(2-(methylphenyl)quinazolin-4-YL)amine derivatives as BFL-1 inhibitors for the treatment of cancer

Abstract

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

Description

(2-(METHYLPHENYL)QUINAZOLIN-4-YL)AMINE DERIVATIVES AS BFL-1 INHIBITORS FOR THE TREATMENT OF CANCERCROSS-REFERENCE TO RELATED APPLICATIONSThis application claims priority from United States Provisional Application Serial No. 63 / 706,797 filed October 14, 2024, the contents of which is incorporated by reference in its entirety.FIELD OF THE INVENTION

[0001] The present invention is directed towards quinazoline derivatives, stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing said compounds, and the use of said compounds in the treatment of leukemias, lymphomas and related cancers.Background of the Invention

[0002] Non-Hodgkin lymphoma (NHL) is a heterogeneous group of malignancies, from B- or T-cell origin, accounting for about 4% of all malignancies in the US (Bibikova et al., Blood. 2019; 134 (Supplement_1 : 2571). Worldwide, diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of NHL, accounting for 30% to 40% of all newly diagnosed cases (Sehn LH & Gascoyne RD, Blood. 2015;125(1 ):22-32). DLBCL typically presents as an aggressive lymphoma, evolving over months and resulting in symptomatic disease that is fatal without treatment (Ibid).

[0003] Outcomes in DLBCL have improved dramatically over the last decade with the addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (R CHOP). This regimen remains the current standard of care. However, R CHOP treatment fails in about 30% to 50% of patients with DLBCL (Coiffier B & Sarkozy C,. Hematology Am Soc Hematol Educ Program. 2016;2016(1):366-378). Less than half of these patients can be cured with stem cell transplantation (Gisselbrecht et al., J Clin Oncol. 2010; 28(27): 4184-4190), and those who are not cured will typically die from their disease (Crump et al., Blood. 2017; 130(16):1800-1808). Since the best chance for cure is front-line treatment, there have been many attempts to improve upon RCHOP but so far, these treatments have failed to significantly improve outcomes (Goy A., J Clin Oncol.2017;35(31):3519-3522). Recently, several studies have explored 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 et al., Lancet Oncol. 2014;15(9):1019-1026). Thus, optimization of front-line therapy, as well as the development of more effective salvage strategies, remains an important objective.

[0004] Follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL) and Waldenström macroglobulinemia (WM) are considered largely incurable lymphomas that require therapies throughout the course of disease. Currently, there are limited lines of therapy available for these diseases, and treatments are needed that avoid the use of cytotoxic chemotherapy.

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

[0006] In addition, patients with newly diagnosed intermediate or higher-risk myelodysplastic syndrome (MDS) and those who relapse after standard care have a poor prognosis and high risk of progression to AML. Therefore, there is an urgent need for new treatment modalities for relapsed / refractory (R / R) AML and MDS patients, newlydiagnosed AML patients ineligible for induction chemotherapy based on age and co- morbidities, and newly diagnosed intermediate / high / very high risk MDS patients.

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

[0008] BFL-1 (‘Bcl-2 related gene expressed in fetal liver’ (Choi et al., Oncogene.1995; 11: 1693-1698), gene name BCL2A1 (B-cell lymphoma 2-related protein A1)) is a lesser-known anti-apoptotic family member, physiologically mainly expressed in the hematopoietic system. BFL-1 was found to be a direct transcriptional target of nuclear factor-κB (NF-κB) (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-1S, predominantly expressed in the lymph nodes (Ko et al., Oncogene.2003; 22: 2457- 2465).

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

[0010] BFL-1 overexpression has been reported in many types of B cell lymphoma. Diffuse large B cell lymphoma (DLBCL) patient sample analysis shows, with regards to expression of anti-apoptotic family members, expression levels of BFL-1 are second only to MCL-1 (Reddy et al., Cell.2017; 171, 481–494). Expression of BFL-1 wasshown to be upregulated in MYC / BCL2 double hit lymphoma cell lines treated with Venetoclax 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.

[0011] There remains a need for inhibitors of the BFL-1 protein, which may be useful for the treatment of cancer, more particularly for the treatment of leukemias and related cancers. Summary of the Invention The present invention is directed to compounds of Formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1is selected from: H, C1-4alkyl, NH2, NH(CH3), N(CH3)2, NH-CH2CH2N(CH3)2, OH, hydroxy substituted C1-4alkyl, OCH3, CH2OCH3, OCF2H, SCH3, SO2CH3, SO2- cyclopropyl, CN, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 4-methylpiperazin-1-yl, and ; R2is , wherein L is absent, CH(CH3) or CH2;Rais phenyl or pyridyl, wherein each phenyl or pyridyl is optionally substituted with one or two members each independently selected from C1-4alkyl, fluorinated-C1-4alkyl, O- fluorinated-C1-4alkyl, NH2, CH2NH2, NH-C(=O)-C2-5alkenyl, NH-C(=O)-C2-5alkynyl, , and ; Rbis , hydroxy substituted C1-4alkyl, or fluorinated-C1-4alkyl; Rfis selected from: CH3; CD3; CH2CH2N(CH3)2; and (CH2)0-1-C3-4cycloalkyl, wherein theC3-4cycloalkyl is optionally substituted with one or two members each independently selected from OH, C1-4alkyl, fluorinated-C1-4alkyl, and hydroxy substituted C1-4alkyl; and Rcis H or CH3; R3is selected from: a 4 to 14 membered nitrogen linked heterocyclyl selected from the group consisting of: monocyclic heterocycloalkyl; spiro-cyclic heterocycloalkyl, bridged heterocycloalkyl or fused heterocycloalkyl; wherein each monocyclic heterocycloalkyl, spiro-cyclic heterocycloalkyl, bridged heterocycloalkyl, and fused heterocycloalkyl contains at least one N atom, optionally containing one, two, or three additional heteroatoms independently selected from N, O, and S; and is optionally substituted with one, two, three or four members each independently selected from: hydroxy, oxo, halo, (=N)-CH3, C1-4alkyl, C1-4alkyl substituted with OH, fluorinated-C1-4alkyl, OC1-4alkyl, CH2- C(=O)-NH(CH3), CH2C(=O)-NH2, C(=O)CH3, SO2-CH3, CH2-SO2-CH3, NH2, N(CH3)2, C(=O)OCH3, C(=O)N(CH3)2, (P=O)(CH3)2, C3-6cycloalkyl, ,R4is selected from: H, C1-4alkyl, hydroxy substituted C1-4alkyl, -OCH3, and -C(=O)-NH- CH2-Rd; wherein Rdis a (CH2)0-2C3-8cycloalkyl optionally substituted with one, two or three members independently selected from halo and C1-4alkyl; or (CH2)0-2heterocyclyl, wherein each heterocyclyl is selected from: monocyclic heterocycloalkyl, spiro-cyclic heterocycloalkyl, bridged heterocycloalkyl, and fused heterocycloalkyl, each optionally substituted with one, two or three members independently selected from halo and C1-4alkyl; andR5is selected from: Cl, F, C1-4alkyl, fluorinated-C1-4alkyl, hydroxy substituted C1-4alkyl, and CN; or wherein R4and R5come together to form a heterocycloalkyl ring wherein -R4-R5- is -CH2N(CH3)CH2CH2-.

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

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

[0014] Exemplifying the invention are methods of treating a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is a leukemia (selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), (acute) T-cell leukemia, acute monocytic leukemia, acute promyelocytic leukemia (APL), bisphenotypic B myelomonocytic leukemia, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia, and myelodysplastic syndrome (MDS)) comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.

[0015] Exemplifying the invention are methods of treating a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is a lymphoma (selected from the group consisting of AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell DLBCL, double-hit lymphoma, double-expressor lymphoma, anaplastic large cell lymphoma, marginal B cell lymphoma, primary mediastinal B-cell lymphoma, immunoblastic large celllymphoma, Burkitt lymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoplasmatic lymphoma, precursor B - lymphoblastic lymphoma, lymphoma of the central nervous system, small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia (CLL), precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma, sarcoma of the soft tissue, gliosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma, breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma) comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.

[0016] In an embodiment, the present invention is directed to a compound of Formula (I) for use as a medicament. In another embodiment, the present invention is directed to a compound of Formula (I) for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is a leukemia (selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), (acute) T-cell leukemia, acute monocytic leukemia, acute promyelocytic leukemia (APL), bisphenotypic B myelomonocytic leukemia, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia, and myelodysplastic syndrome (MDS)).

[0017] In another embodiment, the present invention is directed to a compound of Formula (I) for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is a lymphoma (selected from the group consisting of AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell DLBCL, double-hit lymphoma, double- expressor lymphoma, anaplastic large cell lymphoma, marginal B cell lymphoma, primary mediastinal B-cell lymphoma, immunoblastic large cell lymphoma, Burkittlymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoplasmatic lymphoma, precursor B -lymphoblastic lymphoma, lymphoma of the central nervous system, small lymphocytic lymphoma (SLL), lymphocytic leukemia (CLL), T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma, sarcoma of the soft tissue, gliosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma, breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma).

[0018] In another embodiment, the present invention is directed to a composition comprising a compound of Formula (I) for the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is a leukemia (selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), (acute) T-cell leukemia, acute monocytic leukemia, acute promyelocytic leukemia (APL), bisphenotypic B myelomonocytic leukemia, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia, and myelodysplastic syndrome (MDS)).

[0019] In another embodiment, the present invention is directed to a composition comprising a compound of Formula (I) for the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is a lymphoma (selected from the group consisting of AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell DLBCL, double-hit lymphoma, double-expressor lymphoma, anaplastic large cell lymphoma, marginal B cell lymphoma, primary mediastinal B-cell lymphoma, immunoblastic large 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 lymphocyticlymphoma (SLL), chronic lymphocytic leukemia (CLL), precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma; sarcoma of the soft tissue, gliosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma, breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma).

[0020] Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating: (a) acute lymphoblastic leukemia (ALL), (b) acute myeloid leukemia (AML), (c) (acute) T-cell leukemia, (d) acute monocytic leukemia, (e) acute promyelocytic leukemia (APL), (f) bisphenotypic B myelomonocytic leukemia, (g) chronic myeloid leukemia (CML), (h) chronic myelomonocytic leukemia (CMML), (i) large granular lymphocytic leukemia, (j) plasma cell leukemia, or (k) myelodysplastic syndrome (MDS), in a subject in need thereof.

[0021] Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating: (a) AIDS-related lymphoma, (b) Hodgkin lymphoma, (c) non-Hodgkin's lymphoma (NHL), (d) T-non-Hodgkin lymphoma (T-NHL), (e) Diffuse Large Cell Lymphoma (DLBCL), (f) activated B-cell DLBCL, (g) germinal center B-cell DLBCL, (h) double-hit lymphoma, (i) double-expressor lymphoma, (j) anaplastic large cell lymphoma, (k) marginal B cell lymphoma, (l) primary mediastinal B-cell lymphoma, (m) immunoblastic large cell lymphoma, (n) Burkitt lymphoma, (o) follicular lymphoma, (p) hairy cell leukemia, (q) Hodgkin's disease, (r) mantle cell lymphoma (MCL), (s) lymphoplasmatic lymphoma, (t) precursor B - lymphoblastic lymphoma, (u) lymphoma of the central nervous system, (v) small lymphocytic lymphoma (SLL), (w) chronic lymphocytic leukemia (CLL), (x) precursor T- lymphoblastic lymphoma / leukemia, (y) peripheral T-cell lymphoma (PTCL), (z) cutaneous T-cell lymphoma (CTCL), (aa) angioimmunoblastic T-cell lymphoma, (ab) extranodal natural killer T-cell lymphoma, (ac) enteropathy type T-cell lymphoma, (ad) subcutaneous panniculitis-like T-cell lymphoma, (ae) anaplastic large cell lymphoma,(af) sarcoma of the soft tissue, (ag) gliosarcoma, (ah) osteosarcoma, (ai) malignant fibrous histiocytoma, (aj) lymphosarcoma, (ak) rhabdomyosarcoma, (al) breast cancer, (am) colorectal carcinoma, (an) gastric cancer, (ao) gliosarcoma, (ap) head & neck cancer, (aq) hepatocellular carcinoma, (ar) lung cancer, (as) multiple myeloma, (at) neuroblastoma, (au) ovarian cancer, (av) pancreatic cancer, (aw) prostate cancer, or (ax) renal cell carcinoma, in a subject in need thereof.

[0022] In another example, the present invention is directed to a compound as described herein for use in a method for treating a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is a leukemia selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), (acute) T-cell leukemia, acute monocytic leukemia, acute promyelocytic leukemia (APL), bisphenotypic B myelomonocytic leukemia, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia, and myelodysplastic syndrome (MDS), in a subject in need thereof.

[0023] In another example, the present invention is directed to a compound as described herein for use in a method for treating a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is a lymphoma selected from the group consisting of AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), subtypes of NHL such as Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell DLBCL, double-hit lymphoma and double-expressor lymphoma; anaplastic large cell lymphoma, marginal B cell lymphoma and primary mediastinal B-cell lymphoma, immunoblastic large cell lymphoma, Burkitt lymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoplasmatic lymphoma, precursor B -lymphoblastic lymphoma, lymphoma of the central nervous system, small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL); T-cell NHL 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 includingbut not limited to sarcoma of the soft tissue, gliosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma; and other cancers, such as solid tumors, including but not limited to breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma, in a subject in need thereof.

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

[0025] The present invention is further directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and 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. Detailed Description of the Invention

[0026] The present invention is directed to compounds of Formula (I)

[0027] wherein R1, R2, R3, R4, R5, Ra, Rb, Rc, Rd, and Rf, are as herein defined. The compounds of the present invention are useful for the treatment of disorders and diseases or conditions mediated by the BFL-1 protein, including, but not limited to leukemias, lymphomas and related cancers.

[0028] In certain embodiments, the present invention is directed to compounds of Formula (I), wherein R1is H, CH3, CH2CH3, CH(CH3)2, CH2OH, CH2OCH3, NH2, NH(CH3), N(CH3)2, OH, OCH3, OCF2H, SCH3, SO2CH3, CN, NH-CH2CH2N(CH3)2, SO2- cyclopropyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 4-methylpiperazin-1-yl, or .

[0029] In certain embodiments, the present invention is directed to compounds of Formula (I), wherein R3is .

[0030] In certain embodiments, the present invention is directed to compounds of Formula (I), wherein R3is

[0031] In certain embodiments, the present invention is directed to compounds of Formula (I), wherein R3is

[0032] In certain embodiments, the present invention is directed to compounds of Formula (I), wherein R3is.

[0033] In certain embodiments, the present invention is directed to compounds of Formula (I), wherein R3is .

[0034] In certain embodiments, the present invention is directed to compounds of Formula (I), wherein R3is.

[0035] In certain embodiments, the present invention is directed to compounds of Formula (I), wherein R3is.

[0036] In certain embodiments, the present invention is directed to compounds of Formula (I), wherein R3is .

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

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

[0039] In certain embodiments, the present invention is directed to compounds of Formula (I), wherein L is CH2or CH(CH3).

[0040] In certain embodiments, the present invention is directed to compounds of Formula (I), wherein Rais

[0041] In certain embodiments, the present invention is directed to compounds of Formula (I), wherein Rbis.

[0042] Additional embodiments of the present invention, include those wherein the substituents selected for one or more of the variables defined herein (i.e. R1, R2, R3, R4, R5, Ra, Rb, Rc, Rd, Rf, etc.) are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein.

[0043] In another embodiment of the present invention is any single compound or subset of compounds selected from the representative compounds listed in Table 1 below.

[0044] Representative compounds of Formula (I) of the present invention are as listed in Table 1 below. Unless otherwise noted, wherein a stereogenic center is present in the listed compound, the compound was prepared as a mixture of stereo-configurations. Wherein the compound contains at least on stereocenter, and the compound was prepared in a stereogenic excess of a specific stereoisomer, the *S- and *R- designations in are intended to indicate that the exact stereo-configuration of the center has not been determined. Wherein the compound contains at least on stereocenter, and the compound was prepared in a stereogenic excess of a specific stereoisomer, the S- and R- designations in are intended to indicate that measured stereo-configuration of the center.

[0045] Certain examples contain chemical structures that are depicted or labelled as an (*R) or (*S). When (*R) or (*S) is used in the name of a compound or in the chemical representation of the compound, it is intended to convey that the compound is a pure single isomer at that stereocenter; however, absolute configuration of that stereocenter has not been established. For example, (*S)-(4-((2-hydroxy-1-(4- (trifluoromethoxy)phenyl)ethyl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone:

[0046] , refers to a compound that is either: .

[0047] In certain embodiments, the present invention is directed to one or more compounds of Formula (I) independently selected from the group consisting of the compounds of Table 1.

[0048] Table 1: Representative Compounds for Formula (I)x

[0049] and stereoisomers, isotopomers and pharmaceutically acceptable salts thereof.

[0050] In certain embodiments, the present invention is directed to one or more compounds of Formula (I) independently selected from the group consisting of:and stereoisomers, isotopologues andpharmaceutically acceptable salts thereof.

[0051] In certain embodiments, the present invention is directed to compounds of Formula (I), which, when tested for BFL-1 protein inhibition according to the procedure as described in Biological Example 1, which follows hereinafter, exhibit a Ki of less than or equal to about 1 µM, preferably less than or equal to about 100 nM, more preferably less than or equal to about 10 nM, more preferably less than or equal to about 1 nM. Aspects Aspect 1. A compound of Formula (I)or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1is selected from: H, C1-4alkyl, NH2, NH(CH3), N(CH3)2, NH-CH2CH2N(CH3)2, OH, hydroxy substituted C1-4alkyl, OCH3, CH2OCH3, OCF2H, SCH3, SO2CH3, SO2- cyclopropyl, CN, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 4-methylpiperazin-1-yl, andR2is , wherein L is absent, CH(CH3) or CH2; Rais phenyl or pyridyl, wherein each phenyl or pyridyl is optionally substituted with one or two members each independently selected from C1-4alkyl, fluorinated-C1-4alkyl, O-fluorinated-C1-4alkyl, NH2, CH2NH2, NH-C(=O)-C2-5alkenyl, NH-C(=O)-C2-5alkynyl, , and ; Rbis , hydroxy substituted C1-4alkyl, or fluorinated-C1-4alkyl; Rfis selected from: CH3; CD3; CH2CH2N(CH3)2; and (CH2)0-1-C3-4cycloalkyl, wherein the C3-4cycloalkyl is optionally substituted with one or two members each independently selected from OH, C1-4alkyl, fluorinated-C1-4alkyl, and hydroxy substituted C1-4alkyl; and Rcis H or CH3; R3is selected from: a 4 to 14 membered nitrogen linked heterocyclyl selected from the group consisting of: monocyclic heterocycloalkyl; spiro-cyclic heterocycloalkyl, bridged heterocycloalkyl or fused heterocycloalkyl; wherein each monocyclic heterocycloalkyl, spiro-cyclic heterocycloalkyl, bridged heterocycloalkyl, and fused heterocycloalkyl contains at least one N atom, optionally containing one, two, or three additional heteroatoms independently selected from N, O, and S; and is optionally substituted with one, two, three or four members each independently selected from: hydroxy, oxo, halo, (=N)-CH3, C1-4alkyl, C1-4alkyl substituted with OH, fluorinated-C1-4alkyl, OC1-4alkyl, CH2-C(=O)-NH(CH3), CH2C(=O)- NH2, C(=O)CH3, SO2-CH3, CH2-SO2-CH3, NH2, N(CH3)2, C(=O)OCH3, C(=O)N(CH3)2,(P=O)(CH3)2, C3-6cycloalkyl, , , R4is selected from: H, C1-4alkyl, hydroxy substituted C1-4alkyl, -OCH3, and -C(=O)- NH-CH2-Rd; wherein Rdis a (CH2)0-2C3-8cycloalkyl optionally substituted with one, two or three members independently selected from halo and C1-4alkyl; or (CH2)0-2heterocyclyl, wherein each heterocyclyl is selected from: monocyclic heterocycloalkyl, spiro-cyclic heterocycloalkyl, bridged heterocycloalkyl, and fused heterocycloalkyl, each optionally substituted with one, two or three members independently selected from halo and C1-4alkyl; and R5is selected from: Cl, F, C1-4alkyl, fluorinated-C1-4alkyl, hydroxy substituted C1-4alkyl, and CN; or wherein R4and R5come together to form a heterocycloalkyl ring wherein -R4-R5- is -CH2N(CH3)CH2CH2-. Aspect 2. The compound of Aspect 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1is H, CH3, CH2CH3, CH(CH3)2, CH2OH, CH2OCH3, NH2, NH(CH3), N(CH3)2, OH, OCH3, OCF2H, SCH3, SO2CH3, CN, NH-CH2CH2N(CH3)2, SO2-cyclopropyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 4-methylpiperazin-1-yl, or . Aspect 3. The compound of Aspect 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: (i) R3is: or (ii) R3is: (iii) R3is:Aspect 4. The compound of Aspect 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein (i) R3isAspect 5. The compound of Aspect 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:Aspect 6. The compound of Aspect 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: L is absent. Aspect 7. The compound of Aspect 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: L is CH2or CH(CH3). Aspect 8. The compound of Aspect 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RaisAspect 9. The compound of Aspect 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein RbisAspect 10. A compound selected from the group consisting of: (R)-N-(Methyl-d3)-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-N-Methyl-2-((2-methyl-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-2-methyl-8-(4-(4-(methylsulfonyl)phenyl)piperazine- 1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((2-Ethyl-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-[[6-(2,5-Dimethylphenyl)-2-isopropyl-8-[4-(4-methylsulfonylphenyl)piperazine- 1-carbonyl]quinazolin-4-yl]amino]-N-methyl-3-[4-(trifluoromethyl)phenyl]propanamide; (R)-2-((2-Amino-6-(2,5-dimethylphenyl)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-N-Methyl-2-((2-(methylamino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((2-(Dimethylamino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-(2-(Dimethylamino)-4-((3-hydroxy-3-methyl-1-(6-(trifluoromethyl)pyridin-3- yl)butan-2-yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone; (R)-2-((2-((2-(Dimethylamino)ethyl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine- 1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propanamide; (R)-2-((2-Hydroxy-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((2-Hydroxy-8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-(2-Hydroxy-4-((3-hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan-2- yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone; (R)-(2-Hydroxy-4-((3-hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan-2- yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(6-(methylsulfonyl)pyridin-3- yl)piperidin-1-yl)methanone; (R)-(2-Hydroxy-4-((3-hydroxy-3-methyl-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2- yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone; (R)-2-((8-((*R)-2,2-Dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8-carbonyl)-2- hydroxy-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-(1- (trifluoromethyl)cyclopropyl)-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((8-((*S)-2,2-Dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8-carbonyl)-2- hydroxy-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-(1- (trifluoromethyl)cyclopropyl)-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((2-Hydroxy-8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-(1-(trifluoromethyl)cyclopropyl)-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-N-((1s,3S)-3-Hydroxy-3-methylcyclobutyl)-2-((2-hydroxy-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((2-Hydroxy-8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(6-(trifluoromethyl)pyridin-3- yl)propanamide;(R)-2-((2-Hydroxy-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(6-(trifluoromethyl)pyridin-3- yl)propanamide; (2R)-2-((8-(2,2-Dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8-carbonyl)-2-hydroxy- 6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; ((*R)-2,2-Dioxidohexahydropyrazino[2,1-c][1,4]thiazin-8(1H)-yl)(2-hydroxy-4-(((R)-3- hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-6-(2,3,6- trimethylphenyl)quinazolin-8-yl)methanone; ((*S)-2,2-Dioxidohexahydropyrazino[2,1-c][1,4]thiazin-8(1H)-yl)(2-hydroxy-4-(((R)-3- hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-6-(2,3,6- trimethylphenyl)quinazolin-8-yl)methanone; (R)-2-((2-(Hydroxymethyl)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(3-Chloro-2,6-dimethylphenyl)-2-hydroxy-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((2-methoxy-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-(4-((3-Hydroxy-3-methyl-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-yl)amino)-2- methoxy-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin- 1-yl)methanone; (R)-2-((2-(Methoxymethyl)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-(4-((3-Hydroxy-3-methyl-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-yl)amino)-2- (methoxymethyl)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone; (R)-(2-(difluoromethoxy)-4-((3-hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone; (R)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-2- (methylthio)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-(6-(trifluoromethyl)pyridin- 3-yl)propanamide; (R)-N-Methyl-2-((2-(methylsulfonyl)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-N-methyl-2-((2-(methylsulfonyl)-8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-N-methyl-2-((2-(methylsulfonyl)-8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-(4-((3-Hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-2- (methylsulfonyl)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone; (R)-2-((2-(Cyclopropylsulfonyl)-8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((2-Cyano-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(6-(trifluoromethyl)pyridin-3- yl)propenamide; (R)-4-((3-Hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazoline-2- carbonitrile; (R)-4-((3-Hydroxy-3-methyl-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-yl)amino)-8-(4- (4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazoline-2- carbonitrile; (2R)-2-[[6-(2,5-Dimethylphenyl)-8-[4-(4-methylsulfonylphenyl)piperazine-1-carbonyl]- 2-tetrahydropyran-3-yl-quinazolin-4-yl]amino]-N-methyl-3-[4-(trifluoromethyl)phenyl]propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-N-methyl-2-((2-(4-methylpiperazin-1-yl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)-3-(6-(trifluoromethyl)pyridin-3-yl)propanamide; (R)-(4-((3-Hydroxy-3-methyl-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-yl)amino)-2- (morpholinomethyl)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone; (R)-(4-((3-Fluoro-3-methyl-1-(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-6-(2,3,6- trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone; (*S)-(4-((2-Hydroxy-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)-6-(2,3,6- trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone; (*R)-(4-((2-Hydroxy-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)-6-(2,3,6- trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone; (*S)-(4-((2-Hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)amino)-6-(2,3,6- trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone; (*R)-(4-((2-Hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)amino)-6-(2,3,6- trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone; (4-(((3*S,4*RS)-2-Hydroxy-2-methyl-4-(4-(trifluoromethyl)phenyl)pentan-3-yl)amino)- 6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1- yl)methanone; (4-(((3*R,4*RS)-2-hydroxy-2-methyl-4-(4-(trifluoromethyl)phenyl)pentan-3-yl)amino)- 6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1- yl)methanone; (R)-(4-((3-Hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-6-(2,3,6- trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone; (R)-(4-((3-Hydroxy-3-methyl-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-yl)amino)-6- (2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1- yl)methanone;(4-((1-Hydroxy-2-methyl-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-6-(2,3,6- trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone; (2R)-N-Cyclobutyl-2-((6-(2,5-dimethylphenyl)-8-(4-(1-methyl-2-oxopiperidin-4- yl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-N-((1s,3S)-3-Hydroxy-3-methylcyclobutyl)-2-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-(4-((1-(2-Amino-4-(trifluoromethyl)phenyl)-3-hydroxy-3-methylbutan-2-yl)amino)- 6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1- yl)methanone; (R)-3-(3-Amino-5-(trifluoromethyl)pyridin-2-yl)-N-methyl-2-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)propanamide; (R)-3-(2-Amino-6-(trifluoromethyl)pyridin-3-yl)-N-methyl-2-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)propanamide; (R)-N-(2-(3-(Methylamino)-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)- 6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-oxopropyl)-5- (trifluoromethyl)phenyl)acrylamide; (R)-N-(2-(3-Hydroxy-3-methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)butyl)-5- (trifluoromethyl)phenyl)acrylamide; (R)-N-(3-(3-(Methylamino)-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)- 6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-oxopropyl)-6-(trifluoromethyl)pyridin-2- yl)acrylamide; (*S)-2-(3-(Aminomethyl)-4-(trifluoromethyl)phenyl)-N-methyl-2-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)acetamide; (*R)-2-(3-(Aminomethyl)-4-(trifluoromethyl)phenyl)-N-methyl-2-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)acetamide; (*R)-N-(5-(2-(Methylamino)-1-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-2-oxoethyl)-2- (trifluoromethyl)benzyl)acrylamide; (*S)-N-(5-(2-(Methylamino)-1-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-2-oxoethyl)-2- (trifluoromethyl)benzyl)acrylamide; (*R)-N-(5-(2-(Methylamino)-1-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-2-oxoethyl)-2- (trifluoromethyl)phenyl)acrylamide; (*S)-N-(5-(2-(Methylamino)-1-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-2-oxoethyl)-2- (trifluoromethyl)phenyl)acrylamide; (*S)-3-(Diethylamino)-N-(5-(2-(methylamino)-1-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)-2-oxoethyl)-2-(trifluoromethyl)benzyl)propenamide; (*R)-3-(Diethylamino)-N-(5-(2-(methylamino)-1-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)-2-oxoethyl)-2-(trifluoromethyl)benzyl)propenamide; (*R)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)piperazin-1-yl)piperidine-1-carbonyl)-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-2-(6-(trifluoromethyl)pyridin-3- yl)acetamide; (*S)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)piperazin-1-yl)piperidine-1-carbonyl)-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-2-(6-(trifluoromethyl)pyridin-3- yl)acetamide; (*R)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-2-(6-(trifluoromethyl)pyridin-3-yl)acetamide; (*S)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-2-(6-(trifluoromethyl)pyridin-3-yl)acetamide; (*S)-N-(2-(Dimethylamino)ethyl)-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-2-(6-(trifluoromethyl)pyridin-3-yl)acetamide; (*R)-N-(2-(Dimethylamino)ethyl)-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-2-(6-(trifluoromethyl)pyridin-3- yl)acetamide; (*S)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-2-(4-(2,2,2-trifluoroethyl)phenyl)acetamide; (*R)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-2-(4-(2,2,2-trifluoroethyl)phenyl)acetamide; (*S)-2-((*R)-6-Fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methyl-2-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)acetamide; (*S)-2-((*S)-6-Fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methyl-2-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)acetamide; (*R)-2-((*R)-6-Fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methyl-2-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)acetamide; (*R)-2-((*S)-6-Fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methyl-2-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)acetamide; (*R)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-2-(quinolin-6-yl)acetamide; (*S)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-2-(quinolin-6-yl)acetamide; (R)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-3-(4-(2,2,2-trifluoroethyl)phenyl)propanamide; (R)-3-(6-Isopropylpyridin-3-yl)-N-methyl-2-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(4-(methylsulfonyl)phenyl)-3-oxopiperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide;(R)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)-3-oxopiperazine-1-carbonyl)-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4 (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2-(Hydroxymethyl)-3,6-dimethylphenyl)-8-(octahydropyrazino[2,1- c][1,4]oxazine-8-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(2,2-Dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8-carbonyl)-6-(2- (hydroxymethyl)-3,6-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-(9,9-Dioxido-1-oxa-9-thia-4-azaspiro[5.5]undecane-4-carbonyl)-6-(2- (hydroxymethyl)-3,6-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2-(Hydroxymethyl)-3,6-dimethylphenyl)-8-(4-(6-(methylsulfonyl)pyridin-3- yl)piperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2-(Hydroxymethyl)-3,6-dimethylphenyl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2-(Hydroxymethyl)-3,6-dimethylphenyl)-8-(4-(4-(methylsulfonyl)phenyl)-3- oxopiperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2-Methoxy-3,6-dimethylphenyl)-8-(octahydropyrazino[2,1-c][1,4]oxazine- 8-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(2,2-Dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8-carbonyl)-6-(2- methoxy-3,6-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-(9,9-Dioxido-1-oxa-9-thia-4-azaspiro[5.5]undecane-4-carbonyl)-6-(2- methoxy-3,6-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2-Methoxy-3,6-dimethylphenyl)-8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2-Methoxy-3,6-dimethylphenyl)-8-(4-(4-(methylsulfonyl)phenyl)-3- oxopiperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(3-(2,2-Difluoroethyl)-2,6-dimethylphenyl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,7-Dimethyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; N-((2,2-Difluoro-1-methylcyclopropyl)methyl)-3,6-dimethyl-2-(4-(((R)-1- (methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide; (R)-N-((3,3-Difluorocyclobutyl)methyl)-3,6-dimethyl-2-(4-((1-(methylamino)-1-oxo-3- (4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine- 1-carbonyl)quinazolin-6-yl)benzamide; (R)-N-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3,6-dimethyl-2-(4-((1-(methylamino)- 1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide; N-(2-(2,2-Difluoro-1-methylcyclopropyl)ethyl)-3,6-dimethyl-2-(4-(((R)-1- (methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide; (R)-3,6-Dimethyl-2-(4-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2- yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)-N-((1- (trifluoromethyl)cyclopropyl)methyl)benzamide; N-((2,2-Difluoro-1-methylcyclopentyl)methyl)-3,6-dimethyl-2-(4-(((R)-1- (methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide; (R)-N-((4,4-Dimethylcyclohexyl)methyl)-3,6-dimethyl-2-(4-((1-(methylamino)-1-oxo-3- (4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide; (R)-N-((4,4-Difluorocyclohexyl)methyl)-3,6-dimethyl-2-(4-((1-(methylamino)-1-oxo-3- (4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine- 1-carbonyl)quinazolin-6-yl)benzamide; (R)-3,6-Dimethyl-2-(4-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2- yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)-N-((1- methylcycloheptyl)methyl)benzamide; (R)-N-(Bicyclo[2.2.2]octan-1-ylmethyl)-3,6-dimethyl-2-(4-((1-(methylamino)-1-oxo-3- (4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine- 1-carbonyl)quinazolin-6-yl)benzamide; (R)-3,6-Dimethyl-2-(4-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2- yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)-N-((5- methylspiro[2.3]hexan-5-yl)methyl)benzamide; (R)-N-(Bicyclo[2.2.1]heptan-1-ylmethyl)-3,6-dimethyl-2-(4-((1-(methylamino)-1-oxo-3- (4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine- 1-carbonyl)quinazolin-6-yl)benzamide; 3,6-Dimethyl-2-(4-(((R)-1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2- yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)-N-((1- methylazetidin-2-yl)methyl)benzamide; 3,6-Dimethyl-2-(4-(((R)-1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2- yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)-N-(((R)- 1-methylazetidin-2-yl)methyl)benzamide; 3,6-Dimethyl-2-(4-(((R)-1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2- yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)-N-((1- methylpyrrolidin-2-yl)methyl)benzamide; N-(((R)-4,4-Difluoro-1-methylpyrrolidin-2-yl)methyl)-3,6-dimethyl-2-(4-(((R)-1- (methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide; 3,6-Dimethyl-2-(4-(((R)-1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2- yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)-N-((1- methylpyrrolidin-3-yl)methyl)benzamide;N-((1,3-Dimethylpyrrolidin-3-yl)methyl)-3,6-dimethyl-2-(4-(((R)-1-(methylamino)-1- oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide; 3,6-Dimethyl-2-(4-(((R)-1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2- yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)-N-(((S)- 1-methylpiperidin-3-yl)methyl)benzamide; (R)-3,6-Dimethyl-2-(4-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2- yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)-N-((1- methylpiperidin-4-yl)methyl)benzamide; 3,6-Dimethyl-2-(4-(((R)-1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2- yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)-N-((1- methylpiperidin-3-yl)methyl)benzamide; (R)-3,6-Dimethyl-2-(4-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2- yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)-N-(2-(4- methylpiperazin-1-yl)ethyl)benzamide; N-((1,4-Dimethylpiperazin-2-yl)methyl)-3,6-dimethyl-2-(4-(((R)-1-(methylamino)-1- oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide; 3,6-Dimethyl-2-(4-(((R)-1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2- yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)-N-((4- methylmorpholin-3-yl)methyl)benzamide; N-((1,4-Diazabicyclo[2.2.2]octan-2-yl)methyl)-3,6-dimethyl-2-(4-(((R)-1- (methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide; (R)-3,6-Dimethyl-2-(4-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2- yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)-N- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl)benzamide; (R)-3,6-Dimethyl-N-((2-methyl-2-azabicyclo[2.1.1]hexan-1-yl)methyl)-2-(4-((1- (methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide; (R)-2-((6-(3-(Hydroxymethyl)-2,6-dimethylphenyl)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(3-(Difluoromethyl)-2,6-dimethylphenyl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propenamide (*R atropisomer); (R)-2-((6-(3-(Difluoromethyl)-2,6-dimethylphenyl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propenamide (*S atropisomer); (R)-2-((6-(3-Chloro-2,6-dimethylphenyl)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(3-Fluoro-2,6-dimethylphenyl)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(3-Cyano-2,6-dimethylphenyl)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(oxetan-3-yl)azetidine-1-carbonyl)quinazolin-4- yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(1,1-dioxidoisothiazolidin-2-yl)azetidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(4-(oxetan-3-yl)piperazin-1-yl)azetidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(2,4-Bis(hydroxymethyl)pyrrolidine-1-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-dimethylphenyl)-8-((3*S,4*R)-3-hydroxy-4-(2-(methylamino)-2- oxoethyl)pyrrolidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(3-hydroxyazetidin-1-yl)pyrrolidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-hydroxy-[1,3'-bipyrrolidine]-1'- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(1-methylpiperidin-4-yl)pyrrolidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(3-(4-Acetylpiperazin-1-yl)-4-methylpyrrolidine-1-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-(4-hydroxytetrahydro-2H-pyran-3-yl)pyrrolidine- 1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(1-methyl-1H-imidazol-2-yl)pyrrolidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-hydroxy-4-(hydroxymethyl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(4-hydroxy-3-(hydroxymethyl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-((methylsulfonyl)methyl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-methyl-4-((methylsulfonyl)methyl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((8-(4-(Dimethylamino)-4-ethylpiperidine-1-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(4-Amino-3,3-difluoropiperidine-1-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide trifluoroacetate salt; (R)-2-((8-((3*S,4*R)-3,4-dihydroxy-3-methylpiperidine-1-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; Methyl (3*S,4*R)-1-(6-(2,5-dimethylphenyl)-4-(((R)-1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carbonyl)-3,4- dihydroxypiperidine-2-carboxylate; Methyl (2*R,3*S,4*R)-1-(6-(2,5-dimethylphenyl)-4-(((R)-1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carbonyl)-3,4- dihydroxypiperidine-2-carboxylate;methyl 1-(6-(2,5-Dimethylphenyl)-4-(((R)-1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carbonyl)-3,4- dihydroxypiperidine-4-carboxylate; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-((methylsulfonyl)ethynyl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-((methylsulfonyl)methyl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(Trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-methyl-3-((methylsulfonyl)methyl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(1,1-dioxidoisothiazolidin-2-yl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-((1,1-dioxidotetrahydrothiophen-3- yl)amino)piperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-((1,1-dioxidotetrahydro-2H-thiopyran-4- yl)amino)piperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(4-(methylsulfonyl)piperazin-1-yl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(4-hydroxy-3-(4-(methylsulfonyl)piperazin-1- yl)piperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(4-(methylsulfonyl)piperazin-1-yl)-4- oxopiperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(3-(1H-Imidazol-1-yl)-4-methylpiperidine-1-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; 1-(6-(2,5-Dimethylphenyl)-4-(((R)-1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carbonyl)-N,N-dimethyl-3-(1- methyl-1H-pyrazol-5-yl)piperidine-4-carboxamide;(2R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(3-hydroxy-3-methylpyrrolidin-1-yl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(1,1-dioxidoisothiazolidin-2-yl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(1,1-dioxido-1,2,5-thiadiazolidin-2-yl)piperidine- 1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4- yl)piperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; rac-(2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-((4-methylpiperazin-1-yl)methyl)morpholine- 4-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(4-(methylsulfonyl)piperazin-1-yl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-hydroxy-4-(4-(methylsulfonyl)piperazin-1- yl)piperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-fluoro-4-(4-(methylsulfonyl)piperazin-1- yl)piperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(3,3-Difluoro-4-(4-(methylsulfonyl)piperazin-1-yl)piperidine-1-carbonyl)-6- (2,5-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamidede; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-((1-(methylsulfonyl)piperidin-4- yl)amino)piperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(3,3-Difluoro-4-((1-(methylsulfonyl)piperidin-4-yl)amino)piperidine-1- carbonyl)-6-(2,5-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4- yl)amino)-3,3-difluoropiperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide;(R)-2-((6-(2,5-Dimethylphenyl)-8-((*R)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4- yl)amino)-3,3-difluoropiperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(1-methyl-1H-imidazol-5-yl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((8-((*R)-3,3-Difluoro-4-(pyridin-3-yl)piperidine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-((*S)-3,3-Difluoro-4-(pyridin-3-yl)piperidine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-((*S)-3,3-Difluoro-4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1-carbonyl)-6- (2,5-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-((*R)-3,3-Difluoro-4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1-carbonyl)-6- (2,5-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-N-Methyl-2-((8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-N-Methyl-2-((8-(4-(5-(methylsulfonyl)pyridin-2-yl)piperidine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(6-(methylsulfonyl)-1',2',3',6'-tetrahydro-[3,4'- bipyridine]-1'-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(5'-fluoro-6-(methylsulfonyl)-1',2',3',6'-tetrahydro- [3,4'-bipyridine]-1'-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(1-oxidothiomorpholine-4-carbonyl)quinazolin-4- yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide;(R)-2-((6-(2,5-Dimethylphenyl)-8-(piperazine-1-carbonyl)quinazolin-4-yl)amino)-N- methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-(2-hydroxyethyl)-4-methylpiperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(2-hydroxypropyl)-3-methylpiperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(2-hydroxypropyl)-2-methylpiperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-((R)-3-(hydroxymethyl)-5-oxopiperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(1,1-dioxidotetrahydrothiophen-3-yl)piperazine- 1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(2-hydroxy-2-(tetrahydrofuran-2- yl)ethyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(tetrahydro-2H-pyran-3-yl)piperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(4-((1,4-Dioxan-2-yl)methyl)piperazine-1-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(6-(methylamino)pyridin-3-yl)piperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(5-(methylamino)pyridin-2-yl)piperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((8-(4-(5-(Dimethylamino)pyridin-2-yl)piperazine-1-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-(4-(6-(Dimethylamino)pyridin-3-yl)piperazine-1-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(4-sulfamoylphenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-N-Methyl-2-((8-(4-(6-(methylsulfonyl)pyridin-3-yl)-3-oxopiperazine-1-carbonyl)-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(2-(pyridin-4-yl)acetyl)piperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(morpholine-4-carbonyl)quinazolin-4-yl)amino)-N- methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-(hydroxymethyl)-5-methylmorpholine-4- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-(1-hydroxyethyl)morpholine-4- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-((R)-1-hydroxyethyl)morpholine-4- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-(dimethylphosphoryl)morpholine-4- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-((methylsulfonyl)methyl)morpholine-4- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(2-(2-Amino-2-oxoethyl)morpholine-4-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-(oxetan-2-yl)morpholine-4-carbonyl)quinazolin- 4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-(tetrahydrofuran-3-yl)morpholine-4- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-((4-methylpiperazin-1-yl)methyl)morpholine-4- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(2-(1H-Imidazol-2-yl)morpholine-4-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(2-(1H-Pyrazol-5-yl)morpholine-4-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(2-hydroxypropyl)-1,4-diazepane-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(1-hydroxypropan-2-yl)-1,4-diazepane-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(1,1-dioxido-1,2,5-thiadiazepane-5- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(1,1-dioxido-1,2,8-thiadiazecane-8- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(1,1-dioxido-1,2,7-thiadiazonane-7- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propenamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(2-oxido-2-thia-6-azaspiro[3.3]heptane-6- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(1,1-dioxido-1-thia-6-azaspiro[3.3]heptane-6- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((8-(6-Cyclopropyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-(6-Acetyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(2-oxa-8-azadispiro[3.1.36.14]decane-8- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((8-((7*R,8*R)-7,8-dihydroxy-5-oxa-2-azaspiro[3.4]octane-2-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-(6-Acetyl-2,6-diazaspiro[3.4]octane-2-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(6,6-dioxido-6-thia-2-azaspiro[3.4]octane-2- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide;(R)-2-((6-(2,5-Dimethylphenyl)-8-(6,6-dioxido-6-thia-2-azaspiro[3.5]nonane-2- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((8-((7*R,8*S)-7,8-dihydroxy-5-oxa-2-azaspiro[3.5]nonane-2-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(7-(oxetan-3-yl)-2,7-diazaspiro[3.5]nonane-2- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(2-methyl-2,6-diazaspiro[3.4]octane-6- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(2-(methylsulfonyl)-2,6-diazaspiro[3.4]octane-6- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(2,2-dioxido-2-thia-6-azaspiro[3.4]octane-6- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2,2-dioxido-2-thia-7-azaspiro[4.4]nonane-7- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(8,8-dioxido-8-thia-2-azaspiro[4.5]decane-2- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(8-(hydroxymethyl)-2-oxa-6-azaspiro[3.4]octane-6- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(8-fluoro-8-(hydroxymethyl)-2-oxa-6- azaspiro[3.4]octane-6-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-2-oxa-6- azaspiro[3.4]octane-6-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(8-(3-(methoxymethyl)-1,2,4-oxadiazol-5-yl)-2- oxa-6-azaspiro[3.4]octane-6-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(8,9-Dihydroxy-6-oxa-2-azaspiro[4.5]decane-2-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide;(R)-2-((8-(8-(Cyanomethyl)-2,8-diazaspiro[4.5]decane-2-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonane-7- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(2,2-dioxido-2-thia-8-azaspiro[4.5]decane-8- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2,2-dioxido-2-thia-7-azaspiro[4.5]decane-7- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2,2-dioxido-6-oxa-2-thia-9-azaspiro[4.5]decane- 9-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(9,9-dioxido-1-oxa-9-thia-4-azaspiro[5.5]undecane- 4-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4,4-dioxido-1-oxa-4-thia-9-azaspiro[5.5]undecane- 9-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(9-(methylimino)-9-oxido-1-oxa-9l6-thia-4- azaspiro[5.5]undecane-4-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(2-oxa-7-azaspiro[3.5]nonane-7- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(1,5-dioxa-9-azaspiro[5.5]undecane-9- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((8-((3*R,4*R)-3,4-dihydroxy-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-((3*R,4*S)-3,4-dihydroxy-9-oxa-1-azaspiro[5.5]undecane-1-carbonyl)-6- (2,5-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2,6-dioxa-9-azaspiro[4.5]decane-9- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(1,9-dioxa-4-azaspiro[5.5]undecane-4-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(6-ethyl-2-oxa-6,9-diazaspiro[4.5]decane-9- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(fluoromethyl)-9-oxo-4,8-dioxa-1,10- diazaspiro[5.5]undecane-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2,2-dioxido-6-oxa-2-thia-9- azaspiro[4.6]undecane-9-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(3,3-dioxido-7-oxa-3-thia-10- azaspiro[5.6]dodecane-10-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(8-oxo-2-oxa-5,9-diazaspiro[3.6]decane-5- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((8-((3a*R,6a*S)-5-acetyloctahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-dimethylphenyl)-8-((3a*R,6a*S)-5,5-dioxidohexahydro-1H-thieno[3,4- b]pyrrole-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-dimethylphenyl)-8-((3a*R,6a*S)-3a-methyl-2,2-dioxidohexahydro-1H- thieno[3,4-c]pyrrole-5-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-dimethylphenyl)-8-((3aR,6aS)-3a-methyl-2,2-dioxidohexahydro-1H- thieno[3,4-c]pyrrole-5-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-dimethylphenyl )-8-((3R,3a*R,6a*S)-3-methoxy-1,1-dioxidohexahydro- 2H-thieno[2,3-c]pyrrole-5-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-oxooctahydro-1H-pyrrolo[3,4-b]pyridine-6- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide;(2R)-2-((8-(5-(Dimethylamino)octahydro-1H-isoindole-2-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(5,6-Dihydroxyoctahydro-1H-isoindole-2-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-dimethylphenyl)-8-((3a*R,7a*S)-7a-(hydroxymethyl)-5- methyloctahydro-1H-pyrrolo[3,4-c]pyridine-2-carbonyl)quinazolin-4-yl)amino)-N-methyl- 3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-((7R,8aS)-7-hydroxyoctahydropyrrolo[1,2- a]pyrazine-2-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-methyloctahydropyrrolo[1,2-a]pyrazine-2- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-dimethylphenyl)-8-((4a*R,7a*S)-6,6-dioxidohexahydro-2H-thieno[3,4- b][1,4]oxazine-4-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2,2-dioxidooctahydrothieno[3,4-c]pyridine-5- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2,2-dioxidooctahydropyrazino[2,1-c][1,4]thiazine- 8-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(octahydropyrazino[2,1-c][1,4]oxazine-8- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-oxodecahydro-1,6-naphthyridine-6- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; Methyl (R)-6-(6-(2,5-dimethylphenyl)-4-(((R)-1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carbonyl)-5,6,7,8-tetrahydro- 1,6-naphthyridine-7-carboxylate; Methyl (R)-7-(6-(2,5-dimethylphenyl)-4-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carbonyl)-5,6,7,8-tetrahydro- 2,7-naphthyridine-1-carboxylate;(R)-2-((6-(2,5-Dimethylphenyl)-8-(4-methoxy-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidine-6-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; Methyl (R)-7-(6-(2,5-dimethylphenyl)-4-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carbonyl)-5,6,7,8-tetrahydro- 1,7-naphthyridine-3-carboxylate; (R)-2-((6-(2,5-Dimethylphenyl)-8-(3-ethyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[3,4- d]pyrimidine-7-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(2-methyl-1-oxo-4-(trifluoromethyl)-1,2,5,6,7,8- hexahydropyrido[3,4-d]pyridazine-6-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(trifluoromethyl)-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(hydroxymethyl)-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(2,2-dioxido-5,6,7,8-tetrahydro-3H-pyrido[4,3- c][1,2,6]thiadiazine-6-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(2-morpholino-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidine-6-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-(3-(1,4-Oxazepan-4-yl)-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine-6- carbonyl)-6-(2,5-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(8-methyl-6,6-dioxido-1,2,3,4,4a,5- hexahydrobenzo[b]pyrazino[1,2-d][1,4]thiazine-3-carbonyl)quinazolin-4-yl)amino)-N- methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-((1S,2R,4S)-2-oxido-2-thia-5-azabicyclo[2.2.1]heptane-5-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-((1S,4S)-2,2-dioxido-2-thia-5- azabicyclo[2.2.1]heptane-5-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-((1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-((1*R,4*R,5*R,6*S)-5,6-dihydroxy-2-azabicyclo[2.2.1]heptane-2-carbonyl)- 6-(2,5-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(1,1-dioxidoisothiazolidin-2-yl)-8- azabicyclo[3.2.1]octane-8-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(6,6-dioxido-6-thia-3-azabicyclo[3.2.1]octane-3- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((8-(Dihydro-1H,3H,4H-3a,6a-(methanooxymethano)furo[3,4-c]pyrrole-5- carbonyl)-6-(2,5-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-((1*R,2*R,3*S,5*S)-2,3-dihydroxy-8-azabicyclo[3.2.1]octane-8-carbonyl)-6- (2,5-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; and (R)-2-((8-((3aR,4S,5S,6R,7R,7aS)-5,6-Dihydroxyoctahydro-1H-4,7- methanoisoindole-2-carbonyl)-6-(2,5-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3- (4-(trifluoromethyl)phenyl)propanamide; or a stereoisomer or pharmaceutically acceptable salt thereof. Aspect 11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Aspect 1. Aspect 12. A pharmaceutical composition made by mixing a compound of Aspect 1and a pharmaceutically acceptable carrier. Aspect 13. A process for making a pharmaceutical composition comprising mixing a compound of Aspect 1 and a pharmaceutically acceptable carrier. Aspect 14. A method of treating a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is a leukemia or a lymphoma, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of Aspect 1. Aspect 15. The method of Aspect 14, wherein the leukemia is selected from the group consisting of lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), (acute) T- cell leukemia, acute monocytic leukemia, acute promyelocytic leukemia (APL), bisphenotypic B myelomonocytic leukemia, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia, and myelodysplastic syndrome (MDS). Aspect 16. The method of Aspect 14, wherein the leukemia is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Aspect 17. The method of Aspect 14, wherein the lymphoma is selected from the group consisting of AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell DLBCL, double-hit lymphoma, double-expressor lymphoma, anaplastic large cell lymphoma, marginal B cell lymphoma, primary mediastinal B-cell lymphoma, immunoblastic large cell lymphoma, Burkitt lymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoplasmatic lymphoma, precursor B -lymphoblastic lymphoma, lymphoma of the central nervous system, small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia (CLL), precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma(CTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma, sarcoma of the soft tissue, gliosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma, breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma. Aspect 18. The method of Aspect 14, wherein the lymphoma is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Aspect 19. The use of the compound of Aspect 1 for the preparation of a medicament for the treatment a cancer mediated by the BFL-1 protein, wherein the cancer mediate by the BFL-1 protein is (a) a leukemia, or (b) a lymphoma, in a subject in need thereof. Aspect 20. The use as in Aspect 20, wherein the leukemia is (a) acute lymphoblastic leukemia (ALL), (b) acute myeloid leukemia (AML), (c) (acute) T-cell leukemia, (d) acute monocytic leukemia, (e) acute promyelocytic leukemia (APL), (f) bisphenotypic B myelomonocytic leukemia, (g) chronic myeloid leukemia (CML), (h) chronic myelomonocytic leukemia (CMML), (i) large granular lymphocytic leukemia, (j) plasma cell leukemia, or (k) myelodysplastic syndrome (MDS). Aspect 21. The use as in Aspect 20, wherein the lymphoma is (a) AIDS-related lymphoma, (b) Hodgkin lymphoma, (c) non-Hodgkin's lymphoma (NHL), (d) T-non- Hodgkin lymphoma (T-NHL), (e) Diffuse Large Cell Lymphoma (DLBCL), (f) activated B- cell DLBCL, (g) germinal center B-cell DLBCL, (h) double-hit lymphoma, (i) double- expressor lymphoma, (j) anaplastic large cell lymphoma, (k) marginal B cell lymphoma, (l) 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) smalllymphocytic lymphoma (SLL), (w) chronic lymphocytic leukemia (CLL), (x) precursor T- lymphoblastic lymphoma / leukemia, (y) peripheral T-cell lymphoma (PTCL), (z) cutaneous T-cell lymphoma (CTCL), (aa) angioimmunoblastic T-cell lymphoma, (ab) extranodal natural killer T-cell lymphoma, (ac) enteropathy type T-cell lymphoma, (ad) subcutaneous panniculitis-like T-cell lymphoma, (ae) anaplastic large cell lymphoma, (af) sarcoma of the soft tissue, (ag) gliosarcoma, (ah) osteosarcoma, (ai) malignant fibrous histiocytoma, (aj) lymphosarcoma, (ak) rhabdomyosarcoma, (al) breast cancer, (am) colorectal carcinoma, (an) gastric cancer, (ao) gliosarcoma, (ap) head & neck cancer, (aq) hepatocellular carcinoma, (ar) lung cancer, (as) multiple myeloma, (at) neuroblastoma, (au) ovarian cancer, (av) pancreatic cancer, (aw) prostate cancer, or (ax) renal cell carcinoma. Aspect 22. The compound of Aspect 1, for use in a method for the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 proteinis (a) a leukemia or (b) a lymphoma, in a subject in need thereof. Aspect 23. The compound of Aspect 1, for use in a method for the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is (a) acute lymphoblastic leukemia (ALL), (b) acute myeloid leukemia (AML), (c) (acute) T-cell leukemia, (d) acute monocytic leukemia, (e) acute promyelocytic leukemia (APL), (f) bisphenotypic B myelomonocytic leukemia, (g) chronic myeloid leukemia (CML), (h) chronic myelomonocytic leukemia (CMML), (i) large granular lymphocytic leukemia, (j) plasma cell leukemia, or (k) myelodysplastic syndrome (MDS) Aspect 24. The compound of Aspect 1, for use in a method for the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is (a) 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, (l) primary mediastinal B-cell lymphoma, (m)immunoblastic large cell lymphoma, (n) Burkitt lymphoma, (o) follicular lymphoma, (p) hairy cell leukemia, (q) Hodgkin's disease, (r) mantle cell lymphoma (MCL), (s) lymphoplasmatic lymphoma, (t) precursor B -lymphoblastic lymphoma, (u) lymphoma of the central nervous system, (v) small lymphocytic lymphoma (SLL), (w) chronic lymphocytic leukemia (CLL), (x) precursor T-lymphoblastic lymphoma / leukemia, (y) peripheral T-cell lymphoma (PTCL), (z) cutaneous T-cell lymphoma (CTCL), (aa) angioimmunoblastic T-cell lymphoma, (ab) extranodal natural killer T-cell lymphoma, (ac) enteropathy type T-cell lymphoma, (ad) subcutaneous panniculitis-like T-cell lymphoma, (ae) anaplastic large cell lymphoma, (af) sarcoma of the soft tissue, (ag) gliosarcoma, (ah) osteosarcoma, (ai) malignant fibrous histiocytoma, (aj) lymphosarcoma, (ak) rhabdomyosarcoma, (al) breast cancer, (am) colorectal carcinoma, (an) gastric cancer, (ao) gliosarcoma, (ap) head & neck cancer, (aq) hepatocellular carcinoma, (ar) lung cancer, (as) multiple myeloma, (at) neuroblastoma, (au) ovarian cancer, (av) pancreatic cancer, (aw) prostate cancer, or (ax) renal cell carcinoma. Aspect 25. The compound of Aspect 1, for use as a medicament. Aspect 26. The compound of Aspect 1, for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is (a) a leukemia or (b) a lymphoma, in a subject in need thereof. Aspect 27. The compound of Aspect 1, for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is (a) acute lymphoblastic leukemia (ALL), (b) acute myeloid leukemia (AML), (c) (acute) T-cell leukemia, (d) acute monocytic leukemia, (e) acute promyelocytic leukemia (APL), (f) bisphenotypic B myelomonocytic leukemia, (g) chronic myeloid leukemia (CML), (h) chronic myelomonocytic leukemia (CMML), (i) large granular lymphocytic leukemia, (j) plasma cell leukemia, or (k) myelodysplastic syndrome (MDS) Aspect 28. The compound of Aspect 1, for use in the treatment of a cancer mediatedby the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is (a) AIDS- related lymphoma, (b) Hodgkin lymphoma, (c) non-Hodgkin's lymphoma (NHL), (d) T- non-Hodgkin lymphoma (T-NHL), (e) Diffuse Large Cell Lymphoma (DLBCL), (f) activated B-cell DLBCL, (g) germinal center B-cell DLBCL, (h) double-hit lymphoma, (i) double-expressor lymphoma, (j) anaplastic large cell lymphoma, (k) marginal B cell lymphoma, (l) primary mediastinal B-cell lymphoma, (m) immunoblastic large cell lymphoma, (n) Burkitt lymphoma, (o) follicular lymphoma, (p) hairy cell leukemia, (q) Hodgkin's disease, (r) mantle cell lymphoma (MCL), (s) lymphoplasmatic lymphoma, (t) precursor B -lymphoblastic lymphoma, (u) lymphoma of the central nervous system, (v) small lymphocytic lymphoma (SLL), (w) chronic lymphocytic leukemia (CLL), (x) precursor T-lymphoblastic lymphoma / leukemia, (y) peripheral T-cell lymphoma (PTCL), (z) cutaneous T-cell lymphoma (CTCL), (aa) angioimmunoblastic T-cell lymphoma, (ab) extranodal natural killer T-cell lymphoma, (ac) enteropathy type T-cell lymphoma, (ad) subcutaneous panniculitis-like T-cell lymphoma, (ae) anaplastic large cell lymphoma, (af) sarcoma of the soft tissue, (ag) gliosarcoma, (ah) osteosarcoma, (ai) malignant fibrous histiocytoma, (aj) lymphosarcoma, (ak) rhabdomyosarcoma, (al) breast cancer, (am) colorectal carcinoma, (an) gastric cancer, (ao) gliosarcoma, (ap) head & neck cancer, (aq) hepatocellular carcinoma, (ar) lung cancer, (as) multiple myeloma, (at) neuroblastoma, (au) ovarian cancer, (av) pancreatic cancer, (aw) prostate cancer, or (ax) renal cell carcinoma. Aspect 29. A composition comprising a compound of Aspect 1, for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is (a) a leukemia or (b) a lymphoma. Aspect 30. A composition comprising a compound of Aspect 1, for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is (a) acute lymphoblastic leukemia (ALL), (b) acute myeloid leukemia (AML), (c) (acute) T-cell leukemia, (d) acute monocytic leukemia, (e) acute promyelocytic leukemia (APL), (f) bisphenotypic B myelomonocytic leukemia, (g) chronic myeloid leukemia (CML), (h) chronic myelomonocytic leukemia (CMML), (i)large granular lymphocytic leukemia, (j) plasma cell leukemia, or (k) myelodysplastic syndrome (MDS) Aspect 31. A composition comprising a compound of Aspect 1, for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is (a) 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, (l) primary mediastinal B-cell lymphoma, (m) immunoblastic large cell lymphoma, (n) Burkitt lymphoma, (o) follicular lymphoma, (p) hairy cell leukemia, (q) Hodgkin's disease, (r) mantle cell lymphoma (MCL), (s) lymphoplasmatic lymphoma, (t) precursor B -lymphoblastic lymphoma, (u) lymphoma of the central nervous system, (v) small lymphocytic lymphoma (SLL), (w) chronic lymphocytic leukemia (CLL), (x) precursor T-lymphoblastic lymphoma / leukemia, (y) peripheral T-cell lymphoma (PTCL), (z) cutaneous T-cell lymphoma (CTCL), (aa) angioimmunoblastic T-cell lymphoma, (ab) extranodal natural killer T-cell lymphoma, (ac) enteropathy type T-cell lymphoma, (ad) subcutaneous panniculitis-like T-cell lymphoma, (ae) anaplastic large cell lymphoma, (af) sarcoma of the soft tissue, (ag) gliosarcoma, (ah) osteosarcoma, (ai) malignant fibrous histiocytoma, (aj) lymphosarcoma, (ak) rhabdomyosarcoma, (al) breast cancer, (am) colorectal carcinoma, (an) gastric cancer, (ao) gliosarcoma, (ap) head & neck cancer, (aq) hepatocellular carcinoma, (ar) lung cancer, (as) multiple myeloma, (at) neuroblastoma, (au) ovarian cancer, (av) pancreatic cancer, (aw) prostate cancer, or (ax) renal cell carcinoma. Aspect 32. A compound, composition, method of treatment or method of preparation as herein described.Definitions and Abbreviations

[0052] Abbreviations used in the specification, for example in the Schemes, Synthesis Examples and Biological Examples, are as listed in the Table 2, below: Table 2: Abbreviations

[0053] As used herein, unless otherwise noted, "cyano" refers to -CN group.

[0054] As used herein, unless otherwise noted, “halogen” or “halo” shall mean chloro, bromo, fluoro and iodo, preferably bromo, fluoro or chloro, more preferably fluoro or chloro.

[0055] As used herein, unless otherwise noted, "hydroxy" refers to -OH group.

[0056] As used herein, unless otherwise noted, the term “oxo” shall mean a functional group of the structure =O (i.e. a substituent oxygen atom connected to another atom by a double bond).

[0057] 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. “C1-6alkyl” refers to straight- or branched-chain alkyl group having from 1 to 6 carbon atoms in the chain. “C1-4alkyl” refers to straight- or branched-chain alkyl group having from 1 to 4 carbon atoms in the chain, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl.

[0058] As used herein, unless otherwise noted, the terms “-(CX-Yalkenyl)-” wherein X and Y are integers, shall denote any CX-Yalkene carbon chain as herein defined. For example, “C2-5alkenyl” refers to straight alkenyl group having from 2 to 5 carbon atoms in the chain, “C3-5alkenyl” refers to straight alkenyl group having from 3 to 5 carbon atoms in the chain.

[0059] As used herein, unless otherwise noted, the terms “-(CX-Yalkynyl)-” wherein X and Y are integers, shall denote any CX-Yalkynyl carbon chain as herein defined. Forexample, “C2-5alkynyl” refers to straight alkynyl group having from 2 to 5 carbon atoms in the chain.

[0060] The term “haloalkyl” refers to a straight- or branched-chain alkyl group having from 1 to 6 carbon atoms in the chain optionally substituting hydrogens with halogens. The term “C1-4haloalkyl” as used here refers to a straight- or branched-chain alkyl group having from 1 to 4 carbon atoms in the chain, optionally substituting hydrogens with halogens. Examples of “haloalkyl” groups include trifluoromethyl (CF3), difluoromethyl (CF2H), monofluoromethyl (CH2F), pentafluoroethyl (CF2CF3), tetrafluoroethyl (CHFCF3), monofluoroethyl (CH2CH2F), trifluoroethyl (CH2CF3), tetrafluorotrifluoromethylethyl (CF(CF3)2), and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.

[0061] As used herein, unless otherwise noted, the term “fluorinated CX-Yalkyl” shall mean any CX-Yalkyl group as defined above substituted with one or more fluoro groups, preferably one to three fluoro group. Suitably examples include, but are not limited to - CH2F, CHF2, -CF3, -CH2-CF3, -CF2-CH3, -CH2-CH2-CH2F, -CH2-CH2-CF3, -C(CH3)2CF3, -C(CF3)3, and the like.

[0062] 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 groups. For example, “fluorinated C2-5alkenyl” refers to an alkenyl group having from 2 to 5 carbon atoms in the chain with one or more fluoro groups.

[0063] As used herein, unless otherwise noted, the term “hydroxy substituted CX-Yalkyl” shall mean any CX-Yalkyl group as defined above substituted with one or more hydroxy (-OH) groups, preferably one to three, more preferably one to two hydroxy groups. Suitable examples include but are not limited to –CH2OH, –CH2CH2OH, -CH(OH)CH3, - CH(OH)CH2OH, -CH2CH2CH2OH, -C(CH2OH)3, -C(CH3)2OH, and the like.

[0064] As used herein, unless otherwise noted, the term “CX-Ycycloalkyl”, wherein X and Y are integers, shall mean any stable X- to Y-membered monocyclic, bicyclic, polycyclic, bridged, or spiro-cyclic saturated ring system, preferably a monocyclic, bicyclic, bridged or spiro-cyclic saturated ring system. For example, “C3-8cycloalkyl”refers to a cycloalkyl having from 3 to 8 carbon atoms in the ring(s), “ C3-6cycloalkyl” refers to a cycloalkyl having from 3 to 6 carbon atoms in the ring, “C3-4cycloalkyl” refers to a cycloalkyl having from 3 to 4 carbon atoms in the ring. The term "cycloalkyl" also encompasses cycloalkyl group, as defined above, which has been fused to a benzene ring. Examples of cycloalkyl groups include the following entities, in the form of properly bonded moieties:

[0065] As used herein, unless otherwise noted, the term “heterocyclyl” shall denote any 4 to 14 membered ring structure, wherein the ring structure is any 4 to 12 membered monocyclic, saturated, partially unsaturated or aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; or any 7 to 14 saturated, partially unsaturated, partially aromatic or aromatic bicyclic, fused, bridged or spiro-cyclic ring system containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S.

[0066] Unless otherwise noted, any 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.

[0067] The term "heteroaryl" as used herein, refers to an aromatic monocyclic or multicyclic ring system comprising 4 to 14 ring atoms, wherein from 1 to 4 of the ring atoms is independently O, N or S and the remaining ring atoms are carbon atoms. In one embodiment, a heteroaryl group has 5 to 10 ring atoms. In another embodiment, a heteroaryl group is monocyclic and has 5 or 6 ring atoms. In another embodiment, a heteroaryl group is multicyclic and has 6 or 14 ring atoms and at least one nitrogen ring atom. A heteroaryl group is joined via a ring carbon atom and any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. The term“heteroaryl" also encompasses a heteroaryl group, as defined above, which has been fused to a benzene ring. Suitably examples include, but are not limited to: Unless otherwise noted, any 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.

[0068] As used herein, unless otherwise noted, the term “heterocycloalkyl” shall denote any 4 to 14 membered ring structure, wherein the ring structure is any monocyclic, bicyclic, spiro-cyclic, bridged or fused saturated or partially unsaturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S. The term "heterocycloalkyl" also encompasses heterocycloalkyl group, as defined above, which has been fused to a benzene or heteroaryl ring. Unless otherwise noted, any 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.

[0069] Examples of monocyclic heterocycloalkyl include, but are not limited to:

[0070] Examples of spiro-cyclic heterocycloalkyl include, but are not limited to:

[0071] Examples of fused heterocycloalkyl group include, but are not limited to:

[0072] Examples of bridged heterocycloalkyl include, but are not limited to:

[0073] Examples of heterocycloalkyl group which has been fused to a benzene or heteroaryl ring include, but are not limited to:

[0074] In some embodiments of the present invention, the heterocyclyl is a 4 to 14 membered monocyclic heterocycloalkyl. In additional embodiments of the present invention, the heterocyclyl is a 4 to 12 membered monocyclic heterocycloalkyl, a 5 to 12 membered monocyclic heterocycloalkyl, a 5 to 11 membered monocyclic heterocycloalkyl, a 5 to 10 membered monocyclic heterocycloalkyl, a 5 to 8 membered monocyclic heterocycloalkyl, or a 4 to 6 membered monocyclic heterocycloalkyl.

[0075] In some embodiments of the present invention, the heterocyclyl is a 7 to 14 membered spiro-cyclic heterocycloalkyl. In additional embodiments of the present invention, the heterocyclyl is an 8 to 12 membered spiro-cyclic heterocycloalkyl, an 8 to 11 membered spiro-cyclic heterocycloalkyl, or an 8 to 10 membered spiro-cyclic heterocycloalkyl.

[0076] In some embodiments of the present invention, the heterocyclyl is a 7 to 14 membered bridged heterocycloalkyl. In additional embodiments of the present invention, the heterocyclyl is a 7 to 11 membered bridged heterocycloalkyl, or a 7 to 10 membered bridged heterocycloalkyl.

[0077] In some embodiments of the present invention, the heterocyclyl is a 7 to 14 membered fused heterocycloalkyl. In additional embodiments of the present invention, the heterocyclyl is a 8 to 12 membered fused heterocycloalkyl, a 9 to 12 membered fused heterocycloalkyl, a 10 to 14 membered fused heterocycloalkyl, or a 10 to 12 membered fused heterocycloalkyl.

[0078] As used herein, the term “tetrahydropyran-3-yl” represents the following moiety: .

[0079] As used herein, the term “tetrahydropyran-4-yl” represents the following moiety: .

[0080] As used herein, the term “4-methylpiperazin-1-yl” represents the following moiety: .

[0081] As used herein, the term “phenyl” represents the following moiety: .

[0082] As used herein, the term “pyridyl” represents the following moiety: .

[0083] When a particular group is "substituted" (e.g. CX-Yalkyl, aryl, heterocyclyl, etc.), said group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents. With reference to substituents, the term “independently” means that when more than one substituent is possible, such substituents may be the same or different from each other.

[0084] Lines drawn into ring systems indicate that the bond may be attached to any of the suitable and available ring atoms. The term “variable point of attachment” means that a group is allowed to be attached at more than one alternative position in a structure. The attachment will always replace a hydrogen atom on one of the ring atoms. In other words, all permutations of bonding are represented by the single diagram, as shown in the illustrations below.

[0085] Those skilled in the art will recognize that if more than one such substituent is present for a given ring, the bonding of each substituent is independent of all of the others. The groups listed or illustrated above are not exhaustive.

[0086] One skilled in the art will further recognize that in the chemical structures provided herein, a methyl substituent group may be denoted as “ ”, as “ ” or as “ ”. For example, a 4-methyl-pyridin-2-yl substituent may be drawn as , , or , respectively.

[0087] 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.

[0088] 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.

[0089] In some embodiments, the present invention is directed to pharmaceutically acceptable salts of the compounds of Formula (I).

[0090] 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 pharmaceuticallyacceptable 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.

[0091] 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.

[0092] Representative acids which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: acids including acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L- aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)- camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D- glucoronic acid, L-glutamic acid, ^-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.

[0093] Representative bases which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2- hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)- pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

[0094] 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).

[0095] As used herein, the “*” symbol or notation shall denote the presence of a stereogenic center.

[0096] Where the compounds of the present invention contain at least one chiral center, they may accordingly exist as enantiomers. Where the compounds of the present invention contain two or more chiral centers, they may additionally exist as diastereomers or stereoisomers. It is to be understood that all such isomers / stereoisomers and mixtures thereof are encompassed within the scope of the present invention. It is further understood that atropisomers (a specific type of stereoisomer resulting from steric or other hinderances to rotation) are also encompassed within the scope of the present invention.

[0097] 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 orequal 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%.

[0098] As used herein, unless otherwise noted, the term “isotopologues” shall mean molecules that differ only in their isotopic composition. More particularly, an isotopologue of a molecule differs from the parent molecule in that it contains at least one atom which is an isotope (i.e. has a different number of neutrons from its parent atom). For example, isotopologues of water include, but are not limited to, "light water" (HOH or H2O), "semi-heavy water" with the deuterium isotope in equal proportion to protium (HDO or1H2HO), “heavy water” with two deuterium isotopes of hydrogen per molecule (d2O or2H2O), "super-heavy water" or tritiated water (T2O or3H2O), where the hydrogen atoms are replaced with tritium (3H) isotopes, two heavy-oxygen water isotopologues (H218O and H217O) and isotopologues where the hydrogen and oxygen atoms may each independently be replaced by isotopes, for example the doubly labeled water isotopologue d218O.

[0099] 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.

[0100] 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), and 3H (T). Similarly, references to carbon and oxygen include within their scope respectively 12C, 13C and 14C and 16O and 18O. 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 of 3H, 11C, 18F, 122I, 123I, 125I, 131I, 75Br, 76Br, 77Br and 82Br. Preferably, the radioactive isotope is selected from the group of 3H, 11C and 18F.

[0101] 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.

[0102] 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.

[0103] As used herein, unless otherwise noted, the term “substantially free of a corresponding salt form(s)” when used to described a compound of the present invention shall mean that mole percent of the corresponding salt form(s) in the isolated free acid or free base of said compound, is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably less than about 0.1 mole percent. In an embodiment of the present invention, the compound of Formula (I) is present in a form which is substantially free of corresponding salt form(s). General Synthesis Schemes

[0104] Compounds of Formula (I) of the present invention may be prepared by coupling suitably selected substituent groups onto a central 5-C(O)-quinazoline scaffold of the following structure (A) (A) wherein the numbering denotes the ring atoms around the 5-C(O)-quinazoline 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: a. an R1group (herein referred to as the “top" substituent) to the carbon ring atom at the 3-position of the 5-C(O)-quinazoline scaffold (for example, as described in the Schemes below); b. an R2group (herein referred to as the “right hand side” substituent) to the carbon ring atom at the 1-position of the 5-C(O)-quinazoline scaffold (for example, as described in the Schemes below); and c. an R3group (herein referred to as the “left hand side” substituent) to the -C(O)- at the 5-position of the 5-C(O)-quinazoline scaffold (for example, as described in the Schemes below); d. a group (herein referred to as the “bottom” substituent) to the carbon ring atom at the 7-position of the 5-C(O)-quinazoline scaffold (for example, as described in the Schemes below).

[0105] One skilled in the art will recognize that the “top”, “bottom”, “right hand side,” and “left hand side” substituent groups may be introduced / coupled onto the 5-C(O)- quinazoline 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 / coupled onto the 5-C(O)-quinazoline scaffold, reactive terminal groups and / 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. SCHEME 1

[0106] According to SCHEME 1, 2-aminoisophthalic acid, a known compound, is reacted with a suitably selected acid such as AcOH, H2SO4, HCl, and the like; with a suitably selected iodination reagent, such as ICl, N-iodosuccinimide, I2, and the like; in a suitably selected solvent or mixture of solvents such as AcOH, DMF, DMA, and the like; at a temperature in the range from about 20 °C to about 100 °C; to yield 2-amino-5- iodoisophthalic acid.

[0107] 2-Amino-5-iodoisophthalic acid is reacted with a suitably selected formamidine of formula (III), wherein R1is H, such as formamidine acetate, and the like; in a suitably selected solvent or mixture of solvents such as formamide, and the like; at atemperature in the range from about 150 °C to about 180 °C, preferably at about 170 °C; to yield the corresponding compound of the formula (IV).

[0108] Esterification of compound of formula (IV) is achieved by reaction with a suitably selected acid such as H2SO4, para-toluenesulfonic acid, AcOH, HCl, and the like; in a suitably selected alcoholic solvent such as MeOH, EtOH, tBuOH, and the like; at an elevated temperature, for example at about 80 °C or reflux temperature; to yield the corresponding compound of formula (V).

[0109] The compound of formula (V) is reacted with a suitably selected chlorinating reagent such as SOCl2, POCl3, MsCl, TMSCl, and the like; in a suitably selected solvent or mixture of solvents such as DMF, and the like; at an elevated temperature, in the range of about 80 °C to about 100 °C; to yield the corresponding compound of formula (VI).

[0110] Alternatively, 2-amino-5-iodoisophthalic acid is reacted with a suitably selected anhydride such as acetic anhydride, propionic anhydride, methoxyacetic anhydride, and the like; at a temperature in the range from about 120 °C to about 160 °C; to afford a compound of formula (XIII) wherein R1is alkyl.

[0111] A compound of formula (XIII) is reacted with a suitably selected aqueous ammonia source such as NH3•H2O, and the like; with a suitably selected ammonium salt such as NH4OAc, NH4Cl, NH4HCO3, and the like; at a temperature in the range from about 50 °C to about 100 °C, preferably at about 80 °C; to afford a compound of formula (IV). SCHEME 2

[0112] According to SCHEME 2, a compound of formula (VI) is reacted with a commercially available or synthetically accessible amine of formula (VII), preferably aprimary amine, wherein L is absent, CH(CH3) or CH2, and Rcis H or CH3, and Raand Rbare as defined as in Claim 1; a suitably selected base such as DIPEA, NEt3, K2CO3, Cs2CO3, and the like; in a suitably selected solvent or mixture of solvents such as MeCN, DMF, DCM, DMSO, and the like; at a temperature in the range from about 20 °C to about 85 °C; to yield the corresponding compound of formula (VIII).

[0113] The compound of formula (VIII) is reacted with a suitably substituted compound of formula (IX), wherein LGA 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 known compound or compound prepared by known methods; in the presence of a suitably selected palladium catalyst such as CataCXium A Pd G3, Pd(dppf)Cl2, Pd(PPh3)4, and the like; in the presence of a suitably selected base such as K3PO4, K2CO3, Cs2CO3, TEA, CsF, and the like; in a suitably selected solvent or mixture of solvents such as 1,4-dioxane / H2O, DMF / H2O, MeTHF / H2O, toluene, DMSO, and the like; at a temperature in the range of from about 80 °C to about 100 °C; to yield the corresponding compound of formula (X). SCHEME 3

[0114] According to SCHEME 3, a compound of formula (X) is reacted with a suitable salt such as LiCl, LiBr, LiI, and the like; in a suitably selected solvent or mixture of solvents such as THF, H2O, and the like; at a temperature in the range from about 20 °C to about 70 °C; to afford a compound of formula (XI).

[0115] A compound of Formula (I) is prepared by conventional amide bond forming techniques. A compound of formula (XI) is reacted with a commercially available or synthetically accessible amine (R3), where R3is as defined in Claim 1; in the presence of a suitably selected coupling reagent such as HATU, T3P®, TCFH, PyBOP / HOBt, and the like; in the presence of a suitably selected base such as DIPEA, NEt3, NMM, DMAP, and the like; in a suitably selected solvent or mixture of solvents such as DMF, DMA, DCM, DCE, and the like; at a temperature in the range from about 20 °C to about 70 °C; to yield the corresponding compound of Formula (I). SCHEME 4

[0116] According to SCHEME 4, a commercially available or synthetically accessible compound of formula (XIIa) or (XIIb), where Rais an optionally substituted phenyl or heteroaryl and L is CH2, is protected employing methods known to one skilled in the art. For example, a compound of formula (XIV) where Rdis C1-4alkyl, and PG is a suitable nitrogen protecting group such as tert-butoxycarbonyl (BOC), is prepared according to procedures known to one skilled in the art such as by treatment of (XIIa) with Boc anhydride, a suitable base such as TEA, DIEA, and the like; in a suitable solvent such as EtOAc, DCM, THF and the like. A compound of formula (XIV) where Rdis C1-4alkyl, and PG is a suitable nitrogen protecting group such as tert-butoxycarbonyl (BOC), is prepared according to procedures known to one skilled in the art such as by reaction of a compound of formula (XIIb) with a suitable alkylating agent, such as iodoethane, employing a base such as NaH, K2CO3, Na2CO3, TEA, Cs2CO3, and the like, in a suitable solvent such as DMF, ACN, DCM, at temperatures ranging from 0 ˚C to 85 °C. A compound of formula (XIV) where Rdis C1-6alkyl and PG is BOC; is reactedwith a Grignard reagent such as MeMgBr, in a suitable solvent such as THF, ether, or a mixture thereof; and the like; at temperatures of about 0 °C, for period of about 2-6 hrs; to provide a compound of formula (XV). Deprotection of BOC group on a compound of formula (XV) is achieved according to procedures known to one skilled in the art and employing established methodologies, such as those described in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 3 ed., John Wiley & Sons, 1999, pgs 518-525. For example, deprotection under acidic conditions such as trifluoroacetic acid (TFA) / CH2Cl2, HCl / Dioxane, and the like, at room temperature for a period of 2 h, provides a compound of formula (VII), where Rbis C(CH3)2(OH), and Rcis H.

[0117] A compound of formula (VII) where Rbis , Rcis H, and L is CH2, is prepared in two steps from a compound of formula (XIIb). In a first step, a compound of formula (XIIb) is reacted in an amide bond forming reaction with 3-amino- 1-methylcyclobutanol employing conventional amide bond forming techniques as described herein or as known to one skilled in the art. In a second step, deprotection of the BOC protecting group is achieved employing methods previously described to provide a compound of formula (VII). SCHEME 5

[0118] According to SCHEME 5, an aryl halide or heteroaryl halide compound of formula (XVI), where X is Br, such as 1-bromo-4-(trifluoromethoxy)benzene or 5-bromo-2-(trifluoromethyl)pyrimidine, is reacted under palladium-catalyzed α-arylation conditions with a protected glycine such as ethyl n-(diphenylmethylene)glycinate; with a palladium catalyst such as CataCXium A-Pd-G4, and the like; a suitable base such as K3PO4, and the like; in a suitable solvent such as toluene, and the like; at temperatures ranging from 80 ˚C to 100 °C; to provide a compound of formula (XVII) where L is absent. An ester compound of formula (XVII) is converted into a secondary amide by an aminolysis reaction with methylamine; in a suitable solvent such as MeOH, and the like; to provide a compound of formula (XVIII), where L is absent. Deprotection of a Schiff base compound of formula (XVIII) with a suitable acid such as HCl; a suitable solvent such as EtOH, and the like; provides a corresponding compound of formula (XVIII), where L is absent.

[0119] In a similar fashion, a commercially available or synthetically accessible alkyl halide, such as 3-(bromomethyl)-7,7-difluorobicyclo[4.1.0]heptane, is reacted with protected glycine such as ethyl n-(diphenylmethylene)glycinate in a suitable solvent such as ACN, and the like; with a suitable base such as Cs2CO3, and the like; in the presence of TBAI; to provide ethyl 2-amino-3-(7,7-difluorobicyclo[4.1.0]heptan-3- yl)propanoate. Aminolysis reaction with methylamine and ethyl 2-amino-3-(7,7- difluorobicyclo[4.1.0]heptan-3-yl)propanoate under conditions previously described provides 2-amino-3-(7,7-difluorobicyclo[4.1.0]heptan-3-yl)-N-methylpropanamide.

[0120] In an alternate method, a compound of formula (XVI), where X is Br, is reacted in a Ni-catalyzed cross-electrophile coupling between aryl or heteroaryl bromides and primary alkyl iodides by employing an alkyl iodide such as methyl (S)-2-((tert- butoxycarbonyl)amino)-3-iodopropanoate; a ligand such as dtbbpy, and the like; a nickel catalyst such as NiBr2; with Mn powder; in a suitable solvent such as DMA to provide a compound of formula (XIX), where L is CH2. Subsequent aminolysis and deprotection employing methods previously described provides a compound of formula (VII). SCHEME 6

[0121] According to SCHEME 6, a compound of formula (XII) is prepared by conventional amide bond forming techniques, wherein a compound of the formula (IV) is reacted with a commercially available or synthetically accessible amine (R3) such as nitrogen containing heterocyclyl selected from the group consisting of: monocyclic heterocycloalkyl; spiro-cyclic heterocycloalkyl, bridged heterocycloalkyl or fused heterocycloalkyl; employing methods as previously described, to provide a compoiund of formula (XII).

[0122] A compound of formula (XII) is then reacted with a suitably substituted compound of formula (IX), wherein LGA 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 known compound or compound prepared by known methods; in the presence of a suitably selected palladium catalyst such as CataCXium A Pd G3, Pd(dppf)Cl2,Pd(PPh3)4, and the like; in the presence of a suitably selected base such as K3PO4, K2CO3, Cs2CO3, TEA, CsF, and the like; in a suitably selected solvent or mixture of solvents such as 1,4-dioxane / H2O, DMF / H2O, MeTHF / H2O, toluene, DMSO, and the like; at a temperature in the range of from about 80 °C to about 100 °C; to yield the corresponding compound of formula (XIV).

[0123] The compound of formula (XIV) is reacted with a suitably selected chlorinating reagent such as SOCl2, POCl3, MsCl, TMSCl, and the like; at an elevated temperature, in the range of about 80 °C to about 100 °C; to yield the corresponding compound of formula (XV).

[0124] The compound of formula (XV) is reacted using either standard SNAr reaction conditions or Buchwald-Hartwig C-N bond formation conditions to provide a compound of Formula (I). For example, SNAr conditions employ the reaction of compound of formula (XV) in the presence of a commercially available or synthetically accessible amine of formula (VII), preferably a primary amine, wherein L is absent, CH(CH3) or CH2, and Rcis H or CH3, and Raand Rbare as defined as in Claim 1; in the presence of a suitably selected base such as DIPEA, NEt3, Cs2CO3, and the like; in a suitably selected solvent or mixture of solvents such as MeCN, DMF, DCM, THF, DMSO, and the like; at a temperature in the range of from about 20 °C to about 110 °C, preferably at about 45 °C. An example of Buchwald-Hartwig conditions includes reacting a compound of the formula (XV) with a commercially available or synthetically accessible amine (R2) such as a nitrogen containing heterocyclyl selected from the group consisting of: monocyclic heterocycloalkyl; spiro-cyclic heterocycloalkyl, bridged heterocycloalkyl or fused heterocycloalkyl; in the presence of a suitably selected palladium catalyst such as rac-BINAP Pd G4, SPhos Pd G3, SPhos Pd G4, GPhos Pd G3, and the like; in the presence of a suitably selected base such as Cs2CO3, K2CO3, K3PO4, NaBHT, LiHMDS, and the like; in a suitably selected solvent or mixture of solvents such as 1,4-dioxane, MeCN, THF, 2-MeTHF, DMA, and the like; at a temperature in the range of about 70 °C to about 100 °C; to yield the corresponding compound of Formula (I). SCHEME 7

[0125] According to SCHEME 7, a compound of formula (XII) is then reacted with a suitably selected chlorinating reagent such as SOCl2, POCl3, MsCl, TMSCl, and the like; employing methods previously described to afford a compound of formula (XXI). A compound of formula (XXI) was reacted in the presence of a commercially available or synthetically accessible amine (R2); employing methods previously described to afford a compound of formula (XXII). SCHEME 8

[0126] The compound of formula (XXII) is reacted with a suitably substituted compound of formula (IX), wherein LGA 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 boronicester 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), employing methods previously described to afford a compound of Formula (I).

[0127] Alternatively, a compound of formula (XXII) is reacted in the presence of a suitably selected reagent such as hypodiboric acid, B2pin2, and the like; with a suitably selected palladium catalyst such as Pd(dppf)Cl2, PdCl2(PPh3)2, Pd(PPh3)4, and the like; with a suitably selected base such as KOAc, K2CO3, K3PO4, and the like; in a suitably selected solvent or mixture of solvents such as 1,4-dioxane, 1,2-dimethoxyethane, DMSO, and the like; at a temperature in the range of from about 70 °C to about 110 °C; to yield the corresponding compound of formula (XXV).

[0128] A compound of formula (XXV) is reacted with a suitably substituted compound of formula (XXVI), wherein LGB is a suitably selected reactive coupling group such as a halogen or pseudohalogen (-I, -Br, -OTf), a known compound or a compound prepared by known methods; in the presence of a suitably selected palladium catalyst such as CataCXium A Pd G3, and the like; with a suitably selected base such as K3PO4, and the like; in a suitably selected solvent or mixture of solvents such as 1,4-dioxane, DMF, H2O, and the like; at a temperature in the range of from about 80 °C to about 100 °C; to provide a compound of Formula (I). SCHEME 9

[0129] According to SCHEME 9, a compound formula (XXII) is reacted in a metal mediated cross coupling reaction with 3,6-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzaldehyde; in the presence of a suitably selected palladiumcatalyst such as CataCXium A Pd G3, Pd(dppf)Cl2•DCM, and the like; with a suitably selected base such as K3PO4, Cs2CO3, and the like; in a suitably selected solvent or mixture of solvents such as 1,4-dioxane, DMF, H2O, and the like; at a temperature in the range of from about 80 °C to about 100 °C; to afford a compound of formula (XXVII).

[0130] A compound of formula (XXVII) is reacted with a suitably selected oxidizing agent, such as NaClO2 / NaH2PO4; in the presence of suitably selected scavenger such as 2-methyl-2-butene, resorcinol, sulfamic acid, hydrogen peroxide, and the like; in a suitably selected solvent or mixture of solvents such as DMSO / H2O, MeCN / H2O, tBuOH, and the like; at a temperature in the range of from about 20 °C to about 50 °C; to afford a compound of formula (XXVIII).

[0131] A compound of Formula (I) is prepared by conventional amide bond forming techniques by reaction of a compound of formula (XXVIII) with a commercially available or synthetically accessible amine of the formula (XXIX); employing methods previously described. SCHEME 10

[0132] According to SCHEME 10, 2-amino-5-iodoisophthalic acid is reacted with a suitably selected base, such as Cs2CO3, K2CO3, and the like; with a suitably selected alkylating agent, such as MeI; in a suitably selected solvent or mixture of solvents such as DMF, THF, and the like; at a temperature in the range from about 20 °C to about 70 °C, preferably at about 20 °C; to afford dimethyl 2-amino-5-iodoisophthalate. Dimethyl 2-amino-5-iodoisophthalate is reacted with a suitably selected source of hydroxide, such as NaOH, LiOH, and the like; in a suitably selected solvent or mixture of solvents, such as EtOH / THF / H2O, and the like; at a temperature in the range of about 50 °C to about 80 °C; to afford 2-amino-3-(ethoxycarbonyl)-5-iodobenzoic acid.2-Amino-3- (ethoxycarbonyl)-5-iodobenzoic acid is reacted with urea; at a temperature in the rangeof about 140 °C to about 180 °C; to afford 6-iodo-2,4-dioxo-1,2,3,4,4a,8a- hexahydroquinazoline-8-carboxylic acid. SCHEME 11

[0133] According to SCHEME 11, 6-iodo-2,4-dioxo-1,2,3,4,4a,8a-hexahydroquinazoline- 8-carboxylic acid is reacted with a commercially available or synthetically accessible amine (R3) such as nitrogen containing heterocyclyl selected from the group consisting of: monocyclic heterocycloalkyl; spiro-cyclic heterocycloalkyl, bridged heterocycloalkyl or fused heterocycloalkyl; employing methods as previously described, to provide a compoiund of formula (XXX). A compound of formula (XXX) is then reacted with a suitably substituted compound of formula (IX), wherein LGA 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), employing methods previously described to afford a compound of formula (XXXI). A compound of formula (XXXI) is chlorinated employing methods known to one skilled in the art or as previously described to afford a compound of formula (XXXII). Reaction of a compound of formula (XXXII) with a commercially available or synthetically accessible amine (R2) emplying SNAr reaction conditions orBuchwald-Hartwig C-N bond formation conditions known to one skilled in the art or as previously described provides a compound of formula (XXXIII).

[0134] A compound of Formula (I), wherein R1is NH2, is prepared by reacting a compound of formula (XXXIII) in a cross coupling reaction with a primary or secondary amine (or amine source) such as diphenylmethanimine, and the like; a palladium catalyst as BINAP Pd G4, and the like; a suitable base such as Cs2CO3and the like; in a suitable solvent such as dioxane, and the like; at elevated temperatures. A compound of Formula (I), wherein R1is NH(CH3), N(CH3)2, NH-CH2CH2N(CH3)2, is prepared by reaction of a compound of formula (XXXIII) with a suitable amine such as 40% aq. MeNH2, 40% aq. Me2NH, N,N-dimethylethylenediamine, and the like; in a suitable solvent such as dioxane, DMSO, and the like; at elevated temperatures.

[0135] A compound of Formula (I), wherein R1is OH, is prepared by reaction of a compound of formula (XXXIII) with AgOAc; in a suitable solvent or mixture of solvents such as AcOH, dioxane, water, and the like; at temperatures ranging from 25 °C to 80 °C. Similarly, a compound of formula (XXXIII) is reacted with NH4OAc, in AcOH, at a temperature of about 77-80 °C to provide a compound of Formula (I) wherein R1is OH.

[0136] Alternately, a compound of Formula (I) wherein R1is OH, is prepared from a compound of formula (XXXIII); a palladium catalyst such as RockPhos Pd G3, and the like; benzaldehyde oxime as a hydroxide surrogate; a suitable base such as Cs2CO3, and the like; a suitable solvent such as DMF, toluene, and the like; at elevated temperatures such as 80 °C.

[0137] A compound of formula (XXXIII) is reacted in a palladium catalyzed cross coupling reaction known to one skilled in the art, with an organotrifluoroborate such as potassium (methoxymethyl)trifluoroborate, (tetrahydro-2H-pyran-3-yl) trifluoroborate, potassium (morpholin-4-yl)methyltrifluoroborate, and the like; a palladium catalyst such as cataCXium Pd G4, and the like; a base such as Cs2CO3, and the like; a suitable solvent such as dioxane, acetonitrile, water or a mixture thereof; at elevated temperatures ranging from 80 °C to 100 °C; to provide a compound of Formula (I), wherein R1is CH2OCH3, tetrahydropyran-4-yl, and . A compound of Formula (I), wherein R1is CN, is prepared from a compound of formula (XXXIII), sodium cyanide,DABCO, in a suitable solvent such as DMSO, at elevated temperatures ranging from 80 °C to 100 °C.

[0138] A compound of Formula (I), wherein R1is S-CH3, SO2CH3, SO2-cyclopropyl, is prepared by reaction of a compound of formula (XXXIII) with sulfur reagent such as sodium methanethiolate, sodium methanesulfonate, sodium methyl sulfate, sodium cyclopropanesulfinate, and the like; a suitable base such as Cs2CO3, and the like; in a suitable solvent such as DMF, DMSO, and the like; at temperatures ranging from 95 °C to 100 °C.

[0139] One skilled in the art will recognize that various substituent groups and / 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.

[0140] 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.

[0141] One skilled in the art will recognize that, where not otherwise specified, the reaction step(s) is performed under suitable conditions, according to known methods, to provide the desired product. One skilled in the art will further recognize that, in the specification and claims as presented herein, wherein a reagent or reagent class / type (e.g. base, solvent, etc.) is recited in more than one step of a process, the individual reagents are independently selected for each reaction step and may be the same 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.

[0142] One skilled in the art will recognize that wherein a reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.

[0143] 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) / 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] 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 groupson 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.

[0149] 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.

[0150] 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.

[0151] 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 (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column. 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 = ([α-obs] / [α-max]) X 100. Methods of Treatment / Disorders Mediated by BFL-1 Protein

[0152] The present invention is further directed to methods of treating a cancers mediated by the BFL-1 protein (including, but not limited to leukemias and lymphomascomprising administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula (I).

[0153] As used herein, unless otherwise noted the term “cancer mediated by the BFL-1 protein” shall include leukemias and lymphomas. Leukemias include, but are not limited to, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), (acute) T-cell leukemia, acute monocytic leukemia, acute promyelocytic leukemia (APL), bisphenotypic B myelomonocytic leukemia, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia, myelodysplastic syndrome (MDS) (which can develop into an acute myeloid leukemia).

[0154] 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-expressorlymphoma; anaplastic large cell lymphoma, marginal B cell lymphoma and primary mediastinal B-cell lymphoma, immunoblastic large cell lymphoma, Burkitt lymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoplasmatic lymphoma, precursor B -lymphoblastic lymphoma, lymphoma of the central nervous system, small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL); 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.

[0155] In certain embodiments, the cancer mediated by the BFL-1 protein is a leukemia. In certain embodiments, the cancer mediate by the BFL-1 protein is a leukemia selected from the group consisting of acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS). In certain embodiments, the cancer mediated by the BFL-1 protein is a leukemia is acute myeloid leukemia (AML).

[0156] In certain embodiments, the cancer mediated by the BFL-1 protein is a lymphoma. In certain embodiments, the cancer mediated by the BFL-1 protein is a lymphoma selected from the group consisting of AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), subtypes of NHL such as Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell DLBCL, double-hit lymphoma and double-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 protein is a lymphoma selected from the group consisting of T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma. In certain embodiments, the cancer mediated by the BFL-1 protein is a sarcoma selected from the group consisting sarcoma of the soft tissue, gliosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma. In certain embodiments, the cancer mediated by the BFL-1 protein is a solid tumor, selected from the group consisting of breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head & neck cancer, hepatocellular carcinoma, lung cancer, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma. In certain embodiments, the cancer mediated by the BFL-1 protein is a leukemia is Diffuse Large Cell Lymphoma (DLBCL).

[0157] 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.

[0158] 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 / or exhibited at least one symptom of the disease, disorder or condition to be treated.

[0159] The term “therapeutically effective amount” as used herein, means the amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. Preferably, the therapeutically effective amount results in the alleviation of at least one symptom of the disease, disorder or condition being treated. Pharmaceutical Compositions

[0160] The present invention is further directed to pharmaceutical compositions comprising, consisting of or consisting essentially of a compound of Formula (I) as described herein. The present invention is further directed to pharmaceutical compositions comprising, consisting of or consisting essentially of a compound of Formula (I) as described herein and one or more pharmaceutically acceptable carriers or excipients.

[0161] 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.

[0162] 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.

[0163] The present invention further comprises pharmaceutical compositions containing a compound of Formula (I), with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing one or more of the compounds of the 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 andadditives 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.

[0164] 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.

[0165] 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.

[0166] Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these pre-formulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid pre- formulation composition is then subdivided into unit dosage forms of the type described above containing from about 0.01 mg to about 1,000 mg, or any amount or range therein, of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form yielding the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelopeover 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.

[0167] 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.

[0168] The method of the treatment of the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.01 mg and about 1000 mg of the compound, or any amount or range therein, preferably from about 0.05 mg to about 500 mg of the compound, or any amount or range therein, more preferably from about 0.1 mg to about 500 mg of the compound, or any amount or range therein, more preferably from about 0.1 mg to about 500 mg of the compound, or any amount or range therein, more preferably from about 10 mg to about 500 mg of the compound, or any amount or range therein; and may be constituted into any form suitable for the mode of administration selected. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

[0169] 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.

[0170] 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.

[0171] 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.

[0172] 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 innumerous publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.

[0173] Compounds of the present invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of thromboembolic disorders, inflammatory disorders or diseases or conditions in which plasma kallikrein activity is implicated is required.

[0174] The daily dosage of the products may be varied over a wide range from about 0.01 mg to about 1,000 mg per adult human per day, or any amount or range therein. For oral administration, the compositions are preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug may be ordinarily supplied at a dosage level of from about 0.005 mg / kg to about 10 mg / kg of body weight per day, or any amount or range therein. Preferably, the range is from about 0.01 to about 5.0 mg / kg of body weight per day, or any amount or range therein, more preferably, from about 0.1 to about 1.0 mg / kg of body weight per day, or any amount or range therein, more preferably, from about 0.1 to about 0.5 mg / kg of body weight per day, or any amount or range therein. The compounds may be administered on a regimen of 1 to 4 times per day. Examples

[0175] 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.

[0176] 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 knownmethods, for example according to literature procedures. When solutions were “concentrated to dryness”, they were concentrated using a rotary evaporator under reduced pressure; when solutions were dried, they were typically dried over a drying agent such as MgSO4or Na2SO4. Where a synthesis product is listed as having been isolated as a residue, it will be understood by those skilled in the art that the term “residue” does not limit the physical state in which the product was isolated and may include, for example, a solid, an oil, a foam, a gum, a syrup, and the like.

[0177] 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.

[0178] 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 µm. 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 µm. 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.

[0179] Preparative HPLC: Unless otherwise noted, preparative HPLC purifications were performed with Waters Auto purification system. The column was selected from one of the following: Waters C18, 19 x150 mm, 5 μm; XBridge Prep OBD C18 Column, 30×150 mm 5 μm; XSelect CSH Prep C18 OBD Column, 5μm,19*150 mm; XBridge Shield RP18 OBD Column, 30x150 mm, 5μm; Xselect CSH Fluoro Phenyl, 30 x 150 mm, 5 μm; or YMC-Actus Triart C18, 30 x 150 mm, 5 μm. The mobile phases consisted of mixtures of acetonitrile (5-95%) in water containing 0.1% FA or 10 mmol / L NH4HCO3. Flow rates were maintained at 25 mL / min, the injection volume was 1200 μL, and the UV detector used two channels 254 nm and 220 nm. Mobile phase gradients were optimized for the individual compounds.

[0180] Chiral chromatography: Chiral analytical chromatography was performed on one of Chiralpak AS, AD, Chiralcel OD,OJ Chiralpak IA,IB,IC,ID,IE,IF,IG,IH columns (Daicel Chemical Industries, Ltd.) (R,R)-Whelk-O1, (S,S)-Whelk-O1 columns (Regis technologies, Inc. ) CHIRAL Cellulose-SB, SC, SA columns (YMC Co., Ltd.) as noted, at different column size (50x4.6mm, 100x4.6mm, 150x4.6mm, 250x4.6mm, 50x3.0mm, 100x3.0mm), with percentage of either ethanol in hexane (%Et / Hex) or isopropanol in hexane (%IPA / Hex) as isocratic solvent systems, or using supercritical fluid (SFC) conditions.

[0181] Normal phase flash chromatography: Unless otherwise noted, normal phase flash column chromatography (FCC) was performed on silica gel with pre-packaged silica gel columns (such as RediSep®), using ethyl acetate (EtOAc) / hexanes, ethyl acetate (EtOAc) / Petroleum ether, CH2Cl2 / MeOH, or CH2Cl2 / 10% 2N NH3in MeOH, as eluent.

[0182] 1H NMR: Unless otherwise noted,1H NMR spectra were acquired using 400 MHz spectrometers in CDCl3, CD3OD, or DMSO-d6solutions. The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (δ) are expressed in parts per million (ppm). Coupling constants (J) are reported in hertz (Hz). The nature of the shifts as to multiplicity is reported as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), dt (double triplet), m (multiplet), br (broad).

[0183] Chemical names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye). Intermediate 1: (R)-2-Amino-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide.

[0184] Step A: Methyl (R)-2-amino-3-(4-(trifluoromethyl)phenyl)propanoate hydrochloride. To a solution of (R)-2-amino-3-(4-(trifluoromethyl)phenyl)propanoic acid hydrochloride (420 g, 1.56 mol) in MeOH (3200 mL) was added SOCl2(371 g, 3.12 mol, 226 mL) at 10 °C. The mixture was stirred at 70 °C for 6 h. The reaction mixture was concentrated under reduced pressure to give methyl (R)-2-amino-3-(4-(trifluoromethyl)phenyl)propanoate hydrochloride as a white solid. MS (ESI): mass calcd. for C11H12F3NO2, 247.1; m / z found, 248.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 8.80 (br s, 3H) 7.70 (d, J = 8.00 Hz, 2H) 7.50 (d, J = 8.00 Hz, 2H) 4.34 (br d, J = 4.63 Hz,1H) 3.68 (s, 3H) 3.36 - 3.19 (m, 2H).

[0185] Step B: (R)-2-Amino-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide. 2 batches were carried out in parallel. To a solution of CH3NH2(1.64 kg, 15.86 mol, 30.0% purity) was added (R)-2-amino-3-(4-(trifluoromethyl)phenyl)propanoate hydrochloride (450 g, 1.59 mol) in ten portions at 10 °C. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to provide a residue which was purified (FCC, SiO2, gradient DCM / MeOH = 10 / 1 to 2 / 1). The isolated material was then stirred in water (1000 mL) at 25 °C for 2 h, then filtered and dried at 45 °C under vacuum to provide (R)-2-amino-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide as a white solid. MS (ESI): mass calcd. for C11H13F3N2O, 246.1; m / z found, 247.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ = 7.81 (br d, J = 4.38 Hz,1H) 7.62 (d, J = 8.00 Hz, 2H) 7.42 (d, J = 8.00 Hz, 2H) 3.37 (dd, J = 8.13, 5.13 Hz, 1H) 2.99 (dd, J = 13.26, 5.13 Hz,1H) 2.70 (dd, J = 13.26, 8.13 Hz, 1H) 2.57 (d, J = 4.75 Hz, 3H) 1.74 (br s, 2H). Intermediate 2: (R)-6-(2,5-Dimethylphenyl)-4-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carboxylic acid.

[0186] Step A: 2-Amino-5-iodoisophthalic acid. To a solution of 2-aminoisophthalic acid (212 g, 1.17 mol) in HOAc (1.69 L) was added dropwise a solution of ICl (285 g, 1.76 mol, 89.6 mL) in HOAc (636 mL) at 25 °C, the reaction mixture was stirred at 25 °C for ~12 h under N2. The reaction mixture was poured into water (5 L) while stirring, and the resulting mixture was stirred at 25 °C for ~3 h. The resulting mixture was filtered and washed with water (500 mL x 3). The filter cake was triturated with MeOH (800 mL)stirred and then filtered and washed with cool MeOH (600 mL x2) and petroleum ether (1.0 L x 2). The obtained solid was dried under reduced pressure to give 2-amino-5- iodoisophthalic acid as a yellow solid. MS (ESI): mass calcd. for C8H6INO4, 306.9; m / z found, 308.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 13.96 - 12.36 (m, 1H), 8.19 (s, 2H).

[0187] Step B: 4-Hydroxy-6-iodoquinazoline-8-carboxylic acid. In a 3 L round bottom flask equipped with a magnetic stirrer and 2-amino-5-iodoisophthalic acid (345 g, 1.12 mol), was added acetic acid;methanimidamide (351 g, 3.37 mol) and formamide (53.1 g, 1.18 mol, 47.0 mL). The resulting mixture was stirred directly at 175 °C for 1 h. The mixture was cooled to 25 °C and diluted with water (2.5 L) and stirred. The resulting mixture was filtered, and the filter cake was washed with water (500 mL x2). The obtained solid was triturated with cold MeOH (1 L) and stirred. The mixture was filtered, washed with cool MeOH (200 mL x3) and petroleum ether (300 mL x3), and the filtrate was concentrated under reduced pressure at 55 °C to remove solvent and yield 4- hydroxy-6-iodoquinazoline-8-carboxylic acid as a light-yellow solid. MS (ESI): mass calcd. for C9H5IN2O3, 315.9; m / z found, 316.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 15.09 - 13.41 (m, 2H), 8.52 (d, J = 2.0 Hz, 1H), 8.49 - 8.46 (m, 2H).

[0188] Step C: Methyl 4-hydroxy-6-iodoquinazoline-8-carboxylate. To a solution of 4- hydroxy-6-iodoquinazoline-8-carboxylic acid (250 g, 791 mmol) in MeOH (1.25 L) was added H2SO4(155 g, 1.58 mol, 84.3 mL). The mixture was stirred at 80 °C for 12 h. The mixture was cooled to 25 °C, concentrated under reduced pressure to give a residue, to which was added H2SO4(77.5 g, 791 mmol, 42.2 mL) and MeOH (1.25 L). The mixture was stirred at 80 °C for 12 h. The mixture was cooled to 25 °C and concentrated under reduced pressure to give a residue. Saturated NaHCO3solution was added to adjust the pH to ~8, and the solid was collected by filtration, washing with water (1 L x3). The filter cake was dried under reduced pressure to provide methyl 4-hydroxy-6- iodoquinazoline-8-carboxylate as a light-yellow solid. MS (ESI): mass calcd. for C10H7IN2O3, 330.0; m / z found, 330.8 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 12.59 (br s, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.18 (s, 1H), 3.85 (s, 3H).

[0189] Step D: Methyl 4-chloro-6-iodoquinazoline-8-carboxylate. To a solution of methyl 4-hydroxy-6-iodoquinazoline-8-carboxylate (120 g, 363 mmol) in SOCl2(720 mL) wasadded DMF (5.31 g, 72.7 mmol, 5.59 mL) at 25 °C. The reaction mixture was then heated to 90 °C for 9 hrs. The mixture was cooled to 25 °C. The reaction mixture was concentrated under reduced pressure to give a residue. To the residue was added toluene (300 mL) and concentrated under reduced pressure to remove excess SOCl2to provide methyl 4-chloro-6-iodoquinazoline-8-carboxylate as a light-yellow solid.1H NMR (400 MHz, CDCl3) δ = 9.17 (s, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 4.05 (s, 3H).

[0190] Step E: Methyl (R)-6-iodo-4-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carboxylate. To a solution of methyl 4-chloro-6-iodoquinazoline-8-carboxylate (80.0 g, 229 mmol) in CH3CN (800 mL) was added (R)-2-Amino-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide (Intermediate 1, 59.20 g, 240.5 mmol) as one portion, followed by DIEA (89.0 g, 689 mmol, 119 mL) at 25 °C. The mixture was heated to 85 °C and stirred at 85 °C for 12 h under N2 atmosphere. The mixture was cooled to 25 °C, and the reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (500 mL) at 25°C for 1 h. The solid was filtered and washed with MTBE (200 mL x 3). The filter cake was further triturated with H2O (500 mL) at 25 °C for 30 min, then the pH was adjusted to between 2-3 with saturated 1 M HCl. The solid was collected by filtration then dried under reduced pressure to give methyl (R)-6-iodo-4-((1- (methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8- carboxylate as a white solid. MS (ESI): mass calcd. for C21H18F3IN4O3, 558.0; m / z found, 559.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 8.97 (d, J = 1.6 Hz, 1H), 8.69 (br d, J = 8.0 Hz, 1H), 8.42 (s, 1H), 8.22 - 8.14 (m, 2H), 7.64 - 7.52 (m, 4H), 5.14 - 5.06 (m, 1H), 3.84 (s, 3H), 3.31 - 3.16 (m, 2H), 2.61 (d, J = 4.5 Hz, 3H).

[0191] Step F: Methyl (R)-6-(2,5-dimethylphenyl)-4-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carboxylate. To a solution of methyl (R)-6-iodo-4-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2- yl)amino)quinazoline-8-carboxylate (70.0 g, 125 mmol) and (2,5-dimethylphenyl)boronic acid (24.4 g, 163 mmol) in a mixture of DMF (700 mL) and H2O (14.0 mL) was added K2CO3(34.6 g, 250 mmol) and CataCXium A Pd G3(1.83 g, 2.51 mmol) at 25 °C. The mixture was heated to 80 °C and stirred at 80 °C for 12 h under N2atmosphere. Themixture was cooled to 25 °C and filtered through a Celite® pad. The solid was washed with EtOAc (100 mL x3). The filtrate was poured into water (200 mL), filtered again to collect remaining solids, and the filter cake was washed with EtOAc (100 mL x2) and dried under vacuum to give methyl (R)-6-(2,5-dimethylphenyl)-4-((1-(methylamino)-1- oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carboxylate as a white solid. The remaining filtrate was washed with water (200 mL x2), and the combined aqueous layers were extracted with EtOAc (200 mL x2). The combined organic layers were concentrated under reduced pressure to afford a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g Sepa Flash® Silica Flash Column, Eluent of 0~15% Petroleum ether: Ethyl acetate @ 110 mL / min), to provide additional methyl (R)-6-(2,5-dimethylphenyl)-4-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carboxylate as a white solid. MS (ESI): mass calcd. for C29H27F3N4O3, 536.2; m / z found, 537.5 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 8.60 - 8.49 (m, 2H), 8.43 (s, 1H), 8.14 (br d, J = 4.5 Hz, 1H), 7.88 (s, 1H), 7.61 - 7.52 (m, 4H), 7.29 - 7.11 (m, 3H), 5.14 - 5.06 (m, 1H), 3.85 (s, 3H), 3.30 - 3.16 (m, 2H), 2.61 (br d, J = 4.4 Hz, 3H), 2.35 (s, 3H), 2.22 (s, 3H).

[0192] Step G: (R)-6-(2,5-Dimethylphenyl)-4-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carboxylic acid. A mixture of methyl (R)-6-(2,5-dimethylphenyl)-4-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carboxylate (58.0 g, 108 mmol), LiI (43.4 g, 324 mmol in THF (580 mL) was degassed and purged with N23 times, and then the mixture was stirred at 70 °C for 8 h under N2 atmosphere. The mixture was cooled to 25 °C, then additional LiI (34.0 g, 254 mmol) was added, and the mixture was stirred at 70 °C for 12 h under N2 atmosphere. The mixture was cooled to 25 °C, then LiI (50.6 g, 378 mmol) was added, and the mixture was stirred at 70 °C for 12 h under N2 atmosphere. The mixture was cooled to 25 °C and poured into H2O (300 mL), 0.5M HCl (60.0 mL), and EtOAc (300 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (200 mL x3). The combined organic layers were washed with Na2S2O3(200 mL x2) and brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduce pressure to afford (R)-6-(2,5-dimethylphenyl)-4- ((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carboxylic acid as a light-yellow solid. MS (ESI): mass calcd. for C28H25F3N4O3, 522.2; m / z found, 523.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 9.64 - 9.54 (m, 1H), 8.82 (d, J = 1.6 Hz, 1H), 8.66 (s, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.34 (br d, J = 4.8 Hz, 1H), 7.58 (s, 4H), 7.31 - 7.15 (m, 3H), 5.28 - 5.21 (m, 1H), 3.33 - 3.22 (m, 2H), 2.63 (d, J = 4.4 Hz, 3H), 2.36 (s, 3H), 2.23 (s, 3H). Intermediate 3: (2,3,6-Trimethylphenyl)boronic acid.

[0193] Step A: 1-(Bromomethyl)-3-iodo-2,4-dimethylbenzene. To a solution of 2-iodo- 1,3-dimethylbenzene (1.00 kg, 4.31 mol, 621 mL) and paraformaldehyde (1.30 kg, 8.62 mol) in AcOH (6.00 L) was added HBr (6.00 L, 47.0% purity) at 25°C. The resulting brown mixture was stirred at 130 °C for 3 hrs. The reaction was diluted with H2O (10.0 L) and extracted with petroleum ether (5.00 L x3). The combined organic layers were washed with H2O (5.00 L x2), NaHCO3(aq.5.00 L x2), and brine (5.00 L), dried over Na2SO4, and concentrated to dryness under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 6.0 kg SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ether gradient @ 200 mL / min) to provide 1- (bromomethyl)-3-iodo-2,4-dimethylbenzene as a pink solid.1H NMR (400 MHz, CDCl3) δ = 7.18 (d, J = 7.75 Hz, 1H) 7.04 - 7.10 (m, 1H) 4.57 (s, 2H) 2.59 (s, 3H) 2.49 (s, 3H).

[0194] Step B: 2-Iodo-1,3,4-trimethylbenzene. To a solution of LiBH4 (223 g, 10.2 mol) in THF (7.00 L) was added 1-(bromomethyl)-3-iodo-2,4-dimethylbenzene (950 g, 2.92 mol) in THF (3.00 L) at 0 °C under N2 gas flow over 30 mins. The turbid white mixture was stirred at 25 °C under N2 gas flow for 12 hrs. The reaction was diluted with citric acid (1.00 kg) in H2O (8.00 L) and extracted with petroleum ether (5.00 L x3). The combined organic layers were washed with H2O (5.00 L x2), brine (5.00 L), dried over Na2SO4, and concentrated to dryness under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 5000 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ether gradient @ 200 mL / min) to provide 2-iodo-1,3,4-trimethylbenzene as a colorless liquid.1H NMR (400 MHz, CDCl3) δ = 7.01 (s, 2H) 2.49 (d, J = 6.00 Hz, 6H) 2.37 (s, 3H)

[0195] Step C: (2,3,6-Trimethylphenyl)boronic acid.8 batches were carried out in parallel; for each batch, 100 g of 2-iodo-1,3,4-trimethylbenzene was used. To a solution of 2-iodo-1,3,4-trimethylbenzene (100 g, 406 mmol) in THF (1.00 L) was added dropwise isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 375 mL, 488 mmol) at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 1.5 h before B(OMe)3 (84.5 g, 812 mmol, 91.8 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. The reaction was diluted with HCl (2 M, 500 mL) and extracted with EtOAc (500 mL x3). The combined organic layers were washed with 2 M HCl (500 mL x2), H2O (500 mL x2), and brine (500 mL), dried over Na2SO4, and concentrated to dryness under reduce pressure to provide a residue. The 8 reactions were combined for purification. The residue was triturated with pentane: DCM = 95: 5 (8.00 L, 10V) at 25 °C for 2 h to provide (2,3,6-trimethylphenyl)boronic acid as a white solid. MS (ESI): mass calcd. for C9H13BO2, 164.1; m / z found, 162.9 [M- H]+.1H NMR (400 MHz, CDCl3) δ = 7.05 (d, J = 7.63 Hz, 1H) 6.93 (d, J = 7.63 Hz, 1H) 3.38 - 5.46 (m, 2H) 2.35 (s, 3H) 2.29 (s, 3H) 2.23 (s, 3H). Intermediate 4: 1-(4-(Methylsulfonyl)phenyl)piperazine.

[0196] Step A: 1-(4-(Methylsulfonyl)phenyl)piperazine. To a mixture of 1-bromo-4- (methylsulfonyl)benzene (165 g, 701 mmol) and piperazine (604 g, 7.02 mol) in toluene (1.15 L) and MeOH (500 mL) were added tBuONa (101 g, 1.05 mol) and BINAP (26.2 g, 42.1 mmol) at 25 °C, then was added Pd2(dba)3 (19.3 g, 21.1 mmol) at 25 °C under N2. The resultant mixture was stirred at 70 °C for 1 h. The reaction mixture added to H2O (6.00 L) and extracted with DCM (2.00 L x2, 1.50 L x2). The combined organic phases was washed with brine (5.00 L x2, 2.50 L x1), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®; 500 g SepaFlash® Silica Flash Column, Eluent of 30% Ethylacetate / Dichloromethane to eluent of 0-10 % Methanol / Dichloromethane @ 350 mL / min). The isolated material was triturated with MTBE (100 mL) at 25 oC for 1 h. The solid was filtered and dried under high vacuum to afford 1-(4- (methylsulfonyl)phenyl)piperazine as a yellow solid. MS (ESI): mass calcd. for C11H16N2O2S, 240.1; m / z found, 241.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 7.61- 7.71 (m, 2H), 6.97-7.11 (m, 2H), 3.21-3.29 (m, 4H), 3.09 (s, 3H), 2.78-2.84 (m, 4H). Intermediate 5: (2,4-Dihydroxy-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone.

[0197] Step A: Dimethyl 2-amino-5-iodoisophthalate. Five batches were carried out in parallel. To a solution of 2-amino-5-iodoisophthalic acid (159 g, 516.8 mmol) in DMF (2.4 L) was added Cs2CO3(842 g, 2.58 mol) at 25 °C. The mixture was stirred at 25 °C for 0.5 h. CH3I (183 g, 1.29 mol, 80.4 mL) was added dropwise to the mixture at 25 °C. The mixture was stirred at 25 °C for 12 h under N2 atmosphere. The reaction mixture was added to H2O (25 L), filtered, and the filter cake was washed with H2O (1 L) and dried under vacuum to give dimethyl 2-amino-5-iodoisophthalate as a yellow solid. MS (ESI): mass calcd. for C10H10INO4, 335.0; m / z found, 335.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 8.21 (s, 2H), 8.00 (s, 2H), 3.82 (s, 6H).

[0198] Step B: 2-Amino-3-(ethoxycarbonyl)-5-iodobenzoic acid. Two batches were carried out in parallel. To a solution of dimethyl 2-amino-5-iodoisophthalate (100 g, 298 mmol) in a mixture of EtOH (1.00 L) and THF (1.00 L) and H2O (500 mL) was added NaOH (12.5 g, 313 mmol) at 25 °C. The mixture was heated to 70 °C and stirred at 70 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give 2- amino-3-(ethoxycarbonyl)-5-iodobenzoic acid as a yellow solid. MS (ESI): mass calcd. for C10H10INO4, 335.0; m / z found, 335.9 [M+H]+.

[0199] Step C: 6-Iodo-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-8-carboxylic acid. Two batches were carried out in parallel. A mixture of 2-amino-3-(ethoxycarbonyl)-5- iodobenzoic acid (110 g, 328 mmol) and urea (192 g, 3.20 mol, 171 mL) was stirred at 180 °C for 2 hrs. The reaction mixture was cooled down to 100 °C, then diluted with H2O (1000 mL) at 100 °C and further stirred at 100 °C for 10 min. The mixture was cooled to 25 °C, and the aqueous phase was acidified with 1N HCl to pH = 4. The suspension was stirred at 25 °C for 1 hr. The resulting solid was collected by filtration, washed with water (100 mL), and concentrated under reduced pressure to give a residue. The residue was triturated with MeCN (2.00 L) at 25 °C for 12 hours. The solid was filtered, washed with MeCN (500 mL), and dried under high vacuum to afford 6- iodo-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-8-carboxylic acid as a white solid. MS (ESI): mass calcd. for C9H5IN2O4, 331.9; m / z found, 332.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 11.75 (s, 1H), 10.76 (s, 1H), 8.44 (s, 1H), 8.36 (s, 1H).

[0200] Step D: 6-Iodo-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazoline- 2,4(1H,3H)-dione. Two batches were carried out in parallel. To a solution of 6-iodo-2,4- dioxo-1,2,3,4-tetrahydroquinazoline-8-carboxylic acid (84.5 g, 254 mmol) and 1-(4- (methylsulfonyl)phenyl)piperazine (73.3 g, 305 mmol) in DMF (1690 mL) was added TCFH (85.6 g, 305 mmol) and 1-methylimidazole (73.1 g, 890 mmol, 71.0 mL) at 25 °C. The mixture was stirred at 25 °C for 12 h under N2 atmosphere. The reaction mixture was added to H2O (17.0 L). The solids were collected by filtration, and the filter cake was washed with H2O (500 mL) then dried under vacuum to give a solid. The solid was triturated with EtOAc (1.70 L) at 25 °C for 3 h. The solid was collected by filtration, washed with EtOAc (100 mL), and dried under high vacuum to afford a solid. The solid was again triturated with EtOAc (1.00 L) at 25 °C for 12 h. The solid was collected by filtration, washed with EtOAc (100 mL), and dried under high vacuum to afford 6-iodo-8- (4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazoline-2,4(1H,3H)-dione as a white solid. MS (ESI): mass calcd. for C20H19IN4O5S, 554.0; m / z found, 555.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ = 11.56 (s, 1H), 10.78 (s, 1H), 8.19 (s, 1H), 7.91 (s, 1H), 7.71-7.69 (d, 2H), 7.09-7.06 (d, 2H), 3.72 (br s, 2H), 3.57 (br s, 2H) 3.37 (br s, 4H), 3.09 (s, 3H).

[0201] Step E: 8-(4-(4-(Methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazoline-2,4(1H,3H)-dione. To a solution of 6-iodo-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazoline-2,4(1H,3H)-dione (45.0 g, 81.2 mmol) and 4,4,5,5-tetramethyl-2-(2,3,6-trimethylphenyl)-1,3,2-dioxaborolane (25.9 g, 105.5 mmol) in a mixture of DMF (1350 mL) and H2O (135 mL) was added K2CO3(50.4 g, 365 mmol) and CataCXium A Pd G3(5.91 g, 8.12 mmol) at 25 °C. The mixture was heated to 80 °C and stirred at 80 °C for 12 h under N2 atmosphere. The mixture was cooled to 50 °C and filtered through a pad of Celite®. The solid was washed with EtOAc (500 mL). The filtrate was poured into water (5.00 L) and EtOAc (1.00 L), the organic phase was separated, the aqueous phase was extracted with EtOAc (1.00 L x2). The combined organic layers were concentrated under reduced pressure to afford a residue. The residue was triturated with H2O (300 mL) at 25 °C for 1 hour. The solid was filtrated, washed with water (100 mL), and dried under high vacuum to afford a solid. The solid was triturated with MTBE (300 mL) at 25 °C for 12 hours. The solid was collected by filtration, washed with MTBE (100 mL), and dried under high vacuum to afford a residue. The residue was purified by prep-HPLC (Column: Phenomenex luna c18250mm x 100mm x10um; Mobile phase: [water(HCl)-ACN]; B%: 30%-60%, 20min) to give 8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazoline-2,4(1H,3H)-dione as a white solid. MS (ESI): mass calcd. for C29H30N4O5S, 546.2; m / z found, 547.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 11.53 (d, J = 1.00 Hz, 1H), 10.66 (s, 1H), 7.62 - 7.73 (m, 3H), 7.39 (d, J = 2.00 Hz, 1H), 7.00 - 7.13 (m, 4H), 3.74 (br s, 2H), 3.37 - 3.62 (m, 6H), 3.09 (s, 3H), 2.24 (s, 3H), 1.95 (s, 3H), 1.90 (s, 3H). Intermediate 6: 4,4,5,5-Tetramethyl-2-(2,3,6-trimethylphenyl)-1,3,2-dioxaborolane.

[0202] Step A: 2,3,6-Trimethylphenyl trifluoromethanesulfonate. To a solution of 2,3,6- trimethylphenol (2.85 kg, 20.9 mol) and DMAP (255 g, 2.09 mol) in DCM (25.6 L) wasadded dropwise TEA (2.54 kg, 25.1 mol, 3.50 L) at 0 °C over 30 mins, followed by (TfO)2O (7.09 kg, 25.1 mol, 4.14 L) at 0 °C for 2 h. The brown mixture was stirred at 25 °C for 12 hrs. The reaction mixture was quenched by addition H2O (15.0 L) and extracted with DCM (5.00 L). The combined organic layers were washed with brine (5.00 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2,3,6-trimethylphenyl trifluoromethanesulfonate as a light-yellow oil.1H NMR (400 MHz, CDCl3) δ = 7.07 - 7.09 (m, 1H) 7.07 - 7.09 (m, 1H) 2.37 (br s, 3H) 2.29 - 2.30 (m, 6H).

[0203] Step B: 4,4,5,5-Tetramethyl-2-(2,3,6-trimethylphenyl)-1,3,2-dioxaborolane. A solution of 2,3,6-trimethylphenyl trifluoromethanesulfonate (2.83 kg, 10.5 mol), Et3N (3.20 kg, 31.6 mol, 4.40 L), Pd(CH3CN)2Cl2(27.3 g, 105 mmol), SPhos (173 g, 421 mmol), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.37 kg, 26.3 mol, 3.83 L) in dioxane (28.3 L) was prepared at 25 °C under N2. The resulting mixture was heated to 75 °C and stirred for 12 h under N2. The reaction was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=20 / 1 to 10 / 1) to give 4,4,5,5- tetramethyl-2-(2,3,6-trimethylphenyl)-1,3,2-dioxaborolane as a white solid.1H NMR (400 MHz, CDCl3) δ = 7.18 - 7.20 (m, 1H) 7.05 - 7.10 (m, 1H) 2.56 (br s, 3H) 2.50 (br s, 3H) 2.40 (br s, 3H) 1.57 (br s, 12H). Intermediate 7: (4-Chloro-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone.

[0204] Step A: (4-Hydroxy-6-iodoquinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin- 1-yl)methanone. To a mixture of 4-hydroxy-6-iodoquinazoline-8-carboxylic acid (100 g, 316 mmol) and 1-(4-(methylsulfonyl)phenyl)piperazine (91.2 g, 379 mmol) in DMF (1.20 L) were added T3P (406 g, 639 mmol, 380 mL, 50% purity) and DIEA (185 g, 1.44 mol, 250 mL) at 25 °C. The mixture was stirred at 60 °C for 12 h. The reaction mixture wasadded to H2O (6.00 L) and extracted with DCM (2.00 L x3, 1.50 L x3). The combined organic phases were washed with brine (5L x 3), dried over anhydrous Na2SO4, filtered, and concentrated to provide (4-hydroxy-6-iodoquinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone as a yellow solid. MS (ESI): mass calcd. for C20H19IN4O4S, 538.0; m / z found, 539.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 12.68 (s, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.17 (s, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 8.9 Hz, 2H), 7.07 (d, J = 9.1 Hz, 2H), 3.71-3.90 (m, 2H), 3.45-3.55 (m, 2H), 3.19- 3.31 (m, 4H), 3.09 (s, 3H).

[0205] Step B: (4-Hydroxy-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone. To a solution of (4-hydroxy-6- iodoquinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone (46.0 g, 85.4 mmol) and 4,4,5,5-tetramethyl-2-(2,3,6-trimethylphenyl)-1,3,2-dioxaborolane (31.5 g, 128 mmol) in a mixture of DMF (1.38 L) and H2O (138 mL) was added CataCXium A Pd G3(6.22 g, 8.54 mmol) and K3PO4(81.6 g, 384 mmol) at 25 °C under N2. The mixture was heated to 80 °C and stirred at 80 °C for 12 h under N2atmosphere. The mixture was added to H2O (3.50 L) and extracted with EtOAc (2.50 L x2, 1L x2). The combined organic phases were concentrated to a residue. The residue was triturated with H2O (500 mL) at 25 oC for 30 mins. The solid was filtrated and triturated with MTBE (300 mL) at 25 oC for 12 h, then the solid was filtered and dried under high vacuum to afford (4-hydroxy-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone as a yellow solid. MS (ESI): mass calcd. for C29H30N4O4S, 530.2; m / z found, 531.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 12.31 (s 1H), 8.18 (s, 1H), 7.85 (s, 1H), 7.69 (br d, J = 8.8 Hz, 2H), 7.52 (br s, 1H), 7.22-7.27 (m, 2H), 7.17 (d, J = 7.4 Hz, 2H), 3.73-3.95 (m, 2H), 3.57-3.63 (m, 2H), 3.25- 3.37 (m, 4H), 3.10 (s, 3H), 2.30 (s, 3H), 1.89-1.98 (m, 6H).

[0206] Step C: (4-Chloro-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone. A mixture of (4-hydroxy-6-(2,3,6- trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone (41.0 g, 77.2 mmol) and POCl3(205 mL) was prepared at 25 °C. The mixture was then stirred at 100 °C for 2 h. The reaction was distilled under vacuum (40 °C) to remove POCl3. The residue was dissolved in DCM (500 mL), poured into ice water (1L), and theorganic phase was separated. The aqueous phase was extracted with DCM (300 mL), and the combined organic layers were washed with H2O (1L), brine (1L x 2), dried over Na2SO4, and concentrated under reduced pressure to afford a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 30% Ethyl acetate / Dichloromethane @ 80 mL / min) to provide (4- chloro-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1- yl)methanone as a yellow solid. MS (ESI): mass calcd. for C29H29ClN4O3S, 548.2; m / z found, 549.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ = 9.10 (s, 1H), 8.16 (d, J = 0.8 Hz, 1H), 7.80 (s, 1H), 7.76-7.79 (m, 2H), 7.15-7.19 (m, 1H), 7.06-7.12 (m, 1H), 6.94 (d, J = 9.0 Hz, 2H), 4.20-4.30 (m, 1H), 3.93-4.05 (m, 1H), 3.50-3.66 (m, 2H), 3.27-3.47 (m, 4H), 3.01 (s, 3H), 2.32 (s, 3H), 2.00 (br t, J = 18.0 Hz, 6H). Intermediate 8: (R)-2-((6-Iodo-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide.

[0207] Step A: (4-Chloro-6-iodoquinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1- yl)methanone. A solution of (4-hydroxy-6-iodoquinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone (80.0 g, 148 mmol) in POCl3(480 mL) was prepared at 25 °C. The mixture was stirred at 100 °C for 2 h. The reaction was distilled under vacuum (45 °C) to remove POCl3. A brown solid was obtained and dissolved with DCM (1.50 L) and filtered. The filtrate was washed with H2O (1.00 L), and the organic layer dried over Na2SO4and concentrated to provide (4-chloro-6- iodoquinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone as a light- brown solid. MS (ESI): mass calcd. for C20H18ClIN4O3S, 556.0; m / z found, 556.9 [M+H]+.

[0208] Step B: (R)-2-((6-Iodo-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide. To a solution of (4-chloro-6-iodoquinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone (46.0 g, 82.6 mmol) in MeCN (450 mL) was added DIEA (53.3 g, 413 mmol, 71.9 mL) at 0 °C. Then (R)-2-amino-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide (26.4 g, 107 mmol) was added at 0 °C. The reaction mixture was stirred at 85 °C for 12 h. The reaction mixture added to H2O (1.50 L) and extracted with EtOAc (1.00 L x1, 500 mL x1). The combined organic phases were washed with brine (1.00 L x1), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 60%-75% THF / Petroleum ether @ 150 mL / min). The material obtained was combined with a previous batch for additional purification by reverse-phase HPLC (column: Phenomenex luna C18250 x 80mm x 10 µm; mobile phase: [water (HCl)-ACN]; B%: 52%-52%, 15 min) to provide (R)-2-((6-Iodo-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4- yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide as a yellow solid. MS (ESI): mass calcd. for C31H30F3IN6O4S, 766.1; m / z found, 767.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 8.93 (dd, J = 5.20, 1.40 Hz, 1H), 8.68 (dd, J = 7.60, 2.92 Hz, 1H), 8.42 (d, J = 2.00 Hz, 1H), 8.22 (dd, J = 12.2, 4.72 Hz, 1H), 8.01 (s, 1H), 7.53-7.73 (m, 6H), 7.03 (t, J = 9.20 Hz, 2H), 5.03-5.18 (m, 1H), 3.69-3.88 (m, 2H), 3.42-3.56 (m, 2H), 3.12-3.33 (m, 6H), 3.09 (s, 3H), 2.63 (d, J = 4.40 Hz, 3H). Intermediate 9: 4-Chloro-6-(2,5-dimethylphenyl)quinazoline-8-carboxylic acid.

[0209] Step A: 6-(2,5-Dimethylphenyl)-4-hydroxyquinazoline-8-carboxylic acid. To a mixture of 4-hydroxy-6-iodoquinazoline-8-carboxylic acid (160 g, 506.25 mmol) in DMF (2 L) were added in portions H2O (400 mL), (2,5-dimethylphenyl)boronic acid (83.52 g, 556.87 mmol), Na2CO3(214.63 g, 2.02 mol) and Pd(PPh3)4 (17.55 g, 15.19 mmol), and then the reaction mixture was stirred at 85 °C for 12 h under N2. The mixture was poured into water (4 L), and the resulting mixture was extracted with EtOAc (1 L x3).The organic phase was discarded, and the pH of the aqueous phase was adjusted to pH ~ 3 with 2 M HCl (aqueous) while stirring. The resulting mixture was filtered, washing with water (500 mL x2). The filter cake was transferred into a 3 L round bottom flask with toluene (800 mL), and the resulting mixture was concentrated under reduced pressure. The procedure with toluene was repeated four times to provide 6-(2,5- dimethylphenyl)-4-hydroxyquinazoline-8-carboxylic acid as a gray solid. MS (ESI): mass calcd. for C17H14N2O3, 294.1; m / z found, 294.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 15.73 - 14.87 (m, 1H), 13.03 (s, 1H), 8.51 (s, 1H), 8.32 (d, J = 4.0 Hz, 1H), 8.21 (d, J = 4.0 Hz, 1H), 7.25 - 7.19 (m, 1H), 7.17 - 7.11 (m, 1H), 7.09 (s, 1H), 2.31 (s, 3H), 2.19 (s, 3H).

[0210] Step B: 4-Chloro-6-(2,5-dimethylphenyl)quinazoline-8-carboxylic acid. To a solution of 6-(2,5-dimethylphenyl)-4-hydroxyquinazoline-8-carboxylic acid (100 g, 339.78 mmol) in SOCl2(2.98 kg, 25.06 mol, 1.82 L) was added DMF (12.4 g, 169.89 mmol, 13.07 mL), and the mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. To the residue was added anhydrous toluene (300 mL), and the mixture was concentrated. The procedure with toluene was repeated three times to give residue. To the residue was added in portions THF (2 L) and then H2O (1.5 L) while stirring at 0 °C for 10 mins. The mixture was then extracted with DCM (1 L x ). The combined organic phases were washed with brine (800 mL), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (Petroleum ether / DCM = 25% / 75 % ~ 0% / 100%,about 35 L) to afford 4-chloro-6-(2,5- dimethylphenyl)quinazoline-8-carboxylic acid as a yellow solid. MS (ESI): mass calcd. for C17H13ClN2O2, 312.1; m / z found, 312.9 [M+H]+.1H NMR (400 MHz, CDCl3) δ = 15.00 (s, 1H), 9.21 - 9.16 (m, 1H), 9.06 (d, J = 4.0 Hz, 1H), 8.50 (d, J = 4.0 Hz, 1H), 7.26 - 7.18 (m, 2H), 7.14 (s, 1H), 2.44 - 2.40 (m, 3H), 2.29 (s, 3H). Intermediate 10: 2-(Methylsulfonyl)-5-(piperidin-4-yl)pyridine dihydrochloride.

[0211] Step A: 5-bromo-2-(methylsulfonyl)pyridine. A solution of 5-bromo-2- (methylthio)pyridine (80.0 g, 392 mmol) in acetone (1000 mL) and H2O (1000 mL) was treated with Oxone™ (330 g, 1.96 mol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The resulting mixture was filtered, and the filter cake was washed with EtOAc (200 mL x3). The filtrate was extracted with EtOAc (1000 mL x3). The combined organic layers were washed with brine (600 mL x3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by trituration with diethyl ether (1000 mL), and the solids were collected by filtration to provide 5-bromo-2- (methylsulfonyl)pyridine as a white solid.

[0212] Step B: Tert-butyl 6-(methylsulfonyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)- carboxylate. A solution of 5-bromo-2-(methylsulfonyl)pyridine (82.0 g, 347 mmol) in dioxane (738 mL) and H2O (82 mL) was treated with K2CO3(144 g, 1.04 mol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (150 g, 486 mmol) at room temperature under nitrogen atmosphere, followed by the addition of Pd(dppf)Cl2(12.7 g, 17.4 mmol) at room temperature. The resulting mixture was stirred overnight at 80 °C. The mixture was cooled to room temperature. The mixture was extracted with EtOAc (2000 mL x2), and the combined organic layers were washed with brine (2000 mL x2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (100:0 - 50:50), to tert-butyl 6- (methylsulfonyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate as a white solid.

[0213] Step C: Tert-butyl 4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1-carboxylate. To a solution of tert-butyl 6-(methylsulfonyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (90.0 g, 266 mmol) in methanol (1800 mL) was added Pd / C (9.0 g, 10%) under nitrogen atmosphere. The mixture was hydrogenated at room temperature overnight under hydrogen atmosphere using a hydrogen balloon, then filtered through a pad of Celite® and concentrated under reduced pressure. The residue was purified by trituration with hexane and Et2O (3:1, 500 mL). The precipitated solids were collected by filtration and washed with hexane (50 mL x3) to provide tert-butyl 4-(6-(methylsulfonyl)pyridin-3- yl)piperidine-1-carboxylate as a white solid.

[0214] Step D: 2-(Methylsulfonyl)-5-(piperidin-4-yl)pyridine dihydrochloride. A solution of tert-butyl 4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1-carboxylate (71.0 g, 209 mmol) in HCl (497 mL, 4 M in 1,4-dioxane) and DCM (497 mL) was stirred overnight at room temperature under nitrogen atmosphere. The precipitated solids were collected by filtration and purified by trituration with n-hexane (500 mL). The precipitated solids were collected by filtration to afford 2-(Methylsulfonyl)-5-(piperidin-4-yl)pyridine dihydrochloride as a white solid. MS (ESI): mass calcd. for C11H16N2O2S, 240.1; m / z found, 241.1 [M+H]+.1H NMR (300 MHz, CD3OD) δ = 8.71 (s, 1H), 8.09-8.04 (m, 2H), 3.57 (d, J = 12.6 Hz, 2H), 3.25-3.14 (m, 6H), 2.17 (d, J = 14.0 Hz, 2H), 2.08-1.94 (m, 2H). Intermediate 11: (R)-2-Amino-N-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propanamide hydrochloride.

[0215] Step A: Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(6-(trifluoromethyl)pyridin-3- yl)propanoate. To a 5 L flask was added Zn (53.7 g, 820 mmol) and DMF (3000 mL), and the mixture was heated to 50 °C. I2 (27.8 g, 109 mmol) was added in several portions over a 10 min period. Then, methyl (S)-2-((tert-butoxycarbonyl)amino)-3- iodopropanoate (180 g, 547 mmol) was added in several portions over a 30 min period at 0 °C. Next, 5-bromo-2-(trifluoromethyl)pyridine (123.6 g, 546.9 mmol) was added in several portions, also at 0 °C. To this mixture was added Pd(PPh3)2Cl2(26.9 g, 38.3 mmol) in several batches at 0 °C. The resulting solution was stirred for 5 h at 50 °C. The mixture was then cooled to room temperature. The reaction mixture was filtered, and the filter cake was washed with Et2O (3 L x3). The filtrate was collected and washed with brine (1 L x6). The organic phase was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluent: 1:4 EtOAc in petroleum ether) to afford methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(6-(trifluoromethyl)pyridin-3- yl)propanoate as a white solid. MS (ESI): mass calcd. for C15H19F3N2O4, 348.1; m / z found, 349.1 [M+H]+.

[0216] Step B: (R)-2-((tert-Butoxycarbonyl)amino)-3-(6-(trifluoromethyl)pyridin-3- yl)propanoic acid. To a mixture of methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(6- (trifluoromethyl)pyridin-3-yl)propanoate (98.0 g, 281 mmol) in MeOH (980 mL) at 0 °C was added dropwise a solution of LiOH•H2O (14.17 g, 337.6 mmol) dissolved in H2O (338 mL). The reaction mixture was stirred for 2 h at 0 °C. The reaction was quenched by the addition of anhydrous citric acid (80 g) at 0 °C. The resulting mixture was diluted with H2O (1 L), and the aqueous layer was extracted with EtOAc (1 L x3). The combined organic layers were concentrated under reduced pressure to provide (R)-2-((tert- butoxycarbonyl)amino)-3-(6-(trifluoromethyl)pyridin-3-yl)propanoic acid as a white solid. MS (ESI): mass calcd. for C14H17F3N2O4, 334.1; m / z found, 335.1 [M+H]+.

[0217] Step C: tert-Butyl (R)-(1-(methylamino)-1-oxo-3-(6-(trifluoromethyl)pyridin-3- yl)propan-2-yl)carbamate. A mixture of DIEA (195 g, 1.51 mol) and HATU (124 g, 327 mmol) were added to a mixture of (R)-2-((tert-butoxycarbonyl)amino)-3-(6- (trifluoromethyl)pyridin-3-yl)propanoic acid (84.0 g, 251 mmol) and MeNH2•HCl (25.5 g, 377 mmol) in DMF (1680 mL) at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with H2O (3 L) and extracted with EtOAc (2 L x3). The organic phase was washed with brine (1 L x6) and concentrated under vacuum. The residue was purified by trituration with Et2O (500 mL). The solids were collected by filtration and washed with Et2O (50 mL x2) to provide tert- butyl (R)-(1-(methylamino)-1-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)propan-2- yl)carbamate as a white solid. MS (ESI): mass calcd. for C15H20F3N3O3, 347.1; m / z found, 348.1 [M+H]+.

[0218] Step D: (R)-2-Amino-N-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propanamide hydrochloride. To a mixture of tert-butyl (R)-(1-(methylamino)-1-oxo-3-(6- (trifluoromethyl)pyridin-3-yl)propan-2-yl)carbamate (87.1 g, 251 mmol) in DCM (1.6 L) was added 4 M HCl / dioxane (313 mL, 1.25 mol). The reaction mixture was stirred at room temperature for 3 h. The precipitated solids were collected by filtration and washed with DCM (500 mL x5) to provide (R)-2-amino-N-methyl-3-(6- (trifluoromethyl)pyridin-3-yl)propanamide hydrochloride as a white solid. MS (ESI): mass calcd. for C10H12F3N3O, 247.1; m / z found, 248.1 [M+H]+.1H NMR (300 MHz, D2O) δ =8.48 (s, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 4.13 (dd, J = 8.6, 6.3 Hz, 1H), 3.26 (m, 2H), 2.57 (d, J = 4.5 Hz, 3H). Intermediate 12: (R)-3-Amino-2-methyl-4-(4-(trifluoromethyl)phenyl)butan-2-ol hydrochloride.

[0219] Step A: Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(4- (trifluoromethyl)phenyl)propanoate. A mixture of Zn (358 g, 5.47 mol) and I2 (23.1 g, 91.1 mmol) in DMA (6 L) was stirred for 30 min at 50 °C under nitrogen atmosphere. To the above mixture was added methyl (S)-2-((tert-butoxycarbonyl)amino)-3- iodopropanoate (600 g, 1.82 mol) in DMA (9 L) dropwise at 0 °C. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. To the above mixture was added 1-iodo-4-(trifluoromethyl)benzene (545 g, 2.01 mol) and Pd(amphos)2Cl2(103 g, 146 mmol) at room temperature. The resulting mixture was stirred overnight at 35 °C. The reaction mixture was diluted with ice water (20 L). The resulting mixture was extracted with EtOAc (4 L x3). The combined organic layers were washed with brine (5 L x3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 1:10 EtOAc in petroleum ether) to provide methyl (R)-2-((tert- butoxycarbonyl)amino)-3-(4-(trifluoromethyl)phenyl)propanoate as an off-white solid.

[0220] Step B: tert-Butyl (R)-(3-hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan-2- yl)carbamate. To a 10 L round bottom flask purged and maintained under an inert atmosphere of N2was added methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(4- (trifluoromethyl)phenyl)propanoate (320 g, 921 mmol) and THF (6.4 L). To this solution was added bromo(methyl)magnesium (1.84 L, 3 M in 2-MeTHF, 5.53 mol) dropwise with stirring at -5 °C. The resulting solution was stirred for 1 h at -5 °C. The reaction was quenched with NH4Cl (3 L) at room temperature. The resulting mixture was extracted with EtOAc (2 L x3). The combined organic layers were washed with brine (2 L x2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent: 15% EtOAc in petroleum ether to provide tert-butyl (R)-(3-hydroxy-3-methyl-1-(4- (trifluoromethyl)phenyl)butan-2-yl)carbamate as an off-white solid.

[0221] Step C: (R)-3-Amino-2-methyl-4-(4-(trifluoromethyl)phenyl)butan-2-ol hydrochloride. A mixture of tert-butyl (R)-(3-hydroxy-3-methyl-1-(4- (trifluoromethyl)phenyl)butan-2-yl)carbamate (263 g, 599 mmol) in EtOAc (1315 mL) and HCl (2 M in EtOAc, 1500 mL) was stirred overnight at room temperature under N2atmosphere. The precipitated solids were collected by filtration and washed with MTBE (500 mL x1) to provide (R)-3-amino-2-methyl-4-(4-(trifluoromethyl)phenyl)butan-2-ol hydrochloride as a white solid. MS (ESI): mass calcd. for C12H16F3NO, 247.1; m / z found, 248.2 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ = 7.92 (s, 3H), 7.70 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 5.37 (s, 1H), 3.19 (dd, J = 9.4, 4.1 Hz, 1H), 3.07 (dd, J = 14.5, 4.0 Hz, 1H), 2.87 (dd, J = 14.5, 9.2 Hz, 1H), 1.21 (d, J = 11.0 Hz, 6H). Intermediate 13: (R)-6-(2-Methoxy-3,6-dimethylphenyl)-4-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carboxylic acid.

[0222] Step A: 2-Bromo-3,6-dimethylphenol. To a solution of 2,5-dimethylphenol (120 g, 982 mmol) in CS2 (2.40 L) was added NBS (157 g, 884 mmol) at 10 °C, over a 10 min period in the dark. After the addition, the resulting mixture was stirred at 20 °C for 2 h to give a colorless suspension. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® neutral alumina, eluent of 100% petroleum ether t @ 100 mL / min) to provide 2-bromo-3,6-dimethylphenol as a white liquid.1H NMR (400 MHz, CDCl3) δ = 6.87-6.80 (d, 1H), 6.65-6.59 (d, 1H), 5.56 (s, br, 1H), 2.25 (s, 3H), 2.17 (s, 3H).

[0223] Step B: 2-bromo-3-methoxy-1,4-dimethylbenzene. To a solution of 2-bromo-3,6- dimethylphenol (102 g, 507 mmol) in DMF (750 mL) was added K2CO3(140 g, 1.01 mol) at 25 °C over 10 mins under N2. After the addition was complete, MeI (180 g, 1.27 mol, 78.9 mL) was added dropwise at 25°C over 10 mins. The mixture was stirred at 50 °C for 12 hrs to give a yellow suspension. The reaction mixture was diluted with H2O (1.00 L) and extracted with EtOAc (1.00 L x3). The combined organic layers were washed with H2O (600 mL x3) and brine (800 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give 2-bromo-3-methoxy-1,4-dimethylbenzene as a yellow liquid.1H NMR (400 MHz, CDCl3) δ = 7.01 (m, 1H) 6.92 (m, 1H) 3.86 - 3.77 (m, 3H) 2.39 (s, 3H) 2.35 - 2.26 (m, 3H).

[0224] Step C: (2-Methoxy-3,6-dimethylphenyl)boronic acid. To a solution of 2-bromo-3- methoxy-1,4-dimethylbenzene (60.0 g, 279 mmol) in MeOH (480 mL) and THF (480 mL) was added dropwise hypoboric acid (37.5 g, 418 mmol) and DIEA (72.1 g, 557 mmol, 97.2 mL) at 25 °C. After the addition was complete, the mixture was stirred at 25 °C for 10 mins, then Pd(amphos)Cl2(5.93 g, 8.37 mmol) at 25 °C under a stream of N2. The resulting mixture was stirred at 50 °C for 16 hrs to give a red suspension. The reaction was diluted with H2O (1.00 L) and extracted with EtOAc (1.00 L x3). The combined organic layers were washed with 1 M HCl (500 mL x2) and brine (500 mL), dried over Na2SO4, and concentrated to dryness under reduced pressure. The residue was triturated with petroleum ether (150 mL) at 25 °C for 1 hr to provide (2-methoxy-3,6- dimethylphenyl)boronic acid as a red solid.1H NMR (400 MHz, CDCl3) δ = 7.16 - 7.14 (d, J = 8.00 Hz, 1H), 6.94-6.92 (d, J = 8.00 Hz, 1H), 5.87 (s, 2H), 3.78 (s, 3H), 2.51 (s, 3H), 2.28 (s, 3H).

[0225] Step D: Methyl (R)-6-(2-methoxy-3,6-dimethylphenyl)-4-((1-(methylamino)-1-oxo- 3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carboxylate. Two reactions were carried out in parallel. For each batch, 12.0 g of starting material was used. To a solution of methyl (R)-6-iodo-4-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carboxylate (12.0 g, 21.5 mmol) in DMF (360 mL) and H2O (72.0 mL) was added CataCXium A Pd G3, (754 mg, 1.07 mmol), K2CO3(5.94 g, 43.0 mmol), and (2-methoxy-3,6-dimethylphenyl)boronic acid (5.80 g, 32.2 mmol) at 25 °C under N2atmosphere. The resulting mixture wasstirred at 80 °C for 16 hrs to give a brown suspension. The reaction was diluted with brine (1.00 L) and extracted with EtOAc (1.00 L x2). The combined organic layers were washed with brine (500 mL x2), dried over Na2SO4, and concentrated to dryness under reduced pressure to provide methyl (R)-6-(2-methoxy-3,6-dimethylphenyl)-4-((1- (methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8- carboxylate as a yellow solid. MS (ESI): mass calcd. for C30H29F3N4O4, 566.2; m / z found, 567.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 8.57 - 8.16 (m, 3H) 7.89 - 7.69 (m, 1H) 7.63 - 7.46 (m, 4H) 7.32 - 7.16 (m, 1H) 7.13 – 6.99 (m, 1H) 5.25 - 5.03 (m, 1H) 3.85 (s, 2H) 3.33 - 3.16 (m, 5H) 2.69 - 2.60 (m, 3H) 2.34 - 2.22 (m, 3H) 2.03 (m, 3H).

[0226] Step E: (R)-6-(2-methoxy-3,6-dimethylphenyl)-4-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carboxylic acid. To a solution of methyl (R)-6-(2-methoxy-3,6-dimethylphenyl)-4-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carboxylate (24.0 g, 42.4 mmol) in THF (260 mL) was added LiI (34.0 g, 254 mmol ) at 25 °C. The mixture was stirred at 70 °C for 12 hrs to give a yellow suspension. Then LiI (22.7 g, 169 mmol, 6.50 mL) was added at 25 °C. The mixture was stirred at 70 °C for 6 hrs to give a yellow suspension. The mixture was stirred at 70 °C for 6 hrs to give a yellow suspension. The reaction mixture was cooled to <10 °C and charged with aq. NH4Cl. (300 mL, 10 V) followed by EtOAc (1.20 L, 40 V). The quenched mixture was stirred for another 10 min. The organic phase was separated and washed with brine (600 mL, 20 V), dried over anhydrous sodium sulfate and concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18250 x 80mm x 10 µm; mobile phase: [water (NH4HCO3)-ACN]; B%: 20% - 50%, 20 min) to provide (R)-6-(2-methoxy-3,6- dimethylphenyl)-4-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2- yl)amino)quinazoline-8-carboxylic acid as a light yellow solid. MS (ESI): mass calcd. for C29H27F3N4O4, 552.2; m / z found, 553.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 9.23 - 9.00 (m, 1H) 9.14 (m, 1H) 8.81 - 8.59 (m, 2H) 8.47 - 8.16 (m, 2H) 7.56 (m, 4H) 7.24 (m, 1H) 7.09 (m, 1H) 5.17 (m, 1H) 3.17 - 3.31 (m, 4H) 2.64 (m, 3H) 2.29 (s, 3H) 2.04 (m, 3H). Intermediate 14: (R)-6-(2-(Hydroxymethyl)-3,6-dimethylphenyl)-4-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carboxylic acid.

[0227] Step A: 2-Formyl-3,6-dimethylphenyl trifluoromethanesulfonate. To a mixture of 2-hydroxy-3,6-dimethylbenzaldehyde (25.0 g, 166 mmol) in DCM (300 mL) was added DMAP (2.03 g, 16.7 mmol) and Et3N (50.5 g, 499 mmol, 69.5 mL) at 0 °C, then 1,1,1- trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (89.2 g, 249 mmol) was added slowly over 1 min. The mixture was stirred at 25 °C for 16 hrs to give a yellow solution. The reaction mixture was then poured into cold (ice) water (300 mL) and extracted with DCM (300 mL x3). The combined organic layers were washed with brine (300 mL x1), dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, eluent of 2-15% ethyl acetate / petroleum ether gradient @ 100 mL / min) to provide 2-formyl-3,6-dimethylphenyl trifluoromethanesulfonate as a yellow solid.1H NMR (400 MHz, CDCl3) δ = 10.41 (s, 1 H), 7.43-7.40 (d, 2H), 7.22-7.20 (d, 2H), 2.60 (s, 3H), 2.42 (s, 3H).

[0228] Step B: 3,6-Dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzaldehyde. To a solution of 2-formyl-3,6-dimethylphenyl trifluoromethanesulfonate (30.0 g, 106 mmol), B2Pin2 (32.4 g, 127 mmol), KOAc (31.3 g, 319 mmol) in dioxane (300 mL) was added Pd(PPh3)2Cl2(5.97 g, 8.50 mmol) at 25 °C under N2atmosphere. The mixture was stirred at 100 °C for 12 hrs to give a yellow solution. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, eluent of 0~10% ethyl acetate / petroleum ether gradient @ 100 mL / min) to provide 3,6- dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 10.57 - 9.99 (m, 1H) 7.18 (m, 1H) 7.02 (m, 1H) 2.61 - 2.45 (m, 3H) 2.33 (s, 3H) 1.40 (s, 13H).

[0229] Step C: Methyl (R)-6-(2-formyl-3,6-dimethylphenyl)-4-((1-(methylamino)-1-oxo-3- (4-(trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carboxylate. Two reactions were carried out in parallel. For each batch, 17.0 g of starting material was used. To a solution of methyl (R)-6-iodo-4-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carboxylate (17.0 g, 30.5 mmol, 123 uL) in DMF (340 mL) and H2O (17.0 mL) was added CataCXium A Pd G3(1.07 g, 1.52 mmol), K2CO3(8.42 g, 60.9 mmol) , and 3,6-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzaldehyde (9.51 g, 36.5 mmol) at 25 °C under N2atmosphere. The resulting mixture was stirred at 80 °C for 16 hrs to give a brown suspension. The reaction was diluted with brine (1.00 L) and extracted with ethyl acetate (1.00 L x3). The combined organic layers were washed with brine (1.00 L x3), dried over Na2SO4, and concentrated to dryness under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® neutral alumina, eluent of 10% DCM : MeOH gradient @ 120 mL / min) to provide methyl (R)-6-(2-formyl-3,6- dimethylphenyl)-4-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2- yl)amino)quinazoline-8-carboxylate as a yellow solid. MS (ESI): mass calcd. for C30H27F3N4O4, 564.2; m / z found, 565.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 9.92 - 9.70 (m, 1H) 8.62 - 8.40 (m, 3H) 8.23 - 8.09 (m, 1H) 7.91 - 7.80 (m, 1H) 7.60 - 7.48 (m, 5H) 7.43 - 7.32 (m, 1H) 5.14 – 4.89 (m, 1H) 3.86 (m, 2H) 3.32 - 3.08 (m, 2H) 2.61 (m, 3H) 2.58 (s, 2H) 2.14 – 1.96 (m, 3H).

[0230] Step D: Methyl (R)-6-(2-(hydroxymethyl)-3,6-dimethylphenyl)-4-((1- (methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8- carboxylate. To a solution of methyl (R)-6-(2-formyl-3,6-dimethylphenyl)-4-((1- (methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8- carboxylate (19.0 g, 28.9 mmol) in THF (200 mL) was added NaBH4 (547 mg, 14.5 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 hrs to give a yellow suspension. The reaction mixture was cooled to <10 °C and charged with aq. NH4Cl. (500 mL) followed by EtOAc (500 mL). The quenched mixture was stirred for another 10 min. The organic phase was separated and washed with brine (500 mL), dried over anhydrous sodium sulfate and concentrated. Methyl (R)-6-(2-(hydroxymethyl)-3,6- dimethylphenyl)-4-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carboxylate was obtained as a yellow solid. MS (ESI): mass calcd. for C30H29F3N4O4, 566.2; m / z found, 567.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 8.53 - 8.30 (m, 2H) 8.24 – 7.99 (m, 1H) 7.79 (m, 1H) 7.67 - 7.40 (m, 5H) 7.26 - 7.01 (m, 2H) 5.13 – 4.89 (m, 1H) 4.68 - 4.48 (m, 1H) 4.33 - 4.06 (m, 3H) 3.85 (s, 2H) 3.21 - 3.10 (m, 4H) 2.62 - 2.57 (m, 3H) 2.47 - 2.37 (m, 3H), 2.00 – 1.89 (m, 3H).

[0231] Step E: (R)-6-(2-(Hydroxymethyl)-3,6-dimethylphenyl)-4-((1-(methylamino)-1- oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carboxylic acid. To a solution of methyl (R)-6-(2-(hydroxymethyl)-3,6-dimethylphenyl)-4-((1-(methylamino)-1- oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carboxylate (32.0 g, 56.5 mmol) in THF (300 mL) was added LiI (45.4 g, 338 mmol), at 25°C. The mixture was stirred at 70 °C for 12 hrs to give a yellow suspension. Then LiI (22.7 g, 169 mmol, 6.50 mL) was added at 25 °C. The mixture was stirred at 70 °C for 6 hrs to give a yellow suspension. The reaction mixture was cooled to <10 °C and charged with aq. NH4Cl. (300 mL) followed by EtOAc (1.2 L). The quenched mixture was stirred for another 10 min. The organic phase was separated and washed with brine (600 mL), dried over anhydrous sodium sulfate and concentrated.. The residue was purified by prep-HPLC (column: Phenomenex luna C18250 x 80 mm x10 µm; mobile phase: [water( NH4HCO3)-ACN]; B%: 15% - 45%, 25min) to provide (R)-6-(2-(hydroxymethyl)-3,6- dimethylphenyl)-4-((1-(methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2- yl)amino)quinazoline-8-carboxylic acid as a yellow solid. MS (ESI): mass calcd. for C29H27F3N4O4, 552.2; m / z found, 553.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 9.06 (m, 1H) 8.68 - 8.56 (m, 2H) 8.36 (m, 1H) 8.24 (m, 1H) 7.62 - 7.49 (m, 4H) 7.26 - 7.12 (m, 2H) 5.24 - 5.07 (m, 1H) 4.86 - 4.51 (m, 1H) 4.34 - 4.05 (m, 2H) 3.32 - 3.15 (m, 2H) 2.67 - 2.57 (m, 3H) 2.44 (m, 3H) 1.91 (s, 3H). Intermediate 15: (R)-2-((6-(2-formyl-3,6-dimethylphenyl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide.

[0232] Step A.2-Formyl-3,6-dimethylphenyl trifluoromethanesulfonate. To a suspension of 2-hydroxy-3,6-dimethylbenzaldehyde (1.00 g, 6.66 mmol) and DMAP (84 mg, 0.688 mmol) in DCM (19 mL) was added Et3N (2.8 mL, 20.1 mmol). Next, N,N- bis(trifluoromethylsulfonyl)aniline (3.64 g, 9.99 mmol) was added in portions over 1 min. The reaction mixture was stirred for 16 h at room temperature then poured into sat. aq. NaHCO3and extracted x2 with EtOAc. The combined organic extracts were washed x1 with brine, dried over MgSO4, and concentrated to afford an orange residue. Purification by silica gel column chromatography (0-30% EtOAc in heptanes) provided the title compound (2.26 g) as a colorless slurry. MS (ESI): mass calcd. for C10H9F3O4S, 282.0; m / z found, 283.0 [M+H]+.

[0233] Step B.3,6-Dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzaldehyde. A suspension of 2-formyl-3,6-dimethylphenyl trifluoromethanesulfonate (2.24 g), B2Pin2 (1.73 g), KOAc (1.64 g), and Pd(dppf)Cl2(408 mg) in 1,4-dioxane (27 mL) was sparged with Argon for 15 min before it was evacuated and backfilled with N2and heated to 100°C for 16 h. The reaction mixture was cooled to room temperature and filtered through a pad of Celite®. The filtrate was concentrated and purified by silica gel column chromatography (0-60% EtOAc in heptanes) to provide the title compound (1.63 g) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 10.35 (s, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 2.61 (s, 3H), 2.40 (s, 3H), 1.47 (s, 12H) 1.47 (s, 12H).

[0234] Step C. (R)-2-((6-(2-Formyl-3,6-dimethylphenyl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide. A suspension of 3,6-dimethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.24 g, 4.77 mmol), (R)-2-((6-iodo-8- (4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3- (4-(trifluoromethyl)phenyl)propanamide (Intermediate 8, 2.00 g, 2.61 mmol), CataCXiumA Pd G3(300 mg, 0.391 mmol), and K3PO4(1.98 g, 9.14 mmol) in 8:7:1 DMF:dioxane:H2O (16.5 mL) was sparged with Argon for 15 min then heated to 85°C for 16 h. The reaction mixture was cooled to room temperature, diluted with H2O, and extracted x3 with EtOAc. The combined organic extracts were washed x1 with H2O, x1 with brine, dried over Na2SO4, and concentrated to afford a brown residue. Purification by silica gel column chromatography (0-10% MeOH in DCM) provided the title compound (1.45 g) as a tan solid. MS (ESI): mass calcd. for C40H39F3N6O5S, 772.3; m / z found, 773.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ = 10.02-9.74 (m, 1H), 8.73-8.61 (m, 1H), 7.78 (d, J = 8.8 Hz, 2H), 7.72-7.49 (br m, 4H), 7.45-7.31 (br m, 3H), 7.27-7.17 (m, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.76-6.61 (br m, 1H), 6.17-5.75 (br m, 1H), 5.12-4.99 (m, 1H), 4.27-3.88 (br m, 2H), 3.71-3.10 (br m, 8H), 3.01 (s, 3H), 2.79-2.67 (m, 3H), 2.67- 2.55 (m, 3H), 2.10-2.03 (m, 3H). Intermediate 16: (R)-3,6-Dimethyl-2-(4-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-6-yl)benzoic acid.

[0235] A suspension of (R)-2-((6-(2-formyl-3,6-dimethylphenyl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide (Intermediate 15) (1.26 g, 1.63 mmol) and sodium phosphate monobasic (414 mg, 3.42 mmol) in DMSO (84 mL) and H2O (55 mL) was stirred for 5 min at room temperature before sodium chlorite (367 mg, 3.25 mmol) was added in one portion. The reaction mixture was covered loosely and heated to 50°C with vigorous stirring for 2.5 h. The reaction was stopped and poured into H2O. The layers were separated, and the aqueous layer was acidified to pH ~2 with HCl then extracted x1 with EtOAc. The combined organic extracts were washed x3 with ice-cold H2O then dried over Na2SO4and concentrated to provide the title compound (1.20 g) asa yellow solid, which was used in subsequent steps without further purification. MS (ESI): mass calcd. for C40H39F3N6O6S, 788.3; m / z found, 789.2 [M+H]+. Intermediate 17: (R)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide.

[0236] A suspension of (R)-2-((6-iodo-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide (Intermediate 8) (1000 mg, 1.30 mmol), B2Pin2(435 mg, 1.70 mmol), Pd(dppf)Cl2DCM complex (96 mg, 0.131 mmol), and KOAc (445 mg, 4.53 mmol) in 1,4-dioxane (6.5 mL) was sparged with Argon for 15 min before being heated to 85°C for 16 h. The reaction mixture was cooled to room temperature and diluted with H2O. The aqueous layer was extracted x3 with EtOAc and the combined organic extracts were washed x1 with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (0-5% MeOH in DCM) then preparative reverse-phase HPLC (Stationary phase: Kinetex EVO C18, 5 µm, 100 x 30 mm; Mobile phase: water (+ 10 mM NH3H2O) (A) - MeCN (B), gradient elution: 30 - 100% B in A over 11 min, flow rate: 60 mL / min) to give the first eluting compound (Intermediate 18) as a white solid and the second eluting compound as the title compound (52 mg) as a white solid. MS (ESI): mass calcd. for C37H42BF3N6O6S, 766.3; m / z found, 767.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ = 8.67-8.42 (m, 1H), 8.19-7.86 (m, 2H), 7.79 (d, J = 9.3 Hz, 2H), 7.64-7.55 (m, 2H), 7.50-7.37 (m, 2H), 6.97-6.82 (m, 3H), 6.76-6.21 (m, 1H), 5.01 (q, J = 7.3 Hz, 1H), 4.24-4.01 (br m, 1H), 4.01-3.88 (br m, 1H), 3.66-3.15 (br m, 8H), 3.02 (s, 3H), 2.84-2.73 (m, 3H), 1.57 (s, 12H). Intermediate 18: (R)-(4-((1-(Methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)boronic acid.

[0237] The title compound was isolated using the same procedure as Intermediate 17, however, the first peak was isolated. MS (ESI): mass calcd. for C31H32BF3N6O6S, 684.2; m / z found, 685.2 [M+H]+. Intermediate 19: (R)-3-amino-2-methyl-4-(6-(trifluoromethyl)pyridin-3-yl)butan-2-ol.

[0238] Step A: A solution of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3- hydroxypropanoate (200 g, 912.25 mmol) in THF (3 L) under nitrogen atmosphere followed by the addition of PPh3 (358.92 g, 1368.38 mmol), I2 (347.31 g, 1368.38 mmol) and pyridine (137.11 g, 1733.28 mmol). The solution was stirred for 2 h at 25 °C. The resulting mixture was diluted with ice water (2 L). The resulting mixture was extracted with EtOAc (3 × 3 L). The combined organic layers were washed with brine (3 × 3 L), dried over anhydrous Na2SO4and concentrated under reduced pressure. Further purification was accomplished via SiO2column chromatography, using EtOAc / petroleum ether (85:15) as an eluent. Methyl (2S)-2-[(tert- butoxycarbonyl)amino]-3-iodopropanoate was obtained as a yellow solid. MS (ESI): mass calcd. for C9H16INO4, 329.0 ; m / z found, = 330.0 [M+H]+..

[0239] Step B: A mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3- iodopropanoate (180 g, 546.89 mmol), Zn (125.14 g, 1914.11 mmol), 5-bromo-2- (trifluoromethyl)pyridine (148.31 g, 656.26 mmol) and Ni(dtbbpy)Br2•4H2O (16.8 g, 54.7mmol) in DMA (2.7 L) was stirred for overnight at 80°C under N2. The mixture was allowed to cool down to r.t. The resulting mixture was diluted with ice water (5 L). The resulting mixture was extracted with EtOAc (2 × 3 L). The combined organic layers were washed with brine (2 × 3 L), dried over anhydrous Na2SO4and was concentrated under reduced pressure. Further purification was accomplished via SiO2column chromatography, using EtOAc / petroleum ether (9:1) as an eluent. Methyl (2R)-2-[(tert- butoxycarbonyl)amino]-3-[6-(trifluoromethyl)pyridin-3-yl]propanoate was obtained as a white solid. MS (ESI): mass calcd. for C15H19F3N2O4, 348.1; m / z found, = 349.0 [M+H]+.

[0240] Step C: Into a 2 L 4-necked round-bottom flask purged and maintained with an inert atmosphere of N2, was placed methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-[6- (trifluoromethyl)pyridin-3-yl]propanoate (98 g, 281.34 mmol) and THF (1.5 L). This was followed by the addition of bromo(methyl)magnesium (375 mL, 2 M, 4.0 equiv) dropwise with stirring at –5 °C. The resulting solution was stirred for 1 h at –5 °C. The reaction was quenched with NH4Cl (500 mL) at rt. The resulting mixture was extracted with EtOAc (2 × 2 L). The combined organic layers were washed with brine (2 × 2 L), dried over anhydrous Na2SO4and concentrated under reduced pressure. Further purification was accomplished via SiO2column chromatography, using EtOAc / petroleum ether (85:15) as an eluent. Tert-butyl N-[(2R)-3-hydroxy-3-methyl-1-[6- (trifluoromethyl)pyridin-3-yl]butan-2-yl]carbamate was obtained as a white solid. MS (ESI): mass calcd. for C16H23F3N2O3, 348.1; m / z found, = 349.0 [M+H]+.

[0241] Step D: A mixture of tert-butyl N-[(2R)-3-hydroxy-3-methyl-1-[6- (trifluoromethyl)pyridin-3-yl]butan-2-yl]carbamate (67 g, 192.32 mmol) in EtOAc (1.05 L) and 4 M HCl in 1,4-dioxane (1.05 L) was stirred for overnight at 25 °C under N2. The precipitated solids were collected by filtration and washed with Et2O (500 mL). (3R)-3- amino-2-methyl-4-[6-(trifluoromethyl)pyridin-3-yl]butan-2-ol hydrochloride was obtained as a white solid. C15H19F3N2O4, 248.1 ; m / z found, = 249.0 [M+H]+.1H NMR (400 MHz, DMSO-d6, ppm) δ 8.78 (d, J = 2.0 Hz, 1H), 8.12 (dd, J = 8.1, 2.1 Hz, 1H), 7.99 (br, 3H), 7.88 (d, J = 8.1 Hz, 1H), 3.24 (dt, J = 9.8, 4.5 Hz, 1H), 3.13 (dd, J = 14.6, 3.6 Hz, 1H), 2.91 (dd, J = 14.6, 10.0 Hz, 1H), 1.28 (s, 3H), 1.22 (s, 3H).19F NMR (376 MHz, DMSO- d6, ppm) δ -65.74 - -66.13 (m), -66.15, -66.14 - -67.09 (m).EXAMPLES Example 1: N-Methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide. Intermediate 7 (250 mg, 0.455 mmol), (R)-2-amino-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide (Intermediate 1, 134 mg, 0.546 mmol), (2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (35.5 mg, 0.0455 mmol), Cs2CO3(445 mg, 1.37 mmol), and 1,4- dioxane (9 mL) was added into a vial. The reaction vial was filled and purged with argon three times. The reaction was stirred at 90 °C for 24h. The reaction mixture was filtered through Celite® and silica plug. Example 2: (R)-N-(Methyl-d3)-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)- 6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide.

[0242] The title compound was prepared in a manner analogous to Example 60, using (R)-2-amino-N-(methyl-d3)-3-(4-(trifluoromethyl)phenyl)propanamide in Step C. MS (ESI): mass calcd. for C40H38D3F3N6O4S, 761.3; m / z found, 762.3 [M+H]+.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.37 - 1.81 (m, 4H) 1.93 (s, 3H) 1.98 (d, J=2.45 Hz, 3H) 2.31 (d, J=4.89 Hz, 4H) 3.20 - 3.28 (m, 1H) 3.29 - 3.37 (m, 2H) 3.39 - 3.48 (m, 2H) 3.50 - 3.64 (m, 2H) 4.09 (br s, 2H) 5.01 - 5.20 (m, 1H) 6.92 (d, J=9.29 Hz, 2H) 7.03- 7.10 (m, 1H) 7.10 - 7.17 (m, 1H) 7.33 - 7.44 (m, 3H) 7.51 - 7.58 (m, 4H) 7.60 (br s, 1H) 7.79 (d, J=9.29 Hz, 3H) 8.72 (s, 1H). Example 3: (R)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide.

[0243] Intermediate 7 (250 mg, 0.455 mmol), (R)-2-amino-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide (Intermediate 1, 134 mg, 0.546 mmol), (2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (35.5 mg, 0.0455 mmol), Cs2CO3(445 mg, 1.37 mmol), and 1,4- dioxane (9 mL) was added into a vial. The reaction vial was filled and purged with argon three times. The reaction was stirred at 90 °C for 24h. The reaction mixture was filtered through Celite® and silica plug. The filtrate is concentrated down 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). Desired fractions were lyophilized to afford product. MS (ESI): mass calculated for C40H41F3N6O4S was 758.3 and the m / z found was 759.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 1.85 - 2.06 (m, 6 H) 2.28 (d, J=4.89 Hz, 3 H) 2.62 (d, J=3.91 Hz, 3 H) 3.14 - 3.37 (m, 9 H) 3.49 (br s, 2 H) 3.82 (br s, 2 H) 5.00 - 5.11 (m, 1 H) 7.00 - 7.19 (m, 4 H) 7.47 - 7.52 (m, 1 H) 7.57 (s, 4 H) 7.67 (d, J=9.29 Hz, 2 H) 8.12 - 8.22 (m, 1 H) 8.24 - 8.33 (m, 1 H) 8.40 - 8.55 (m, 2 H). Example 4: (R)-N-methyl-2-((2-methyl-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-(4- (trifluoromethyl)phenyl)propenamide.

[0244] Step A.6-Iodo-2-methyl-4-oxo-4H-benzo[d][1,3]oxazine-8-carboxylic acid. A mixture of 2-amino-5-iodoisophthalic acid (500 mg, 1.43 mmol) in Ac2O (3 mL) was stirred at 130 °C for 2 hours. Solvent was evaporated under vacuum to give 6-iodo-2- methyl-4-oxo-4H-benzo[d][1,3]oxazine-8-carboxylic acid as yellow solid. MS (ESI): mass calcd. for C10H6INO4, 330.9; m / z found, 371.8 [M+41]+.

[0245] Step B.4-Hydroxy-6-iodo-2-methylquinazoline-8-carboxylic acid. To a mixture of 6-iodo-2-methyl-4-oxo-4H-benzo[d][1,3]oxazine-8-carboxylic acid (600 mg) in NH3•H2O (28% in water, 4.2 mL) was added NH4OAc (441 mg, 5.72 mmol). The mixture was stirred at 80 °C for 2 hours. The mixture was diluted with ethyl acetate (10 mL) and washed with H2O (5 mL × 3). To the aqueous layer was added 1 N aq. HCl to adjust the pH to 1. The mixture was filtered, and the filter cake was rinsed with H2O (10 mL × 2). The filter cake was collected and dried under vacuum to give 4-hydroxy-6-iodo-2- methylquinazoline-8-carboxylic acid as yellow solid. MS (ESI): mass calcd. for C10H7IN2O3, 330.0; m / z found, 330.9 [M+H]+.1H NMR (400MHz, DMSO-d6) δ = 8.58 (d, J=2.3 Hz, 1H), 8.53 (d, J=2.0 Hz, 1H), 2.47 (s, 3H).

[0246] Step C. (4-Hydroxy-6-iodo-2-methylquinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1 -yl)methanone. DIEA (1.67 g, 12.91 mmol) and HATU (1.06 g, 2.80 mmol) were added to a mixture of 4-hydroxy-6-iodo-2- methylquinazoline-8-carboxylic acid (800 mg, 2.15 mmol) and 1-(4- (methylsulfonyl)phenyl)piperazine (Intermediate 4) (621 mg, 2.58 mmol) in DMF (8 mL). The mixture was stirred at room temperature overnight. The mixture was diluted with H2O (10 mL), filtered, and the solid was washed with H2O (15 mL × 2). The filter cake was collected and dried under vacuum to give (4-hydroxy-6-iodo-2-methylquinazolin-8- yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1 -yl)methanone as yellow solid. MS (ESI): mass calcd. for C21H21IN4O4S, 552.0; m / z found, 552.9 [M+H]+.1H NMR (400MHz, DMSO-d6) δ = 12.47 (s, 1H), 8.38 (d, J=2.0 Hz, 1H), 8.01 (d, J=2.0 Hz, 1H), 7.69 (d,J=8.9 Hz, 2H), 7.07 (d, J=9.1 Hz, 2H), 3.95 - 3.85 (m, 1H), 3.77 - 3.68 (m, 1H), 3.57 (br d, J=9.4 Hz, 2H), 3.50 - 3.40 (m, 2H), 3.22 (br d, J=5.6 Hz, 2H), 3.09 (s, 3H), 2.31 (s, 3H).

[0247] Step D. (4-Hydroxy-2-methyl-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl) phenyl)piperazin-1-yl)methanone. CataCXium A-Pd-G3(25.8 mg, 35.5 μmol) was added to a mixture of (4-hydroxy-6-iodo-2-methylquinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone (200 mg, 355 μmol), (2,3,6- trimethylphenyl)boronic acid (Intermediate 3, 70 mg, 426 μmol), and K3PO4(147 mg, 693 μmol) in dioxane / H2O (v / v, 9 / 1, 6 mL) under N2. The reaction mixture was heated at 100 °C overnight, then cooled to room temperature. The mixture was filtered, and the filter cake was rinsed with ethyl acetate (30 mL). The filtrate was diluted with brine (25 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was dried with Na2SO4, filtered, and concentrated under vacuum. It was purified by column chromatography (SiO2, gradient elution: 0 – 10% MeOH in DCM) to (4-hydroxy-2- methyl-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl) phenyl)piperazin- 1-yl)methanone as yellow solid. MS (ESI): mass calcd. for C30H32N4O4S, 544.2; m / z found, 545.1 [M+H]+.1H NMR (400MHz, DMSO-d6) δ = 12.40 (s, 1H), 7.80 (t, J=2.5 Hz, 1H), 7.69 (d, J=8.5 Hz, 2H), 7.45 (t, J=2.1 Hz, 1H), 7.14 - 7.02 (m, 4H), 3.87 (s, 1H), 3.77 (s, 1H), 3.58 - 3.38 (m, 4H), 3.26 (s, 2H), 3.09 (s, 3H), 2.35 (s, 3H), 2.25 (s, 3H), 1.97 - 1.88 (m, 6H).

[0248] Step E. (R)-N-Methyl-2-((2-methyl-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide. To a mixture of (4-hydroxy-2-methyl-6-(2,3,6- trimethylphenyl)quinazolin-8-yl) (4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone (54.7 mg, 100 μmol), (R)-2-amino-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide (Intermediate 1) (123 mg, 500 μmol), and Cs2CO3(164 mg, 502 μmol) in DMF (3 mL) was added BOP (66.6 mg, 151 μmol). The mixture was stirred at 60 °C overnight. The mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (40 mL × 3). The organic layer was washed with brine (40 mL), dried with Na2SO4, filtered, and concentrated under vacuum. It was purified by column chromatography (SiO2,DCM / MeOH = 20 / 1) and further purified by preparative reversed phase HPLC (Stationary phase: Boston Prime C18, 5 µm, 150 x 30 mm; Mobile phase: water (0.05% NH3H2O + 10 mMNH4HCO3) (A) - MeCN (B), gradient elution: 55 -85% B in A over 7 min, flow rate: 25 mL / min) to give (R)-N-methyl-2-((2-methyl-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6- (2,3,6-trimethylphenyl)quinazolin-4- yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide as white powder. MS (ESI): mass calcd. for C41H43F3N6O4S, 772.3; m / z found, 773.4 [M+H]+.1H NMR (400MHz, CDCl3) δ = 7.80 (d, J=8.9 Hz, 2H), 7.57 (d, J=7.9 Hz, 2H), 7.50 (s, 2H), 7.44 (d, J=8.1 Hz, 1H), 7.38 (d, J=7.7 Hz, 1H), 7.16 - 7.10 (m, 1H), 7.09 - 7.02 (m, 1H), 6.94 (d, J=8.9 Hz, 2H), 6.40 - 6.28 (m, 1H), 5.86 (s, 1H), 5.05 (s, 1H), 4.31 (d, J=9.2 Hz, 1H), 3.85 (d, J=13.7 Hz, 1H), 3.57 (t, J=5.1 Hz, 2H), 3.49 - 3.18 (m, 6H), 3.02 (s, 3H), 2.77 (dd, J=4.9, 8.0 Hz, 3H), 2.61 (s, 3H), 2.31 (d, J=4.1 Hz, 3H), 2.05 - 1.90 (m, 6H); 19F NMR (376MHz, CDCl3) δ = -62.52 (br d, J=13.9 Hz).

[0249] The compounds in Table 2 were prepared in a manner analogous to Example 4, using the starting material (Building Block in Step No.) listed in the table 2. Table 2, compounds with no stereochemistry indicated are mixtures of stereoisomers. Table 2.Example 7: (2R)-2-[[6-(2,5-Dimethylphenyl)-2-isopropyl-8-[4-(4- methylsulfonylphenyl)piperazine-1-carbonyl]quinazolin-4-yl]amino]-N-methyl-3-[4- (trifluoromethyl)phenyl]propanamide.

[0250] To a vial was added (2R)-2-[[6-(2,5-dimethylphenyl)-8-[4-(4- methylsulfonylphenyl)piperazine-1-carbonyl]quinazolin-4-yl]amino]-N-methyl-3-[4- (trifluoromethyl)phenyl]propanamide (Example 100, 25 mg, 33 µmol), isopropyl trifluoroborate (7.5 mg, 50 µmol), 9-mesityl-10-methylacridinium tetrafluoroborate (0.7 mg, 6.7 µmol), and sodium persulfate (16 mg, 67 µmol). The vial was placed under an inert atmosphere of argon and a 1:1 mixture of H2O:MeCN was added (350 µL) followed by trifluoroacetic acid (2.6 µL, 34 µmol). The reaction was illuminated with Blue Kessil lamps (440 nm) for ~16h. The reaction was quenched with 2M NaOH and extracted with EtOAc (1 mL x 2). The combined extract was dried over Na2SO4then concentrated to dryness in vacuo and purified by reverse phase preparative HPLC to give (R)-2-((6- (2,5-dimethylphenyl)-2-isopropyl-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide as a white powder (4 mg, 5.0 µmol). MS (ESI): mass calcd. for C42H45F3N6O4S, 786.9; m / z found, 787.3 [M+H]+.1H NMR (400 MHz, METHANOL-d4) δ 8.20 (d, J = 10.0 Hz, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.68 (s, 1H), 7.60 – 7.42 (m, 4H), 7.25 – 7.18 (m, 1H), 7.18 – 7.12 (m, 2H), 7.09 (dd, J = 8.4, 4.3 Hz, 2H), 5.26 – 5.12 (m, 1H), 4.63 (br s, 1H), 4.23 –4.07 (m, 1H), 3.90 (br dd, J = 13.3, 5.3 Hz, 1H), 3.69 – 3.54 (m, 2H), 3.48 – 3.35 (m, 4H), 3.31 – 3.21 (m, 1H), 3.06 (s, 3H), 3.00 (dt, J = 13.6, 7.0 Hz, 1H), 2.73 (d, J = 4.4 Hz, 3H), 2.38 (s, 3H), 2.27 (s, 3H), 1.33 – 1.20 (m, 7H), 1.00 – 0.78 (m, 1H). Example 8: (R)-2-((2-Amino-6-(2,5-dimethylphenyl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide.

[0251] Step A: (6-(2,5-Dimethylphenyl)-2,4-dihydroxyquinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone. CataCXium A Pd G3(513 mg, 704 µmol) was added to a mixture of 6-iodo-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazoline-2,4(1H,3H)-dione (3.42 g, 5.56 mmol), (2,5- dimethylphenyl)boronic acid (1.21 g, 8.07 mmol), and K2CO3(3.42 g, 24.8 mmol) in DMF / H2O (v / v, 9 / 1, 342 mL) at room temperature under N2atmosphere. The mixture was heated at 80 °C overnight, then cooled down to room temperature. The reaction mixture was filtered, and the filtrate was concentrated to dryness in vacuo. The residue was purified by flash column chromatography (SiO2, gradient elution: 0 – 5% MeOH in DCM) to give (6-(2,5-dimethylphenyl)-2,4-dihydroxyquinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone as a yellow solid. MS (ESI): mass calcd. for C28H28N4O5S, 532.2; m / z found, 533.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 11.52 (s, 1H), 10.67 (s, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 8.9 Hz, 2H), 7.59 (d, J = 2.1 Hz, 1H), 7.23 - 7.17 (m, 1H), 7.14 - 7.05 (m, 4H), 3.80 - 3.77 (m, 1H), 3.75 (br s, 1H), 3.57 (br s, 2H), 3.49 - 3.37 (m, 4H), 3.08 (s, 3H), 2.30 (s, 3H), 2.21 (s, 3H).

[0252] Step B: (2,4-Dichloro-6-(2,5-dimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone. A mixture of (6-(2,5-dimethylphenyl)- 2,4-dihydroxyquinazolin-8-yl)(4-(4-(methylsulfonyl) phenyl)piperazin-1-yl)methanone (500 mg, 845 µmol) in POCl3(10 mL) was stirred at 100 °C overnight, then cooled downto room temperature. The reaction mixture was concentrated to dryness in vacuo. The residue was purified by flash column chromatography (SiO2, gradient elution: 0 – 5% EtOAc in DCM) to give (2,4-dichloro-6-(2,5-dimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone as a yellow oil. MS (ESI): mass calcd. for C28H26Cl2N4O3S, 568.1; m / z found, 568.8 [M+H]+.

[0253] Step C: (R)-2-((2-Chloro-6-(2,5-dimethylphenyl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide. A solution of (2,4-dichloro-6-(2,5- dimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl) phenyl)piperazin-1-yl)methanone (500 mg, 653 µmol), Et3N (2.20 g, 21.7 mmol), and Intermediate 1 (700 mg, 2.84 mmol) in DCM (50 mL) was stirred at 50 °C overnight under N2. The reaction mixture was concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 – 80% ethyl EtOAc in DCM) to give (R)-2-((2-chloro-6-(2,5- dimethylphenyl)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4- yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide as a yellow solid. MS (ESI): mass calcd. for C39H38ClF3N6O4S, 778.2; m / z found, 779.1 [M+H]+.1H NMR (400 MHz, MeCN-d3) δ = 7.97 (dd, J = 1.6, 5.4 Hz, 1H), 7.72 (d, J = 8.9 Hz, 2H), 7.66 (dd, J = 1.6, 7.2 Hz, 1H), 7.58 - 7.45 (m, 5H), 7.25 - 7.18 (m, 1H), 7.16 - 7.07 (m, 2H), 7.04 - 6.97 (m, 2H), 6.88 - 6.77 (m, 1H), 5.17 - 5.05 (m, 1H), 4.02 - 3.92 (m, 1H), 3.86 - 3.78 (m, 1H), 3.47 (br dd, J = 4.5, 6.9 Hz, 2H), 3.45 - 3.38 (m, 1H), 3.38 - 3.30 (m, 1H), 3.28 - 3.20 (m, 4H), 2.98 (s, 3H), 2.67 (d, J = 4.6 Hz, 3H), 2.35 (s, 3H), 2.20 (s, 3H); 19F NMR (376 MHz, MeCN-d3) δ = -62.89 (br d, J = 10.4 Hz).

[0254] Step D: (R)-2-((2-Amino-6-(2,5-dimethylphenyl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide. The reaction was set up in three parallel batches. To a mixture of (R)-2-((2-chloro- 6-(2,5-dimethylphenyl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide (120 mg, 152 µmol), diphenylmethanimine (33.0 mg, 182 µmol), and Cs2CO3(198 mg, 608 µmol) in dioxane (6 mL) was added BINAP Pd G4 (15 mg, 15 µmol) and 4Å molecular sieves (120 mg) at room temperature in the glovebox. The mixture was stirred at 100 °C overnight, then cooled down to roomtemperature. The mixture was diluted with ethyl acetate (30 mL) and washed with sat. aq. citric acid (35 mL × 3). The organic phase was washed with brine (20 mL), dried with anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. It was purified by purified by preparative reverse-phase HPLC (Stationary phase: Welch Xtimate C18, 5 µm, 150 x 25 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 44 - 74% B in A over 7 min, flow rate: 25 mL / min) and further purified by SFC (Column: DAICEL CHIRALPAK IG, 10 µm, 250 x 30 mm; mobile phase: Supercritical CO2(A) – EtOH (0.1% NH3H2O) (B); isocratic elution: 40% B in A; flow rate: 150 mL / min; column temp.: 40 °C; ABPR: 100 bar.) to give the title compound as a yellow powder. MS (ESI): mass calcd. for C39H40F3N7O4S, 759.3; m / z found, 760.3 [M+H]+.1H NMR (400 MHz, MeCN-d3) δ = 7.74 (d, J = 1.9 Hz, 1H), 7.73 - 7.72 (m, 1H), 7.70 (s, 1H), 7.58 - 7.54 (m, 2H), 7.51 - 7.43 (m, 3H), 7.20 (br d, J = 8.2 Hz, 1H), 7.13 - 7.09 (m, 2H), 7.01 (br d, J = 6.6 Hz, 2H), 6.79 (br s, 1H), 6.69 (br d, J = 7.4 Hz, 1H), 5.23 (br s, 2H), 5.13 - 4.99 (m, 1H), 4.07 (br d, J = 13.5 Hz, 1H), 3.69 (br d, J = 8.5 Hz, 1H), 3.58 - 3.14 (m, 8H), 2.97 (s, 3H), 2.35 (s, 3H), 2.24 (s, 3H), 2.12 - 2.10 (m, 3H); 19F NMR (376 MHz, MeCN-d3) δ = -62.86 (s). Example 9. (R)-N-Methyl-2-((2-(methylamino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide.

[0255] Step A. (2,4-Dichloro-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone.. A suspension of (2,4-dihydroxy-6- (2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl) phenyl)piperazin-1- yl)methanone (Intermediate 5) (7.45 g, 13.63 mmol) in POCl3(130 mL) was stirred at 100°C for 16 h then cooled to room temperature. The reaction mixture was concentrated to dryness in vacuo. The resultant residue was purified by silica gelcolumn chromatography (0-85% ethyl acetate in DCM) to give the title compound (7.45 g) as yellow oil.

[0256] Step B. (R)-2-((2-Chloro-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6- (2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide. A suspension of (2,4-dichloro-6-(2,3,6- trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl) phenyl)piperazin-1-yl)methanone (7.45 g), Et3N (46.2 g, 457 mmol), and (R)-2-amino-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide (Intermediate 1) (17.0 g, 60.1 mmol) in DCM (150 mL) was stirred at 50°C for 16 h under N2then cooled to room temperature. The reaction mixture was diluted with DCM (150 mL) and washed with sat. aq. NaHCO3(100 mL × 2). The aqueous layer was extracted with ethyl acetate (150 mL × 2). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The resultant residue was purified by silica gel column chromatography (0-80% ethyl acetate in DCM) to give the title compound (5.28 g) as a yellow solid. MS (ESI): mass calcd. for C40H40ClF3N6O4S, 792.2; m / z found, 793.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 8.89 (br d, J = 7.9 Hz, 1H), 8.38-8.28 (m, 1H), 8.28-8.21 (m, 1H), 7.69 (br d, J = 8.9 Hz, 2H), 7.63-7.51 (m, 5H), 7.18-7.14 (m, 1H), 7.13-7.02 (m, 3H), 5.06-4.89 (m, 1H), 3.94-3.69 (m, 2H), 3.60-3.41 (m, 2H), 3.27 (br d, J = 12.8 Hz, 4H), 3.17 (br d, J = 5.2 Hz, 2H), 3.09 (s, 3H), 2.65 (d, J = 4.4 Hz, 3H), 2.31-2.26 (m, 3H), 2.04-1.95 (m, 3H), 1.95-1.87 (m, 3H).19F NMR (376 MHz, DMSO-d6) δ = -60.80 (br d, J = 6.9 Hz, 1F).

[0257] Step C. (R)-N-Methyl-2-((2-(methylamino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide. To a solution of (R)-2-((2-chloro-8- (4-(4-(methylsulfonyl)phenyl)piperazine- 1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin- 4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide (50 mg, 54.3 µmol) in dioxane (1 mL) was added 40% aq. MeNH2(0.5 mL). The solution was stirred at 50°C for 16 h and then cooled to room temperature and concentrated to dryness in vacuo. The residue was purified by preparative reversed phase HPLC (Stationary phase: Phenomenex C18, 3 µm, 75 x 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 47 - 77% B in A over 7 min, flow rate: 25 mL / min) to givethe title compound (25 mg) as a white solid. MS (ESI): mass calcd. for C41H44F3N7O4S, 787.3; m / z found, 788.5 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 8.16-7.86 (m, 3H), 7.68 (br d, J = 8.5 Hz, 2H), 7.62-7.47 (m, 4H), 7.20-6.97 (m, 5H), 6.55 (br s, 1H), 4.92- 4.75 (m, 1H), 4.09-3.60 (m, 2H), 3.59-3.42 (m, 2H), 3.18 (br d, J = 11.1 Hz, 6H), 3.09 (s, 3H), 2.73 (br s, 3H), 2.61 (d, J = 4.4 Hz, 3H), 2.27 (br d, J = 6.6 Hz, 3H), 2.07-1.82 (m, 6H).19F NMR (376 MHz, DMSO-d6) δ = -60.70 - -60.91 (m, 1F). Example 10. (R)-2-((2-(Dimethylamino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide.

[0258] To a solution of (R)-2-((2-chloro-8-(4-(4-(methylsulfonyl)phenyl)piperazine- 1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide (Example 9, product from Step B, 50 mg, 54 µmol) in dioxane (1 mL) was added 40% aq. Me2NH (0.5 mL). The solution was stirred at 50°C for 16 h and then cooled to room temperature and concentrated to dryness in vacuo. The residue was purified by preparative reversed phase HPLC (Stationary phase: Phenomenex C18, 3 µm, 75 x 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 50 - 80% B in A over 7 min, flow rate: 25 mL / min) to give the title compound (30 mg) as a white powder. MS (ESI): mass calcd. for C42H46F3N7O4S, 801.3; m / z found, 802.5 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 8.16-8.03 (m, 2H), 8.02-7.90 (m, 1H), 7.68 (br d, J = 8.8 Hz, 2H), 7.64-7.51 (m, 4H), 7.17-6.96 (m, 5H), 4.87-4.71 (m, 1H), 4.05-3.62 (m, 2H), 3.61-3.40 (m, 2H), 3.33-3.13 (m, 6H), 3.10 (s, 3H), 3.04 (s, 6H), 2.61 (br t, J = 5.3 Hz, 3H), 2.27 (br s, 3H), 2.07-1.81 (m, 6H).19F NMR (376 MHz, DMSO-d6) δ = -60.77 (br d, J=6.9 Hz, 1F). Example 11: (R)-(2-(Dimethylamino)-4-((3-hydroxy-3-methyl-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8- yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone.

[0259] A vial was charged with (R)-(2-chloro-4-((3-hydroxy-3-methyl-1-(6- (trifluoromethyl)pyridin-3-yl)butan-2-yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8- yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone (Example 30, product from Step A) (70 mg, 0.088 mmol), zinc cyanide (5 mg, 0.044 mmol), t-BuXPhos Pd G3 complex (3.9 mg, 0.0088 mmol) and 0.9 mL of DMF and then heated at 100 °C overnight. The mixture was filtered through Celite® and then purified by RP-HPLC (Column: Phenomenex Gemini 5uM C-18110A 100 x 30 mm) eluting with a linear gradient of 5-100% B in A in 10 mins (A: 10 mM ammonium carbonate, 0.1% ammonium hydroxide in water; B: 10 mM ammonium carbonate, 0.1% ammonium hydroxide in 90% acetonitrile 10% water) to give 15 mg (21%) of the title compound. MS (ESI): mass calcd. for C42H48F3N7O4S, 803.3; m / z found, 804.3 [M+H]+.1H NMR (400 MHz, METHANOL-d4) δ ppm 8.42 - 8.53 (m, 1 H), 7.63 (br d, J=15.65 Hz, 4 H), 7.34 - 7.50 (m, 1 H), 7.10 (s, 1 H), 6.82 - 7.03 (m, 4 H), 3.91 - 4.08 (m, 1 H), 3.64 - 3.81 (m, 1 H), 3.25 - 3.57 (m, 6 H), 2.82 - 3.00 (m, 10 H), 2.18 (d, J=5.87 Hz, 3 H), 1.83 - 1.97 (m, 6 H), 1.29 (d, J=3.91 Hz, 3 H), 1.21 (d, J=4.89 Hz, 3 H). Example 12: (R)-2-((2-((2-(Dimethylamino)ethyl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)-N-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propanamide.

[0260] A vial was charged with (R)-2-((2-chloro-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide (Example 13, product from step B) (36 mg, 0.045 mmol), N,N-dimethylethylenediamine (16 mg, 0.18 mmol) and 0.18 mL of DMSO and then heated at 80 °C for 4 hrs. The resulting residue was purified by RP-HPLC (Waters X-select CSH Prep, C185uM OBD, 19x150mm. 0.1% Formic acid modifier. Linear gradient of 10 – 45 % acetonitrile in water in 12 mins) to give 19 mg (44%) of the title compound as a formate salt. MS (ESI): mass calcd. for C44H51F3N8O4S, 844.4; m / z found, 845.0 [M+H]+.1H NMR (METHANOL-d4, 400 MHz) δ ppm 8.29 (s, 3H), 7.9-7.9 (m, 1H), 7.76 (s, 2H), 7.4-7.6 (m, 4H), 7.3-7.4 (m, 1H), 7.0- 7.2 (m, 4H), 5.0-5.1 (m, 1H), 3.9-4.1 (m, 2H), 3.4-3.7 (m, 10H), 3.1-3.3 (m, 1H), 3.06 (s, 3H), 2.96 (s, 6H), 2.74 (s, 3H), 2.3-2.4 (m, 3H), 1.9-2.1 (m, 6H). Example 13: (R)-2-((2-Hydroxy-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide.

[0261] Step A: (2,4-Dichloro-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone. A solution of (2,4-dihydroxy-6-(2,3,6- trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone(Intermediate 5, 90.0 g, 165 mmol) in POCl3(743 g, 4.84 mol, 450 mL) was prepared at 25 °C. The mixture was heated to 100 °C and stirred at 100 °C for 12 h. The reaction was distilled under vacuum (40 °C) to remove POCl3. The residue was dissolved in toluene (200 mL) and concentrated under reduced pressure to give a residue. The residue was dissolved in DCM (1.0 L), poured into ice water (500 mL), and the organic phase was separated. The aqueous phase was extracted with DCM (500 mL), and the combined organic layers were washed with water (500 mL), brine (500 mL), dried over Na2SO4, and concentrated under reduced pressure to afford a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 30~50% ethyl acetate / dichloromethane gradient @ 100 mL / min) to give (2,4-dichloro-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone as a yellow solid. MS (ESI): mass calcd. for C29H28Cl2N4O3S, 582.1; m / z found, 583.2 [M+H]+.1H NMR (400 MHz, DMSO- d6) δ = 8.05 (br s, 1H), 7.96 (br s, 1H), 7.70 (d, J = 9.1 Hz, 2H), 7.16 (d, J = 7.5 Hz, 1H), 7.09 (d, J = 8.6 Hz, 3H), 4.05 - 3.89 (m, 1H), 3.85 - 3.74 (m, 1H), 3.61 - 3.54 (m, 1H), 3.36- 3.20 (m, 5H), 3.09 (s, 3H), 2.27 (s, 3H), 1.97 - 1.84 (m, 6H).

[0262] Step B: (R)-2-((2-Chloro-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide. To a solution of (2,4-dichloro-6-(2,3,6- trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone (50.0 g, 85.69 mmol) and (R)-2-amino-N-methyl-3-(4- (trifluoromethyl)phenyl)propenamide (Intermediate 1, 42.20 g, 171.37 mmol) in DCM (1.00 L) was added TEA (130 g, 1.29 mol, 179 mL) at 25 °C. The mixture was heated to 40 °C and stirred at 40 °C for 12 h under N2atmosphere. The mixture was cooled to 25 °C, poured into water (1000 mL), and the organic phase was separated. The aqueous phase was extracted with DCM (500 mL x2), and the combined organic layers were washed with water (1.0 L), brine (1.0 L), dried over Na2SO4, and concentrated under reduce pressure to afford a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 30~50% Ethyl acetate / Dichloromethane gradient @ 100 mL / min) to give (R)-2-((2-chloro-8-(4- (4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide as a yellow solid. MS (ESI): mass calcd. for C40H40ClF3N6O4S, 792.2; m / z found, 793.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 8.89 (d, J = 8.8 Hz, 1H) 8.37 - 8.18 (m, 2H), 7.69 (d, J = 8.1 Hz 2H), 7.62 - 7.52 (m, 4H), 7.15-6.97 (m, 5H), 5.02 - 4.95 (m, 1H), 3.97 - 3.87 (m, 1H), 3.83 - 3.74 (m, 1H), 3.59 - 3.50 (m, 1H), 3.44- 3.37 (m, 1H), 3.303.13 (s, 5H), 3.09 (s, 3H) 2.64 (d, J = 5.0, 3H) 2.28-2.24 (m, 3H), 2.05 - 1.82 (m, 7H).

[0263] Step C: (R)-2-((2-Hydroxy-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)- 6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide. To a solution of (R)-2-((2-chloro-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide (63.0 g, 79.4 mmol) in a mixture of AcOH (630 mL) and dioxane (630 mL) and H2O (630 mL) was added AgOAc (26.5 g, 159 mmol, 8.13 mL) at 25 °C. The mixture was heated to 80 °C and stirred at 80 °C for 2 h under N2atmosphere. The mixture was cooled to 25 °C and filtered through a pad of Celite®, and the filter cake was washed with EtOAc (500 mL). The filtrate was collected, and the layers were separated. The aqueous phase was extracted with EtOAc (500 mL x2), and the combined organic layers were washed with sat. NaHCO3(1000 mL x2), brine (1000 mL), dried over Na2SO4, and concentrated under reduced pressure to afford a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column; Eluent of ~10% dichloromethane : methanol gradient @ 100 mL / min) to give a yellow solid. This material was further purified by reverse-phase HPLC (column: Phenomenex luna C18 250 x 80 mm x 10 µm; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 40%-70%, 20 min) to give (R)-2-((2-Hydroxy-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)- 6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide as a yellow solid. MS (ESI): mass calcd. for C40H41F3N6O5S, 774.3; m / z found, 775.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 9.98 (br s, 1H), 8.41 (br d, J = 8.1 Hz, 1H), 8.23 - 8.02 (m, 2H), 7.68 (d, J = 8.9 Hz, 2H), 7.63 - 7.52 (m, 4H), 7.34 (d, J = 5.7 Hz, 1H), 7.17 - 7.01 (m, 4H), 5.12 - 4.88 (m, 1H), 3.83 - 3.67 (m, 2H), 3.54 (br s, 2H), 3.49 - 3.39 (m, 4H), 3.24 (br s, 1H), 3.20 - 3.11 (m,1H), 3.09 (s, 3H), 2.64 (d, J = 4.4 Hz, 3H), 2.28 (d, J = 6.4 Hz, 3H), 2.05 - 1.97 (m, 3H), 1.91 (d, J = 16.2 Hz, 3H). Example 14: (R)-2-((2-Hydroxy-8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide.

[0264] Rockphos Pd G3 (9.4 mg, 11 µmol) was added to the mixture of (R)-2-((2-chloro- 8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1-carbonyl)-6-(2,3,6- trimethyl)phenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide (Example 37 product from Step D, 60 mg, 73 µmol), benzaldehyde oxime (15.7 mg, 130 µmol), and Cs2CO3(75.0 mg, 230 µmol) in DMF (3.3 mL) under N2. The reaction mixture was stirred at 80 °C overnight, then cooled down to room temperature. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with 3% aq. LiCl (10 mL × 2). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was purified by preparative reverse-phase HPLC (Stationary phase: Welch Xtimate C18, 5 µm, 150 x 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 40-70% B in A over 8 min, flow rate: 30 mL / min) to give (R)-2-((2-hydroxy-8-(4- (6-(methylsulfonyl)pyridin-3-yl)piperidine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide as an off-white powder. MS (ESI): mass calcd. for C40H41F3N6O5S, 774.3; m / z found, 775.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 9.91 (br s, 1H), 8.72 (s, 1H), 8.40 (br d, J = 8.0 Hz, 1H), 8.20 - 8.13 (m, 1H), 8.06 (br d, J = 10.0 Hz, 2H), 8.01 - 7.95 (m, 1H), 7.62 - 7.52 (m, 4H), 7.37 (br s, 1H), 7.16 - 7.11 (m, 1H), 7.07 (br s, 1H), 4.98 (br d, J = 8.0 Hz, 1H), 4.62 (br s, 1H), 3.61 (br s, 1H), 3.25 (s, 3H), 3.23 - 3.08 (m, 3H), 3.02 (br s, 1H), 2.86 (br s, 1H), 2.63 (d, J = 4.4 Hz, 3H),2.26 (br d, J = 6.4 Hz, 3H), 2.06 - 1.81 (m, 8H), 1.70 (br s, 2H); 19F NMR (376 MHz, DMSO-d6) δ = -60.76 (d, J = 8.3 Hz). Example 15: (R)-(2-Hydroxy-4-((3-hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan- 2-yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone.

[0265] A vial was charged with (R)-(2-chloro-4-((3-hydroxy-3-methyl-1-(4- (trifluoromethyl)phenyl)butan-2-yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone (Example 42, product from Step A) (200 mg, 0.25 mmol), ammonium acetate (194 mg, 2.52 mmol) and 2.5 mL of acetic acid and then heated at 77 °C for 3 hrs. The mixture was concentrated and the resulting residue was purified by RP-HPLC (Column: Phenomenex Gemini 5uM C-8110A 150 x 30 mm) eluting with a linear gradient of 50-100% B in A in 12 mins (A: 10 mM ammonium carbonate, 0.1% ammonium hydroxide in water; B: 10 mM ammonium carbonate, 0.1% ammonium hydroxide in 90% acetonitrile 10% water) to give 140 mg (72%) of the title compound. MS (ESI): mass calcd. for C41H44F3N5O5S, 775.3; m / z found, 776.0 [M+H]+.1H NMR (DMSO-d6, 400 MHz) δ ppm 9.6-9.9 (m, 1H), 8.1-8.2 (m, 1H), 7.8-7.9 (m, 1H), 7.68 (d, 2H, J=9.3 Hz), 7.4-7.5 (m, 4H), 7.3-7.4 (m, 1H), 7.06 (d, 4H, J=8.8 Hz), 4.5-5.0 (m, 2H), 3.3-3.8 (m, 8H), 3.2-3.2 (m, 1H), 3.08 (s, 3H), 2.9-3.1 (m, 1H), 2.27 (d, 3H, J=11.2 Hz), 1.9-2.0 (m, 6H), 1.1-1.3 (m, 6H). Example 16: (R)-(2-Hydroxy-4-((3-hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan- 2-yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(6-(methylsulfonyl)pyridin-3- yl)piperidin-1-yl)methanone.

[0266] Step A: (R)-(2-Chloro-4-((3-hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan- 2-yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(6-(methylsulfonyl)pyridin-3- yl)piperidin-1-yl)methanone. A mixture of (2,4-dichloro-6-(2,3,6- trimethylphenyl)quinazolin-8-yl)(4-(6-(methylsulfonyl)pyridin-3-yl)piperidin-1- yl)methanone (800 mg, 1.37 mmol, Et3N (1.67 g, 16.5 mmol), and (R)-3-amino-2- methyl-4-(4-(trifluoromethyl)phenyl)butan-2-ol (Intermediate 12, 1.36 g, 5.50 mmol) in DCM (8 mL) was stirred at 45 °C overnight under N2. The mixture was diluted with DCM (50 mL), washed with sat. aq. NaHCO3(20 mL) and H2O (40 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 2). The combined organic phase was dried with anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 – 70% EtOAc in DCM) to give (R)-(2-chloro-4-((3-hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan-2- yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(6-(methylsulfonyl)pyridin-3- yl)piperidin-1-yl)methanone as a white solid. MS (ESI): mass calcd. for C41+ H43ClF3N5O4S, 793.3; m / z found, 794.3 [M+H] .1H NMR (400 MHz, CDCl3) δ = 8.68 (br s, 1H), 8.08 (br d, J = 7.4 Hz, 1H), 8.01 - 7.71 (m, 1H), 7.60 - 7.42 (m, 2H), 7.40 (br s, 1H), 7.35 (br s, 3H), 7.18 - 7.12 (m, 1H), 7.08 (br d, J = 7.6 Hz, 1H), 6.21 (br d, J = 6.7 Hz, 1H), 5.07 (br d, J = 13.9 Hz, 1H), 4.82 - 4.60 (m, 1H), 3.55 - 3.35 (m, 1H), 3.31 (br dd, J = 4.0, 14.5 Hz, 1H), 3.25 (d, J = 3.8 Hz, 3H), 3.22 - 3.08 (m, 1H), 3.02 - 2.74 (m, 2H), 2.42 - 2.17 (m, 4H), 2.05 - 1.88 (m, 7H), 1.80 (br s, 2H), 1.51 - 1.31 (m, 6H); 19F NMR (376 MHz, CDCl3) δ = -62.40 - -62.54 (m).

[0267] Step B: (R)-(2-Hydroxy-4-((3-hydroxy-3-methyl-1-(4- (trifluoromethyl)phenyl)butan-2-yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(6- (methylsulfonyl)pyridin-3-yl)piperidin-1-yl)methanone. The reaction was set up in two parallel batch. Rockphos Pd G3(20 mg, 24 µmol) was added to a mixture of (R)-(2- chloro-4-((3-hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(6-(methylsulfonyl)pyridin-3-yl)piperidin-1- yl)methanone (200 mg, 247 µmol), benzaldehyde oxime (44.0 mg, 363 µmol), and Cs2CO3(200 mg, 614 µmol) in DMF (10 mL). The mixture was stirred at 80 °C overnight, then cooled down to room temperature. The reaction mixture was filtered over Celite®, and the solid was rinsed with ethyl acetate (30 mL). The filtrate was washed with 3% aq. LiCl (20 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. It was purified by preparative reverse-phase HPLC (Stationary phase: Phenomenex C18, 3 µm, 80 x 40 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 50 - 80% B in A over 7 min, flow rate: 25 mL / min) to give the title compound as an off-white powder. MS (ESI): mass calcd. for C41+H44F3N5O5S, 775.3; m / z found, 776.4 [M+H] .1H NMR (400 MHz, DMSO-d6) δ = 9.66 (br s, 1H), 8.72 (s, 1H), 8.13 (br s, 1H), 8.09 - 8.02 (m, 1H), 8.01 - 7.93 (m, 1H), 7.81 (br d, J = 9.3 Hz, 1H), 7.48 (d, J = 2.3 Hz, 4H), 7.35 (s, 1H), 7.16 - 7.03 (m, 2H), 4.85 (br s, 1H), 4.63 (br s, 2H), 3.63 (br s, 1H), 3.25 (s, 3H), 3.20 (br d, J = 11.8 Hz, 2H), 3.06 - 2.93 (m, 2H), 2.86 (br s, 1H), 2.26 (br d, J = 11.5 Hz, 3H), 2.03 - 1.89 (m, 6H), 1.83 (br s, 4H), 1.24 (s, 3H), 1.17 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ = -60.72 (br s). Example 17: (R)-(2-hydroxy-4-((3-hydroxy-3-methyl-1-(6-(trifluoromethyl)pyridin-3- yl)butan-2-yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone.

[0268] Step A: (R)-(2-(Benzyloxy)-4-((3-hydroxy-3-methyl-1-(6-(trifluoromethyl)pyridin-3- yl)butan-2-yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone. A vial was charged with 5-[di(1- adamantyl)phosphino]-1',3',5'-triphenyl-1'H-[1,4']bipyrazole (3.3 mg, 0.005 mmol), palladium(II)(π-cinnamyl) chloride dimer (0.68 mg, 0.001 mmol), Cs2CO3(25 mg, 0.08mmol) and 0.5 mL toluene and then degassed under vacuum and backfilled with Ar and stirred for 5 mins at Rt. (R)-(2-Chloro-4-((3-hydroxy-3-methyl-1-(6- (trifluoromethyl)pyridin-3-yl)butan-2-yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8- yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone (Example 30, product from step A) (40 mg, 0.05 mmol) and benzyl alcohol (22 mg, 0.20 mmol) were then added and the mixture heated at 90 °C for 3 hrs. The mixture was concentrated, filtered through a silica gel plug and then purified by RP-HPLC (Column: Phenomenex Gemini 5uM C-18110A 150 x 30 mm) eluting with a linear gradient of 50-100% B in A in 10 mins (A: 10 mM ammonium carbonate, 0.1% ammonium hydroxide in water; B: 10 mM ammonium carbonate, 0.1% ammonium hydroxide in 90% acetonitrile 10% water) to give 20 mg (46%) of the title compound. MS (ESI): mass calcd. for C47H49F3N6O5S, 866.3; m / z found, 867.2 [M+H]+.

[0269] Step B: (R)-(2-Hydroxy-4-((3-hydroxy-3-methyl-1-(6-(trifluoromethyl)pyridin-3- yl)butan-2-yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone. A solution of (R)-(2-(benzyloxy)-4-((3- hydroxy-3-methyl-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-yl)amino)-6-(2,3,6- trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone (20 mg, 0.023 mmol) in 0.5 methanol was hydrogenated in an H-cube flow apparatus over 10% Pd / carbon at 60 °C, 20 bar and 1 mL / min. The resulting residue was then purified by RP-HPLC (Column: Phenomenex Gemini 5uM C-8110A 150 x 30 mm) eluting with a linear gradient of 50-100% B in A in 10 mins (A: 10 mM ammonium carbonate, 0.1% ammonium hydroxide in water; B: 10 mM ammonium carbonate, 0.1% ammonium hydroxide in 90% acetonitrile 10% water) to give 12 mg (67%) of the title compound. MS (ESI): mass calcd. for C40H43F3N6O5S, 776.3; m / z found, 777.3 [M+H]+.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.83 - 8.98 (m, 1 H), 8.42 - 8.52 (m, 1 H), 7.89 - 8.03 (m, 1 H), 7.80 (d, J=8.80 Hz, 3 H), 7.56 (dd, J=8.31, 1.96 Hz, 1 H), 7.29 - 7.36 (m, 2 H), 7.02 - 7.20 (m, 3 H), 6.94 (d, J=9.29 Hz, 3 H), 6.07 (d, J=9.78 Hz, 1 H), 4.99 (td, J=9.54, 3.91 Hz, 1 H), 3.22 - 4.10 (m, 13 H), 3.02 (s, 5 H), 2.30 (d, J=8.31 Hz, 4 H), 1.88 - 2.07 (m, 9 H), 1.20 - 1.48 (m, 10 H). Example 18 and Example 19: (R)-2-((8-((*R)-2,2-dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8-carbonyl)-2-hydroxy-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N- (1-(trifluoromethyl)cyclopropyl)-3-(4-(trifluoromethyl)phenyl)propanamide and (R)-2-((8- ((*S)-2,2-dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8-carbonyl)-2-hydroxy-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-(1-(trifluoromethyl)cyclopropyl)-3-(4- (trifluoromethyl)phenyl)propanamide. and

[0270] Step A: 8-(2,2-Dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8-carbonyl)-6- iodoquinazoline-2,4(1H,3H)-dione. TCFH (4.00 g, 14.3 mmol) was added to a mixture of 6-iodo-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-8-carboxylic acid (1.0 g, 3.0 mmol), octahydropyrazino[2,1-c][1,4]thiazine 2,2-dioxide dihydrochloride (1.0 g, 3.8 mmol) and NMI (3.40 g, 41.4 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with brine (60 mL) and extracted with EtOAc (20 mL x3). The combined extract was dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 – 10% MeOH in DCM) to give 8-(2,2- dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8-carbonyl)-6-iodoquinazoline-2,4(1H,3H)- dione as a yellow solid. MS (ESI): mass calcd. for C16H17IN4O5S, 504.0; m / z found, 505.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 11.55 (br s, 1H), 10.79 (br s, 1H), 8.17 (d, J = 1.8 Hz, 1H), 7.87 (br d, J = 18.1 Hz, 1H), 4.03 (br d, J = 7.3 Hz, 2H), 3.43 - 3.34 (m, 2H), 3.22 (br s, 1H), 3.12 (br d, J = 12.0 Hz, 2H), 3.07 - 2.95 (m, 1H), 2.88 (br d, J = 7.3 Hz, 2H), 2.74 - 2.63 (m, 2H), 2.56 (br s, 1H).

[0271] Step B: (2,4-Dihydroxy-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(2,2- dioxidohexahydropyrazino[2,1-c][1,4]thiazin-8(1H)-yl)methanone. CataCXium A Pd G3(92.0 mg, 126 µmol) was added to a mixture of 8-(2,2-dioxidooctahydropyrazino[2,1- c][1,4]thiazine-8-carbonyl)-6-iodoquinazoline-2,4(1H,3H)-dione (494 mg, 919 µmol), (2,3,6-trimethylphenyl)boronic acid (Intermediate 3, 185 mg, 1.13 mmol), and K2CO3(574 mg, 4.15 mmol) in DMF / H2O (v / v, 9 / 1, 64 mL) at room temperature under N2atmosphere. The reaction mixture was heated at 80 °C overnight, then cooled down to room temperature. The reaction mixture was filtered, and the filter cake was rinsed with 50 mL of EtOAc. The filtrate was concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 – 100% EtOAc in DCM, then 0 – 10% MeOH in DCM) to give (2,4-dihydroxy-6-(2,3,6-trimethylphenyl)quinazolin- 8-yl)(2,2-dioxidohexahydropyrazino[2,1-c][1,4]thiazin-8(1H)-yl)methanone as a yellow solid. MS (ESI): mass calcd. for C25H28N4O5S, 496.2; m / z found, 497.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 11.50 (s, 1H), 10.67 (br s, 1H), 7.70 - 7.51 (m, 2H), 7.14 - 6.98 (m, 2H), 4.29 (br s, 1H), 3.59 - 3.34 (m, 4H), 3.26 - 3.05 (m, 4H), 2.90 (br s, 4H), 2.24 (s, 3H), 1.98 - 1.86 (m, 6H).

[0272] Step C: (2,4-Dichloro-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(2,2- dioxidohexahydropyrazino[2,1-c][1,4]thiazin-8(1H)-yl)methanone. A mixture of (2,4- dihydroxy-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(2,2- dioxidohexahydropyrazino[2,1- c][1,4]thiazin-8(1H)-yl)methanone (292 mg, 579 µmol) in POCl3(6 mL) was stirred at 100 °C for 2 days, then cooled down to room temperature. The mixture was concentrated to dryness in vacuo and directly purified by column chromatography (SiO2, DCM / EtOAc from 1 / 0 to 1 / 5) to give (2,4-dichloro-6-(2,3,6-trimethylphenyl)quinazolin-8- yl)(2,2-dioxidohexahydropyrazino[2,1-c][1,4]thiazin-8(1H)-yl)methanone as a brown oil. MS (ESI): mass calcd. for C25H26Cl2N4O3S, 532.1; m / z found, 533.2 [M+H]+.

[0273] Step D: Tert-butyl (R)-(1-oxo-1-((1-(trifluoromethyl)cyclopropyl)amino)-3-(4- (trifluoromethyl)phenyl)propan-2-yl)carbamate. To a mixture of (R)-2-((tert- butoxycarbonyl)amino)-3-(4-(trifluoromethyl)phenyl)propanoic acid (200 mg, 600 µmol), 1-(trifluoromethyl)cyclopropanamine hydrochloride (160 mg, 990 µmol) and DIEA (310 mg, 2.40 mmol) in DMF (4 mL) was added HATU (300 mg, 789 µmol). The mixture was stirred at room temperature for 1 day. The mixture was diluted with brine (10 mL) and extracted with EtOAc (15 mL x2). The combined extract was dried with anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. It was purified by column chromatography (SiO2, gradient elution: 0 – 30% ethyl acetate in petroleum ether) to give tert-butyl (R)-(1-oxo-1-((1-(trifluoromethyl)cyclopropyl)amino)-3-(4- (trifluoromethyl)phenyl)propan-2-yl)carbamate as a white solid. (ESI): mass calcd. forC19H22F6N2O3, 440.2; m / z found, 340.9 [M-99]+.1H NMR (400 MHz, CDCl3) δ = 7.57 (d, J = 8.0 Hz, 2H), 7.32 (br d, J = 8.0 Hz, 2H), 6.57 (br s, 1H), 5.12 - 4.90 (m, 1H), 4.29 (br d, J = 7.3 Hz, 1H), 3.11 (dq, J = 7.2, 14.0 Hz, 2H), 1.41 (s, 9H), 1.30 - 1.25 (m, 2H), 1.07 - 0.87 (m, 2H); 19F NMR (376 MHz, CDCl3) δ = -62.06 - -63.01 (m), -74.02 (br s).

[0274] Step E: (R)-2-Amino-N-(1-(trifluoromethyl)cyclopropyl)-3-(4- (trifluoromethyl)phenyl)propanamide. To a mixture of tert-butyl (R)-(1-oxo-1-((1- (trifluoromethyl)cyclopropyl)amino)-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamate (190 mg, 431 µmol) in DCM (6 mL) was added 4 M HCl / dioxane (1.9 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness in vacuo. The pH of the residue was adjusted to pH ~ 8 with sat. aq. Na2CO3and extracted with EtOAc (20 mL x3). The combined extract was dried with anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give (R)-2-amino-N-(1- (trifluoromethyl)cyclopropyl)-3-(4-(trifluoromethyl)phenyl)propanamide as a yellow solid. MS (ESI): mass calcd. for C14H14F6N2O, 340.1; m / z found, 341.3 [M+H]+.1H NMR (400 MHz, CDCl3) δ = 7.82 (br s, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 3.64 (dd, J = 4.4, 8.5 Hz, 1H), 3.27 (dd, J = 4.3, 13.8 Hz, 1H), 2.89 (dd, J = 8.6, 13.8 Hz, 1H), 1.38 - 1.33 (m, 1H), 1.31 - 1.24 (m, 1H), 1.11 - 1.01 (m, 2H); 19F NMR (376 MHz, CDCl3) δ = -62.53 (br s), -74.15 (s).

[0275] Step F: (2R)-2-((2-Chloro-8-(2,2-dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-(1- (trifluoromethyl)cyclopropyl)-3-(4-(trifluoromethyl)phenyl)propanamide. To a mixture of (2,4-dichloro-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(2,2- dioxidohexahydropyrazino[2,1-c][1,4]thiazin-8(1H)-yl)methanone (220 mg, 0.41 mmol) and Et3N (270 mg, 2.67 mmol) in DCM (5 mL) was added (R)-2-amino-N-(1- (trifluoromethyl)cyclopropyl)-3-(4-(trifluoromethyl)phenyl)propanamide (344 mg, 1.01 mmol). The mixture was stirred at 50 °C overnight, then cooled down to room temperature. The mixture was diluted with H2O (5 mL) and extracted with DCM (5 mL x3). The combined extract was dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 – 80% EtOAc in DCM) to give (2R)-2-((2-chloro-8-(2,2- dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-(1-(trifluoromethyl)cyclopropyl)-3-(4- (trifluoromethyl)phenyl)propanamide as a yellow solid. MS (ESI): mass calcd. for C39H39ClF6N6O4S, 836.2; m / z found, 837.2 [M+H]+.

[0276] Step G: (R)-2-((8-((*R)-2,2-dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8- carbonyl)-2-hydroxy-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-(1- (trifluoromethyl)cyclopropyl)-3-(4-(trifluoromethyl)phenyl)propanamide and (R)-2-((8- ((*S)-2,2-dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8-carbonyl)-2-hydroxy-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-(1-(trifluoromethyl)cyclopropyl)-3-(4- (trifluoromethyl)phenyl)propanamide. To a mixture of (2R)-2-((2-chloro-8-(2,2- dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8- carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-(1-(trifluoromethyl)cyclopropyl) -3-(4- (trifluoromethyl)phenyl)propanamide (430 mg, 514 µmol), benzaldehyde oxime (99.0 mg, 817 µmol), and Cs2CO3(406 mg, 1.25 mmol) in DMF (12 mL) was added Rockphos Pd G3(46 mg, 55 µmol) under N2atmosphere. The mixture was stirred at 80 °C overnight then cooled down to room temperature. The mixture was filtered through a pad of Celite®, and the filtrate was concentrated to dryness in vacuo. The residue was purified by preparative reverse-phase HPLC (Stationary phase: Welch Xtimate C18, 5 µm, 150 x 25 mm; Mobile phase: water (aq. NH3+ NH4HCO3) (A) - MeCN (B), gradient elution: 50 - 80% B in A over 7 min, flow rate: 25 mL / min) to give (2R)-2-((8-(2,2- dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8-carbonyl)-2-hydroxy-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-(1-(trifluoromethyl)cyclopropyl)-3-(4- (trifluoromethyl)phenyl)propanamide as a white solid. The isomers were separated by preparative SFC (Column: DAICEL CHIRALPAK OJ, 10 µm, 250 x 30 mm; mobile phase: Supercritical CO2(A) – EtOH (0.1% aq. NH3) (B); isocratic elution: 20% B in A; flow rate: 60 mL / min; column temp.: 40 °C; ABPR: 100 bar.) to give: (R)-2-((8-((*S)-2,2- dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8-carbonyl)-2-hydroxy-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-(1-(trifluoromethyl)cyclopropyl)-3-(4- (trifluoromethyl)phenyl)propanamide as the first eluting compound (0.761 min) and (R)- 2-((8-((*R)-2,2-dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8-carbonyl)-2-hydroxy-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-(1-(trifluoromethyl)cyclopropyl)-3-(4- (trifluoromethyl)phenyl)propanamide as the second eluting compound (0.973 min), bothas white powders. (R)-2-((8-((*S)-2,2-dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8- carbonyl)-2-hydroxy-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-(1- (trifluoromethyl)cyclopropyl)-3-(4-(trifluoromethyl)phenyl)propanamide MS (ESI): mass calcd. for C39H40F6N6O5S, 818.3; m / z found, 819.3 [M+H]+.1H NMR (400 MHz, DMSO- d6) δ = 10.07 - 9.90 (m, 1H), 9.03 (s, 1H), 8.39 (br d, J = 8.1 Hz, 1H), 8.11 (br d, J = 4.8 Hz, 1H), 7.66 - 7.51 (m, 4H), 7.32 (br s, 1H), 7.17 - 7.11 (m, 1H), 7.09 - 7.04 (m, 1H), 4.98 (br dd, J = 3.0, 6.6 Hz, 1H), 4.35 - 4.22 (m, 1H), 3.53 - 3.36 (m, 1H), 3.26- 3.05 (m, 6H), 3.04 - 2.79 (m, 3H), 2.78 - 2.71 (m, 1H), 2.64 (br s, 2H), 2.44 (br d, J = 3.3 Hz, 1H), 2.27 (br d, J = 3.2 Hz, 3H), 2.06 - 1.85 (m, 6H), 1.24 (br d, J = 5.0 Hz, 2H), 1.01 (br s, 2H); 19F NMR (376 MHz, DMSO-d6) δ = -60.79 (br d, J = 6.9 Hz), -72.04 (br s). (R)-2- ((8-((*R)-2,2-dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8-carbonyl)-2-hydroxy-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-(1-(trifluoromethyl)cyclopropyl)-3-(4- (trifluoromethyl)phenyl)propanamide MS (ESI): mass calcd. for C39H40F6N6O5S, 818.3; m / z found, 819.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 9.98 (br s, 1H), 9.03 (s, 1H), 8.39 (br d, J = 7.4 Hz, 1H), 8.11 (br d, J = 5.1 Hz, 1H), 7.65 - 7.52 (m, 4H), 7.32 (br s, 1H), 7.15 - 7.11 (m, 1H), 7.10 - 7.06 (m, 1H), 4.98 (br dd, J = 3.0, 7.7 Hz, 1H), 4.35 - 4.21 (m, 1H), 3.56 - 3.36 (m, 1H), 3.27 - 3.04 (m, 6H), 3.03 - 2.79 (m, 3H), 2.70 (br s, 1H), 2.65 - 2.55 (m, 2H), 2.48 - 2.37 (m, 1H), 2.27 (br d, J = 3.2 Hz, 3H), 2.06 - 1.83 (m, 6H), 1.24 (br d, J = 4.8 Hz, 2H), 1.01 (br s, 2H); 19F NMR (376 MHz, DMSO-d6) δ = - 60.79 (br d, J = 6.9 Hz), -72.04 (br s, 1F). Example 20: (R)-2-((2-Hydroxy-8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-(1- (trifluoromethyl)cyclopropyl)-3-(4-(trifluoromethyl)phenyl)propenamide.

[0277] Step A: (R)-2-((2-Chloro-8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-(1-(trifluoromethyl)cyclopropyl)-3-(4-(trifluoromethyl)phenyl)propanamide. To a mixture of (2,4-dichloro-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(6-(methylsulfonyl)pyridin-3- yl)piperidin-1-yl)methanone (168 mg, 288 µmol) and Et3N (160 mg, 1.58 µmol) in DCM (2.5 mL) was added (R)-2-amino-N-(1-(trifluoromethyl)cyclopropyl)-3-(4- (trifluoromethyl)phenylpropanamide (310 mg, 911 µmol). The mixture was stirred at 50 °C overnight, then cooled down to room temperature. The mixture was diluted with H2O (2 mL) and extracted with DCM (3 mL x3). The combined extract was dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 – 100% ethyl acetate in petroleum ether) to give (R)-2-((2-chloro-8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine- 1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-(1- (trifluoromethyl)cyclopropyl)-3-(4-(trifluoromethyl)phenyl)propanamide as a yellow solid. MS (ESI): mass calcd. for C43H41ClF6N6O4S, 886.3; m / z found, 887.2 [M+H]+.

[0278] Step B: (R)-2-((2-Hydroxy-8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-(1- (trifluoromethyl)cyclopropyl)-3-(4-(trifluoromethyl)phenyl)propanamide. To a mixture of (R)-2-((2-chloro-8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-(1-(trifluoromethyl)cyclopropyl)-3-(4- (trifluoromethyl)phenyl)propanamide (65 mg, 52 µmol), benzaldehyde oxime (9.8 mg, 81 µmol) and Cs2CO3(43.5 mg, 134 µmol) in DMF (2.6 mL) was added Rockphos Pd G3(4.3 mg, 5.1 µmol) under N2atmosphere. The mixture was stirred at 80 °C overnight, then cooled down to room temperature. The reaction mixture was filtered over Celite®, and the solid was rinsed with EtOAc (30 mL). The filtrate was washed with 3% aq. LiCl (20 mL x3), dried over Na2SO4, filtered, and concentrated to dryness in vacuo. The resulting residue was purified by preparative reverse-phase HPLC (Stationary phase: Welch Xtimate C18, 5 µm, 150 x 25 mm; Mobile phase: water (aq. NH3+ NH4HCO3) (A) - MeCN (B), gradient elution: 60 - 90% B in A over 7 min, flow rate: 25 mL / min) to give (R)-2-((2-hydroxy-8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-(1-(trifluoromethyl)cyclopropyl)-3-(4- (trifluoromethyl)phenyl)propanamide as a white powder. MS (ESI): mass calcd. for C43H42F6N6O5S, 868.3; m / z found, 869.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ =9.95 - 9.83 (m, 1H), 9.04 (s, 1H), 8.73 (d, J = 1.5 Hz, 1H), 8.41 (br d, J = 7.6 Hz, 1H), 8.15 - 8.04 (m, 2H), 8.02 - 7.96 (m, 1H), 7.64 - 7.36 (m, 5H), 7.17 - 7.11 (m, 1H), 7.11 - 7.03 (m, 1H), 5.04 - 4.92 (m, 1H), 4.70 - 4.55 (m, 1H), 3.76 - 3.55 (m, 1H), 3.26 (s, 3H), 3.16 (br d, J = 7.6 Hz, 3H), 3.08 - 2.97 (m, 1H), 2.94 - 2.80 (m, 1H), 2.27 (br d, J = 3.0 Hz, 3H), 2.08 - 1.76 (m, 9H), 1.75 - 1.67 (m, 1H), 1.24 (br d, J = 4.5 Hz, 2H), 1.01 (br s, 2H); 19F NMR (376 MHz, DMSO-d6) δ = -60.80 (br s), -72.04 (s). Example 21: (R)-N-((1s,3S)-3-Hydroxy-3-methylcyclobutyl)-2-((2-hydroxy-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide.

[0279] Step A: Tert-butyl ((R)-1-(((1s,3S)-3-hydroxy-3-methylcyclobutyl)amino)-1-oxo-3- (4-(trifluoromethyl)phenyl)propan-2-yl)carbamate. HATU (2.60 g, 6.84 mmol) was added to a mixture of (R)-2-((tert-butoxycarbonyl)amino)-3-(4-(trifluoromethyl)phenyl)propanoic acid (1.9 g, 5.7 mmol), (1s,3s)-3-amino-1-methylcyclobutanol hydrochloride (950 mg, 6.90 mmol), and Et3N (2.80 g, 27.7 mmol) in DMF (38 mL). The reaction mixture was stirred at room temperature overnight. The mixture was quenched with H2O (50 mL) and filtered. The filter cake was washed with H2O (10 mL x3), collected, and dried in vacuo to give tert-butyl ((R)-1-(((1s,3S)-3-hydroxy-3-methylcyclobutyl)amino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)carbamate as a white solid. MS (ESI): mass calcd. for C20H27F3N2O4, 416.2; m / z found, 361.3 [M-55]+.1H NMR (400 MHz, CDCl3) δ = 7.56 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 6.04 (d, J = 7.7 Hz, 1H), 4.98 (s, 1H), 4.29 (d, J = 7.4 Hz, 1H), 3.93 (sxt, J = 7.8 Hz, 1H), 3.21 - 3.02 (m, 2H), 2.55 - 2.39 (m, 2H), 1.97 - 1.78 (m, 2H), 1.41 (s, 9H), 1.37 (s, 3H); 19F NMR (376 MHz, CDCl3) δ = -62.50 (s).

[0280] Step B: (R)-2-Amino-N-((1s,3S)-3-hydroxy-3-methylcyclobutyl)-3-(4- (trifluoromethyl)phenyl)propanamide hydrochloride.4 M HCl / dioxane (42 mL) wasadded to a mixture of tert-butyl ((R)-1-(((1s,3S)-3-hydroxy-3-methylcyclobutyl)amino)-1- oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)carbamate (2.2 g, 5.3 mmol) in DCM (84 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness in vacuo to give (R)-2-amino-N-((1s,3S)-3- hydroxy-3-methylcyclobutyl)-3-(4-(trifluoromethyl)phenyl)propanamide hydrochloride as a white solid. MS (ESI): mass calcd. for C15H19F3N2O2, 316.1; m / z found, 317.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 8.81 - 8.72 (m, 1H), 8.36 (br s, 3H), 7.69 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 5.03 (br s, 1H), 3.96 (br s, 1H), 3.73 (qd, J = 7.9, 15.9 Hz, 1H), 3.11 (br d, J = 6.9 Hz, 2H), 2.25 - 2.08 (m, 2H), 1.97 - 1.87 (m, 1H), 1.73 - 1.66 (m, 1H), 1.20 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ = -60.87 (s).

[0281] Step C: (R)-2-((2-Chloro-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-((1s,3S)-3-hydroxy-3-methylcyclobutyl)- 3-(4-(trifluoromethyl)phenyl)propanamide. A mixture of (2,4-dichloro-6-(2,3,6- trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone (200 mg, 343 µmol), Et3N (420 mg, 4.15 mmol), and (R)-2-amino-N-((1s,3S)-3-hydroxy- 3-methylcyclobutyl)-3-(4-(trifluoromethyl)phenyl)propanamide hydrochloride (500 mg, 1.41 mmol) in DCM (3 mL) was stirred at 45 °C overnight under N2. The mixture was diluted with DCM (20 mL) and washed with sat. aq. NaHCO3(10 mL) and H2O (5 mL). The aqueous phase was extracted with ethyl acetate (5 mL × 2). The combined extract was dried with anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, gradient elution: 0 – 70% EtOAc in DCM) to give (R)-2-((2-chloro-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)- 6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-((1s,3S)-3-hydroxy-3- methylcyclobutyl)-3-(4-(trifluoromethyl)phenyl)propanamide as a white solid. MS (ESI): mass calcd. for C44H46ClF3N6O5S, 862.3; m / z found, 863.4 [M+H]+.

[0282] Step D: (R)-N-((1s,3S)-3-Hydroxy-3-methylcyclobutyl)-2-((2-hydroxy-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide. To a mixture of (R)-2-((2-chloro-8- (4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin- 4-yl)amino)-N-((1s,3S)-3-hydroxy-3-methylcyclobutyl)-3- (4- (trifluoromethyl)phenyl)propanamide (40 mg, 31 µmol), benzaldehyde oxime (4.8 mg, 40µmol), and Cs2CO3(24 mg, 74 µmol) in DMF (1.6 mL) was added Rockphos Pd G3(2.4 mg, 2.9 µmol) under N2. The mixture was stirred at 80 °C overnight, then cooled down to room temperature. The reaction mixture was filtered over Celite®, and the solid was rinsed with ethyl acetate (10 mL). The filtrate was washed with 3% aq. LiCl (5 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. It was purified by preparative reverse-phase HPLC (Stationary phase: Phenomenex C18, 3 µm, 80 x 40 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) - MeCN (B), gradient elution: 50 - 80% B in A over 7 min, flow rate: 25 mL / min) to give the title compound as a white powder. MS (ESI): mass calcd. for C44H47F3N6O6S, 844.3; m / z found, 845.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 9.95 (br s, 1H), 8.46 (br d, J = 6.5 Hz, 1H), 8.37 (br d, J = 8.0 Hz, 1H), 8.13 (br d, J = 6.3 Hz, 1H), 7.68 (d, J = 9.0 Hz, 2H), 7.62 - 7.52 (m, 4H), 7.34 (d, J = 4.3 Hz, 1H), 7.18 - 6.99 (m, 4H), 5.02 (s, 2H), 3.83 - 3.65 (m, 2H), 3.53 (br s, 2H), 3.46 - 3.41 (m, 2H), 3.26 - 3.20 (m, 2H), 3.18 - 3.12 (m, 2H), 3.08 (s, 3H), 2.30 - 2.18 (m, 5H), 2.06 - 1.83 (m, 8H), 1.22 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ = -60.74 (br s). Example 22: (R)-2-((2-Hydroxy-8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(6- (trifluoromethyl)pyridin-3-yl)propanamide.

[0283] Step A: (R)-2-((2-Chloro-8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(6- (trifluoromethyl)pyridin-3-yl)propanamide. A mixture of (2,4-dichloro-6-(2,3,6- trimethylphenyl)quinazolin-8-yl)(4-(6-(methylsulfonyl) pyridin-3-yl)piperidin-1- yl)methanone (Example 37, product from Step C, 200 mg, 343 µmol), Et3N (400 mg, 3.95 mmol), and (R)-2-amino-N-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propanamidehydrochloride (Intermediate 11, 390 mg, 1.38 mmol) in DCM (2 mL) was stirred at 45 °C overnight under N2. The mixture was diluted with DCM (20 mL), then washed with sat. aq. NaHCO3(10 mL) and H2O (20 mL). The aqueous phrase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were dri...

Claims

What is claimed:

1. A compound of Formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1is selected from: H, C1-4alkyl, NH2, NH(CH3), N(CH3)2, NH-CH2CH2N(CH3)2, OH, hydroxy substituted C1-4alkyl, OCH3, CH2OCH3, OCF2H, SCH3, SO2CH3, SO2- cyclopropyl, CN, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 4-methylpiperazin-1-yl, and ; R2is , wherein L is absent, CH(CH3) or CH2; Rais phenyl or pyridyl, wherein each phenyl or pyridyl is optionally substituted with one or two members each independently selected from C1-4alkyl, fluorinated-C1-4alkyl, O- fluorinated-C1-4alkyl, NH2, CH2NH2, NH-C(=O)-C2-5alkenyl, NH-C(=O)-C2-5alkynyl, , and ; Rbis , hydroxy substituted C1-4alkyl, or fluorinated-C1-4alkyl;Rfis selected from: CH3; CD3; CH2CH2N(CH3)2; and (CH2)0-1-C3-4cycloalkyl, wherein the C3-4cycloalkyl is optionally substituted with one or two members each independently selected from OH, C1-4alkyl, fluorinated-C1-4alkyl, and hydroxy substituted C1-4alkyl; and Rcis H or CH3; R3is selected from: a 4 to 14 membered nitrogen linked heterocyclyl selected from the group consisting of: monocyclic heterocycloalkyl; spiro-cyclic heterocycloalkyl, bridged heterocycloalkyl or fused heterocycloalkyl; wherein each monocyclic heterocycloalkyl, spiro-cyclic heterocycloalkyl, bridged heterocycloalkyl, and fused heterocycloalkyl contains at least one N atom, optionally containing one, two, or three additional heteroatoms independently selected from N, O, and S; and is optionally substituted with one, two, three or four members each independently selected from: hydroxy, oxo, halo, (=N)-CH3, C1-4alkyl, C1-4alkyl substituted with OH, fluorinated-C1-4alkyl, OC1-4alkyl, CH2- C(=O)-NH(CH3), CH2C(=O)-NH2, C(=O)CH3, SO2-CH3, CH2-SO2-CH3, NH2, N(CH3)2, C(=O)OCH3, C(=O)N(CH3)2, (P=O)(CH3)2, C3-6cycloalkyl, , ,R4is selected from: H, C1-4alkyl, hydroxy substituted C1-4alkyl, -OCH3, and -C(=O)-NH- CH2-Rd; wherein Rdis a (CH2)0-2C3-8cycloalkyl optionally substituted with one, two or three members independently selected from halo and C1-4alkyl; or (CH2)0-2heterocyclyl, wherein each heterocyclyl is selected from: monocyclic heterocycloalkyl, spiro-cyclic heterocycloalkyl, bridged heterocycloalkyl, and fused heterocycloalkyl, each optionally substituted with one, two or three members independently selected from halo and C1-4alkyl; and R5is selected from: Cl, F, C1-4alkyl, fluorinated-C1-4alkyl, hydroxy substituted C1-4alkyl, and CN; or wherein R4and R5come together to form a heterocycloalkyl ring wherein -R4-R5- is -CH2N(CH3)CH2CH2-.

2. The compound of Claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1is H, CH3, CH2CH3, CH(CH3)2, CH2OH, CH2OCH3, NH2, NH(CH3), N(CH3)2, OH, OCH3, OCF2H, SCH3, SO2CH3, CN, NH-CH2CH2N(CH3)2, SO2- cyclopropyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 4-methylpiperazin-1-yl, or .

3. The compound of Claim 1 or Claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: (i) R3is: or (ii) R3is: (iii) R3is:

4. The compound of Claim 1 or Claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein (i) R3is(iii) R3is5. The compound of any one of Claims 1-4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

6. The compound of any one of Claims 1-5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: L is absent.

7. The compound of any one of Claims 1-5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: L is CH2or CH(CH3).

8. The compound of any one of Claims 1-7, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Rais 9. The compound of any one of Claims 1-8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Rbis 10. A compound selected from the group consisting of: (R)-N-(Methyl-d3)-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-N-Methyl-2-((2-methyl-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)- 6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide;(R)-2-((6-(2,5-Dimethylphenyl)-2-methyl-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((2-Ethyl-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-[[6-(2,5-Dimethylphenyl)-2-isopropyl-8-[4-(4- methylsulfonylphenyl)piperazine-1-carbonyl]quinazolin-4-yl]amino]-N-methyl-3-[4- (trifluoromethyl)phenyl]propanamide; (R)-2-((2-Amino-6-(2,5-dimethylphenyl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-N-Methyl-2-((2-(methylamino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((2-(Dimethylamino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)- 6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-(2-(Dimethylamino)-4-((3-hydroxy-3-methyl-1-(6-(trifluoromethyl)pyridin-3- yl)butan-2-yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone; (R)-2-((2-((2-(Dimethylamino)ethyl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)-N-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)propanamide; (R)-2-((2-Hydroxy-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((2-Hydroxy-8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1-carbonyl)-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide;(R)-(2-Hydroxy-4-((3-hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan-2- yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone; (R)-(2-Hydroxy-4-((3-hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan-2- yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(6-(methylsulfonyl)pyridin-3- yl)piperidin-1-yl)methanone; (R)-(2-Hydroxy-4-((3-hydroxy-3-methyl-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2- yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone; (R)-2-((8-((*R)-2,2-Dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8-carbonyl)-2- hydroxy-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-(1- (trifluoromethyl)cyclopropyl)-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((8-((*S)-2,2-Dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8-carbonyl)-2- hydroxy-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-(1- (trifluoromethyl)cyclopropyl)-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((2-Hydroxy-8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1-carbonyl)-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-(1-(trifluoromethyl)cyclopropyl)-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-N-((1s,3S)-3-Hydroxy-3-methylcyclobutyl)-2-((2-hydroxy-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((2-Hydroxy-8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1-carbonyl)-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(6-(trifluoromethyl)pyridin-3- yl)propanamide; (R)-2-((2-Hydroxy-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(6-(trifluoromethyl)pyridin-3- yl)propanamide; (2R)-2-((8-(2,2-Dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8-carbonyl)-2- hydroxy-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide;((*R)-2,2-Dioxidohexahydropyrazino[2,1-c][1,4]thiazin-8(1H)-yl)(2-hydroxy-4- (((R)-3-hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-6-(2,3,6- trimethylphenyl)quinazolin-8-yl)methanone; ((*S)-2,2-Dioxidohexahydropyrazino[2,1-c][1,4]thiazin-8(1H)-yl)(2-hydroxy-4- (((R)-3-hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-6-(2,3,6- trimethylphenyl)quinazolin-8-yl)methanone; (R)-2-((2-(Hydroxymethyl)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)- 6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(3-Chloro-2,6-dimethylphenyl)-2-hydroxy-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((2-methoxy-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-(4-((3-Hydroxy-3-methyl-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-yl)amino)- 2-methoxy-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone; (R)-2-((2-(Methoxymethyl)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)- 6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-(4-((3-Hydroxy-3-methyl-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-yl)amino)- 2-(methoxymethyl)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone; (R)-(2-(difluoromethoxy)-4-((3-hydroxy-3-methyl-1-(4- (trifluoromethyl)phenyl)butan-2-yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone; (R)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-2- (methylthio)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-(6-(trifluoromethyl)pyridin- 3-yl)propanamide;(R)-N-Methyl-2-((2-(methylsulfonyl)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-N-methyl-2-((2-(methylsulfonyl)-8-(4-(6-(methylsulfonyl)pyridin-3- yl)piperidine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-N-methyl-2-((2-(methylsulfonyl)-8-(4-(6-(methylsulfonyl)pyridin-3- yl)piperidine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-(4-((3-Hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-2- (methylsulfonyl)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone; (R)-2-((2-(Cyclopropylsulfonyl)-8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((2-Cyano-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(6-(trifluoromethyl)pyridin-3- yl)propenamide; (R)-4-((3-Hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-8-(4- (4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazoline-2- carbonitrile; (R)-4-((3-Hydroxy-3-methyl-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-yl)amino)-8- (4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazoline-2-carbonitrile; (2R)-2-[[6-(2,5-Dimethylphenyl)-8-[4-(4-methylsulfonylphenyl)piperazine-1- carbonyl]-2-tetrahydropyran-3-yl-quinazolin-4-yl]amino]-N-methyl-3-[4- (trifluoromethyl)phenyl]propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide;(R)-N-methyl-2-((2-(4-methylpiperazin-1-yl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)-3-(6-(trifluoromethyl)pyridin-3-yl)propanamide; (R)-(4-((3-Hydroxy-3-methyl-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-yl)amino)- 2-(morpholinomethyl)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone; (R)-(4-((3-Fluoro-3-methyl-1-(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-6- (2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1- yl)methanone; (*S)-(4-((2-Hydroxy-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)-6-(2,3,6- trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone; (*R)-(4-((2-Hydroxy-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)-6-(2,3,6- trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone; (*S)-(4-((2-Hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)amino)-6- (2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1- yl)methanone; (*R)-(4-((2-Hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)amino)-6- (2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1- yl)methanone; (4-(((3*S,4*RS)-2-Hydroxy-2-methyl-4-(4-(trifluoromethyl)phenyl)pentan-3- yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone; (4-(((3*R,4*RS)-2-hydroxy-2-methyl-4-(4-(trifluoromethyl)phenyl)pentan-3- yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone; (R)-(4-((3-Hydroxy-3-methyl-1-(4-(trifluoromethyl)phenyl)butan-2-yl)amino)-6- (2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1- yl)methanone; (R)-(4-((3-Hydroxy-3-methyl-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-yl)amino)- 6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1- yl)methanone;(4-((1-Hydroxy-2-methyl-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-6-(2,3,6- trimethylphenyl)quinazolin-8-yl)(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)methanone; (2R)-N-Cyclobutyl-2-((6-(2,5-dimethylphenyl)-8-(4-(1-methyl-2-oxopiperidin-4- yl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-N-((1s,3S)-3-Hydroxy-3-methylcyclobutyl)-2-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-(4-((1-(2-Amino-4-(trifluoromethyl)phenyl)-3-hydroxy-3-methylbutan-2- yl)amino)-6-(2,3,6-trimethylphenyl)quinazolin-8-yl)(4-(4- (methylsulfonyl)phenyl)piperazin-1-yl)methanone; (R)-3-(3-Amino-5-(trifluoromethyl)pyridin-2-yl)-N-methyl-2-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)propanamide; (R)-3-(2-Amino-6-(trifluoromethyl)pyridin-3-yl)-N-methyl-2-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)propanamide; (R)-N-(2-(3-(Methylamino)-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-oxopropyl)-5- (trifluoromethyl)phenyl)acrylamide; (R)-N-(2-(3-Hydroxy-3-methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)butyl)-5- (trifluoromethyl)phenyl)acrylamide; (R)-N-(3-(3-(Methylamino)-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-oxopropyl)-6- (trifluoromethyl)pyridin-2-yl)acrylamide; (*S)-2-(3-(Aminomethyl)-4-(trifluoromethyl)phenyl)-N-methyl-2-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)acetamide;(*R)-2-(3-(Aminomethyl)-4-(trifluoromethyl)phenyl)-N-methyl-2-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)acetamide; (*R)-N-(5-(2-(Methylamino)-1-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-2-oxoethyl)-2- (trifluoromethyl)benzyl)acrylamide; (*S)-N-(5-(2-(Methylamino)-1-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-2-oxoethyl)-2- (trifluoromethyl)benzyl)acrylamide; (*R)-N-(5-(2-(Methylamino)-1-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-2-oxoethyl)-2- (trifluoromethyl)phenyl)acrylamide; (*S)-N-(5-(2-(Methylamino)-1-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-2-oxoethyl)-2- (trifluoromethyl)phenyl)acrylamide; (*S)-3-(Diethylamino)-N-(5-(2-(methylamino)-1-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)-2-oxoethyl)-2-(trifluoromethyl)benzyl)propenamide; (*R)-3-(Diethylamino)-N-(5-(2-(methylamino)-1-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)-2-oxoethyl)-2-(trifluoromethyl)benzyl)propenamide; (*R)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)piperazin-1-yl)piperidine-1-carbonyl)-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-2-(6-(trifluoromethyl)pyridin-3- yl)acetamide; (*S)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)piperazin-1-yl)piperidine-1-carbonyl)-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-2-(6-(trifluoromethyl)pyridin-3- yl)acetamide; (*R)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-2-(6-(trifluoromethyl)pyridin-3-yl)acetamide; (*S)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-2-(6-(trifluoromethyl)pyridin-3-yl)acetamide;(*S)-N-(2-(Dimethylamino)ethyl)-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-2-(6-(trifluoromethyl)pyridin-3- yl)acetamide; (*R)-N-(2-(Dimethylamino)ethyl)-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-2-(6-(trifluoromethyl)pyridin-3- yl)acetamide; (*S)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-2-(4-(2,2,2-trifluoroethyl)phenyl)acetamide; (*R)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-2-(4-(2,2,2-trifluoroethyl)phenyl)acetamide; (*S)-2-((*R)-6-Fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methyl-2-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)acetamide; (*S)-2-((*S)-6-Fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methyl-2-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)acetamide; (*R)-2-((*R)-6-Fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methyl-2-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)acetamide; (*R)-2-((*S)-6-Fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methyl-2-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)acetamide; (*R)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-2-(quinolin-6-yl)acetamide; (*S)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-2-(quinolin-6-yl)acetamide; (R)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-3-(4-(2,2,2-trifluoroethyl)phenyl)propanamide; (R)-3-(6-Isopropylpyridin-3-yl)-N-methyl-2-((8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4- yl)amino)propanamide;(R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(4-(methylsulfonyl)phenyl)-3-oxopiperazine- 1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-N-Methyl-2-((8-(4-(4-(methylsulfonyl)phenyl)-3-oxopiperazine-1-carbonyl)-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4 (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2-(Hydroxymethyl)-3,6-dimethylphenyl)-8-(octahydropyrazino[2,1- c][1,4]oxazine-8-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(2,2-Dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8-carbonyl)-6-(2- (hydroxymethyl)-3,6-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-(9,9-Dioxido-1-oxa-9-thia-4-azaspiro[5.5]undecane-4-carbonyl)-6-(2- (hydroxymethyl)-3,6-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2-(Hydroxymethyl)-3,6-dimethylphenyl)-8-(4-(6-(methylsulfonyl)pyridin- 3-yl)piperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2-(Hydroxymethyl)-3,6-dimethylphenyl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2-(Hydroxymethyl)-3,6-dimethylphenyl)-8-(4-(4- (methylsulfonyl)phenyl)-3-oxopiperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3- (4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2-Methoxy-3,6-dimethylphenyl)-8-(octahydropyrazino[2,1- c][1,4]oxazine-8-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(2,2-Dioxidooctahydropyrazino[2,1-c][1,4]thiazine-8-carbonyl)-6-(2- methoxy-3,6-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide;(R)-2-((8-(9,9-Dioxido-1-oxa-9-thia-4-azaspiro[5.5]undecane-4-carbonyl)-6-(2- methoxy-3,6-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2-Methoxy-3,6-dimethylphenyl)-8-(4-(6-(methylsulfonyl)pyridin-3- yl)piperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2-Methoxy-3,6-dimethylphenyl)-8-(4-(4-(methylsulfonyl)phenyl)-3- oxopiperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(3-(2,2-Difluoroethyl)-2,6-dimethylphenyl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,7-Dimethyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; N-((2,2-Difluoro-1-methylcyclopropyl)methyl)-3,6-dimethyl-2-(4-(((R)-1- (methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide; (R)-N-((3,3-Difluorocyclobutyl)methyl)-3,6-dimethyl-2-(4-((1-(methylamino)-1-oxo- 3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide; (R)-N-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3,6-dimethyl-2-(4-((1- (methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide; N-(2-(2,2-Difluoro-1-methylcyclopropyl)ethyl)-3,6-dimethyl-2-(4-(((R)-1- (methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide; (R)-3,6-Dimethyl-2-(4-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-6-yl)-N-((1-(trifluoromethyl)cyclopropyl)methyl)benzamide;N-((2,2-Difluoro-1-methylcyclopentyl)methyl)-3,6-dimethyl-2-(4-(((R)-1- (methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide; (R)-N-((4,4-Dimethylcyclohexyl)methyl)-3,6-dimethyl-2-(4-((1-(methylamino)-1- oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide; (R)-N-((4,4-Difluorocyclohexyl)methyl)-3,6-dimethyl-2-(4-((1-(methylamino)-1- oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide; (R)-3,6-Dimethyl-2-(4-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-6-yl)-N-((1-methylcycloheptyl)methyl)benzamide; (R)-N-(Bicyclo[2.2.2]octan-1-ylmethyl)-3,6-dimethyl-2-(4-((1-(methylamino)-1- oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide; (R)-3,6-Dimethyl-2-(4-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-6-yl)-N-((5-methylspiro[2.3]hexan-5-yl)methyl)benzamide; (R)-N-(Bicyclo[2.2.1]heptan-1-ylmethyl)-3,6-dimethyl-2-(4-((1-(methylamino)-1- oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide; 3,6-Dimethyl-2-(4-(((R)-1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-6-yl)-N-((1-methylazetidin-2-yl)methyl)benzamide; 3,6-Dimethyl-2-(4-(((R)-1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-6-yl)-N-(((R)-1-methylazetidin-2-yl)methyl)benzamide; 3,6-Dimethyl-2-(4-(((R)-1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-6-yl)-N-((1-methylpyrrolidin-2-yl)methyl)benzamide;N-(((R)-4,4-Difluoro-1-methylpyrrolidin-2-yl)methyl)-3,6-dimethyl-2-(4-(((R)-1- (methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide; 3,6-Dimethyl-2-(4-(((R)-1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-6-yl)-N-((1-methylpyrrolidin-3-yl)methyl)benzamide; N-((1,3-Dimethylpyrrolidin-3-yl)methyl)-3,6-dimethyl-2-(4-(((R)-1-(methylamino)- 1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide; 3,6-Dimethyl-2-(4-(((R)-1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-6-yl)-N-(((S)-1-methylpiperidin-3-yl)methyl)benzamide; (R)-3,6-Dimethyl-2-(4-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-6-yl)-N-((1-methylpiperidin-4-yl)methyl)benzamide; 3,6-Dimethyl-2-(4-(((R)-1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-6-yl)-N-((1-methylpiperidin-3-yl)methyl)benzamide; (R)-3,6-Dimethyl-2-(4-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-6-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide; N-((1,4-Dimethylpiperazin-2-yl)methyl)-3,6-dimethyl-2-(4-(((R)-1-(methylamino)- 1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide; 3,6-Dimethyl-2-(4-(((R)-1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-6-yl)-N-((4-methylmorpholin-3-yl)methyl)benzamide; N-((1,4-Diazabicyclo[2.2.2]octan-2-yl)methyl)-3,6-dimethyl-2-(4-(((R)-1- (methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide;(R)-3,6-Dimethyl-2-(4-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)quinazolin-6-yl)-N-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl)benzamide; (R)-3,6-Dimethyl-N-((2-methyl-2-azabicyclo[2.1.1]hexan-1-yl)methyl)-2-(4-((1- (methylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-6-yl)benzamide; (R)-2-((6-(3-(Hydroxymethyl)-2,6-dimethylphenyl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(3-(Difluoromethyl)-2,6-dimethylphenyl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propenamide (*R atropisomer); (R)-2-((6-(3-(Difluoromethyl)-2,6-dimethylphenyl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propenamide (*S atropisomer); (R)-2-((6-(3-Chloro-2,6-dimethylphenyl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(3-Fluoro-2,6-dimethylphenyl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(3-Cyano-2,6-dimethylphenyl)-8-(4-(4- (methylsulfonyl)phenyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(oxetan-3-yl)azetidine-1-carbonyl)quinazolin- 4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(1,1-dioxidoisothiazolidin-2-yl)azetidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(4-(oxetan-3-yl)piperazin-1-yl)azetidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide;(2R)-2-((8-(2,4-Bis(hydroxymethyl)pyrrolidine-1-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-dimethylphenyl)-8-((3*S,4*R)-3-hydroxy-4-(2-(methylamino)-2- oxoethyl)pyrrolidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(3-hydroxyazetidin-1-yl)pyrrolidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-hydroxy-[1,3'-bipyrrolidine]-1'- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(1-methylpiperidin-4-yl)pyrrolidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(3-(4-Acetylpiperazin-1-yl)-4-methylpyrrolidine-1-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-(4-hydroxytetrahydro-2H-pyran-3- yl)pyrrolidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(1-methyl-1H-imidazol-2-yl)pyrrolidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-hydroxy-4-(hydroxymethyl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(4-hydroxy-3-(hydroxymethyl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-((methylsulfonyl)methyl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-methyl-4-((methylsulfonyl)methyl)piperidine- 1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((8-(4-(Dimethylamino)-4-ethylpiperidine-1-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide;(2R)-2-((8-(4-Amino-3,3-difluoropiperidine-1-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide trifluoroacetate salt; (R)-2-((8-((3*S,4*R)-3,4-dihydroxy-3-methylpiperidine-1-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; Methyl (3*S,4*R)-1-(6-(2,5-dimethylphenyl)-4-(((R)-1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carbonyl)-3,4- dihydroxypiperidine-2-carboxylate; Methyl (2*R,3*S,4*R)-1-(6-(2,5-dimethylphenyl)-4-(((R)-1-(methylamino)-1-oxo-3- (4-(trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carbonyl)-3,4- dihydroxypiperidine-2-carboxylate; methyl 1-(6-(2,5-Dimethylphenyl)-4-(((R)-1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carbonyl)-3,4- dihydroxypiperidine-4-carboxylate; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-((methylsulfonyl)ethynyl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-((methylsulfonyl)methyl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(Trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-methyl-3-((methylsulfonyl)methyl)piperidine- 1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(1,1-dioxidoisothiazolidin-2-yl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-((1,1-dioxidotetrahydrothiophen-3- yl)amino)piperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-((1,1-dioxidotetrahydro-2H-thiopyran-4- yl)amino)piperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(4-(methylsulfonyl)piperazin-1-yl)piperidine- 1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide;(2R)-2-((6-(2,5-Dimethylphenyl)-8-(4-hydroxy-3-(4-(methylsulfonyl)piperazin-1- yl)piperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(4-(methylsulfonyl)piperazin-1-yl)-4- oxopiperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(3-(1H-Imidazol-1-yl)-4-methylpiperidine-1-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; 1-(6-(2,5-Dimethylphenyl)-4-(((R)-1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carbonyl)-N,N-dimethyl-3-(1- methyl-1H-pyrazol-5-yl)piperidine-4-carboxamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(3-hydroxy-3-methylpyrrolidin-1- yl)piperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(1,1-dioxidoisothiazolidin-2-yl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(1,1-dioxido-1,2,5-thiadiazolidin-2- yl)piperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4- yl)piperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; rac-(2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-((4-methylpiperazin-1- yl)methyl)morpholine-4-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(4-(methylsulfonyl)piperazin-1-yl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-hydroxy-4-(4-(methylsulfonyl)piperazin-1- yl)piperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide;(2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-fluoro-4-(4-(methylsulfonyl)piperazin-1- yl)piperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(3,3-Difluoro-4-(4-(methylsulfonyl)piperazin-1-yl)piperidine-1- carbonyl)-6-(2,5-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamidede; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-((1-(methylsulfonyl)piperidin-4- yl)amino)piperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(3,3-Difluoro-4-((1-(methylsulfonyl)piperidin-4-yl)amino)piperidine-1- carbonyl)-6-(2,5-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4- yl)amino)-3,3-difluoropiperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-((*R)-4-((1,1-dioxidotetrahydro-2H-thiopyran-4- yl)amino)-3,3-difluoropiperidine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(1-methyl-1H-imidazol-5-yl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((8-((*R)-3,3-Difluoro-4-(pyridin-3-yl)piperidine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-((*S)-3,3-Difluoro-4-(pyridin-3-yl)piperidine-1-carbonyl)-6-(2,3,6- trimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-((*S)-3,3-Difluoro-4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1- carbonyl)-6-(2,5-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide;(R)-2-((8-((*R)-3,3-Difluoro-4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1- carbonyl)-6-(2,5-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-N-Methyl-2-((8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1-carbonyl)-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(6-(methylsulfonyl)pyridin-3-yl)piperidine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-N-Methyl-2-((8-(4-(5-(methylsulfonyl)pyridin-2-yl)piperidine-1-carbonyl)-6- (2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(6-(methylsulfonyl)-1',2',3',6'-tetrahydro-[3,4'- bipyridine]-1'-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(5'-fluoro-6-(methylsulfonyl)-1',2',3',6'- tetrahydro-[3,4'-bipyridine]-1'-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(1-oxidothiomorpholine-4-carbonyl)quinazolin-4- yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(piperazine-1-carbonyl)quinazolin-4-yl)amino)- N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-(2-hydroxyethyl)-4-methylpiperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(2-hydroxypropyl)-3-methylpiperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(2-hydroxypropyl)-2-methylpiperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-((R)-3-(hydroxymethyl)-5-oxopiperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(1,1-dioxidotetrahydrothiophen-3- yl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide;(2R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(2-hydroxy-2-(tetrahydrofuran-2- yl)ethyl)piperazine-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(tetrahydro-2H-pyran-3-yl)piperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(4-((1,4-Dioxan-2-yl)methyl)piperazine-1-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(6-(methylamino)pyridin-3-yl)piperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(5-(methylamino)pyridin-2-yl)piperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((8-(4-(5-(Dimethylamino)pyridin-2-yl)piperazine-1-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-(4-(6-(Dimethylamino)pyridin-3-yl)piperazine-1-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(4-sulfamoylphenyl)piperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-N-Methyl-2-((8-(4-(6-(methylsulfonyl)pyridin-3-yl)-3-oxopiperazine-1- carbonyl)-6-(2,3,6-trimethylphenyl)quinazolin-4-yl)amino)-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(2-(pyridin-4-yl)acetyl)piperazine-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(morpholine-4-carbonyl)quinazolin-4-yl)amino)- N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-(hydroxymethyl)-5-methylmorpholine-4- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-(1-hydroxyethyl)morpholine-4- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide;(2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-((R)-1-hydroxyethyl)morpholine-4- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-(dimethylphosphoryl)morpholine-4- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-((methylsulfonyl)methyl)morpholine-4- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(2-(2-Amino-2-oxoethyl)morpholine-4-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-(oxetan-2-yl)morpholine-4- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-(tetrahydrofuran-3-yl)morpholine-4- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-((4-methylpiperazin-1-yl)methyl)morpholine- 4-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(2-(1H-Imidazol-2-yl)morpholine-4-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(2-(1H-Pyrazol-5-yl)morpholine-4-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(2-hydroxypropyl)-1,4-diazepane-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(4-(1-hydroxypropan-2-yl)-1,4-diazepane-1- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(1,1-dioxido-1,2,5-thiadiazepane-5- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(1,1-dioxido-1,2,8-thiadiazecane-8- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(1,1-dioxido-1,2,7-thiadiazonane-7- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propenamide;(R)-2-((6-(2,5-Dimethylphenyl)-8-(2-oxido-2-thia-6-azaspiro[3.3]heptane-6- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(1,1-dioxido-1-thia-6-azaspiro[3.3]heptane-6- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((8-(6-Cyclopropyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-(6-Acetyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(2-oxa-8-azadispiro[3.1.36.14]decane-8- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((8-((7*R,8*R)-7,8-dihydroxy-5-oxa-2-azaspiro[3.4]octane-2-carbonyl)-6- (2,5-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-(6-Acetyl-2,6-diazaspiro[3.4]octane-2-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(6,6-dioxido-6-thia-2-azaspiro[3.4]octane-2- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(6,6-dioxido-6-thia-2-azaspiro[3.5]nonane-2- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((8-((7*R,8*S)-7,8-dihydroxy-5-oxa-2-azaspiro[3.5]nonane-2-carbonyl)-6- (2,5-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(7-(oxetan-3-yl)-2,7-diazaspiro[3.5]nonane-2- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(2-methyl-2,6-diazaspiro[3.4]octane-6- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(2-(methylsulfonyl)-2,6-diazaspiro[3.4]octane-6- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide;(R)-2-((6-(2,5-Dimethylphenyl)-8-(2,2-dioxido-2-thia-6-azaspiro[3.4]octane-6- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2,2-dioxido-2-thia-7-azaspiro[4.4]nonane-7- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(8,8-dioxido-8-thia-2-azaspiro[4.5]decane-2- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(8-(hydroxymethyl)-2-oxa-6- azaspiro[3.4]octane-6-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(8-fluoro-8-(hydroxymethyl)-2-oxa-6- azaspiro[3.4]octane-6-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-2-oxa-6- azaspiro[3.4]octane-6-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(8-(3-(methoxymethyl)-1,2,4-oxadiazol-5-yl)-2- oxa-6-azaspiro[3.4]octane-6-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(8,9-Dihydroxy-6-oxa-2-azaspiro[4.5]decane-2-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-(8-(Cyanomethyl)-2,8-diazaspiro[4.5]decane-2-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonane-7- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(2,2-dioxido-2-thia-8-azaspiro[4.5]decane-8- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2,2-dioxido-2-thia-7-azaspiro[4.5]decane-7- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide;(2R)-2-((6-(2,5-Dimethylphenyl)-8-(2,2-dioxido-6-oxa-2-thia-9- azaspiro[4.5]decane-9-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(9,9-dioxido-1-oxa-9-thia-4- azaspiro[5.5]undecane-4-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4,4-dioxido-1-oxa-4-thia-9- azaspiro[5.5]undecane-9-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(9-(methylimino)-9-oxido-1-oxa-9l6-thia-4- azaspiro[5.5]undecane-4-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(2-oxa-7-azaspiro[3.5]nonane-7- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(1,5-dioxa-9-azaspiro[5.5]undecane-9- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((8-((3*R,4*R)-3,4-dihydroxy-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)-6- (2,5-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-((3*R,4*S)-3,4-dihydroxy-9-oxa-1-azaspiro[5.5]undecane-1-carbonyl)-6- (2,5-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2,6-dioxa-9-azaspiro[4.5]decane-9- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(1,9-dioxa-4-azaspiro[5.5]undecane-4- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(6-ethyl-2-oxa-6,9-diazaspiro[4.5]decane-9- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(fluoromethyl)-9-oxo-4,8-dioxa-1,10- diazaspiro[5.5]undecane-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide;(2R)-2-((6-(2,5-Dimethylphenyl)-8-(2,2-dioxido-6-oxa-2-thia-9- azaspiro[4.6]undecane-9-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(3,3-dioxido-7-oxa-3-thia-10- azaspiro[5.6]dodecane-10-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(8-oxo-2-oxa-5,9-diazaspiro[3.6]decane-5- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((8-((3a*R,6a*S)-5-acetyloctahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-dimethylphenyl)-8-((3a*R,6a*S)-5,5-dioxidohexahydro-1H- thieno[3,4-b]pyrrole-1-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-dimethylphenyl)-8-((3a*R,6a*S)-3a-methyl-2,2-dioxidohexahydro- 1H-thieno[3,4-c]pyrrole-5-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-dimethylphenyl)-8-((3aR,6aS)-3a-methyl-2,2-dioxidohexahydro-1H- thieno[3,4-c]pyrrole-5-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-dimethylphenyl )-8-((3R,3a*R,6a*S)-3-methoxy-1,1- dioxidohexahydro-2H-thieno[2,3-c]pyrrole-5-carbonyl)quinazolin-4-yl)amino)-N-methyl- 3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-oxooctahydro-1H-pyrrolo[3,4-b]pyridine-6- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(5-(Dimethylamino)octahydro-1H-isoindole-2-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((8-(5,6-Dihydroxyoctahydro-1H-isoindole-2-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide;(R)-2-((6-(2,5-dimethylphenyl)-8-((3a*R,7a*S)-7a-(hydroxymethyl)-5- methyloctahydro-1H-pyrrolo[3,4-c]pyridine-2-carbonyl)quinazolin-4-yl)amino)-N-methyl- 3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-((7R,8aS)-7-hydroxyoctahydropyrrolo[1,2- a]pyrazine-2-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-methyloctahydropyrrolo[1,2-a]pyrazine-2- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-dimethylphenyl)-8-((4a*R,7a*S)-6,6-dioxidohexahydro-2H- thieno[3,4-b][1,4]oxazine-4-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2,2-dioxidooctahydrothieno[3,4-c]pyridine-5- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2,2-dioxidooctahydropyrazino[2,1- c][1,4]thiazine-8-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(octahydropyrazino[2,1-c][1,4]oxazine-8- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(2-oxodecahydro-1,6-naphthyridine-6- carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; Methyl (R)-6-(6-(2,5-dimethylphenyl)-4-(((R)-1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carbonyl)-5,6,7,8-tetrahydro- 1,6-naphthyridine-7-carboxylate; Methyl (R)-7-(6-(2,5-dimethylphenyl)-4-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carbonyl)-5,6,7,8-tetrahydro- 2,7-naphthyridine-1-carboxylate; (R)-2-((6-(2,5-Dimethylphenyl)-8-(4-methoxy-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidine-6-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide;Methyl (R)-7-(6-(2,5-dimethylphenyl)-4-((1-(methylamino)-1-oxo-3-(4- (trifluoromethyl)phenyl)propan-2-yl)amino)quinazoline-8-carbonyl)-5,6,7,8-tetrahydro- 1,7-naphthyridine-3-carboxylate; (R)-2-((6-(2,5-Dimethylphenyl)-8-(3-ethyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[3,4- d]pyrimidine-7-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(2-methyl-1-oxo-4-(trifluoromethyl)-1,2,5,6,7,8- hexahydropyrido[3,4-d]pyridazine-6-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(trifluoromethyl)-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(hydroxymethyl)-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(2,2-dioxido-5,6,7,8-tetrahydro-3H-pyrido[4,3- c][1,2,6]thiadiazine-6-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-(2-morpholino-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidine-6-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-(3-(1,4-Oxazepan-4-yl)-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine-6- carbonyl)-6-(2,5-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(8-methyl-6,6-dioxido-1,2,3,4,4a,5- hexahydrobenzo[b]pyrazino[1,2-d][1,4]thiazine-3-carbonyl)quinazolin-4-yl)amino)-N- methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((6-(2,5-Dimethylphenyl)-8-((1S,2R,4S)-2-oxido-2-thia-5- azabicyclo[2.2.1]heptane-5-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide;(R)-2-((6-(2,5-Dimethylphenyl)-8-((1S,4S)-2,2-dioxido-2-thia-5- azabicyclo[2.2.1]heptane-5-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-((1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-6-(2,5- dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-((1*R,4*R,5*R,6*S)-5,6-dihydroxy-2-azabicyclo[2.2.1]heptane-2- carbonyl)-6-(2,5-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(3-(1,1-dioxidoisothiazolidin-2-yl)-8- azabicyclo[3.2.1]octane-8-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (2R)-2-((6-(2,5-Dimethylphenyl)-8-(6,6-dioxido-6-thia-3-azabicyclo[3.2.1]octane- 3-carbonyl)quinazolin-4-yl)amino)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide; (R)-2-((8-(Dihydro-1H,3H,4H-3a,6a-(methanooxymethano)furo[3,4-c]pyrrole-5- carbonyl)-6-(2,5-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; (R)-2-((8-((1*R,2*R,3*S,5*S)-2,3-dihydroxy-8-azabicyclo[3.2.1]octane-8- carbonyl)-6-(2,5-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3-(4- (trifluoromethyl)phenyl)propanamide; and (R)-2-((8-((3aR,4S,5S,6R,7R,7aS)-5,6-Dihydroxyoctahydro-1H-4,7- methanoisoindole-2-carbonyl)-6-(2,5-dimethylphenyl)quinazolin-4-yl)amino)-N-methyl-3- (4-(trifluoromethyl)phenyl)propanamide; or a stereoisomer or pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any one of Claims 1-10.

12. A pharmaceutical composition made by mixing a compound of any one of Claims 1-10 and a pharmaceutically acceptable carrier.

13. A process for making a pharmaceutical composition comprising mixing a compound of any one of Claims 1-10 and a pharmaceutically acceptable carrier.

14. A method of treating a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is a leukemia or a lymphoma, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of Claims 1-10.

15. The method of Claim 14, 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).

16. The method of Claim 14, wherein the leukemia is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

17. The method of Claim 14, 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 celllymphoma, 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.

18. The method of Claim 14, wherein the lymphoma is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

19. The use of the compound of any one of Claims 1-10 for the preparation of a medicament for the treatment a cancer mediated by the BFL-1 protein, wherein the cancer mediate by the BFL-1 protein is (a) a leukemia, or (b) a lymphoma, in a subject in need thereof.

20. The use as in Claim 19, 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).

21. The use as in Claim 19, 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, (l) 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.

22. The compound of any one of Claims 1-10, for use in a method for the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 proteinis (a) a leukemia or (b) a lymphoma, in a subject in need thereof.

23. The compound of any one of Claims 1-10, for use in a method for the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is (a) acute lymphoblastic leukemia (ALL), (b) acute myeloid leukemia (AML), (c) (acute) T-cell leukemia, (d) acute monocytic leukemia, (e) acute promyelocytic leukemia (APL), (f) bisphenotypic B myelomonocytic leukemia, (g) chronic myeloid leukemia (CML), (h) chronic myelomonocytic leukemia (CMML), (i) large granular lymphocytic leukemia, (j) plasma cell leukemia, or (k) myelodysplastic syndrome (MDS) 24. The compound of any one of Claims 1-10, for use in a method for the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is (a) AIDS-related lymphoma, (b) Hodgkin lymphoma, (c) non-Hodgkin's lymphoma (NHL), (d) T-non-Hodgkin lymphoma (T-NHL), (e) Diffuse Large Cell Lymphoma (DLBCL), (f) activated B-cell DLBCL, (g) germinal center B-cell DLBCL, (h) double-hit lymphoma, (i) double-expressor lymphoma, (j) anaplastic large cell lymphoma, (k) marginal B cell lymphoma, (l) 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.

25. The compound of any one of Claims 1-10, for use as a medicament.

26. The compound of any one of Claims 1-10, for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is (a) a leukemia or (b) a lymphoma, in a subject in need thereof.

27. The compound of any one of Claims 1-10, for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is (a) acute lymphoblastic leukemia (ALL), (b) acute myeloid leukemia (AML), (c) (acute) T- cell leukemia, (d) acute monocytic leukemia, (e) acute promyelocytic leukemia (APL), (f) bisphenotypic B myelomonocytic leukemia, (g) chronic myeloid leukemia (CML), (h) chronic myelomonocytic leukemia (CMML), (i) large granular lymphocytic leukemia, (j) plasma cell leukemia, or (k) myelodysplastic syndrome (MDS) 28. The compound of any one of Claims 1-10, for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is (a)AIDS-related lymphoma, (b) Hodgkin lymphoma, (c) non-Hodgkin's lymphoma (NHL), (d) T-non-Hodgkin lymphoma (T-NHL), (e) Diffuse Large Cell Lymphoma (DLBCL), (f) activated B-cell DLBCL, (g) germinal center B-cell DLBCL, (h) double-hit lymphoma, (i) double-expressor lymphoma, (j) anaplastic large cell lymphoma, (k) marginal B cell lymphoma, (l) 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.

29. A composition comprising a compound of any one of Claims 1-10, for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is (a) a leukemia or (b) a lymphoma.

30. A composition comprising a compound of any one of Claims 1-10, for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is (a) acute lymphoblastic leukemia (ALL), (b) acute myeloid leukemia (AML), (c) (acute) T-cell leukemia, (d) acute monocytic leukemia, (e) acute promyelocytic leukemia (APL), (f) bisphenotypic B myelomonocytic leukemia, (g) chronic myeloid leukemia (CML), (h) chronic myelomonocytic leukemia (CMML), (i)large granular lymphocytic leukemia, (j) plasma cell leukemia, or (k) myelodysplastic syndrome (MDS) 31. A composition comprising a compound of any one of Claims 1-10, for use in the treatment of a cancer mediated by the BFL-1 protein, wherein the cancer mediated by the BFL-1 protein is (a) AIDS-related lymphoma, (b) Hodgkin lymphoma, (c) non- Hodgkin's lymphoma (NHL), (d) T-non-Hodgkin lymphoma (T-NHL), (e) Diffuse Large Cell Lymphoma (DLBCL), (f) activated B-cell DLBCL, (g) germinal center B-cell DLBCL, (h) double-hit lymphoma, (i) double-expressor lymphoma, (j) anaplastic large cell lymphoma, (k) marginal B cell lymphoma, (l) 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 compound, composition, method of treatment or method of preparation as herein described.

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