- 1 - yl, 4-cyano-piperidin-1 -yl, piperazin-1 -yl, piperazin-1 -yl-3-one, 3S-(hydroxy-methyl)- piperazin-1 -yl, 2R-methyl-piperazin-1 -yl, 2-(amino-carbonyl)-piperazin-1 -yl, and morpholin-4-yl; whereinis selected from the group consisting of 4-(1 -hydroxy- cycloprop-1 -yl), 4-(1 -(methyl-sulfonyl)-cycloprop-l -yl), 4-cis-(4-(methyl-sulfonyl)- cyclohex-1 -yl), 4-trans-(4-(methyl-sulfonyl)-cyclohex-1 -yl), 4-cis-(4-(methyl-sulfonyl- amino)-cyclohex-1 -yl), 4-trans-(4-(methyl-sulfonyl-amino)-cyclohex-1 -yl), 4-(3-(methyl- sulfonyl)-azetidin-1 -yl), 4-((1 -methyl-sulfonyl)-pyrrolidin-3-y I) , 2-(tetrahydro-furan-3-yl), 4-(1 -methyl-2-oxo-tetrahydro-pyrimidin-3-yl), 4-(tetrahydro-thiophen-3R*-yl), 4- (tetrahydro-thiophen-3S*-yl), 4-(tetrahydro-thiophen-3-yl-1 ,1 -dioxide), 4-(tetrahydro- pyran-4-yl-1 ,1 -dioxide), 4-(tetrahydro-thiopyran-4-yl-1 ,1 -dioxide), 3-(thiomorpholin-4-yl- 1 ,1 -dioxide), 4-(thiomorpholin-4-yl-1 ,1 -dioxide), (1 -methyl-carbonyl)-azepan-4-yl, 4-(4-(methyl-sulfonyl)-l ,4-diazepan-1 -yl), 4-(2-oxo-piperidin-1 -yl), 4-(6-oxo-piperidin-3-yl), 4- (1 -methyl-pi perid in-4-yl) , 4-(1 -methyl-2-oxo-piperidin-4-yl), 4-(4-(methyl-sulfonyl)- piperidi n-1 -yl) , 4-(1 -(methyl-sulfony l)-piperid in-4-yl) , 4-(1 -(methyl-sulfonyl)-3,3-difluoro- piperidi n-4-yl) , 4-(4-(methyl-sulfonyl-amino)-piperidin-1 -yl), 4-(1 -(methyl-carbonyl)- piperidin-4-yl), 4-(1 -(methyl-carbonyl)-4-hydroxy-piperidin-4-yl), (1 -cyclopropyl-2-oxo- piperidin-4-yl), 4R*-(4-methyl-piperazin-4-yl), 4S*-(4-methyl-piperazin-4-yl), 4-(3-oxo-4- methyl-piperazin-1 -yl), 4R*-(3-oxo-4-methyl-piperazin-1 -yl), 4S*-(3-oxo-4-methyl- piperazin-1 -yl), 4-(3-oxo-4-isopropyl-piperazin-1 -yl), 4-(3-oxo-4-cyclopropyl-piperazin-1 - yl), 3-(4-(methyl-sulfonyl)-piperazin-1 -yl), 4-(4-(methyl-sulfonyl)-piperazin-1 -yl), 4R*-(4- (methyl-sulfonyl)-piperazin-1 -yl), 4S*-(4-(methyl-sulfonyl)-piperazin-1 -yl), 4-(2-oxo-4- (methyl-sulfonyl)-piperazin-1 -yl), 3-(4-oxetan-3-yl-piperazin-1 -yl), 4-(4-(trif luoro- methoxy)-phenyl), 4-(4-(azetidin-1 -yl-carbonyl)-phenyl, 4-(4-(methyl-sulfonyl)-phenyl), 4- (4-(trifluoro-methyl-sulfonyl)-phenyl), 4-(4-(methyl-amino-carbonyl)-phenyl), 4-(4- (dimethyl-amino-carbonyl)-phenyl), 4-(4-(amino-sulfonyl)-phenyl), 4-(4-carboxy-phenyl), 4-(4-(ethoxy-carbonyl)-phenyl), 3-(pyrazol-4-yl), 4-(pyrazol-4-yl), 3-(1 -(methyl-sulfonyl)- pyrazol-4-yl), 4-(1 -(methyl-sulfonyl)-pyrazol-4-yl), 4-(pyridin-3-yl), 4-(2-chloro-6-(methyl- sulfonyl)-pyridin-3-yl), 4-(6-hydroxy-pyridin-2-yl), 4-(2-methyl-pyridin-4-yl), 4-(2- isopropyl-6-(methyl-sulfonyl)-pyridin-3-yl), 4-(2-(difluoro-methyl)-6-(methyl-sulfonyl)- pyridin-3yl), 4-(2-(trifluoro-methyl)-6-methyl-sulfonyl)-pyridin-3-yl), 4-(6-(2,2,2-trifluoro- ethyl)-pyridin-3-yl), 4-(4-methoxy-6-(methyl-sulfonyl)-pyridin-3-yl), 4-(6-(trifluoro- methoxy)-pyridin-3-yl), 4-(6-methoxy-pyridin-2-yl), 4-(6-(methyl-sulfonyl)-pyridin-2-yl), 4- (4-(methyl-sulfonyl)-pyridin-3-yl), 4-(6-(methyl-sulfonyl)-pyridin-3-yl), 4R*-(6-(methyl- sulfonyl)-pyridin-3-yl), 4S*-(6-(methyl-sulfonyl)-pyridin-3-yl), 4-(2-methyl-6-(methyl- sulfonyl)-pyridin-3-yl), 4-(2-ethyl-6-(methyl-sulfonyl)-pyridin-3-yl), 4-(6-(2-hydroxy- isobutyl-amino-sulfonyl)-pyridin-3-yl), 4-(6-(2,2,2-trifluoro-ethyl-amino-sulfonyl)-pyridin-3-yl), 4-(6-(methyl-sulfonimidoyl)-pyridin-3-yl), 4-(5-cyano-pyridin-2-yl), 4-(6-(dimethyl- amino)-pyridin-3-yl), 4-(6-(amino-carbonyl)-pyridin-3-yl), 4-(1 -cyclopropyl)-2-oxo-pyridin-4-yl), 4-(2-cyclopropyl-6-(methyl-sulfonyl)-pyridin-3-yl),-(6-(3-hydroxy-3-methyl-azetidin- 1 -yl-su If ony l)-pyridin-3-yl) , 4-(6-(piperazin-1 -yl-su If ony l)-pyridi n-3-yl , 4-(6-(morpholin-4- yl-sulfonyl)-pyridin-3-yl), 4-(6-(2,2,2-trifluoro-ethyl)-piperazin-1 -yl-sulfonyl)-pyridin-3-yl), (6-(4-methyl-piperazin-1 -yl-sulfonyl)-pyridin-3-y I) , 4-(6-((thiomorpholin-4-yl-1 ,1 -dioxide)-sulfonyl)-pyridin-3-yl, 4-(5-(methyl-sulfonyl)-pyrimidin-2-yl), 4-(5-(methyl-sulfonyl)- pyrazin-2-yl), 4-(6-(methyl-sulfonyl)-pyridazin-3-yl), 3-(methyl-sulfonyl-amino)- bicyclo[1 .1 .1 ]pentan-1 -yl, (1 ,4)-2-(methyl-sulfonyl)-2-azabicyclo[2.2.1]heptan-5-yl, and (1 R,4R)-5-methyl-2-(methylsulfonyl)-2-azabicyclo[2.2.1]heptan-5-yl; or a stereoisomer or pharmaceutically acceptable salt thereof.

6. A compound as in Claim 3, whereinR1is selected from the group consisting of hydrogen, chloro and cyano;R2is selected from the group consisting of R-(2-hydroxy-isopropyl), R-(methyl- amino-carbonyl), S-(methyl-amino-carbonyl-methyl) and R-(thiomorpholin-4-yl 1 ,1- dioxide-methyl); a is an integer from 0 to 1 ; and L1is -CH2-;R3is selected from the group consisting of 4-trifluoro-methyl-phenyl and 6- (trifluoro-methyl)-pyridin-3-yl;R4is selected from the group consisting of 2,5-dimethyl-phenyl and 2,3,6- trimethyl-phenyl;R8is; whereinis selected from the group consisting of piperidin-1 -yl, 3,3-difluoro-piperidin-1 -yl, 4,4-difluoro-piperidin-1 -yl, and piperazin-1 -yl;L3is selected from the group consisting of 4-(-CH2-), 4-(-C(O)-(CH2)-), 3-(-NH-), 4-(-NH-), 3R*-(-NH-), 3S*-(-NH-), 4R*-(-NH-), 4S*-(-NH-), and 3-(-O-);R10is selected from the group consisting of 3-(methyl-sulfonyl)-azetidin-1 -yl, 4- (methyl-sulfonyl)-piperidin-1 -yl, 1 -(methyl-sulfony l)-piperid in-4-yl , tetrahydro-thiophen-3- yl-1 ,1 -dioxide, 1 ,4-dioxan-3-yl, pyridin-4-yl, and 6-(methyl-sulfonyl)-pyridin-3-yl; or a stereoisomer or pharmaceutically acceptable salt thereof.

7. A compound as in Claim 3, whereinR1is selected from the group consisting of hydrogen, chloro, cyano and methylsulfonyl-;R2is selected from the group consisting of 2-hydroxy-isopropyl, R-(2-hydroxy-isopropyl), R-(methyl-amino-carbonyl), R*-(methyl-amino-carbonyl), S*-(methyl-amino- carbonyl) and R-(2-hydroxy-isobutyl-amino-carbonyl); a is an integer from 0 to 1 ; L1is -CH2-;R3is selected from the group consisting of 4-trifluoro-methyl-phenyl, 4-(2,2,2- trifluoro-ethyl)-phenyl and 6-(trifluoro-methyl)-pyridin-3-yl;R4is selected from the group consisting of 2,3,6-trimethyl-phenyl, 2,6-dimethyl-3- chloro-phenyl, 2-(4-(trifluoro-methyl)-1 ,2,3-triazol-1 -yl)-3,6-dimethyl-phenyl and 2-(1 - methyl-azetidin-3-yl-amino-carbonyl)-3,6-dimethyl-phenyl;R8is; whereinis selected from the group consisting of6-cyclopropyl-2,6-diazaspiro[3.3]heptan-2-yl, 2,3-dihydroxy-(1 S,4S)-2- azabicyclo[2.2.1 ]heptan-2-yl, 2,6-diazaspiro[3.4]octan-2-yl, 2-(methyl-sulfonyl)-2,6- diazaspiro[3.4]octan-2-yl, 2-(methyl-carbonyl)-2,6-diazaspiro[3.4]octan-2-yl, 2-thia-6- azaspiro[3.4]octan-6-yl 2,2-dioxide, 2,7-diazaspiro[3.5]nonan-7-yl-3-one, 2-oxa-6- azaspiro[3.5]nonan-6-yl, 2-oxa-5,8-diazaspiro[3.5]nonan-8-yl, 2-oxa-7- azaspiro[3.5]nonan-7-yl, 2-thia-7-azaspiro[3.5]nonan-7-yl 2,2-dioxide, 2-hydroxy-7- azaspiro[3.5]nonan-7-yl, 2-hydroxy-2-methyl-7-azaspiro[3.5]nonan-7-yl, 2-oxa-8- azaspiro[4.5]decan-8-yl, 2-thia-8-azaspiro[4.5]decan-8-yl 2,2-dioxide, 8-thia-2- azaspiro[4.5]decan-2-yl 8,8-dioxide, 3-azaspiro[5.5]undecan-3-yl; 3-oxa-9- azaspiro[5.5]undecan-9-yl, 3-(methyl-sulfonyl)-3,9-diazaspiro[5.5]undecan-3-yl, 6-oxa-2- thia-9-azaspiro[4.6]undecan-9-yl 2,2-dioxide, 3-thia-9-azaspiro[5.5]undecan-9-yl 3,3- dioxide, 1 -oxa-9-thia-4-azaspiro[5.5]undecan-4-yl 9,9-dioxide, 7-oxa-3-thia-10- azaspiro[5.6]dodecan-10-yl 3,3-dioxide, octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2- dioxide, (R*)-octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2-dioxide, (S*)- octahydropyrazino[2,1 -c] [ 1 ,4]thiazin-8-y I 2,2-dioxide, 7,7-dimethyl- octahydropyrazino[2,1 -c] [ 1 ,4]thiazin-8-y I 2,2-dioxide, 7,7-dimethyl-(R*)- octahydropyrazino[2,1 -c] [ 1 ,4]thiazin-8-y I 2,2-dioxide, 7,7-dimethyl-(S*)- octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2-dioxide, (4aR,8aR)-octahydro-1 H- pyrano[3,4-c]pyridin-7-yl, (4aR,8aS)-octahydro-1 H-pyrano[3,4-c]pyridin-7-yl, (4aS,8aR)- octahydro-1 H-pyrano[3,4-c]pyridin-7-yl, (4aS,8aS)-octahydro-1 H-pyrano[3,4-c]pyridin-7- yl, hexahydro-pyrazino[2,1 -c][1 ,4]oxazin-8-yl-4-one, octahydropyrazino[2,1 -c][1 ,4]oxazin-8-yl, (S)-octahydropyrazino[2,1 -c][1 ,4]oxazin-8-yl, octahydropyrazino[2,1 - c][1 ,4]oxazin-8-yl-6,6-d2, (S)-hexahydro-pyrazino[2,1 -c][1 ,4]oxazin-8-yl-4-one, (S*)- hexahydro-pyrazino[2,1 -c] [ 1 ,4]oxazin-8-yl-6-one, (R*)-hexahydro-pyrazino[2,1 - c][1 ,4]oxazin-8-yl-6-one, 8-methyl-(R*)-hexahydro-1 H-pyrazino[1 ,2-a]pyrazin-2-yl, 8- methyl-(S*)-hexahydro-1 H-pyrazino[1 ,2-a]pyrazin-2-yl, 8-(2,2,2-trifluoro-ethyl)-(R*)- octahydro-2H-pyrazino[1 ,2-a]pyrazin-2-yl, 8-(2,2,2-trifluoro-ethyl)-(S*)-octahydro-2H- pyrazino[1 ,2-a]pyrazin-2-yl, 2-(methyl-sulfonyl)-3,4,6,7,9,9aR*-hexahydro-1 H- pyrazino[1 ,2-a]pyrazin-8-yl, 2-(methyl-sulfonyl)-3,4,6,7,9,9aS*-hexahydro-1 H- pyrazino[1 ,2-a]pyrazin-8-yl, 2-imino-2-oxo-3,4,6,7,9,9a-hexahydro-1 H-pyrazino[2,1 - c][1 ,4]thiazin-8-yl, 7-(methyl-sulfonyl)-3,4-dihydro-1 H-isoqu inolin-2-yl, 6-chloro- spiro[isobenzofuran-1 ,4'-piperid in- 1 -yl], 6-(methyl-sulfonyl)-(1 R*)-spiro[isobenzofuran- 1 ,4'-pi peridin]- 1 '-yl, 6-(methyl-sulfonyl)-(1 S*)-spiro[isobenzofuran-1 ,4'-pi peridin]- 1 '-yl, 3- fluoro-6-(methyl-sulfonyl)-spiro[isobenzofuran-1 ,4'-pi peridin- 1 -yl], 5-(methyl-sulfonyl)- octahydropyrrolo[3,4-b]pyrrol-1 -yl, hexahydro-1 H-thieno[3,4-b]pyrrol-1 -yl 5,5-dioxide, 3- (trifluoro-methyl)-5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3-c]pyrimidin-6-yl, and 5-(4-(methyl- sulfonyl)-phenyl)-2,5-diazabicyclo[2.2.2]octan-2-yl; or a stereoisomer or pharmaceutically acceptable salt thereof.

8. A compound as in Claim 1 , whereinR1is selected from the group consisting of cyano, methyl-sulfonyl, H, morpholin- 4-yl-methyl, amino-carbonyl, methyl, chloro, dimethyl-amino-methyl, methoxy-methyl, cyclopropyl-sulfonyl, morpholin-4-yl, hydroxy-methyl, -(CO)-(morpholin-4-yl), ethoxy, 2,2,2-trifluoro-ethyl-amino-methyl, methyl-amino-methyl, methoxy, piperazin-1 -yl, difluoro-methyl, trifluoro-methyl, 3 , 3-difl uoro-pyrrolidi n-1 -yl-methyl, 3-fluoro-azetidin-1 -yl, and hydroxy;R2is selected from the group consisting of R-(1 -methyl-piperidin-2-yl-methyl- amino-carbonyl), R-(2-hydroxy-isobutyl-amino-carbonyl), R-(dimethyl-amino-ethyl- amino-carbonyl), R-(methyl-amino-carbonyl), R-(2-hydroxy-isopropyl), R-(hexahydro- 1 H-pyrrolizin-7a-yl-methyl-amino-carbonyl), R-(2,2-difluoro-ethyl)-amino-carbonyl), R-(1 - cyano-cycloprop-1 -yl-methyl-amino-carbonyl), R-(cis-(3-hydroxy-3-methyl-cyclobut-1 - yl)-amino-carbonyl), R-(2,2,2-trifluoro-ethyl-amino-carbonyl), R*-(methyl-amino-carbonyl), R-(1 -methyl-pyrrolidin-2-yl-methyl-amino-carbonyl), S*-(methyl-amino- carbonyl), R-(1 -cyano-cycloprop-1 -yl-amino-carbonyl), R-(2,2-difluoro-ethyl-amino- carbonyl), R-(2-methoxy-isobutyl-amino-carbonyl), R-(trans-(2-trifluoro-methyl- cycloprop-1 -yl)-amino-carbonyl), R-(1 -trifluoro-methyl-cycloprop-1 -yl-amino-carbonyl), S*-(methyl-amino-carbonyl-methyl), R-(4-methyl-morpholin-2-yl-methyl-amino-carbonyl), R-(2-hydroxy-isobutyl-amino-methyl), R-(dimethyl-amino-carbonyl), R-(1 -methyl-1 ,2,3- triazol-4-yl), R-(2-isobutyl-amino-carbonyl), R-(cis-(3-hydroxy-3-methyl-cyclobut-1 -yl)- amino-methyl), R-(methyl-amino-methyl), R-(trans-(3-hydroxy-3-methyl-cyclobut-1 -yl)- amino-carbonyl), R-(dimethyl-amino-methyl), R-(tetrahydro-furan-2-yl-methyl-amino- carbonyl), R*-(methyl-amino-carbonyl-methyl), methyl-amino-carbonyl, S-(methyl- amino-carbonyl-methyl), S-(2-hydroxy-isobutyl-amino-carbonyl-methyl), morpholin-4-yl- ethyl-amino-carbonyl, R-(S-(1 -methyl-4,4-difluoro-pyrrolidin-2-yl)-methyl-amino- carbonyl), R-(1 S-amino-2,2,2-trifluoro-ethyl), R-(D3-methyl-amino-carbonyl), R*-(3- hydroxy-oxetan-3-yl), R-(2,2-difluoro-ethyl)-amino-methyl), R-(isopropyl-amino- carbonyl), R-(oxetan-3-yl-amino-methyl), R-(morpholin-4-yl-methyl), S*-(4-hydroxy- piperidin-4-yl), R-(5-methyl-1 ,2,4-oxadiazol-2-yl), R-(2-cyano-ethyl-amino-methyl), R-(2- methyl-1 ,3,4-thiadiazol-5-yl), R*-(amino-carbonyl), R-(methyl-amino-carbonyl-methyl), R-(thietan-3-yl 1 ,1 -dioxide-amino-carbonyl), R-(thietan-3-yl 1 ,1 -dioxide-amino-methyl), S*-(1 S*-hydroxy-ethyl), S-(2,2-difluoro-ethyl-amino-carbonyl-methyl), R-(5-methyl-1 ,3,4- oxadiazol-2-yl), 1 -(pi peridi n-4-yl)- 1 S*-hydroxy-methyl, R-(1 -trifluoro-methyl-cycloprop-1 - yl-methyl-amino-carbonyl), R-(hydroxy-methyl), 1 S*-(hydroxy-ethyl), R-(3,3-difluoro- pyrrolidin-1 -yl-carbonyl), R-(thiomorpholin-4-yl 1 ,1 -dioxide-methyl), R-((3-cyano- bicyclo[1 .1 .1]pentan-1 -yl)-amino-carbonyl), R-(2-hydroxy-3,3,3-trifluoro-n-propyl-amino- carbonyl), R-(1 R*,3-dihydroxy-1 -methyl-n-propyl), R-trans((1 -trifluoro-methyl-cycloprop- 1 -yl)-methyl-amino-carbonyl), R-(cyclobutyl-amino-carbonyl), R-(3,3-difluoro-cyclobut-1 - yl-amino-carbonyl), R-(2-hydroxy-isobutyl), R-(amino-methyl), and S*-(dimethyl-amino- ethyl-amino-carbonyl); a is an integer from 0 to 1 and L1is -CH2-;R3is selected from the group consisting of 4-trifluoro-methyl-phenyl, 6-(trifluoro- methyl)-pyridin-3-yl , 2-(vinyl-carbonyl-amino)-4-trifluoro-methyl)-phenyl, 2-(propa-1 ,2- dienyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(1 -cyano-vinyl-4-trifluoro-methyl-phenyl), 2-(trifluoro-methyl)-thiazol-4-yl, 2-(prope-1 -nyl-carbonyl-amino)-4-trifluoro- methyl-phenyl, 2-(trifluoro-methyl)-pyrimidin-5-yl, 4-(2,2,2-trifluoro-ethyl)-phenyl, 2-nitro- 4-trifluoro-methyl-phenyl, 2-amino-4-trifluoro-methyl-phenyl, 4-(trifluoro-methoxy)- phenyl, 2-(vinyl-carbonyl-amino)-4-(pentafluoro-ethyl)-phenyl, 3-(amino-methyl)-4- trifluoro-methyl-phenyl, 2-chloro-4-trifluoro-methyl-phenyl, 2-(bicyclo[1 .1 .0]butan-1 -yl- carbonyl-amino)-4-(trifluoro-methyl)-phenyl, 3-(propy-2-nyl-carbonyl-amino)-4-(trifluoro- methyl)-phenyl, 2-(1 -fluoro-vinyl-carbonyl-amino)-4-(trifluoro-methyl)-phenyl, 4-(trif luoro- methyl)-bicyclo[2.2.2]octan-1 -yl, 3-(hydroxy-methyl)-4-trifluoro-methyl-phenyl, 4-(cyano- methyl)-phenyl, 3-(vinyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 4-(1 -cyano-vinyl)- phenyl, 2-(vinyl-carbonyl-amino)-4-trifluoro-methyl-phenyl), 3-(vinyl-carbonyl-amino-(4- trifluoro-methyl)-phenyl, 2-(N-methyl, N-vinyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(3-dimethyl-amino-prope-1 -nyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(propy-1 - nyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(morpholin-4-yl-propen-1 -yl-carbonyl- amino)-4-trifluoro-methyl-phenyl, and 2-(vinyl-carbonyl-amino)-4-trifluoro-methoxy- phenyl);R4is selected from the group consisting of 2,3,6-trimethyl-phenyl, 2-(hydroxy- methyl)-3,6-dimethyl-phenyl, 2-(1 ,2,3-triazol-5-yl)-3,6-dimethyl-phenyl, 2-(2-pyridin-2-yl- 2,2-difluoro-ethyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(methoxy-ethyl-amino- carbonyl)-3,6-dimethyl-phenyl, 2,6-dimethyl-3-chloro-phenyl, 2,6-dimethyl-3-D3-methyl- phenyl, 2-(1 -methyl-piperidin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(3- methoxy-pyridin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(methyl-amino)- 3,6-dimethyl-phenyl, 2,6-dimethyl-3-methoxy-phenyl, 2-(1 -methyl-azetidin-3-yl-amino- carbonyl)-3,6-dimethyl-phenyl, 2-(2,2,2-trifluoro-ethyl-amino-carbonyl)-3,6-dimethyl- phenyl, 2,5-dimethyl-phenyl, 2-amino-3,6-dimethyl-phenyl, 2-methoxy-3,6-dimethyl- phenyl, 2-(amino-methyl)-3,6-dimethyl-phenyl, 2-(2,2-difluoro-ethyl-amino-methyl)-3,6- dimethyl-phenyl, 2-(methyl-carbonyl-amino-methyl)-3,6-dimethyl-phenyl, 2-pyrazol-5-yl- 3,6-dimethyl-phenyl, 2-(4-(trifluoro-methyl)-1 ,2,3-triazol-5-yl)-3,6-dimethyl-phenyl, 2-(1 - piperidin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(4-trifluoro-methyl-1 ,2,3- triazol-5-yl)-3,6-dimethyl-phenyl, 2-(isopropyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2- (tetrahydropyran-4-yl-carbonyl-amino)-3,6-dimethyl-phenyl, 2,6-dimethyl-3-hydroxy- methyl-phenyl, 2-(dimethyl-amino)-3,6-dimethyl-phenyl, 3-methoxy-2,6-dimethyl-phenyl,2-(methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(pyrimidin-2-yl-methyl-amino- carbonyl)-3,6-dimethyl-phenyl, 2-((3-methoxy-pyridin-2-yl)-methyl-amino-carbonyl)-3,6- dimethyl-phenyl, 2-(pyridin-4-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(pyridin-3-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(2-(dimethyl-amino)-ethyl-amino- carbonyl)-3,6-dimethyl-phenyl, and 2-(1 -azetidin-3-yl-amino-carbonyl)-3,6-dimethyl- phenyl;R8is selected from the group consisting of; and whereinis selected from the group consisting of 4-(methyl-SO(NH2)-methyl)-piperidin-1 -yl, 4-(methyl-sulfonyl-methyl)-piperidin-1 -yl, 4- (methyl-sulfonyl-amino)-piperidin-1 -yl , 4-(dimethyl-amino-carbonyl-methyl)-piperidin-1 - yl, 4-(ethyl-sulfonyl-amino)-piperidin-1 -yl, 4-(isopropyl-sulfonyl-methyl)-piperidin-1 -yl, 4- (cyclopropyl-sulfonyl-amino)-piperidin-1 -yl, 4-(methoxy-methyl)-piperidin-1 -yl, 4-(cyano- methyl)-pi peridin- 1 -yl, 4-(methyl-dicarbonyl-amino)-piperidin-1 -yl, 4-(amino-carbonyl- methyl)-piperidin-1 -yl, 4-(methoxy-ethyl)-piperazin-1 -yl, and 3-(hydroxy-methyl)-4- methyl-piperazin-1 -yl;(b); whereinis selected from the group consisting of piperazin-1 -yl, piperidin-1 -yl, 3,3,-difluoro-piperidin-1 -yl, piperazin-1 - yl-3-one, 3,3-difluoro-4S*-hydroxy-piperidin-1 -yl, 3,3-difluoro-piperidin-1 -yl, , piperidin- 1 -yl-3-one, 3-fluoro-piperidin-1 -yl, 3,3-difluoro-4R*-hydroxy-piperidin-1 -yl, 2R-methyl- piperazin-1 -yl, 4-hydroxy-piperidin-1 -yl, and 4-cyano-piperidin-1 -yl; and whereinis selected from the group consisting of 4-(4-(methyl-sulfonyl)- phenyl), 4-(6-(methyl-sulfonyl)-pyridin-3-yl), 4-(4-(methyl-sulfonyl)-pyridin-3-yl), 4S*-(6- (methyl-sulfonyl)-pyridin-3-yl), 4R-(6-(methyl-sulfonyl)-pyridin-3-yl), 4R*-(6-(methyl- sulfonyl)-pyridin-3-yl), 4-(6-(methyl-sulfonyl)-pyridin-2-yl), (6-(methyl-sulfonyl)-pyridin-3- yl), (1 -cyclopropyl-2-oxo-piperidin-4-yl), 4-(1 -cyclopropyl-2-oxo-pyridin-4-yl), 4-(4- methyl-sulfonyl-phenyl), (4-(methyl-sulfonyl)-piperazin-1 -yl), (6-(3-oxo-4-methyl- piperazin-1 -yl-su If onyl)-pyridi n-3-yl) , 4-(4-(methyl-sulfonyl)-piperazin-1 -yl), (4-(methyl- sulfonyl)-piperidi n-1 -yl), 4-(4-(amino-sulfonyl)-phenyl), (6-(4-methyl-piperazin-1 -yl-sulfonyl)-pyridin-3-yl) , 4-trans-(4-(methyl-sulfonyl)-cyclohex-1 -yl) , 4-(6-(3-hydroxy-3- methyl-azetidin-1 -yl-su If ony l)-pyridi n-3-yl) , 4-(6-(piperazin-1 -yl-sulf onyl)-py rid in-3-yl , 4- (6-(2,2, 2-trif I uoro-ethyl)-pyridi n-3-yl) , 4-(1 -methyl-2-oxo-piperidin-4-yl), 4-(6-(2-hydroxy- isobutyl-amino-sulfonyl)-pyridin-3-yl), 4-(4-methyl-sulfonyl)-phenyl), 4-(1 -(methyl- sulfonyl)-piperidin-4-yl) , 4-(thiomorpholin-4-yl-1 ,1 -dioxide), 4-(6-(methyl-sulfonimidoyl))- pyridin-3-yl), 4S*-(3-oxo-4-methyl-piperazin-1 -yl), 4-(2-methyl-6-(methyl-sulfonyl)- pyridin-3-yl), 4-(5-(methyl-sulfonyl)-pyrimidin-2-yl), 4-(6-(methyl-sulfonyl)-pyridazin-3-yl), 4-(4-(dimethyl-amino-carbonyl)-phenyl), 4R*-(3-oxo-4-methyl-piperazin-1 -yl), 4-(6- (morpholin-4-yl-sulfonyl)-pyridin-3-yl), 4-(4-(trifluoro-methoxy)-phenyl), 4-(4-(azetidin-1 - yl-carbonyl)-phenyl, 4-(6-((thiomorpholin-4-yl-1 ,1 ,-dioxide)-sulfonyl)-pyridin-3-yl), 4-(4-(methyl-amino-carbonyl)-phenyl), 4-(1 -(methyl-sulfonyl)-cyclopropyl), 4-(6-(trif luoro- methoxy)-pyridin-3-yl), 4-(tetrahydro-thiopyran-4-yl 1 ,1 -dioxide), 4-(4-(methyl-sulfonyl- amino)-piperidin-1 -yl), 4-(2-methyl-pyridin-4-yl), 4-(2-chloro-6-(methyl-sulfonyl)-pyridin- 3-yl), 4-(tetrahydro-thiophen-3R*-yl), 4-(6-(dimethyl-amino)-pyridin-3-yl), 4S-(6-(methyl- sulfonyl)-pyridin-3-yl), 4-(tetrahydro-thiophen-3-yl-1 ,1 -dioxide), 4-(tetrahydro-thiophen- 3S*-yl), 4-(4-(methyl-sulfonyl)-piperidin-1 -yl), 4-(2-cyclopropyl-6-(methyl-sulfonyl)- pyridin-3-yl), and 4-(2-isopropyl-6-(methyl-sulfonyl)-pyridin-3-yl);(c)whereinis selected from the group consisting of 3,3-difluoro-piperidin-1 -yl, piperidin-1 -yl, and piperazin-1 -yl; wherein L3is selected from the group consisting of 4-(NH), 4S*-(NH), 3R*-(NH), 3-(NH), 4-(CH2), and 4R*-(NH); and wherein R10is selected from the group consisting of 1 -(methyl-sulfonyl- piperidin-4-yl), 1 -(methyl-sulfonyl)-piperidin-4-yl, 4-(methyl-sulfonyl)-piperidin-1 -yl, and 1 ,4-dioxan-3-yl; (e) — F; wherein5is selected from the group consisting of (S*)-octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2-dioxide, octahydropyrazino[2,1 - c][1 ,4]thiazin-8-yl 2,2-dioxide, 7,7-dimethyl-octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2- dioxide, (S)-octahydropyrazino[2,1 -c][1 ,4]oxazin-8-yl, 2-thia-8-azaspiro[4.5]decan-8-yl 2,2-dioxide, 1 -oxa-9-thia-4-azaspiro[5.5]undecan-4-yl 9,9-dioxide, 3-thia-9- azaspiro[5.5]undecan-9-yl 3,3-dioxide, 3-oxa-9-azaspiro[5.5]undecan-9-yl, 2-oxa-7-azaspiro[3.5]nonan-7-yl, 7-oxa-3-thia-10-azaspiro[5.6]dodecan-10-yl 3,3-dioxide, and 2,3-dihydroxy-(1 S,4S)-2-azabicyclo[2.2.1]heptan-2-yl; or a stereoisomer or pharmaceutically acceptable salt thereof.

9. A compound as in Claim 1 , whereinR1is selected from the group consisting of cyano, methyl-sulfonyl, H, morpholin- 4-yl-methyl, amino-carbonyl, methyl, chloro, dimethyl-amino-methyl, methoxy-methyl, cyclopropyl-sulfonyl, morpholin-4-yl, hydroxy-methyl, and -(CO)-(morpholin-4-yl);R2is selected from the group consisting of R-(1 -methyl-piperidin-2-yl-methyl- amino-carbonyl), R-(2-hydroxy-isobutyl-amino-carbonyl), R-(dimethyl-amino-ethyl- amino-carbonyl), R-(methyl-amino-carbonyl), R-(2-hydroxy-isopropyl), R-(hexahydro- 1 H-pyrrolizin-7a-yl-methyl-amino-carbonyl), R-(2,2-difluoro-ethyl)-amino-carbonyl), R-(1 - cyano-cycloprop-1 -yl-methyl-amino-carbonyl), R-(cis-(3-hydroxy-3-methyl-cyclobut-1 - yl)-amino-carbonyl), R-(2,2,2-trifluoro-ethyl-amino-carbonyl), R*-(methyl-amino- carbonyl), R-(1 -methyl-pyrrolidin-2-yl-methyl-amino-carbonyl), S*-(methyl-amino- carbonyl), R-(1 -cyano-cycloprop-1 -yl-amino-carbonyl), R-(2,2-difluoro-ethyl-amino- carbonyl), R-(2-methoxy-isobutyl-amino-carbonyl), R-(trans-(2-trifluoro-methyl- cycloprop-1 -yl)-amino-carbonyl), R-(1 -trifluoro-methyl-cycloprop-1 -yl-amino-carbonyl), S*-(methyl-amino-carbonyl-methyl), R-(4-methyl-morpholin-2-yl-methyl-amino-carbonyl), R-(2-hydroxy-isobutyl-amino-methyl), R-(dimethyl-amino-carbonyl), R-(1 -methyl-1 ,2,3- triazol-4-yl), R-(2-isobutyl-amino-carbonyl), R-(cis-(3-hydroxy-3-methyl-cyclobut-1 -yl)- amino-methyl), R-(methyl-amino-methyl), R-(trans-(3-hydroxy-3-methyl-cyclobut-1 -yl)- amino-carbonyl), R-(dimethyl-amino-methyl), R-(tetrahydro-furan-2-yl-methyl-amino- carbonyl), R*-(methyl-amino-carbonyl-methyl), and S*-(dimethyl-amino-ethyl-amino- carbonyl); a is an integer from 0 to 1 ; and L1is -CH2-;R3is selected from the group consisting of 4-trifluoro-methyl-phenyl, 6-(trifluoro- methyl)-pyridin-3-yl , 2-(vinyl-carbonyl-amino)-4-trifluoro-methyl)-phenyl, 2-(propa-1 ,2- dienyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(1 -cyano-vinyl-4-trifluoro-methyl- phenyl), 2-(trifluoro-methyl)-thiazol-4-yl, 2-(prope-1 -nyl-carbonyl-amino)-4-trifluoro- methyl-phenyl, 2-(trifluoro-methyl)-pyrimidin-5-yl, 4-(2,2,2-trifluoro-ethyl)-phenyl, 2-nitro-4-trifluoro-methyl-phenyl, 2-amino-4-trifluoro-methyl-phenyl, 4-(trifluoro-methoxy)- phenyl, 3-(vinyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 4-(1 -cyano-vinyl)-phenyl, 2- (vinyl-carbonyl-amino)-4-trifluoro-methyl-phenyl), 3-(vinyl-carbonyl-amino-(4-trifluoro- methyl)-phenyl, 2-(N-methyl,N-vinyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(3- dimethyl-amino-prope-1 -nyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(propy-1 -nyl- carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(morpholin-4-yl-propen-1 -yl-carbonyl- amino)-4-trifluoro-methyl-phenyl, and 2-(vinyl-carbonyl-amino)-4-trifluoro-methoxy- phenyl);R4is selected from the group consisting of 2,3,6-trimethyl-phenyl, 2-(hydroxy- methyl)-3,6-dimethyl-phenyl, 2-(1 ,2,3-triazol-5-yl)-3,6-dimethyl-phenyl, 2-(2-pyridin-2-yl- 2,2-difluoro-ethyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(methoxy-ethyl-amino- carbonyl)-3,6-dimethyl-phenyl, 2,6-dimethyl-3-chloro-phenyl, 2,6-dimethyl-3-D3-methyl- phenyl, 2-(1 -methyl-piperidin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(3- methoxy-pyridin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(methyl-amino)- 3,6-dimethyl-phenyl, 2,6-dimethyl-3-methoxy-phenyl, 2-(1 -methyl-azetidin-3-yl-amino- carbonyl)-3,6-dimethyl-phenyl, 2-(2,2,2-trifluoro-ethyl-amino-carbonyl)-3,6-dimethyl- phenyl, 2,5-dimethyl-phenyl, 2-amino-3,6-dimethyl-phenyl, 2-methoxy-3,6-dimethyl- phenyl, 2-(amino-methyl)-3,6-dimethyl-phenyl, 2-(2,2-difluoro-ethyl-amino-methyl)-3,6- dimethyl-phenyl, 2-(methyl-carbonyl-amino-methyl)-3,6-dimethyl-phenyl, 2-pyrazol-5-yl- 3,6-dimethyl-phenyl, 2-(methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(pyrimidin-2-yl- methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-((3-methoxy-pyridin-2-yl)-methyl-amino- carbonyl)-3,6-dimethyl-phenyl, 2-(pyridin-4-yl-methyl-amino-carbonyl)-3,6-dimethyl- phenyl, 2-(pyridin-3-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(2-(dimethyl- amino)-ethyl-amino-carbonyl)-3,6-dimethyl-phenyl, and 2-(1 -azetidin-3-yl-amino- carbonyl)-3,6-dimethyl-phenyl;R8is selected from the group consisting ofis selected from the group consisting of 4-(methyl-SO(NH2)-methyl)-piperidin-1 -yl and 4-(methyl-sulfonyl-methyl)-piperidin-1 - yi;(b); whereinis selected from the group consisting of piperazin-1 -yl, piperidin-1 -yl, 3,3,-difluoro-piperidin-1 -yl, piperazin-1 - yl-3-one, 3,3-difluoro-4S*-hydroxy-piperidin-1 -yl, 3,3-difluoro-piperidin-1 -yl, , piperidin-1 -yl-3-one, 3-fluoro-piperidin-1 -yl, 3,3-difluoro-4R*-hydroxy-piperidin-1 -yl, and 2R- methyl-piperazin-1 -yl; and whereinis selected from the group consisting of 4-(4-(methyl-sulfonyl)-phenyl), 4-(6-(methyl-sulfonyl)-pyridin-3-yl), 4-(4- (methyl-sulfonyl)-pyridin-3-yl), 4S*-(6-(methyl-sulfonyl)-pyridin-3-yl), 4R-(6-(methyl- sulfonyl)-pyridin-3-yl), 4R*-(6-(methyl-sulfonyl)-pyridin-3-yl), 4-(6-(methyl-sulfonyl)- pyridin-2-yl), (6-(methyl-sulfonyl)-pyridin-3-yl), (1 -cyclopropyl-2-oxo-piperidin-4-yl), 4-(1 - cyclopropyl-2-oxo-pyridin-4-yl), 4-(4-methyl-sulfonyl-phenyl), (4-(methyl-sulfonyl)- piperazin- 1 -yl) , (6-(3-oxo-4-methyl-piperazin-1 -yl-sulfonyl)-pyridin-3-y I) , 4-(4-(methyl- sulfonyl)-piperazin-1 -yl), (4-(methyl-sulfonyl)-piperidin-1 -yl), 4-(4-(amino-sulfonyl)- phenyl), (6-(4-methyl-piperazin-1 -yl-sulfonyl)-pyridin-3-yl), 4-trans-(4-(methyl-sulfonyl)- cyclohex-1 -yl), 4-(6-(3-hydroxy-3-methyl-azetidin-1 -yl-su If ony l)-pyridi n-3-yl) , 4-(6- (piperazin-1 -yl-su If onyl)-pyridi n-3-yl , 4-(6-(2,2,2-trif lu oro-ethyl)-py ridin-3-yl) , 4-(1 -methyl-2-oxo-piperidin-4-yl), 4-(6-(2-hydroxy-isobutyl-amino-sulfonyl)-pyridin-3-yl), 4-(4-methyl- sulfonyl)-phenyl), 4-(1 -(methyl-sulfonyl)-piperidin-4-yl), and 4-(thiomorpholin-4-yl-1 ,1 - dioxide);(c); whereinis 3,3-difluoro-piperidin-1 -yl; wherein L3is 4-(NH), 4S*-(NH), 3R*-(NH), 3-(NH), 4-(CH2), and 4R*-(NH); and wherein R10is 1 -(methyl-sulfonyl-piperidin-4-yl);whereinF is selected from the group consisting of octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2-dioxide, and (S*)-octahydropyrazino[2,1 - c][1 ,4]thiazin-8-yl 2,2-dioxide; or a stereoisomer or pharmaceutically acceptable salt thereof.

10. A compound as in Claim 1 , whereinR1is selected from the group consisting of cyano, methyl-sulfonyl, H, morpholin- 4-yl-methyl, amino-carbonyl, methyl, chloro, dimethyl-amino-methyl, methoxy-methyl, cyclopropyl-sulfonyl, and morpholin-4-yl;R2is selected form the group consisting of R-(1 -methyl-piperidin-2-yl-methyl- amino-carbonyl), R-(2-hydroxy-isobutyl-amino-carbonyl), R-(dimethyl-amino-ethyl- amino-carbonyl), R-(methyl-amino-carbonyl), R-(2-hydroxy-isopropyl), R-(hexahydro- 1 H-pyrrolizin-7a-yl-methyl-amino-carbonyl), R-(2,2-difluoro-ethyl)-amino-carbonyl), R-(1 - cyano-cycloprop-1 -yl-methyl-amino-carbonyl), R-(cis-(3-hydroxy-3-methyl-cyclobut-1 - yl)-amino-carbonyl), R-(2,2,2-trifluoro-ethyl-amino-carbonyl), R*-(methyl-amino- carbonyl), R-(1 -methyl-pyrrolidin-2-yl-methyl-amino-carbonyl), S*-(methyl-amino- carbonyl), R-(1 -cyano-cycloprop-1 -yl-amino-carbonyl), R-(2,2-difluoro-ethyl-amino- carbonyl), R-(2-methoxy-isobutyl-amino-carbonyl), R-(trans-(2-trifluoro-methyl- cycloprop-1 -yl)-amino-carbonyl), R-(1 -trifluoro-methyl-cycloprop-1 -yl-amino-carbonyl), S*-(methyl-amino-carbonyl-methyl), R-(4-methyl-morpholin-2-yl-methyl-amino-carbonyl), R-(2-hydroxy-isobutyl-amino-methyl), R-(dimethyl-amino-carbonyl), and S*-(dimethyl- amino-ethyl-amino-carbonyl); a is an integer from 0 to 1 ; and L1is -CH2-;R3is selected form the group consisting of 4-trifluoro-methyl-phenyl, 6-(trifluoro- methyl)-pyridin-3-yl , 2-(vinyl-carbonyl-amino)-4-trifluoro-methyl)-phenyl, 2-(propa-1 ,2- dienyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(1 -cyano-vinyl-4-trifluoro-methyl- phenyl), 2-(trifluoro-methyl)-thiazol-4-yl, 2-(prope-1 -nyl-carbonyl-amino)-4-trifluoro- methyl-phenyl, 2-(trifluoro-methyl)-pyrimidin-5-yl, 3-(vinyl-carbonyl-amino)-4-trifluoro- methyl-phenyl, 4-(1 -cyano-vinyl)-phenyl, 2-(vinyl-carbonyl-amino)-4-trifluoro-methyl- phenyl), 3-(vinyl-carbonyl-amino-(4-trifluoro-methyl)-phenyl, 2-(N-methyl,N-vinyl- carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(3-dimethyl-amino-prope-1 -nyl-carbonyl- amino)-4-trifluoro-methyl-phenyl, 2-(propy-1 -nyl-carbonyl-amino)-4-trifluoro-methyl- phenyl, 2-(morpholin-4-yl-propen-1 -yl-carbonyl-amino)-4-trifluoro-methyl-phenyl, and 2- (vinyl-carbonyl-amino)-4-trifluoro-methoxy-phenyl);R4is selected form the group consisting of 2,3,6-trimethyl-phenyl, 2-(hydroxy- methyl)-3,6-dimethyl-phenyl, 2-(1 ,2,3-triazol-5-yl)-3,6-dimethyl-phenyl, 2-(2-pyridin-2-yl- 2,2-difluoro-ethyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(methoxy-ethyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2,6-dimethyl-3-chloro-phenyl, 2,6-dimethyl-3-D3-methyl- phenyl, 2-(1 -methyl-piperidin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(3- methoxy-pyridin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(methyl-amino)- 3,6-dimethyl-phenyl, 2,6-dimethyl-3-methoxy-phenyl, 2-(1 -methyl-azetidin-3-yl-amino- carbonyl)-3,6-dimethyl-phenyl, 2-(2,2,2-trifluoro-ethyl-amino-carbonyl)-3,6-dimethyl- phenyl, 2,5-dimethyl-phenyl, 2-(methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-pyrazol- 5-yl-3,6-dimethyl-phenyl, 2-(pyrimidin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-((3-methoxy-pyridin-2-yl)-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(pyridin-4-yl- methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(pyridin-3-yl-methyl-amino-carbonyl)- 3,6-dimethyl-phenyl, 2-(2,2-difluoro-ethyl-amino-methyl)-3,6-dimethyl-phenyl, 2-(2-(dimethyl-amino)-ethyl-amino-carbonyl)-3,6-dimethyl-phenyl, and 2-(1 -azetidin-3-yl- amino-carbonyl)-3,6-dimethyl-phenyl;R8is selected from the group consisting of(b); whereinis selected from the group consisting ofpiperazin-1 -yl, piperidin-1 -yl, 3,3,-difluoro-piperidin-1 -yl, piperazin-1 - yl-3-one, 3,3-difluoro-4S*-hydroxy-piperidin-1 -yl, 3,3-difluoro-piperidin-1 -yl, piperidin-1 - yl-3-one, 3-fluoro-piperidin-1 -yl, and 3,3-difluoro-4R*-hydroxy-piperidin-1 -yl; whereinis selected from the group consisting of 4-(4-(methyl-sulfonyl)- phenyl), 4-(6-(methyl-sulfonyl)-pyridin-3-yl), 4-(4-(methyl-sulfonyl)-pyridin-3-yl), 4S*-(6- (methyl-sulfonyl)-pyridin-3-yl), 4R-(6-(methyl-sulfonyl)-pyridin-3-yl), 4R*-(6-(methyl- sulfonyl)-pyridin-3-yl), 4-(6-(methyl-sulfonyl)-pyridin-2-yl), (6-(methyl-sulfonyl)-pyridin-3- yl), (1 -cyclopropyl-2-oxo-piperidin-4-yl), 4-(1 -cyclopropyl-2-oxo-pyridin-4-yl), 4-(4- methyl-sulfonyl-phenyl), (4-(methyl-sulfonyl)-piperazin-1 -yl), (6-(3-oxo-4-methyl- piperazin- 1 -yl-su If onyl)-pyridi n-3-yl) , 4-(4-(methyl-sulfonyl)-piperazin-1 -yl), (4-(methyl- sulfonyl)-piperidi n-1 -yl), 4-(4-(amino-sulfonyl)-phenyl), (6-(4-methyl-piperazin-1 -yl- sulfonyl)-pyridin-3-yl), 4-traand ns-(4-(methyl-sulfonyl)-cyclohex-1 -yl);(c)whereinis 3,3-difluoro-piperidin-1 -yl; wherein L3is 4-(NH), 4S*-(NH), 3R*-(NH), 3-(NH), 4-(CH2), and 4R*-(NH); wherein R10is 1 -(methyl-sulfonyl-piperidin-4-yl);is selected from the group consisting of octahydropyrazino[2,1 -c][1 ,4]thiazin-8-yl 2,2-dioxide, and (S*)-octahydropyrazino[2,1 - c][1 ,4]thiazin-8-yl 2,2-dioxide; or a stereoisomer or pharmaceutically acceptable salt thereof.

11. A compound as in Claim 1 , whereinR1is selected from the group consisting of cyano, methyl-sulfonyl, H, morpholin- 4-yl-methyl, amino-carbonyl, methyl, and chloro;R2is selected from the group consisting of R-(1 -methyl-piperidin-2-yl-methyl- amino-carbonyl), R-(2-hydroxy-isobutyl-amino-carbonyl), R-(dimethyl-amino-ethyl- amino-carbonyl), R-(methyl-amino-carbonyl), R-(2-hydroxy-isopropyl), R-(hexahydro- 1 H-pyrrolizin-7a-yl-methyl-amino-carbonyl), R-(2,2-difluoro-ethyl)-amino-carbonyl), R-(1 - cyano-cycloprop-1 -yl-methyl-amino-carbonyl), R-(cis-(3-hydroxy-3-methyl-cyclobut-1 - yl)-amino-carbonyl), R-(2,2,2-trifluoro-ethyl-amino-carbonyl), R*-(methyl-amino- carbonyl), R-(1 -methyl-pyrrolidin-2-yl-methyl-amino-carbonyl), S*-(methyl-amino- carbonyl), R-(1 -cyano-cycloprop-1 -yl-amino-carbonyl), R-(2,2-difluoro-ethyl-amino- carbonyl), and S*-(dimethyl-amino-ethyl-amino-carbonyl); a is 1 ; and L1is -CH2;R3is selected from the group consisting of 4-trifluoro-methyl-phenyl, 6-(trifluoro- methyl)-pyridin-3-yl , 2-(vinyl-carbonyl-amino)-4-trifluoro-methyl)-phenyl, 2-(propa-1 ,2- dienyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(1 -cyano-vinyl-4-trifluoro-methyl- phenyl), 2-(trifluoro-methyl)-thiazol-4-yl, 3-(vinyl-carbonyl-amino)-4-trifluoro-methyl- phenyl, 4-(1 -cyano-vinyl)-phenyl, 2-(vinyl-carbonyl-amino)-4-trifluoro-methyl-phenyl), 3- (vinyl-carbonyl-amino-(4-trifluoro-methyl)-phenyl, 2-(N-methyl,N-vinyl-carbonyl-amino)- 4-trifluoro-methyl-phenyl, 2-(3-dimethyl-amino-prope-1 -nyl-carbonyl-amino)-4-trifluoro- methyl-phenyl, 2-(propy-1 -nyl-carbonyl-amino)-4-trifluoro-methyl-phenyl, 2-(morpholin- 4-yl-propen-1 -yl-carbonyl-amino)-4-trifluoro-methyl-phenyl, and 2-(vinyl-carbonyl- amino)-4-trifluoro-methoxy-phenyl);R4is selected from the group consisting of 2,3,6-trimethyl-phenyl, 2-(hydroxy-methyl)-3,6-dimethyl-phenyl, 2-(1 ,2,3-triazol-5-yl)-3,6-dimethyl-phenyl, 2-(2-pyridin-2-yl- 2,2-difluoro-ethyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(methoxy-ethyl-amino- carbonyl)-3,6-dimethyl-phenyl, 2,6-dimethyl-3-chloro-phenyl, 2-(1 -methyl-pi peridi n-2-yl- methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(3-methoxy-pyridin-2-yl-methyl-amino- carbonyl)-3,6-dimethyl-phenyl, 2-(methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2- pyrazol-5-yl-3,6-dimethyl-phenyl, 2-(pyrimidin-2-yl-methyl-amino-carbonyl)-3,6-dimethyl- phenyl, 2-((3-methoxy-pyridin-2-yl)-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2- (pyridin-4-yl-methyl-amino-carbonyl)-3,6-dimethyl-phenyl, 2-(pyridin-3-yl-methyl-amino- carbonyl)-3,6-dimethyl-phenyl, 2-(2,2-difluoro-ethyl-amino-methyl)-3,6-dimethyl-phenyl, 2-(2-(dimethyl-amino)-ethyl-amino-carbonyl)-3,6-dimethyl-phenyl, and 2-(1 -azetidin-3-yl- amino-carbonyl)-3,6-dimethyl-phenyl;R8is selected from the group consisting ofselected from the group consisting of piperazin-1 -yl, piperidin-1 -yl, 3,3,-difluoro-piperidin-1 -yl, piperazin-1 - yl-3-one, 3,3-difluoro-4S*-hydroxy-piperidin-1 -yl, and 3,3-difluoro-piperidin-1 -yl; and whereinis selected from the group consisting of 4-(4-(methyl- sulfonyl)-phenyl), 4-(6-(methyl-sulfonyl)-pyridin-3-yl), 4-(4-(methyl-sulfonyl)-pyridin-3-yl), 4S*-(6-(methyl-sulfonyl)-pyridin-3-yl), 4R-(6-(methyl-sulfonyl)-pyridin-3-yl), 4R*-(6- (methyl-sulfonyl)-pyridin-3-yl), 4-(6-(methyl-sulfonyl)-pyridin-2-yl), (6-(methyl-sulfonyl)- pyridin-3-yl), and (1 -cyclopropyl-2-oxo-piperidin-4-yl); and (c)whereinis 3,3-difluoro-piperidin-1 -yl; wherein L3is 4-(NH); wherein R10is 1 -(methyl-sulfonyl-piperidin-4-yl) ; or a stereoisomer or pharmaceutically acceptable salt thereof.

12. A compound as in Claim 3, selected from the group consisting of(2R)-N-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6- trimethylphenyl)-1 -isoquinolyl]amino]-3-[6-(trifluoromethyl)-3-pyridyl]propenamide;N-[2-[(2R)-3-hydroxy-3-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 - carbonyl]-7-(2,3,6-trimethylphenyl)-1 -isoquinolyl]amino]butyl]-5- (trifluoromethyl)phenyl]prop-2-enamide;(2R)-N-methyl-2-[[5-[4-(4-methylsulfonylphenyl)piperazine-1 -carbonyl]-7-(2,3,6- trimethylphenyl)-1 -isoquinolyl]amino]-3-[2-(prop-2-enoylamino)-4- (trifluoromethyl)phenyl]propenamide;[1 -[[(1 R)-2-hydroxy-2-methyl-1 -[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]-7- (2,3,6-trimethylphenyl)-5-isoquinolyl]-[4-(6-methylsulfonyl-3-pyridyl)-1 - piperidyl]methanone;[3,3-difluoro-4S-[(1 -methylsulfonyl-4-piperidyl)amino]-1 -piperidy l]-[ 1 -[[2-hydroxy- 2-methyl-1 R-[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]-7-(2,3,6-trimethylphenyl)- 5-isoquinolyl]methanone;[(4S*)-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)-5- isoquinolyl]methanone;[(4RS)-3,3-difluoro-4-(6-methylsulfonyl-3-pyridyl)-1 -piperidyl]-[ 1 -[[(1 R)-2-hydroxy- 2-methyl-1 -[[6-(trifluoromethyl)-3-pyridyl]methyl]propyl]amino]-7-(2,3,6-trimethylphenyl)- 5-isoquinolyl]methanone;1 -[[(1 R)-2-hydroxy-2-methyl-1 -[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]-5- [4-(6-methylsulfonyl-3-pyridyl)piperidine-1 -carbonyl]-7-(2,3,6- trimethylphenyl)isoquinoline-3-carbonitrile;[1 -[[(1 R)-2-hydroxy-2-methyl-1 -[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]-3- methylsulfonyl-7-(2,3,6-trimethylphenyl)-5-isoquinolyl]-[4-(6-methylsulfonyl-3-pyridyl)-1 - piperidyl]methanone;[1 -[[(1 R)-2-hydroxy-2-methyl-1 -[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]-3- (morpholinomethyl)-7-(2,3,6-trimethylphenyl)-5-isoquinolyl]-[4-(6-methylsulfonyl-3- pyridyl)- 1 -piperidyl]methanone;[3-chloro-1 -[[(1 R)-2-hydroxy-2-methyl-1 -[[6-(trifluoromethyl)-3- pyridyl]methyl]propyl]amino]-7-(2,3,6-trimethylphenyl)-5-isoquinolyl]-[4-(6- methylsulfonyl-3-pyridyl)-1 -piperidyl]methanone;[3-chloro- 1 -[[(1 R)-2-hydroxy-2-methyl-1 -[[4-(trifluoromethyl)phenyl]methyl]propyl]amino]-7-(2,3,6-trimethylphenyl)-5-isoquinolyl]-[4- (4-methylsulfonylcyclohexyl)piperazin-1 -yl]methanone;(2R)-2-[[5-[(4S*)-3,3-difluoro-4-(6-methylsulfonyl-3-pyridyl)piperidine-1 -carbonyl]- 3-methylsulfonyl-7-(2,3,6-trimethylphenyl)-1 -isoquinolyl]amino]-N-methyl-3-[6- (trifluoromethyl)-3-pyridyl]propenamide;(2R)-2-[[3-cyano-5-[(4S*)-3,3-difluoro-4-(6-methylsulfonyl-3-pyridyl)piperidine-1 - carbonyl]-7-(2,3,6-trimethylphenyl)-1 -isoquinolyl]amino]-N-methyl-3-[4- (trifluoromethyl)phenyl]propenamide; and stereoisomers, and pharmaceutically acceptable salts thereof.

13. A compound selected from the group consisting of(R)-2-methyl-3-((4-(4-(4-(methylsulfonyl)phenyl)piperazine-1 -carbonyl)-7-(2,3,6- trimethylphenyl)isoquinolin-1 -yl)amino)-4-(4-(trifluoromethyl)phenyl)butan-2-yl dihydrogen phosphate;(R)-2-((3-cyano-5-(4-((dimethylphosphoryl)methyl)piperazine-1 -carbonyl)-7- (2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propenamide; and (R)-2-((5-(4-(2-(dimethylphosphoryl)morpholino)piperidine-1 -carbonyl)-7- (2,3,6-trimethylphenyl)isoquinolin-1 -yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof.

14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Claim 1 .

15. A pharmaceutical composition made by mixing a compound of Claim 1 and a pharmaceutically acceptable carrier.

16. A process for making a pharmaceutical composition comprising mixing a compound of Claim 1 and a pharmaceutically acceptable carrier.

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

18. The method of Claim 17, 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).

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

20. The method of Claim 17, 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, colorectalcarcinoma, gastric cancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma.21 . The method of Claim 17, wherein the lymphoma is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

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

23. The use as in Claim 22, 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).

24. The use as in Claim 22, 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, (at) sarcoma of the soft tissue, (ag) gliosarcoma, (ah) osteosarcoma, (ai) malignant fibrous histiocytoma, (aj) lymphosarcoma, (ak) rhabdomyosarcoma, (al) breast cancer, (am) colorectal carcinoma, (an) gastric cancer, (ao) gliosarcoma, (ap) head & neck cancer, (aq) hepatocellular carcinoma, (ar) lung cancer, (as) multiple myeloma, (at) neuroblastoma, (au) ovarian cancer, (av) pancreatic cancer, (aw) prostate cancer, or (ax) renal cell carcinoma.

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

26. The compound of Claim 1 , for use in a method for the treatment of a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is (a) acute lymphoblastic leukemia (ALL), (b) acute myeloid leukemia (AML), (c) (acute) T-cell leukemia, (d) acute monocytic leukemia, (e) acute promyelocytic leukemia (APL), (f) bisphenotypic B myelomonocytic leukemia, (g) chronic myeloid leukemia (CML), (h) chronic myelomonocytic leukemia (CMML), (i) large granular lymphocytic leukemia, (j) plasma cell leukemia, or (k) myelodysplastic syndrome (MDS)27. The compound of Claim 1 , for use in a method for the treatment of a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is (a) AIDS-related lymphoma, (b) Hodgkin lymphoma, (c) non-Hodgkin's lymphoma (NHL), (d) T-non-Hodgkin lymphoma (T-NHL), (e) Diffuse Large Cell Lymphoma (DLBCL), (f) activated B-cell DLBCL, (g) germinal center B-cell DLBCL, (h) double-hit lymphoma, (i) double-expressor lymphoma, (j) anaplastic large cell lymphoma, (k) marginal B cell lymphoma, (I) primary mediastinal B-cell lymphoma, (m) immunoblastic large cell lymphoma, (n) Burkitt lymphoma, (o) follicular lymphoma, (p) hairy cell leukemia, (q) Hodgkin's disease, (r) mantle cell lymphoma (MCL), (s) lymphoplasmatic lymphoma, (t) precursor B -lymphoblastic lymphoma, (u) lymphoma of the central nervous system, (v) small lymphocytic lymphoma (SLL), (w) chronic lymphocyticleukemia (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, (at) sarcoma of the soft tissue, (ag) gliosarcoma, (ah) osteosarcoma, (ai) malignant fibrous histiocytoma, (aj) lymphosarcoma, (ak) rhabdomyosarcoma, (al) breast cancer, (am) colorectal carcinoma, (an) gastric cancer, (ao) gliosarcoma, (ap) head & neck cancer, (aq) hepatocellular carcinoma, (ar) lung cancer, (as) multiple myeloma, (at) neuroblastoma, (au) ovarian cancer, (av) pancreatic cancer, (aw) prostate cancer, or (ax) renal cell carcinoma.

28. The compound of Claim 1 , for use as a medicament.

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

30. The compound of Claim 1 , for use in the treatment of a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is (a) acute lymphoblastic leukemia (ALL), (b) acute myeloid leukemia (AML), (c) (acute) T-cell leukemia, (d) acute monocytic leukemia, (e) acute promyelocytic leukemia (APL), (f) bisphenotypic B myelomonocytic leukemia, (g) chronic myeloid leukemia (CML), (h) chronic myelomonocytic leukemia (CMML), (i) large granular lymphocytic leukemia, (j) plasma cell leukemia, or (k) myelodysplastic syndrome (MDS)31 . The compound of Claim 1 , for use in the treatment of a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is (a) AIDS-related lymphoma, (b) Hodgkin lymphoma, (c) non-Hodgkin's lymphoma (NHL), (d) T-non- Hodgkin lymphoma (T-NHL), (e) Diffuse Large Cell Lymphoma (DLBCL), (f) activated B- cell DLBCL, (g) germinal center B-cell DLBCL, (h) double-hit lymphoma, (i) double- expressor lymphoma, (j) anaplastic large cell lymphoma, (k) marginal B cell lymphoma,(I) primary mediastinal B-cell lymphoma, (m) immunoblastic large cell lymphoma, (n) Burkitt lymphoma, (o) follicular lymphoma, (p) hairy cell leukemia, (q) Hodgkin's disease, (r) mantle cell lymphoma (MCL), (s) lymphoplasmatic lymphoma, (t) precursor B -lymphoblastic lymphoma, (u) lymphoma of the central nervous system, (v) small lymphocytic lymphoma (SLL), (w) chronic lymphocytic leukemia (CLL), (x) precursor T- lymphoblastic lymphoma / leukemia, (y) peripheral T-cell lymphoma (PTCL), (z) cutaneous T-cell lymphoma (CTCL), (aa) angioimmunoblastic T-cell lymphoma, (ab) extranodal natural killer T-cell lymphoma, (ac) enteropathy type T-cell lymphoma, (ad) subcutaneous panniculitis-like T-cell lymphoma, (ae) anaplastic large cell lymphoma, (af) sarcoma of the soft tissue, (ag) gliosarcoma, (ah) osteosarcoma, (ai) malignant fibrous histiocytoma, (aj) lymphosarcoma, (ak) rhabdomyosarcoma, (al) breast cancer, (am) colorectal carcinoma, (an) gastric cancer, (ao) gliosarcoma, (ap) head & neck cancer, (aq) hepatocellular carcinoma, (ar) lung cancer, (as) multiple myeloma, (at) neuroblastoma, (au) ovarian cancer, (av) pancreatic cancer, (aw) prostate cancer, or (ax) renal cell carcinoma.

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

33. A composition comprising a compound of Claim 1 , for use in the treatment of a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is (a) acute lymphoblastic leukemia (ALL), (b) acute myeloid leukemia (AML), (c) (acute) T-cell leukemia, (d) acute monocytic leukemia, (e) acute promyelocytic leukemia (APL), (f) bisphenotypic B myelomonocytic leukemia, (g) chronic myeloid leukemia (CML), (h) chronic myelomonocytic leukemia (CMML), (i) large granular lymphocytic leukemia, (j) plasma cell leukemia, or (k) myelodysplastic syndrome (MDS)34. A composition comprising a compound of Claim 1 , for use in the treatment of a cancer mediated by the BFL-1 receptor, wherein the cancer mediated by the BFL-1 receptor is (a) AIDS-related lymphoma, (b) Hodgkin lymphoma, (c) non-Hodgkin'slymphoma (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.

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

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