WDR5 inhibitors and modulators

Abstract

Isoquinolinone compounds and derivatives inhibit WDR5 and associated protein-protein interactions, and the compounds and pharmaceutical compositions thereof are useful for treating disorders and conditions, such as cancer cell proliferation, in a subject.

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 184,904, filed May 6, 2021, which is incorporated by reference herein in its entirety.

[0002] Government Interest Statement This invention was made with Federal support awarded by the National Institutes of Health under Contract No. HHSN261200800001E. The Federal Government has certain rights in this invention.

[0003] Technical Field The present invention generally relates to compounds that inhibit the binding of transcription factors, regulators and chromatin to WDR5, and methods of using the same. In certain embodiments, the present invention provides compositions that include imino-azacyclic-benzamide compounds that inhibit or modulate the interaction of WDR5 with chromatin, cognate transcripts and other regulators, including histone methyltransferase MLL1, for the treatment of leukemia, solid cancer and other diseases that depend on the activity of WDR5, and methods of using the same. [Background technology]

[0004] Mixed lineage leukemia (MLL) represents a heterogeneous group of acute myeloid and acute lymphoblastic leukemias with characteristics of more than one hematopoietic cell lineage. MLL accounts for approximately 80% of acute leukemia cases in young children (Tomizawa, D.; et. al. Leukemia, 2007, 21, 2258-63.) and 10% of all acute leukemia cases (Marschalek, R. Br. J. Haematol. 2011, 152, 141-54.). Patients with MLL leukemia have a poor prognosis, with an overall 5-year survival rate of approximately 35% (Dimartino, JF; Cleary, ML, Br. J. Haematol. 1999, 106, 614-626; Pui, C., et al. Leukemia, 2003, 4, 700-706.; Tomizawa, D.; et. al. Leukemia, 2007, 21, 2258-63.).

[0005] MLL is composed of heterogeneous cell lineages with different molecular, cell biological and immunological characteristics. However, MLL shares common features, including chromosomal rearrangements of the mixed lineage leukemia (MLL) gene. The MLL gene is located on chromosome 11q23, and the encoded MLL protein is a homolog of Drosophila trithorax (Trx) (Thachuk, DC; et al. Cell, 1992, 71, 691-700.). Wild-type MLL binds to the regulatory regions of homeobox (HOX) genes through its amino-terminal fragment (Milne, TA; et al. Cancer Res., 2005, 65, 11367-74.), while its catalytic C-terminal domain catalyzes histone 3 lysine 4 (H3K4) methylation through interaction with WDR5, upregulating target gene transcription (Nakamura, T.; et al. Mol. Cell, 2002, 10, 1119-28; Yokoyama, A. et al. Mol. Cell Biol., 2004, 24, 5639-49.; Milne, TA; et al. Mol. Cell, 2002, 10, 1107-17). Wild-type MLL together with WDR5 is required for the maintenance of HOX gene expression and is widely expressed not only during embryonic development but also in adult tissues, including bone marrow and lymphoid cells (Yu, BD; et al. Proc. Natl. Acad. Sci., 1998, 95, 10632-10636.). Reciprocal translocations of MLL genes result in an in-frame fusion of the 5'-end MLL with the 3'-end of another partner gene. A common feature of MLL1 abnormalities in leukemia is the preservation of one of the wild-type MLL1 alleles. Recently, more than 80 partner genes have been identified, with MLL-AF4, MLL-AF9 and MLL-ENL being the three most frequently found fusion genes (Pui, C., et al. Leukemia, 2003, 4, 700-706, which is incorporated herein by reference in its entirety).Expression of MLL fusion proteins promotes overexpression of target genes such as HOXA9 and MEIS1, which blocks differentiation, enhances blast proliferation, and ultimately leads to leukemic transformation (Caslini, C.; et al. Cancer Res., 2007, 67, 7275-83., Yokoyama, A.; et al. Cell, 2005, 123, 207-18.). Numerous chromosomal translocations of MLL genes and partner genes further complicate MLL leukemia treatment. HOX9 and MEIS1 overexpression are commonly observed among MLL leukemia patients, but individual rearrangements lead to distinct dysregulated target gene expression patterns and downstream events (Slany, RK, Haematologica, 2009, 94, 984-993). Clinical studies have revealed that different MLL chromosomal translocations are associated with different prognoses and, under current protocols, treatment differs (Tamai, H., et al. J. Clin. Exp. Hematop., 2010, 50, 91-98; Balgobind, BV, et al. Leukemia, 2011, 8, 1239-1248; Pigazzi, M.; et al. Leukemia, 2011, 25, 560-563).

[0006] The intrinsic histone methyltransferase (HMT) activity of MLL1 is remarkably low and requires the complex assembly of WDR5, RbBP5, ASH2L and DPY30 protein partners, the so-called WRAD complex, for effective H3K4 trimethylation (Patel, A.; et al. J. Biol. Chem., 2009, 284, 24242-56). Binding of MLL1 to WDR5 (WD40 repeat protein 5) is particularly important for HMT activity and occurs through a conserved arginine-containing motif in MLL1 called the "Win" or WDR5 interaction motif. Thus, targeted inhibitors of the MLL1-WDR5 interaction at the WIN site to block MLL1 methyltransferase activity represent a promising therapeutic strategy for treating MLL leukemia patients. A peptide mimetic was discovered that tightly binds to WDR5 at the MLL site, inhibits MLL1 methyltransferase activity, and blocks MLL1 cell proliferation by inducing cell cycle arrest, apoptosis, and myeloid differentiation (Cao, F.; et al. Molecular Cell, 2014, 53, 247-61., Karatas, H.; et al. J. Med. Chem., 2017, 60, 4818-4839.). Furthermore, altered gene expression patterns similar to MLL1 deletion have been observed, supporting a role for MLL1 activity in regulating MLL1-dependent leukemia transcription. Thus, blocking WDR5-MLL1 interaction may be a useful strategy to treat patients with MLL leukemia. In addition to the well-characterized WDR5-MLL1 interaction, disruption of WDR5 by other transcription factors / epigenetic writers, or displacement from chromatin itself, may have desirable benefits as a cancer treatment strategy.For example, WDR5 binds to histone H3 (through the R2 residue, see e.g., Song, J.-J., et al. J. Biol. Chem. 2008, 283, 35258-64), NSL / MOF (Li, X., et al. Molecular and Cellular Biology, 2010, 30, 5335-47.; Dias, J., et al. Genes & Development, 2014, 28, 929-942.), C / EBPα p30 (Senisterra, G., et al. Biochem. J., 2013, 449, 151-159.), c-MYC (Thomas, LR; et al. Molecular Cell, 2015, 58, 102-104, which are incorporated by reference in their entirety). 440-52.) and NuRD complex (Ee, L.-S., et al. Stem Cell Reports, 2017, 8, 1488-96.). In addition, WDR5 expression levels have been reported to correlate and be associated with patient prognosis in several other cancer types, including neuroblastoma (Sun, Y. et al. Cancer Research, 2015, 75, 5143-54.), breast cancer (Dai, X. et al. PLoSOne, 2015, 10, PMC4565643), bladder cancer (Chen, X. et al. Scientific Reports, 2015, 5, 8293.) and colorectal cancer (Tan, X. et al. Cell Death & Disease, 2017, 8, PMC5386518). Furthermore, in an unbiased shRNA screen in human xenografts, WDR5 was identified as a key target in pancreatic cancer (Carugo, A. et al. Cell Reports, 2016, 16, 133-147.). Based on the growing number of identified complexes that utilize WDR5 to maintain tumor fitness and growth, the emerging importance of WDR5 in several cancer types is not unexpected.In the case of the c-MYC-WDR5 interaction, the MYC oncoprotein utilizes a molecularly defined interaction with WDR5 to bind to its target genes on chromatin. MYC is overexpressed in the majority of malignant tumors and contributes to an estimated 70,000-100,000 cancer deaths per year in the United States. Thus, disruption of WDR5 from chromatin as a strategy to displace MYC from its target genes could provide a beneficial strategy to treat MYC-driven tumors. Summary of the Invention

[0007] The molecules described herein can inhibit or modulate the interaction of WDR5 with chromatin, cognate transcripts and other regulators, including, for example, the histone methyltransferase MLL1, and can provide therapeutic approaches to treat cancers associated with such interactions (e.g., MLL1-WDR5 interactions).

[0008] In one aspect, the present invention provides a compound of formula (I):

[0009] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, G 1 teeth,

[0010] [ka]

[0011] [ka] and R 10a is hydrogen, fluoro, chloro, C 1~3 Alkyl or C 1~3 is a fluoroalkyl; R 10b is hydrogen, fluoro, chloro, C1~3 Alkyl, C 1~3 Fluoroalkyl, C 3~6 Cycloalkyl, NH 2 , -NHC 1~4 Alkyl, -N(C 1~4 Alkyl) 2 or a 4-8 membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of N, O and S, wherein the heterocyclyl is selected from halogen, cyano, oxo, C 1~4 Alkyl, C 1~4 Fluoroalkyl, OH, -OC 1~4 Alkyl, -OC 1~4 Fluoroalkyl, NH 2 , -NHC 1~4 Alkyl and -N(C 1~4 Alkyl) 2 and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: R 10c is independently for each occurrence fluoro, chloro, C 1~3 Alkyl or C 1~3 is a fluoroalkyl; R 10d X 1 , -L 1 -X 1 , hydrogen, halogens, C 1~4 Alkyl, C 1~4 Fluoroalkyl, G 1a or -L 1 -G 1a and R 10e is halogen, cyano, C 1~4 Alkyl, C 1~4 Fluoroalkyl, OH, -OC 1~4 Alkyl, -OC 1~4 Fluoroalkyl, -OG 1c , -OC 1~3 Alkylene-G 1c , -OC 2~3 Alkylene-Y, NH 2 , -NHC 1~4 Alkyl, -N(C 1~4 Alkyl) 2or a 4-8 membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of N, O and S, wherein the heterocyclyl is selected from halogen, cyano, oxo, C 1~4 Alkyl, C 1~4 Fluoroalkyl, OH, -OC 1~4 Alkyl, -OC 1~4 Fluoroalkyl, NH 2 , -NHC 1~4 Alkyl and -N(C 1~4 Alkyl) 2 and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: R 10f is independently for each occurrence a halogen, cyano, C 1~4 Alkyl, C 1~4 Fluoroalkyl, OH, -OC 1~4 Alkyl, -OC 1~4 Fluoroalkyl, -OC 3~4 Cycloalkyl, -OC 1~3 Alkylene-C 3~4 Cycloalkyl, -OPG or -OSO 2 CF 3 and R 10g is hydrogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 3~4 Cycloalkyl or -C 1~3 Alkylene-C 3~4 is cycloalkyl, m is 0 or 1; n is 0, 1 or 2; PG is a hydroxy protecting group; L 1 is C 1~3 is alkylene, X 1 is -C(O)N(R 1a ) 2 , -OR 1a , -N(R 1a ) 2 , cyano, -C(O)OR 1a , -C(O)R 1b , -SO 2 R1b , -SO 2 N(R 1a ) 2 , -NR 1a C(O)H or -NR 1a C(O)R 1b and R 1a are independently defined for each occurrence as hydrogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, -C 2~3 Alkylene-OR 1e , -C 2~3 Alkylene-N(R 1e ) 2 , -C 2~3 Alkylene-N(R 1e )C(O)R 1e , G 1a or -C 1~3 Alkylene-G 1a and R 1b independently for each occurrence, C 1~4 Alkyl, C 1~4 Fluoroalkyl, -C 1~3 Alkylene-OR 1e , -C 1~3 Alkylene-N(R 1e ) 2 , -C 1~3 Alkylene-N(R 1e )C(O)R 1e , G 1a or -C 1~3 Alkylene-G 1a and G 1a independently for each occurrence, C 3~8 cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 8-membered heterocyclyl; G 1a is a halogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, oxo, -L 2 -X 2 and -L 2 -G 1b and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: L 2 is, for each occurrence independently, a bond or C1~3 is alkylene, X 2 is, independently for each occurrence, -OR 1c , -N(R 1c ) 2 , -SR 1c , cyano, -C(O)OR 1c , -C(O)N(R 1c ) 2 , -C(O)R 1c , -SOR 1d , -SO 2 R 1d , -SO 2 N(R 1c ) 2 , -NR 1c C(O)R 1c , -NR 1c C(O)OR 1c , -NR 1c C(O)N(R 1c ) 2 , -NR 1c S(O) 2 R 1d or -NR 1c S(O) 2 N(R 1c ) 2 and R 1c are independently defined for each occurrence as hydrogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, G 1b or -C 1~3 Alkylene-G 1b Alternatively, two R 1c This R 1c Together with the common nitrogen atom to which it is bonded, C 1~4 Alkyl, C 1~4 Fluoroalkyl, oxo, -OH and -OC 1~4 forming a 4-8 membered saturated or partially unsaturated heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; R 1d independently for each occurrence, C 1~4 Alkyl, C 1~4 Fluoroalkyl, G 1b or -C 1~3 Alkylene-G1b and R 1e are independently defined for each occurrence as hydrogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, G 1b or -C 1~3 Alkylene-G 1b Alternatively, two R 1e This R 1e Together with the common nitrogen atom to which it is bonded, C 1~4 Alkyl, C 1~4 Fluoroalkyl, oxo, -OH and -OC 1~4 forming a 4-8 membered saturated or partially unsaturated heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; G 1b independently for each occurrence, C 3~6 cycloalkyl, 4-6 membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from O, N and S, 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, or phenyl; 1b is halogen, cyano, C 1~4 Alkyl, C 1~4 Fluoroalkyl, oxo, -OH and -OC 1~4 and optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, Y is OH, -OC 1~4 Alkyl, -OC 1~4 Fluoroalkyl, -OC 3~4 Cycloalkyl or -OC 1~3 Alkylene-C 3~4 is cycloalkyl, G 1c is C 3~6 cycloalkyl, 4-7 membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from O, N and S, or 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S; 1c is halogen, cyano, C 1~4 Alkyl, C1~4 Fluoroalkyl, oxo, -OH, -OC 1~4 Alkyl, C 3~4 Cycloalkyl and -C 1~3 Alkylene-C 3~4 cycloalkyl; G 2 is a 5-6 membered heteroaryl or phenyl; G 2 is C 1~6 Alkyl, C 1~6 Haloalkyl, halogen, -OR 4c , -N(R 4c ) 2 , cyano, -C(O)OR 4c , -C(O)N(R 4c ) 2 , -C(O)R 4c , -SO 2 R 4d , -SO 2 N(R 4c ) 2 , -NR 4c C(O)R 4c , C 3~8 Cycloalkyl and -C 1~3 Alkylene-C 3~8 Optionally substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyl, C 3~8 Each cycloalkyl is C 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl and halogen; R 4c are independently defined for each occurrence as hydrogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 3~8 Cycloalkyl or -C 1~6 Alkylene-C 3~8 Cycloalkyl, C 3~8 Each cycloalkyl is C 1~4 Optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl and halogen, alternatively, two R 4c This R 4cTogether with the common nitrogen atom to which it is bonded, C 1~4 Alkyl, C 1~4 Fluoroalkyl, oxo, -OH and -OC 1~4 forming a 4-8 membered saturated or partially unsaturated heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; R 4d independently for each occurrence, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 3~8 Cycloalkyl or -C 1~6 Alkylene-C 3~8 Cycloalkyl, C 3~8 Each cycloalkyl is C 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl and halogen; R 5 and R 6 are each independently hydrogen, halogen, or C 1~4 Alkyl, C 1~4 Fluoroalkyl or -OC 1~4 is alkyl, R 8 is unsubstituted imidazolyl or halogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, NO 2 , N.H. 2 , -NH(C 1~4 alkyl), -N(C 1~4 Alkyl) 2 , C 3~8 Cycloalkyl and -C 1~3 Alkylene-C 3~8 imidazolyl substituted by 1 to 3 substituents independently selected from the group consisting of cycloalkyl, 3~8 Cycloalkyl is halogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, OH and -OC 1~4 and optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl. wherein the compound is selected from the group consisting of: 7-((1H-imidazol-1-yl)methyl)-2-(6-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-methoxy-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; ((S)-7-((1H-imidazol-1-yl)methyl)-2-(6-chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-methoxycinnolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2-(5,6,7,8-tetrahydroquinolin-5-yl)-3,4-dihydroisoquinolin-1(2H)-one; 2-(3-methoxy-5,6,7,8-tetrahydroquinolin-5-yl)-7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; (S)-2-(3-methoxy-5,6,7,8-tetrahydroquinolin-5-yl)-7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; (S)-7-((1H-imidazol-1-yl)methyl)-2-(3-methoxy-5,6,7,8-tetrahydroquinolin-5-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; ((S)-7-((1H-imidazol-1-yl)methyl)-2-(6-chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; or a pharma- ceutically acceptable salt thereof.

[0012] In another aspect, the present invention provides a compound of formula (I):

[0013] [ka] or a pharma- ceutically acceptable salt thereof, G 1 teeth,

[0014] [ka] and R 10d X 1 , hydrogen, halogens, C 1~4 Alkyl, C 1~4 Fluoroalkyl or G 1a and R 10f is halogen, cyano, C 1~4 Alkyl, C 1~4 Fluoroalkyl, OH, -OC 1~4 Alkyl, -OC 1~4 Fluoroalkyl, -OC 3~4 Cycloalkyl, -OC 1~3 Alkylene-C 3~4 Cycloalkyl, -OPG or -OSO 2 CF 3 and PG is a hydroxy protecting group; X 1 is -C(O)N(R 1a ) 2 , -OR 1a , -N(R 1a ) 2 , cyano, -C(O)OR 1a , -C(O)R 1b , -SO 2 R 1b , -SO 2 N(R 1a ) 2 , -NR 1a C(O)H or -NR 1a C(O)R 1b and R 1a are independently defined for each occurrence as hydrogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, -C 2~3 Alkylene-OR 1e , -C 2~3 Alkylene-N(R 1e ) 2 , -C 2~3 Alkylene-N(R 1e )C(O)R 1e , G 1a or -C 1~3 Alkylene-G 1a and R 1b independently for each occurrence, C 1~4 Alkyl, C 1~4 Fluoroalkyl, -C 1~3 Alkylene-OR 1e , -C 1~3 Alkylene-N(R 1e ) 2 , -C 1~3 Alkylene-N(R 1e )C(O)R 1e , G 1a or -C 1~3 Alkylene-G 1a and G 1a independently for each occurrence, C 3~8 cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 8-membered heterocyclyl; G 1a is a halogen, C1~4 Alkyl, C 1~4 Fluoroalkyl, oxo, -L 2 -X 2 and -L 2 -G 1b and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: L 2 is, for each occurrence independently, a bond or C 1~3 is alkylene, X 2 is, independently for each occurrence, -OR 1c , -N(R 1c ) 2 , -SR 1c , cyano, -C(O)OR 1c , -C(O)N(R 1c ) 2 , -C(O)R 1c , -SOR 1d , -SO 2 R 1d , -SO 2 N(R 1c ) 2 , -NR 1c C(O)R 1c , -NR 1c C(O)OR 1c , -NR 1c C(O)N(R 1c ) 2 , -NR 1c S(O) 2 R 1d or -NR 1c S(O) 2 N(R 1c ) 2 and R 1c are independently defined for each occurrence as hydrogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, G 1b or -C 1~3 Alkylene-G 1b Alternatively, two R 1c This R 1c Together with the common nitrogen atom to which it is bonded, C 1~4 Alkyl, C 1~4 Fluoroalkyl, oxo, -OH and -OC1~4 forming a 4-8 membered saturated or partially unsaturated heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; R 1d independently for each occurrence, C 1~4 Alkyl, C 1~4 Fluoroalkyl, G 1b or -C 1~3 Alkylene-G 1b and R 1e are independently defined for each occurrence as hydrogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, G 1b or -C 1~3 Alkylene-G 1b Alternatively, two R 1e This R 1e Together with the common nitrogen atom to which it is bonded, C 1~4 Alkyl, C 1~4 Fluoroalkyl, oxo, -OH and -OC 1~4 forming a 4-8 membered saturated or partially unsaturated heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; G 1b independently for each occurrence, C 3~6 cycloalkyl, 4-6 membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from O, N and S, 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, or phenyl; 1b is halogen, cyano, C 1~4 Alkyl, C 1~4 Fluoroalkyl, oxo, -OH and -OC 1~4 and optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, G 2 is a 5-6 membered heteroaryl; G 2 is C 1~4 Alkyl, C 1~4 Fluoroalkyl, halogen, -OR 4c , -N(R 4c) 2 , cyano, -C(O)OR 4c , -C(O)N(R 4c ) 2 , -C(O)R 4c , -SO 2 R 4d , -SO 2 N(R 4c ) 2 , -NR 4c C(O)R 4c , C 3~8 Cycloalkyl and -C 1~3 Alkylene-C 3~8 Optionally substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyl, C 3~8 Each cycloalkyl is C 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl and halogen; R 4c are independently defined for each occurrence as hydrogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 3~8 Cycloalkyl or -C 1~6 Alkylene-C 3~8 Cycloalkyl, C 3~8 Each cycloalkyl is C 1~4 Optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl and halogen, alternatively, two R 4c This R 4c Together with the common nitrogen atom to which it is bonded, C 1~4 Alkyl, C 1~4 Fluoroalkyl, oxo, -OH and -OC 1~4 forming a 4-8 membered saturated or partially unsaturated heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; R 4d independently for each occurrence, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 3~8 Cycloalkyl or -C 1~6 Alkylene-C 3~8Cycloalkyl, C 3~8 Each cycloalkyl is C 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl and halogen; R 5 and R 6 are each independently hydrogen, halogen, or C 1~4 Alkyl, C 1~4 Fluoroalkyl or -OC 1~4 is alkyl, R 8 teeth,

[0015] [ka] is) wherein the compound is provided that it is not 2-(6-methoxy-8-methylquinolin-4-yl)-7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one or a pharma- ceutically acceptable salt thereof.

[0016] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0017] In another aspect, the present invention provides a method of treating cancer, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt or composition thereof.

[0018] In another aspect, the present invention provides a method for inhibiting binding of MLL1 to WDR5, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt or composition thereof.

[0019] In another aspect, the present invention provides a compound of formula (I), or a pharma- ceutically acceptable salt or composition thereof, for use in the treatment of cancer.

[0020] In another aspect, the invention provides a compound of formula (I), or a pharma- ceutically acceptable salt or composition thereof, for use in inhibiting the binding of MLL1 to WDR5.

[0021] In another aspect, the present invention provides the use of a compound of formula (I), or a pharma- ceutically acceptable salt or composition thereof, in the manufacture of a medicament for the treatment of cancer.

[0022] In another aspect, the invention provides the use of a compound of formula (I), or a pharma- ceutically acceptable salt or composition thereof, in the manufacture of a medicament for inhibiting binding of MLL1 to WDR5.

[0023] In another aspect, the invention provides a kit comprising a compound of formula (I), or a pharma- ceutically acceptable salt or composition thereof, and instructions for use. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Detailed Description Disclosed herein is an inhibitor of WDR5 that binds to WDR5 interaction site or WIN site.The inhibitor can be a compound of formula (I).The compound of formula (I) can be used to treat cancer associated with MLL1-WDR5 interaction.In one embodiment, the compound of formula (I) is disclosed as an inhibitor of WDR5-WIN site.

[0025] 1.Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. In case of conflict, the present specification, including definitions, will prevail. Although preferred methods and materials are described below, methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods and examples disclosed herein are merely illustrative and are not intended to be limiting.

[0026] The terms "comprise(s)", "include(s)", "having", "has", "can", "contain(s)", and variations thereof, as used herein, are intended to be open-ended transitional phrases, terms or words that do not exclude the possibility of additional acts or configurations. The singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments that "comprising", "consisting of" and "consisting essentially of" the embodiments or elements presented herein, whether or not explicitly described.

[0027] The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., it includes at least the degree of error associated with measuring the particular quantity). The modifier "about" should also be considered as disclosing a range defined by the absolute values ​​of the two endpoints. For example, the phrase "about 2 to about 4" also discloses a range of "2 to 4". The term "about" can refer to plus or minus 10% of the indicated number. For example, "about 10%" can indicate a range of 9% to 11%, and "about 1" can mean 0.9 to 1.1. Other meanings of "about" can be apparent from the context, such as rounding, thus, for example, "about 1" can also mean 0.5 to 1.4.

[0028] Definitions of certain functional groups and chemical terms are described in more detail below. For purposes of this disclosure, chemical elements are defined as defined in the Handbook of Chemistry and Physics, 75 th The functional groups are generally defined as described herein in accordance with the Periodic Table of the Elements (CAS version) of the Periodic Table of the Elements, Ed., and specific functional groups are generally defined as described herein. Further, general principles of organic chemistry, as well as specific functional group moieties and reactivities, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999, Smith and March March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987. The entire contents of each of the above are incorporated herein by reference.

[0029] The term "alkoxy" as used herein refers to an alkyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy.

[0030] The term "alkyl" as used herein means a straight or branched chain saturated hydrocarbon. The terms "lower alkyl" or "C 1~6 "Alkyl" means a straight or branched chain hydrocarbon containing 1 to 6 carbon atoms. 1~4 "Alkyl" means a straight or branched chain hydrocarbon containing 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0031] The term "alkenyl," as used herein, means a straight or branched chain hydrocarbon containing at least one carbon-carbon double bond.

[0032] The term "alkylene" as used herein refers to a divalent group derived from a straight or branched chain hydrocarbon of, for example, 1 to 6 carbon atoms. Representative examples of alkylene include, but are not limited to, -CH 2 -, -CD 2 -, -CH 2 CH 2 -, -C(CH 3 )(H)-, -C(CH 3 )(D)-, -CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2-, -C(CH 3 ) 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 - and -CH 2 CH 2 CH 2 CH 2 CH 2 -Includes.

[0033] The term "aryl" as used herein refers to phenyl or a phenyl bonded to a parent molecular moiety that is fused to a cycloalkane group (e.g., the aryl can be indan-4-yl), fused to a six-membered arene group (i.e., the aryl can be naphthyl), or fused to a non-aromatic heterocycle (e.g., the aryl can be benzo[d][1,3]dioxol-5-yl). The term "phenyl" is used when referring to a substituent and the term six-membered arene is used when referring to a fused ring. A six-membered arene is a monocyclic ring (e.g., benzene or benzo). An aryl can be monocyclic (phenyl) or bicyclic (e.g., a 9-12 membered fused bicyclic system).

[0034] The term "cycloalkyl" or "cycloalkane" as used herein refers to a saturated ring system containing all carbon atoms as ring members and no double bonds. The term "cycloalkyl" is used herein to refer to cycloalkanes when present as a substituent. Cycloalkyl may be a monocyclic cycloalkyl (e.g., cyclopropyl), a fused bicyclic cycloalkyl (e.g., decahydronaphthalenyl), or a bridged cycloalkyl (e.g., bicyclo[2.2.1]heptanyl) in which two non-adjacent atoms of the ring are connected by an alkylene bridge of 1, 2, 3, or 4 carbon atoms. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclo[1.1.1]pentanyl.

[0035] The term "cycloalkenyl" or "cycloalkene" as used herein means a non-aromatic monocyclic or polycyclic ring system containing all carbon atoms and at least one carbon-carbon double bond as ring members, preferably having 5 to 10 carbon atoms per ring. The term "cycloalkenyl" is used herein to refer to a cycloalkene when present as a substituent. A cycloalkenyl may be a monocyclic cycloalkenyl (e.g., cyclopentenyl), a fused bicyclic cycloalkenyl (e.g., octahydronaphthalenyl), or a bridged cycloalkenyl (e.g., bicyclo[2.2.1]heptenyl) in which two non-adjacent atoms of a ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, or cycloheptenyl.

[0036] The term "carbocyclyl" means "cycloalkyl" or "cycloalkenyl." The term "carbocycle" means "cycloalkane" or "cycloalkene." The term "carbocyclyl," when present as a substituent, refers to a "carbon ring."

[0037] The term "fluoroalkyl" as used herein means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by a fluoro group. Representative examples of fluoroalkyl include CH 2 F, CHF 2 , C.F. 3 and C.H. 2 CHF 2 Includes:

[0038] The term "halogen" or "halo" as used herein means Cl, Br, I or F.

[0039] The term "haloalkyl," as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven, or eight hydrogen atoms are replaced by halogen.

[0040] The term "heteroaryl" as used herein refers to an aromatic monocyclic heteroatom-containing ring (monocyclic heteroaryl) or a bicyclic ring system (bicyclic heteroaryl) containing at least one monocyclic heteroaromatic ring. The term "heteroaryl" is used herein to refer to heteroarenes when present as a substituent. A monocyclic heteroaryl is a 5- or 6-membered ring containing at least one heteroatom independently selected from the group consisting of N, O and S (e.g., 1, 2, 3 or 4 heteroatoms independently selected from O, S and N). A 5-membered aromatic monocyclic ring has two double bonds, and a 6-membered aromatic monocyclic ring has three double bonds. Bicyclic heteroaryls are 8-12 membered ring systems and include fused bicyclic heteroaromatic ring systems (i.e., 10 π electron systems) such as monocyclic heteroaryl rings fused to 6 membered arenes (e.g., quinolin-4-yl, indol-1-yl), monocyclic heteroaryl rings fused to monocyclic heteroarenes (e.g., naphthyridinyl), and phenyls fused to monocyclic heteroarenes (e.g., quinolin-5-yl, indol-4-yl). Bicyclic heteroaryl / heteroarene groups include 9 membered fused bicyclic heteroaromatic ring systems with four double bonds and at least one heteroatom contributing an unpaired electron to a fully aromatic 10 π electron system, such as ring systems with a nitrogen atom at the ring junction (e.g., imidazopyridine) or benzoxadiazolyl. Bicyclic heteroaryl also includes fused bicyclic ring systems composed of one heteroaromatic ring and one non-aromatic ring, such as a monocyclic heteroaryl ring fused to a monocyclic carbocyclic ring (e.g., 6,7-dihydro-5H-cyclopenta[b]pyridinyl) or a monocyclic heteroaryl ring fused to a monocyclic heterocyclic ring (e.g., 2,3-dihydrofuro[3,2-b]pyridinyl). A bicyclic heteroaryl is attached to the parent molecular moiety at an aromatic ring atom.Other representative examples of heteroaryl include, but are not limited to, indolyl (e.g., indol-1-yl, indol-2-yl, indol-4-yl), pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl (e.g., pyrazol-4-yl), pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl (e.g., triazol-4-yl), 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl (e.g., thiazol-4-yl), isothiazolyl, thienyl, benzimidazolyl (e.g., , benzimidazol-5-yl), benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, furanyl, oxazolyl, isoxazolyl, purinyl, isoindolyl, quinoxalinyl, indazolyl (e.g., indazol-4-yl, indazol-5-yl), quinazolinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl, imidazo[1,2-a]pyridinyl (e.g., imidazo[1,2-a]pyridin-6-yl), naphthyridinyl, pyridoimidazolyl, thiazolo[5,4-b]pyridin-2-yl and thiazolo[5,4-d]pyrimidin-2-yl.

[0041] The term "heterocycle" or "heterocyclic" as used herein means a monocyclic heterocycle, a bicyclic heterocycle or a tricyclic heterocycle. The term "heterocyclyl" is used herein to refer to a heterocycle when it is present as a substituent. A monocyclic heterocycle is a 3-, 4-, 5-, 6-, 7- or 8-membered ring containing at least one heteroatom independently selected from the group consisting of O, N and S. A 3- or 4-membered ring contains zero or one double bond and one heteroatom selected from the group consisting of O, N and S. A 5-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. A 6-membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The seven and eight membered rings contain zero, one, two or three double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. Representative examples of monocyclic heterocyclyls include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxoazepan-3-yl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl. , oxetanyl, oxepanyl, oxocanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1,2-thiazinanyl, 1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholinesulfone), thiopyranyl, and trithianyl.A bicyclic heterocycle is a monocyclic heterocycle fused to a 6-membered arene, or a monocyclic heterocycle fused to a monocyclic cycloalkane, or a monocyclic heterocycle fused to a monocyclic cycloalkene, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a monocyclic heterocycle fused to a monocyclic heteroarene, or a spiroheterocyclic group, or a bridged monocyclic heterocyclic ring system in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms or an alkenylene bridge of 2, 3, or 4 carbon atoms. A bicyclic heterocyclyl is attached to the parent molecular moiety at a non-aromatic ring atom (e.g., indolin-1-yl). Representative examples of bicyclic heterocyclyls include, but are not limited to, chroman-4-yl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzothien-2-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 2-azaspiro[3.3]heptan-2-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), azabicyclo[3.1.0]hexanyl (including 3-azabicyclo[3.1.0]hexan-3-yl), 2,3-dihydro-1H-indol-1-yl, isoindolin-2-yl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a 6-membered arene, or a bicyclic heterocycle fused to a monocyclic cycloalkane, or a bicyclic heterocycle fused to a monocyclic cycloalkene, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non-adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms or an alkenylene bridge of 2, 3, or 4 carbon atoms.Examples of tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[b]furan, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane (1-azatricyclo[3.3.1.13,7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13,7]decane). The monocyclic, bicyclic, and tricyclic heterocycles are attached to the parent molecular moiety at a non-aromatic ring atom.

[0042] The term "imino" refers to the group "=NH".

[0043] The terms "alkyl," "cycloalkyl," "alkylene," and the like may be preceded by a designation indicating the number of atoms present in the group at a particular instance (e.g., "C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 These designations are generally used as understood by those of ordinary skill in the art. For example, the designation "C" followed by a subscript number indicates the number of carbon atoms present in the following group. Thus, "C 3 "Alkyl" refers to an alkyl group having three carbon atoms (i.e., n-propyl, isopropyl). 1~4 When a range is given, such as ", the members of the subsequent group may have any number of carbon atoms that fall within the range recited. For example, "C 1~4 "Alkyl" refers to an alkyl group having from 1 to 4 carbon atoms arranged (ie, straight or branched).

[0044] The term "substituted" refers to a group that may be further substituted with one or more non-hydrogen substituents. Substituents may include, for example, halogen, =O (oxo), =S (thioxo), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketone, amide, carbamate, and acyl.

[0045] With regard to the compounds described herein, the groups and substituents may be selected with reference to the permissible valences of atoms and substituents, such that the selection and substitution result in stable compounds that do not spontaneously undergo transformation, for example, by rearrangement, cyclization, elimination, and the like. 2.Compound

[0046] In one embodiment, G 1 , G 2 , R 5 , R 6 and R 8 Disclosed are compounds of formula (I), wherein: 1 , G 2 , R 5 , R 6 and R 8 , as well as any combination thereof.

[0047] Throughout the embodiments and descriptions of the compounds of the present invention, all examples of haloalkyl may also be fluoroalkyl (e.g., any of the C 1~4 Haloalkyl, C 1~4It may be fluoroalkyl.

[0048] The hydroxy protecting group PG is described in PGM Wuts and TW Greene, in Greene's book titled Protective Groups in Organic Synthesis (4 th ed.), John Wiley & Sons, NY (2006), and are well known in the art. Suitable hydroxy protecting groups include, for example, trityl groups (e.g., trityl, dimethoxytrityl, methoxytrityl), acetyl, benzoyl, benzyl, p-methoxybenzyl, β-methoxyethoxymethyl (MEM), methoxymethyl (MOM), methylthiomethyl, pivaloyl, tetrahydropyranyl (THP), tetrahydrofuranyl (THF), silyl (e.g., trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-isopropylsilyloxymethyl (TOM), triisopropylsilyl (TIPS), methyl, and ethoxyethyl.

[0049] An unsubstituted or substituted ring, such as an aryl, heteroaryl, etc., is composed of both the ring system and the optional substituents of the ring system. Thus, the ring system may be defined independently of its substituents, and thus, when only the ring system is redefined, any previously present optional substituents remain. For example, a 5-12 membered heteroaryl having optional substituents can be further defined by specifying that the ring system of the 5-12 membered heteroaryl is a 5-6 membered heteroaryl (i.e., a 5-6 membered heteroaryl ring system), in which case the optional substituents of the 5-12 membered heteroaryl are still present on the 5-6 membered heteroaryl unless otherwise expressly indicated.

[0050] In the following, numbered embodiments of the present invention are disclosed. In the numbered embodiments, references to the scope of the previous embodiment in multiple dependent form are otherwise references to each embodiment recited sequentially herein to the extent recited.

[0051] E1. Compound of formula (I)

[0052] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, G 1 teeth,

[0053] [ka]

[0054] [ka] and R 10a is hydrogen, fluoro, chloro, C 1~3 Alkyl or C 1~3 is a fluoroalkyl; R 10b is hydrogen, fluoro, chloro, C 1~3 Alkyl, C 1~3 Fluoroalkyl, C 3~6 Cycloalkyl, NH 2 , -NHC 1~4 Alkyl, -N(C 1~4 Alkyl) 2 or a 4-8 membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of N, O and S, wherein the heterocyclyl is selected from halogen, cyano, oxo, C 1~4 Alkyl, C 1~4 Fluoroalkyl, OH, -OC 1~4 Alkyl, -OC 1~4 Fluoroalkyl, NH 2 , -NHC 1~4 Alkyl and -N(C 1~4 Alkyl) 2 and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: R 10cis independently for each occurrence fluoro, chloro, C 1~3 Alkyl or C 1~3 is a fluoroalkyl; R 10d X 1 , -L 1 -X 1 , hydrogen, halogens, C 1~4 Alkyl, C 1~4 Fluoroalkyl, G 1a or -L 1 -G 1a and R 10e is halogen, cyano, C 1~4 Alkyl, C 1~4 Fluoroalkyl, OH, -OC 1~4 Alkyl, -OC 1~4 Fluoroalkyl, -OG 1c , -OC 1~3 Alkylene-G 1c , -OC 2~3 Alkylene-Y, NH 2 , -NHC 1~4 Alkyl, -N(C 1~4 Alkyl) 2 or a 4-8 membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of N, O and S, wherein the heterocyclyl is selected from halogen, cyano, oxo, C 1~4 Alkyl, C 1~4 Fluoroalkyl, OH, -OC 1~4 Alkyl, -OC 1~4 Fluoroalkyl, NH 2 , -NHC 1~4 Alkyl and -N(C 1~4 Alkyl) 2 and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: R 10f is independently for each occurrence a halogen, cyano, C 1~4 Alkyl, C 1~4 Fluoroalkyl, OH, -OC 1~4 Alkyl, -OC 1~4 Fluoroalkyl, -OC 3~4 Cycloalkyl, -OC 1~3 Alkylene-C3~4 Cycloalkyl, -OPG or -OSO 2 CF 3 and R 10g is hydrogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 3~4 Cycloalkyl or -C 1~3 Alkylene-C 3~4 is cycloalkyl, m is 0 or 1; n is 0, 1 or 2; PG is a hydroxy protecting group; L 1 is C 1~3 is alkylene, X 1 is -C(O)N(R 1a ) 2 , -OR 1a , -N(R 1a ) 2 , cyano, -C(O)OR 1a , -C(O)R 1b , -SO 2 R 1b , -SO 2 N(R 1a ) 2 , -NR 1a C(O)H or -NR 1a C(O)R 1b and R 1a are independently defined for each occurrence as hydrogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, -C 2~3 Alkylene-OR 1e , -C 2~3 Alkylene-N(R 1e ) 2 , -C 2~3 Alkylene-N(R 1e )C(O)R 1e , G 1a or -C 1~3 Alkylene-G 1a and R 1b independently for each occurrence, C 1~4 Alkyl, C 1~4Fluoroalkyl, -C 1~3 Alkylene-OR 1e , -C 1~3 Alkylene-N(R 1e ) 2 , -C 1~3 Alkylene-N(R 1e )C(O)R 1e , G 1a or -C 1~3 Alkylene-G 1a and G 1a independently for each occurrence, C 3~8 cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 8-membered heterocyclyl; G 1a is a halogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, oxo, -L 2 -X 2 and -L 2 -G 1b and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: L 2 is, for each occurrence independently, a bond or C 1~3 is alkylene, X 2 is, independently for each occurrence, -OR 1c , -N(R 1c ) 2 , -SR 1c , cyano, -C(O)OR 1c , -C(O)N(R 1c ) 2 , -C(O)R 1c , -SOR 1d , -SO 2 R 1d , -SO 2 N(R 1c ) 2 , -NR 1c C(O)R 1c , -NR 1c C(O)OR 1c , -NR 1c C(O)N(R 1c ) 2 , -NR 1c S(O) 2 R 1d or -NR1c S(O) 2 N(R 1c ) 2 and R 1c are independently defined for each occurrence as hydrogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, G 1b or -C 1~3 Alkylene-G 1b Alternatively, two R 1c This R 1c Together with the common nitrogen atom to which it is bonded, C 1~4 Alkyl, C 1~4 Fluoroalkyl, oxo, -OH and -OC 1~4 forming a 4-8 membered saturated or partially unsaturated heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; R 1d independently for each occurrence, C 1~4 Alkyl, C 1~4 Fluoroalkyl, G 1b or -C 1~3 Alkylene-G 1b and R 1e are independently defined for each occurrence as hydrogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, G 1b or -C 1~3 Alkylene-G 1b Alternatively, two R 1e This R 1e Together with the common nitrogen atom to which it is bonded, C 1~4 Alkyl, C 1~4 Fluoroalkyl, oxo, -OH and -OC 1~4 forming a 4-8 membered saturated or partially unsaturated heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; G 1b independently for each occurrence, C 3~6cycloalkyl, 4-6 membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from O, N and S, 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, or phenyl; 1b is halogen, cyano, C 1~4 Alkyl, C 1~4 Fluoroalkyl, oxo, -OH and -OC 1~4 and optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, Y is OH, -OC 1~4 Alkyl, -OC 1~4 Fluoroalkyl, -OC 3~4 Cycloalkyl or -OC 1~3 Alkylene-C 3~4 is cycloalkyl, G 1c is C 3~6 cycloalkyl, 4-7 membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from O, N and S, or 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S; 1c is halogen, cyano, C 1~4 Alkyl, C 1~4 Fluoroalkyl, oxo, -OH, -OC 1~4 Alkyl, C 3~4 Cycloalkyl and -C 1~3 Alkylene-C 3~4 cycloalkyl; G 2 is a 5-6 membered heteroaryl or phenyl; G 2 is C 1~4 Alkyl, C 1~4 Fluoroalkyl, halogen, -OR 4c , -N(R 4c ) 2 , cyano, -C(O)OR 4c , -C(O)N(R 4c ) 2 , -C(O)R 4c , -SO 2R 4d , -SO 2 N(R 4c ) 2 , -NR 4c C(O)R 4c , C 3~8 Cycloalkyl and -C 1~3 Alkylene-C 3~8 Optionally substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyl, C 3~8 Each cycloalkyl is C 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl and halogen; R 4c are independently defined for each occurrence as hydrogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 3~8 Cycloalkyl or -C 1~6 Alkylene-C 3~8 Cycloalkyl, C 3~8 Each cycloalkyl is C 1~4 Optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl and halogen, alternatively, two R 4c This R 4c Together with the common nitrogen atom to which it is bonded, C 1~4 Alkyl, C 1~4 Fluoroalkyl, oxo, -OH and -OC 1~4 forming a 4-8 membered saturated or partially unsaturated heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; R 4d independently for each occurrence, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 3~8 Cycloalkyl or -C 1~6 Alkylene-C 3~8 Cycloalkyl, C 3~8 Each cycloalkyl is C 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl and halogen; R5 and R 6 are each independently hydrogen, halogen, or C 1~4 Alkyl, C 1~4 Fluoroalkyl or -OC 1~4 is alkyl, R 8 is unsubstituted imidazolyl or halogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, NO 2 , N.H. 2 , -NH(C 1~4 alkyl), -N(C 1~4 Alkyl) 2 , C 3~8 Cycloalkyl and -C 1~3 Alkylene-C 3~8 imidazolyl substituted by 1 to 3 substituents independently selected from the group consisting of cycloalkyl, 3~8 Cycloalkyl is halogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, OH and -OC 1~4 and optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl. with the proviso that the compound 7-((1H-imidazol-1-yl)methyl)-2-(6-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-methoxy-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; ((S)-7-((1H-imidazol-1-yl)methyl)-2-(6-chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-methoxycinnolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2-(5,6,7,8-tetrahydroquinolin-5-yl)-3,4-dihydroisoquinolin-1(2H)-one; 2-(3-methoxy-5,6,7,8-tetrahydroquinolin-5-yl)-7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; (S)-2-(3-methoxy-5,6,7,8-tetrahydroquinolin-5-yl)-7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; (S)-7-((1H-imidazol-1-yl)methyl)-2-(3-methoxy-5,6,7,8-tetrahydroquinolin-5-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; ((S)-7-((1H-imidazol-1-yl)methyl)-2-(6-chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; or a pharma- ceutically acceptable salt thereof, a compound of formula (I), or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0055] E1.1.G 1 but,

[0056] [ka]

[0057] [ka] and R 10b is hydrogen, fluoro, chloro, C 1~3 Alkyl or C 1~3 is a fluoroalkyl; R 10d But X 1 , hydrogen, halogens, C 1~4 Alkyl, C 1~4 Fluoroalkyl or G 1a and R 10e But halogen, cyano, C 1~4 Alkyl, C 1~4 Fluoroalkyl, OH, -OC 1~4 Alkyl, -OC 1~4 Fluoroalkyl, -OG 1c , -OC 1~3 Alkylene-G 1c or -OC 2~3 alkylene-Y; G 2 is a 5-6 membered heteroaryl; G 2 is C 1~4 Alkyl, C 1~4 Fluoroalkyl, halogen, -OR 4c , -N(R 4c ) 2 , cyano, -C(O)OR 4c , -C(O)N(R 4c ) 2 , -C(O)R 4c , -SO 2 R 4d , -SO 2 N(R 4c ) 2 , -NR 4c C(O)R 4c , C 3~8 Cycloalkyl and -C 1~3 Alkylene-C 3~8Optionally substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyl, C 3~8 Each cycloalkyl is C 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl and halogen; E1 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0058] E1.2. A compound of E1 or E1.1, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, wherein m is 0.

[0059] E1.3. A compound of E1 or E1.1, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, wherein m is 1.

[0060] E1.4. Any of the compounds according to E1 to E1.3, or tautomers thereof, wherein n is 0, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0061] E1.5. Any of the compounds of E1 to E1.3, wherein n is 1, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0062] E1.6. Any of the compounds of E1 to E1.3, or tautomers thereof, wherein n is 2, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0063] E2.R 8 but,

[0064] [ka] and R 20a But hydrogen, C 1~4 Alkyl, NH 2 , -NH(C 1~4 alkyl), -N(C1~4 Alkyl) 2 or C 3~8 is cycloalkyl, R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h and R 20i are independently hydrogen, C 1~4 Alkyl or C 3~8 is cycloalkyl, Any of the compounds E1 to E1.6 or tautomers thereof, or pharma- ceutically acceptable salts of said compounds or tautomers.

[0065] E3. R 8 but,

[0066] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0067] E3.1. R 8 but,

[0068] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0069] E3.2.R 8 but,

[0070] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0071] E4.G 1 but,

[0072] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0073] E4.1.G 1 but,

[0074] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0075] E4.2.G 1 but,

[0076] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0077] E4.3.R 10b is hydrogen, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0078] E4.4.R 10b But, C 1~3 any of the compounds of E4 to E4.2, or tautomers thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, wherein E4 is alkyl;

[0079] E4.5a.R 10b is methyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0080] E4.5b.R 10bis ethyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0081] E4.6.R 10b But, C 3~6 A compound of any of E4 to E4.2, or a tautomer thereof, which is cycloalkyl, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0082] E4.7.R 10b is cyclopropyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0083] E4.8.R 10b But -NHC 1~4 Alkyl (e.g., -NHCH 3 ) or -N(C 1~4 Alkyl) 2 (For example, -N(CH 3 )CH 2 CH 3 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0084] E4.9.R 10b is optionally substituted 4-8 membered monocyclic heterocyclyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0085] E4.10. Any of the compounds E4-E4.2, or E4.9, or tautomers thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein an optionally substituted 4-8 membered monocyclic heterocyclyl ring system contains at least one ring nitrogen atom and is attached to the parent molecular moiety at at least one ring nitrogen atom (e.g., azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholino, 1,4-oxazepan-4-yl, thiomorpholino, piperazin-1-yl, 1,4-diazepan-1-yl).

[0086] E4.11.R 10b but,

[0087] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0088] E4.12. A compound of any of E4-E4.2 or E4.9, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, wherein an optionally substituted 4-8 membered monocyclic heterocyclyl is attached to the parent molecular moiety at a ring carbon atom.

[0089] E4.13. The compound of E4.12 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, wherein the optionally substituted 4-8 membered monocyclic heterocyclyl ring system contains one ring heteroatom which is oxygen (e.g., oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl).

[0090] E4.14.R 10b but,

[0091] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0092] E4.15.G 1 but,

[0093] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0094] E4.16.G 1 but,

[0095] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0096] E4.17.G 1 but,

[0097] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0098] E4.18.G 1 but,

[0099] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0100] E4.19.G 1 but,

[0101] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0102] E4.20.G 1 but,

[0103] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0104] E4.21.G 1 but,

[0105] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0106] E4.22.G 1 but,

[0107] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0108] E4.23.G 1 but,

[0109] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0110] E4.24.G 1 but,

[0111] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0112] E4.25.G 1 but,

[0113] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0114] E4.26.G 1 but,

[0115] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0116] E4.27.G 1 but,

[0117] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0118] E4.28.G 1 but,

[0119] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0120] E4.29.G 1 but,

[0121] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0122] E4.30.G 1 but,

[0123] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0124] E4.31.G 1 but,

[0125] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0126] E4.32.G 1 but,

[0127] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0128] E4.33.G 1 but,

[0129] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0130] E4.34.G 1 but,

[0131] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0132] E4.35.G 1 but,

[0133] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0134] E4.36.G 1 but,

[0135] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0136] E4.37.G 1 but,

[0137] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0138] E4.38.G 1 but,

[0139] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0140] E4.39.G 1 but,

[0141] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0142] E5.G 1 but,

[0143] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0144] R5.1.G 1 but,

[0145] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0146] E5.2.G 1 but,

[0147] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0148] E5.3.G 1 but,

[0149] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0150] E5.4.G 1 but,

[0151] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0152] E5.5.G 1 but,

[0153] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0154] E5.6.G 1 but,

[0155] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0156] E6.G 1 but,

[0157] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0158] E6.1.G 1 but,

[0159] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0160] E6.2.G 1 but,

[0161] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0162] E6.3.G 1 but,

[0163] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0164] E7.G 1 but,

[0165] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0166] E7.1.G1 but,

[0167] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0168] E7.2.G 1 but,

[0169] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0170] E7.3.G 1 but,

[0171] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0172] E8.G 1 but,

[0173] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0174] E8.1.G 1 but,

[0175] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0176] E8.2.G 1 but,

[0177] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0178] E8.3.G 1 but,

[0179] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0180] E8.4.G 1 but,

[0181] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0182] E8.5.G 1 but,

[0183] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0184] E8.6.G 1 but,

[0185] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0186] E8.7.G 1 but,

[0187] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0188] E8.8.G 1 but,

[0189] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0190] E9.G 1 but,

[0191] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0192] E9.1.G 1 but,

[0193] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0194] E9.2.G 1 but,

[0195] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0196] E9.3.G 1 but,

[0197] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0198] E10. G 1 but,

[0199] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0200] E10.1.G 1 but,

[0201] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0202] E10.2.G 1 but,

[0203] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0204] E10.3.G 1 but,

[0205] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0206] E10.4.G 1 but,

[0207] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0208] E10.5.G 1 but,

[0209] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0210] E10.6.G 1 but,

[0211] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0212] E10.7.G 1 but,

[0213] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0214] E11.G 1 but,

[0215] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0216] E11.1.G 1 but,

[0217] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0218] E11.2.G 1 but,

[0219] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0220] E11.3.G 1 but,

[0221] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0222] E12.G1 but,

[0223] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0224] E12.1.G 1 but,

[0225] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0226] E12.2.G 1 but,

[0227] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0228] E12.3.G 1 but,

[0229] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0230] E13.G 1 but,

[0231] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0232] E13.1.G 1 but,

[0233] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0234] E13.2.G 1 but,

[0235] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0236] E13.3.G 1 but,

[0237] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0238] E14. G 1 but,

[0239] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0240] E14.1.G 1 but,

[0241] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0242] E14.2.G 1 but,

[0243] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0244] E14.3.G 1 but,

[0245] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0246] E14.4.G 1 but,

[0247] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0248] E14.5.G 1 but,

[0249] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0250] E14.6.G 1 but,

[0251] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0252] E14.7.G 1 but,

[0253] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0254] E15. G 1 but,

[0255] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0256] E16.R 10d But X 1 , -L 1 -X 1 , halogen, C 1~4 Alkyl or G 1a or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0257] E16.1.R 10d But X 1 , halogen, C 1~4 Alkyl or G 1aor a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0258] E16.2.R 10d X 1 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0259] E16.3.R 10d Ga-L 1 -X 1 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0260] E16.4.X 1 -C(O)N(R 1a ) 2 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0261] E16.5.X 1 -C(O)NHR 1a or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0262] E16.6.X 1 -C(O)NHCH 3 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0263] E16.7.X 1 but,

[0264] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0265] E16.8.X 1 -C(O)OR 1a or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0266] E16.9.X 1 -C(O)OCH 2 CH 3 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0267] E16.10.X 1 -OR 1a or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0268] E16.11.X 1 -N(R 1a ) 2 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0269] E16.12.X 1 Ga-NHR 1a or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0270] E16.13.R 1a However, each occurrence is independent of hydrogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl or -C 2~3Alkylene-OC 1~4 A compound of any one of E1 to E3.2, E8, E8.1, E8.6, E15, E16 to E16.5, E16.8 or E16.10 to E16.12, which is alkyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0271] E16.14.R 1a is, independently at each occurrence, hydrogen, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0272] E16.15.R 1a But for each occurrence, C 1~4 E16.13, which is alkyl, for example methyl or ethyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0273] E16.16.R 1a But for each occurrence, C 1~4 Fluoroalkyl, e.g., CH 2 CHF 2 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0274] E16.17.R 1a but independently for each occurrence, -C 2~3 Alkylene-OC 1~4 Alkyl, e.g., -CH 2 CH 2 -OCH 3 -CH etc. 2 CH 2 -OC 1~4 A compound of E16.13, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, wherein E16.13 is alkyl.

[0275] E16.18.R 10dis halogen, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0276] E16.19.R 10d or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, wherein the halogen in is chloro.

[0277] E16.20.R 10d But, C 1~4 E16.1, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, wherein E16.1 is alkyl, for example ethyl.

[0278] E16.21.R 10d G 1a or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0279] E16.22.G 1a is 4-8 membered heterocyclyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0280] E16.23.G 1a or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0281] E16.24.G 1aor a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, wherein the 4-8 membered heterocyclyl ring system is pyrrolidin-1-yl, piperazin-1-yl or morpholino.

[0282] E16.25.G 1a is 5-6 membered heteroaryl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0283] E16.26.G 1a E16.25, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, wherein the ring system of the 5-6 membered heteroaryl in the formula:

[0284] E16.27.G 1a E16.26, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, wherein the 5-6 membered heteroaryl ring system is pyridinyl or pyrrolyl.

[0285] E16.28.G 1a E16.27, wherein the 5-6 membered heteroaryl ring system is pyridin-4-yl or pyrrol-1-yl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0286] E16.29.G 1a But, Oxo, C 1~4 Alkyl, OC 1~4 Alkyl, C(O)C 1~4 Alkyl, -NHC(O)C 1~4 Alkyl, -C 2~3 Alkylene-OC 1~4 Alkyl, G 1b and -C 1~3 Alkylene-G 1band optionally substituted with 1 to 2 substituents independently selected from the group consisting of: 1b But, C 3~6 A compound of any of E1-E3.2, E8, E8.1, E8.6, E15 or E16-E16.28 which is a cycloalkyl or a 4-6 membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from O, N and S.

[0287] E16.30.G 1a but,

[0288] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0289] E16.31.G 1a but,

[0290] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0291] E16.32.G 1a but,

[0292] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0293] E16.33.G 1a But, C 3~8A compound of any one of E1 to E3.2, E8, E8.1, E8.6, E15, E16 to E16.21 or E16.29 which is cycloalkyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0294] E16.34.G 1a C in 3~8 A compound or a tautomer thereof of any one of E1 to E3.2, E8, E8.1, E8.6, E15, E16 to E16.21 or E16.33, wherein cycloalkyl is unsubstituted, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0295] E16.35.G 1a C in 3~8 A compound of any of E1 to E3.2, E8, E8.1, E8.6, E15, E16 to E16.21, E16.33 or E16.34, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, wherein the cycloalkyl ring system is cyclopropyl.

[0296] E16.36.L 1 CH 2 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0297] E17.R 10e But halogen, OH, -OC 1~4 Alkyl, -OC 1~3 Alkylene-G 1c or -OC 2~3 A compound of any one of E1 to E4.14, E5 to E-5.1, E5.4, E6 to E6.1 or E15 to E16.36, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, wherein Y is alkylene-Y.

[0298] E17.1.R 10eis halogen, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0299] E17.2.R 10e or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, wherein the halogen in is fluoro.

[0300] E17.3.R 10e is OH, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0301] E17.4.R 10e But, -OC 1~4 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0302] E17.5.R 10e In-OC 1~4 Alkyl is -OCH 3 or -OCH 2 CH 3 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0303] E17.6.R 10e In-OC 1~4 Alkyl is -OCH 3 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0304] E17.7.R 10e But, -OC 1~3 Alkylene-G 1cor a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0305] E17.8.R 10e In-OC 1~3 Alkylene-G 1c But, -OCH 2 -G 1c or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0306] E17.9.G 1c is a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0307] E17.10.G 1c or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, wherein the ring system of the 5- or 6-membered heteroaryl in the formula (I) is pyrazolyl.

[0308] E17.11.G 1c or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, wherein the 5- to 6-membered heteroaryl ring system is pyrazol-5-yl.

[0309] E17.12.G 1c However, 1 to 3 C such as methyl or ethyl 1~4A compound of any of E1 to E4.5, E5 to E-5.1, E5.4, E6 to E6.1, or E15 to E17, E17.2, or E17.5 to E17.11, optionally independently substituted with alkyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0310] E17.13.G 1c but,

[0311] [ka] for example,

[0312] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0313] E17.14.R 10e Ga-OC 2~3 The compound of E17, wherein Y is alkylene-Y, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0314] E17.15.R 10e In-OC 2~3 Alkylene-Y is -O-CH 2 CH 2 -Y, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0315] E17.16. Y is -OC 1~4 Alkyl, e.g. -OCH 3or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0316] E17.17.R 10e But NH 2 , -NHC 1~4 Alkyl, -N(C 1~4 Alkyl) 2 or a 4-8 membered monocyclic heterocyclyl containing 1-2 heteroatoms selected from N, O and S, wherein the heterocyclyl is halogen, cyano, oxo, C 1~4 Alkyl, C 1~4 Fluoroalkyl, OH, -OC 1~4 Alkyl, -OC 1~4 Fluoroalkyl, NH 2 , -NHC 1~4 Alkyl and -N(C 1~4 Alkyl) 2 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer;

[0317] E17.18.R 10e But NH 2 , -NHC 1~4 Alkyl or -N(C 1~4 Alkyl) 2 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0318] E17.19.R 10e But -NHCH 3 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0319] E17.20.R 10e is optionally substituted 4-8 membered monocyclic heterocyclyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0320] E17.21.R 10e wherein the optionally substituted 4-8 membered monocyclic heterocyclyl in the formula (I) contains at least one ring nitrogen atom and is attached to the parent molecular moiety at at least one ring nitrogen atom (e.g., azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholino, 1,4-oxazepan-4-yl, thiomorpholino, piperazin-1-yl, 1,4-diazepan-1-yl), or a tautomer of any of the compounds, E1-E4.14, E5-E-5.1, E5.4, E6-E6.1, E15, E16-E16.35, E17.17, or E17.20, or a pharma- ceutically acceptable salt of the compound or tautomer.

[0321] E17.22.R 10e but,

[0322] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0323] E18.R 10f But for each occurrence, C 1~4 Alkyl, OH, -OC 1~4 Alkyl, -OPG or -OSO 2 CF 3 or E15 to E17.22, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0324] E18.1.R 10f But for each occurrence, C 1~4 The compound of E18, wherein R is alkyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0325] E18.2.R 10f C in 1~4 or E15-E18.1, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, wherein alkyl is, independently at each occurrence, ethyl.

[0326] E18.3.R 10f is, independently at each occurrence, OH; or a tautomer thereof; or a pharma- ceutically acceptable salt of said compound or tautomer.

[0327] E18.4.R 10f But for each occurrence, independently, -OC 1~4 The compound of E18, wherein R is alkyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0328] E18.5.R 10f In-OC 1~4 Alkyl is, independently at each occurrence, -OCH 3 or -OCH 2 CH 3or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0329] E18.6.R 10f In-OC 1~4 Alkyl is, independently at each occurrence, -OCH 3 or E18.2 or E18.4 to E18.5, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0330] E18.7.R 10f is independently at each occurrence -OPG, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0331] E18.8. Any of the compounds E1 to E4.14, E5 to E5.1, E5.4, E6 to E6.1, E7 to E7.1, E8 to E8.1, E8.6, E9 to E9.1, E10 to E10.3, E11 to E11.1, E12 to E12.1, E13 to E13.1, E14 to E14.3, E15 to E18, E18.2 or E18.5 to E18.7, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, wherein PG is benzyl.

[0332] E18.9.R 10f But for each occurrence independently, -OSO 2 CF 3or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0333] E19.G 1 but,

[0334] [ka]

[0335] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0336] E19.1.G 1 but,

[0337] [ka] or a pharma- ceutically acceptable salt thereof.

[0338] E20. Compound of formula (I)

[0339] [ka] or a pharma- ceutically acceptable salt thereof, G 1 teeth,

[0340] [ka] and R 10d X 1 , hydrogen, halogens, C 1~4 Alkyl, C 1~4 Fluoroalkyl or G 1a and R 10f is halogen, cyano, C1~4 Alkyl, C 1~4 Fluoroalkyl, OH, -OC 1~4 Alkyl, -OC 1~4 Fluoroalkyl, -OC 3~4 Cycloalkyl, -OC 1~3 Alkylene-C 3~4 Cycloalkyl, -OPG or -OSO 2 CF 3 and PG is a hydroxy protecting group; X 1 is -C(O)N(R 1a ) 2 , -OR 1a , -N(R 1a ) 2 , cyano, -C(O)OR 1a , -C(O)R 1b , -SO 2 R 1b , -SO 2 N(R 1a ) 2 , -NR 1a C(O)H or -NR 1a C(O)R 1b and R 1a are independently defined for each occurrence as hydrogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, -C 2~3 Alkylene-OR 1e , -C 2~3 Alkylene-N(R 1e ) 2 , -C 2~3 Alkylene-N(R 1e )C(O)R 1e , G 1a or -C 1~3 Alkylene-G 1a and R 1b independently for each occurrence, C 1~4 Alkyl, C 1~4 Fluoroalkyl, -C 1~3 Alkylene-OR 1e , -C 1~3 Alkylene-N(R 1e ) 2 , -C 1~3Alkylene-N(R 1e )C(O)R 1e , G 1a or -C 1~3 Alkylene-G 1a and G 1a independently for each occurrence, C 3~8 cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 8-membered heterocyclyl; G 1a is a halogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, oxo, -L 2 -X 2 and -L 2 -G 1b and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: L 2 is, for each occurrence independently, a bond or C 1~3 is alkylene, X 2 is, independently for each occurrence, -OR 1c , -N(R 1c ) 2 , -SR 1c , cyano, -C(O)OR 1c , -C(O)N(R 1c ) 2 , -C(O)R 1c , -SOR 1d , -SO 2 R 1d , -SO 2 N(R 1c ) 2 , -NR 1c C(O)R 1c , -NR 1c C(O)OR 1c , -NR 1c C(O)N(R 1c ) 2 , -NR 1c S(O) 2 R 1d or -NR 1c S(O) 2 N(R 1c ) 2 and R 1c are independently defined for each occurrence as hydrogen, C1~4 Alkyl, C 1~4 Fluoroalkyl, G 1b or -C 1~3 Alkylene-G 1b Alternatively, two R 1c This R 1c Together with the common nitrogen atom to which it is bonded, C 1~4 Alkyl, C 1~4 Fluoroalkyl, oxo, -OH and -OC 1~4 forming a 4-8 membered saturated or partially unsaturated heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; R 1d independently for each occurrence, C 1~4 Alkyl, C 1~4 Fluoroalkyl, G 1b or -C 1~3 Alkylene-G 1b and R 1e are independently defined for each occurrence as hydrogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, G 1b or -C 1~3 Alkylene-G 1b Alternatively, two R 1e This R 1e Together with the common nitrogen atom to which it is bonded, C 1~4 Alkyl, C 1~4 Fluoroalkyl, oxo, -OH and -OC 1~4 forming a 4-8 membered saturated or partially unsaturated heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; G 1b independently for each occurrence, C 3~6 cycloalkyl, 4-6 membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from O, N and S, 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, or phenyl; 1b is halogen, cyano, C 1~4 Alkyl, C 1~4Fluoroalkyl, oxo, -OH and -OC 1~4 and optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, G 2 is a 5-6 membered heteroaryl; G 2 is C 1~6 Alkyl, C 1~6 Haloalkyl, halogen, -OR 4c , -N(R 4c ) 2 , cyano, -C(O)OR 4c , -C(O)N(R 4c ) 2 , -C(O)R 4c , -SO 2 R 4d , -SO 2 N(R 4c ) 2 , -NR 4c C(O)R 4c , C 3~8 Cycloalkyl and -C 1~3 Alkylene-C 3~8 Optionally substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyl, C 3~8 Each cycloalkyl is C 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl and halogen; R 4c are independently defined for each occurrence as hydrogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 3~8 Cycloalkyl or -C 1~6 Alkylene-C 3~8 Cycloalkyl, C 3~8 Each cycloalkyl is C 1~4 Optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl and halogen, alternatively, two R 4c This R 4c Together with the common nitrogen atom to which it is bonded, C 1~4 Alkyl, C 1~4 Fluoroalkyl, oxo, -OH and -OC 1~4forming a 4-8 membered saturated or partially unsaturated heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; R 4d independently for each occurrence, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 3~8 Cycloalkyl or -C 1~6 Alkylene-C 3~8 Cycloalkyl, C 3~8 Each cycloalkyl is C 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl and halogen; R 5 and R 6 are each independently hydrogen, halogen, or C 1~4 Alkyl, C 1~4 Fluoroalkyl or -OC 1~4 is alkyl, R 8 teeth,

[0341] [ka] is) with the proviso that the compound A compound of formula (I) or a pharma- ceutically acceptable salt thereof, provided that it is not 2-(6-methoxy-8-methylquinolin-4-yl)-7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one or a pharma- ceutically acceptable salt thereof.

[0342] E21.G 1 but,

[0343] [ka] 20. The compound of claim 19, wherein:

[0344] E22.R 10d X 1 or a pharma- ceutically acceptable salt thereof.

[0345] E22.1.X 1 -C(O)N(R 1a ) 2 Any of the compounds E20 to E22, or a pharma- ceutically acceptable salt thereof.

[0346] E22.2.X 1 -C(O)NHR 1a or a pharma- ceutically acceptable salt thereof.

[0347] E22.3.X 1 but,

[0348] [ka] or a pharma- ceutically acceptable salt thereof.

[0349] E22.4.X 1 -C(O)OR 1a Any of the compounds E20 to E22, or a pharma- ceutically acceptable salt thereof.

[0350] E22.5.R 1a However, each occurrence is independent of hydrogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl or -C 2~3 Alkylene-OC 1~4 Any of the compounds of E20 to E22.4, or a pharma- ceutically acceptable salt thereof, wherein E20 is alkyl.

[0351] E22.6.R 1a is, independently at each occurrence, hydrogen; or a pharma- ceutically acceptable salt thereof.

[0352] E22.7.R 1a But for each occurrence, C1~4 The compound of E22.5, or a pharma- ceutically acceptable salt thereof, wherein E22.5 is alkyl, for example methyl or ethyl.

[0353] E23.R 10f But, C 1~4 Any of the compounds of E20 to E22.7, or a pharma- ceutically acceptable salt thereof, wherein E20 is alkyl.

[0354] E23.1.R 10f C in 1~4 The compound of any one of E20 to E23, or a pharma- ceutically acceptable salt thereof, wherein alkyl is ethyl.

[0355] E24. G 1 but,

[0356] [ka] or a pharma- ceutically acceptable salt thereof.

[0357] E24.1.G 1 In

[0358] [ka] but,

[0359] [ka] Any of the compounds E20 to E24, or a pharma- ceutically acceptable salt thereof.

[0360] E24.2.R 8 but,

[0361] [ka] Any of the compounds E20 to E24.1, or a pharma- ceutically acceptable salt thereof,

[0362] E25.G 2 is optionally substituted 5-6 membered heteroaryl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0363] E25.1.G 2 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, any one of E1 to E25, wherein the ring system of the optionally substituted 5- to 6-membered heteroaryl in is pyrazolyl.

[0364] E25.2.G 2 is optionally substituted phenyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0365] E25.3.G 2 But halogen, C 1~4 Alkyl and C 1~4 A compound or tautomer thereof of any of E1-E25.2, or a pharma- ceutically acceptable salt of said compound or tautomer, optionally substituted with one to four substituents independently selected from the group consisting of fluoroalkyl.

[0366] E25.4.G 2 But, C 1~2 Alkyl and C 1~2 A compound of E25.3 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, optionally substituted with one to two substituents independently selected from the group consisting of fluoroalkyl.

[0367] E26.G 2 but,

[0368] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0369] E26.1.G 2 but,

[0370] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0371] E26.2.G 2 but,

[0372] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0373] E26.3.G 2 but,

[0374] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0375] E26.4.G 2 but,

[0376] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0377] E26.5.G 2but,

[0378] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0379] E26.6.G 2 but,

[0380] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0381] E26.7.G 2 but,

[0382] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0383] E26.8.G 2 but,

[0384] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0385] E26.9.G 2 but,

[0386] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0387] E26.10.G 2 but,

[0388] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0389] E26.11.G 2 but,

[0390] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0391] E26.12.G 2 but,

[0392] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0393] E26.13.G 2 but,

[0394] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0395] E26.14.G 2 but,

[0396] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0397] E26.15.G 2 but,

[0398] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0399] E27.R 5 is hydrogen, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0400] E28.R 6 is hydrogen, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

[0401] E29.1. Below: 7-((1H-imidazol-1-yl)methyl)-2-(3-ethyl-1,6-naphthyridin-5-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 2-(3-methoxy-7-methylquinolin-5-yl)-7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; Ethyl 6-ethyl-4-(7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)quinoline-8-carboxylate; 6-ethyl-4-(7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)quinoline-8-carboxylic acid; 6-Ethyl-N-methyl-4-(7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)quinoline-8-carboxamide; 6-Ethyl-4-(7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)quinoline-8-carboxamide; 4-(7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-6-ethyl-1,7-naphthyridin-8(7H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-hydroxy-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(8-chloro-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-(methylamino)-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 2-(6-ethyl-8-methoxy-1,7-naphthyridin-4-yl)-7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; (S)-7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,8-dimethoxy-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-methoxycinnolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 2-(6-ethyl-8-methoxycinnolin-4-yl)-7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxy-2-methylquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxyquinolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-methoxy-1,5-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; Ethyl 4-(7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-6-ethyl-1,7-naphthyridine-8-carboxylate; 4-(7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-6-ethyl-1,7-naphthyridine-8-carboxylic acid; 4-(7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-6-ethyl-N-methyl-1,7-naphthyridine-8-carboxamide; 7-((1H-imidazol-1-yl)methyl)-2-(3-ethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(3-methoxy-2-methyl-5,6,7,8-tetrahydroquinolin-5-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(7-hydroxy-6-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-methoxy-7-((1-methyl-1H-pyrazol-5-yl)methoxy)quinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethoxy-7-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(7-ethoxy-6-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-diethoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxyphthalazin-1-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(7-fluoro-6-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-(2-methoxyethoxy)-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-(pyrrolidin-1-yl)-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-(1H-pyrrol-1-yl)-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(8-ethoxy-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,8-diethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(8-cyclopropyl-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(8-(2,2-difluoroethoxy)-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-(benzyloxy)-7-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-hydroxy-7-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 4-(7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-7-methoxyquinazolin-6-yl trifluoromethanesulfonate; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-7-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-morpholino-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-(pyridin-4-yl)-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-(4-methylpiperazin-1-yl)-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 1. A compound selected from the group consisting of:

[0402] E29.2. Below: 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-methoxy-1,7-naphthyridin-4-yl)-5-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-methoxy-2-methyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxycinnolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,8-dimethoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-methoxy-2-methylquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-(methoxymethyl)-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(7-fluoro-6-methoxy-2-methylquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(7-(azetidin-1-yl)-6-methoxy-2-methylquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-methoxy-2-methyl-7-(methylamino)quinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxy-2-morpholinoquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxy-2-(methylamino)quinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxy-2-methylquinazolin-4-yl)-5-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxy-2-methylquinazolin-4-yl)-5-(1,3-dimethyl-1H-pyrazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one; (S)-7-((1H-imidazol-1-yl)methyl)-3'-ethyl-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4,5',6',7',8'-hexahydro-1H-[2,5'-biisoquinolin]-1-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxy-2-methylquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(2-(ethyl(methyl)amino)-6,7-dimethoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(2-ethyl-6,7-dimethoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(2-cyclopropyl-6,7-dimethoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxy-2-methylquinazolin-4-yl)-5-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxy-2-methylquinazolin-4-yl)-5-(4-fluoro-2-methylphenyl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxy-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; or a pharma- ceutically acceptable salt thereof.

[0403] E30. A pharmaceutical composition comprising any one of the compounds of E1 to E29.2 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, and a pharma- ceutically acceptable carrier.

[0404] E31. A compound of any of E1-E29.2 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, or a pharmaceutical composition of E30, for use in treating cancer.

[0405] E32. Any of the compounds of E1 to E29.2 or tautomers thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, or a pharmaceutical composition of E30, for use in inhibiting the proliferation of cancer cells.

[0406] E33. A method of treating cancer comprising the step of administering to a subject in need thereof a therapeutically effective amount of any of the compounds of E1-E29.2 or tautomers thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, or a pharmaceutical composition of E30.

[0407] E34. A method for inhibiting the proliferation of cancer cells, comprising the step of administering to a subject in need thereof any of the compounds of E1-E29.2 or tautomers thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, or the pharmaceutical composition of E30, in an amount effective to inhibit the proliferation of cancer cells.

[0408] E35. Use of any of the compounds of E1 to E29.2 or tautomers thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, or the pharmaceutical composition of E30, in the manufacture of a medicament for treating cancer.

[0409] E36. Use of any of the compounds of E1 to E29.2 or tautomers thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, or the pharmaceutical composition of E30, in the manufacture of a medicament for inhibiting the proliferation of cancer cells.

[0410] In certain embodiments, the compound of formula (I) is selected from the group consisting of the compounds in Table 1 or a pharma- ceutically acceptable salt thereof.

[0411] [Table 1-1]

[0412] [Table 1-2]

[0413] [Table 1-3]

[0414] [Table 1-4]

[0415] Compound names can be assigned by using the Struct=name naming algorithm as part of CHEMDRAW® ULTRA.

[0416] Compounds may exist as stereoisomers where asymmetric or chiral centers are present. Stereoisomers are "R" or "S" depending on the configuration of the substituents around the chiral carbon atom. As used herein, the terms "R" and "S" are configurations as defined in the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The present disclosure contemplates various stereoisomers and mixtures thereof, which are specifically included within the scope of the present invention. Stereoisomers include enantiomers and diastereomers, as well as mixtures of enantiomers or diastereomers. In compounds of formula (I), when a specific configuration is not indicated at a stereogenic center (e.g., carbon), the compound includes all possible stereoisomers.

[0417] Individual stereoisomers of a compound can be prepared by synthesis from commercially available starting materials containing asymmetric or chiral centers, or by preparation of a racemic mixture followed by resolution methods well known to those skilled in the art. Such methods of resolution are exemplified by (1) coupling of the mixture of enantiomers to a chiral auxiliary, recrystallization or chromatographic separation of the resulting diastereomeric mixture, and optional liberation of the optically pure product from the auxiliary, as described in Furniss, Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England, or (2) direct separation of the mixture of optical enantiomers on a chiral chromatographic column, or (3) fractional recrystallization methods.

[0418] It is to be understood that the compounds may have tautomeric forms and geometric isomers and that these isomers also form an aspect of the present invention.

[0419] In the compounds of formula (I) and any subformula, "hydrogen" or "H", whether explicitly stated or implied in the structure, represents a hydrogen isotope. 1 H (protium) and 2 H (deuterium) is included.

[0420] The present disclosure also includes isotopically labeled compounds (e.g., deuterium labeled), where an atom in an isotopically labeled compound is designated as the particular isotope of that atom. Examples of isotopes suitable for inclusion in compounds of the invention include, but are not limited to, the following, respectively: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P,35 S, 18 F and 36 These are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as Cl.

[0421] Isotopically enriched forms of the compounds of formula (I) or any subformula can generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described in the accompanying examples, substituting an appropriate isotopically enriched reagent for the non-isotopically enriched reagent. The degree of isotopic enrichment can be characterized as the percentage of incorporation of a particular isotope at the isotopically labeled atom (e.g., for deuterium labeling, % deuterium incorporation).

[0422] The disclosed compounds may be present as pharma- ceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts or zwitterions of the compounds that are water- or oil-soluble or dispersible, suitable for treating disorders without undue toxicity, irritation, and allergic reactions, commensurate with a reasonable benefit / risk ratio, and effective for their intended use. The salts may be prepared during or separately from the final isolation and purification of the compounds by reacting the amino group of the compounds with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as, but not limited to, methanol and water, and treated with at least one equivalent of an acid, such as hydrochloric acid. The resulting salt may precipitate, be isolated by filtration, and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to obtain the salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, thrichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloride, hydrobromide, sulfuric acid, phosphoric acid, and the like. The amino groups of the compounds may also be quaternized with alkyl chlorides, bromides, and iodides, such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like.

[0423] Base addition salts can be prepared during the final isolation and purification of the disclosed compounds by reacting the carboxyl group with a suitable base, such as the hydroxide, carbonate or bicarbonate of a metal cation, such as lithium, sodium, potassium, calcium, magnesium or aluminum, or an organic primary, secondary or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine and N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0424] A. Binding to WDR5 The disclosed compounds can bind to WDR5 and block the association of MLL1 or other transcription factors and proteins that are dependent on WDR5. The compounds can bind to WDR5 and block oncogenic processes involving MLL1, c-MYC, or other oncogenic proteins that are dependent on WDR5.

[0425] Compounds of formula (I) bind to WDR5 and have a K in the range of about 0.01 nM to about 250 μM. iThe compounds provide a concentration of about 250 μM, about 200 μM, about 150 μM, about 100 μM, about 90 μM, about 80 μM, about 70 μM, about 60 μM, about 50 μM, about 40 μM, about 30 μM, about 20 μM, about 10 μM, about 9 μM, about 8 μM, about 7 μM, about 6 μM, about 5 μM, about 4 μM, about 3 μM, about 2 μM, about 1 μM, about 950 nM, about 900 nM, about 850 nM, about 800 nM, about 85 K of 0 nM, about 800 nM, about 750 nM, about 700 nM, about 650 nM, about 600 nM, about 550 nM, about 500 nM, about 450 nM, about 400 nM, about 350 nM, about 300 nM, about 250 nM, about 200 nM, about 150 nM, about 100 nM, about 50 nM, about 10 nM, about 5 nM, about 1 nM, about 0.3 nM, about 0.1 nM, about 0.03 nM or about 0.01 nM i Compounds of formula (I) may bind to WDR5 and have a concentration of less than 250 μM, less than 200 μM, less than 150 μM, less than 100 μM, less than 90 μM, less than 80 μM, less than 70 μM, less than 60 μM, less than 50 μM, less than 40 μM, less than 30 μM, less than 20 μM, less than 10 μM, less than 9 μM, less than 8 μM, less than 7 μM, less than 6 μM, less than 5 μM, less than 4 μM, less than 3 μM, less than 2 μM, less than 1 μM, less than 950 nM, less than 900 nM, less than 850 nM K less than 800nM, less than 850nM, less than 800nM, less than 750nM, less than 700nM, less than 650nM, less than 600nM, less than 550nM, less than 500nM, less than 450nM, less than 400nM, less than 350nM, less than 300nM, less than 250nM, less than 200nM, less than 150nM, less than 100nM, less than 50nM, less than 10nM, less than 5nM, less than 1nM, less than 0.3nM, less than 0.1nM or less than 0.03nM i can result.

[0426] B. General synthesis The compounds of formula (I) can be prepared by synthetic processes or by metabolic processes, including processes that occur within the human or animal body (in vivo) or in vitro.

[0427] The compounds of the present disclosure can be prepared by several methods well known to those skilled in the art of organic synthesis. The compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the field of synthetic organic chemistry, or variations thereof recognized by those skilled in the art. Preferred methods include, but are not limited to, the following methods. All references cited herein are incorporated herein in their entirety by reference to the subject matter referred to herein. Compounds of formula (I) may also be prepared by metabolic processes. Preparation of compounds by metabolic processes includes processes that occur in the human or animal body (in vivo) or processes that occur in vitro.

[0428] The compounds of the present disclosure may be prepared using the exemplary reactions and techniques described in this section. The reactions are carried out in solvents appropriate to the reagents and materials used and suitable for efficient conversion. Similarly, in the description of the synthetic methods described below, it is understood that all proposed reaction conditions, including solvents, reaction atmospheres, reaction temperatures, experimental times and work-up procedures, are selected to be standard conditions for the reactions, which conditions should be readily recognized by those skilled in the art. Those skilled in the art of organic synthesis may adjust one or more of the conditions described herein. Those skilled in the art of organic synthesis understand that the functional groups present on various parts of the indicated molecule must be compatible with the proposed reagents and reactions. Not all compounds of the present disclosure that fall within a given class may be compatible with some of the reaction conditions required in some of the methods described. Such limitations on the substituents compatible with the reaction conditions are readily apparent to those skilled in the art, and alternative methods may be used.

[0429] [ka]

[0430] In some embodiments, compounds of formula 13 can be synthesized by the procedures illustrated in Scheme 1, including but not limited to NaBH(OAc)3 or NaCNBH 3 Hemiacetal 1 can be coupled with (2,4-dimethoxyphenyl)methanamine 2 under reductive amination conditions using reducing agents including , followed by spontaneous cyclization to give intermediate 3. After activation of the phenol moiety of 3 as the trifluoromethanesulfonate ester, intermediate 4 can be reacted with a variety of boronic acids 5 or boronic esters 6, which are either commercially available or can be prepared, for example, by Suzuki-Miyaura coupling protocols (Miyaura, N., Suzuki, A., Chem. Rev. (1995), 2457), with Pd(PPh 3 ) 4 , PdCl 2 (dppf), Pd(PPh 3 ) 2 Cl 2 , Pd(OAc) 2 , Pd 2 (dba) 3 Pd catalyst species such as PPh 3 , AsPh 3 or other such Pd catalysts, and Na 2 CO 3 , Cs 2 CO 3 , K 2 CO 3 , Ba(OH) 2 or Et 3 Coupling in the presence of a base such as N can provide the biaryl adduct 7. The dimethoxybenzyl moiety of 7 can be removed using, but not limited to, TFA to prepare lactam 8. The methyl ester functionality of 8 can be converted to an alcohol under a variety of reducing conditions routine to one skilled in the art of organic synthesis. The hydroxy group of formula 9 can be activated by converting the hydroxy group to a bromide, chloride, mesylate or tosylate group by a number of conditions routine to one skilled in the art of organic synthesis. The resulting intermediate 10 can be further purified by elution with DIEA, TEA, Cs 2 CO 3 , K 2 CO 3The lactam NH of 11 can be reacted with various nucleophiles such as optionally substituted imidazoles in the presence of a suitable base such as LiOH or NaOH to give intermediate 11. The lactam NH of 11 can be reacted with Pd(OAc) 2 or Pd 2 (dba) 3 a Pd catalytic species such as Pd(III) or Pd(III)-P ... 2 CO 3 , Cs 2 CO 3 or K 2 CO 3 In the presence of a base such as , a compound of formula 13 can undergo a cross-coupling reaction with various aryl or heteroaryl halides of formula 12, where X' is Br or I, to produce a compound of formula 13. Alternatively, a compound of formula 13 can be reacted with CuI and a suitable ligand such as (trans)-1,2-N,N'-dimethylaminocyclohexane or L-proline, and Cs in a suitable solvent such as toluene or DMF. 2 CO 3 , K 2 CO 3 or K 2 PO 4 The compound can be generated using Ullman coupling conditions in the presence of a base such as

[0431] [ka]

[0432] In some embodiments, compounds disclosed herein can be prepared as shown in Scheme 2. An optionally substituted partially unsaturated fused bicyclic amine of formula 14 can be coupled with hemiacetal 1 under reductive amination conditions described above to provide intermediate 15. Intermediate 15 can then be subjected to the reaction sequence of intermediates 3 through 7 illustrated in Scheme 1 to provide intermediate 16, which can then be subjected to the reaction sequence of intermediates 8 through 11 to provide compounds of formula 17.

[0433] [ka]

[0434] Optically pure amine intermediates of formula 22 can be prepared by the procedures illustrated in Scheme 3. Suitably, substituted bicyclic ketones 18 are reacted with Ti(OEt) as a Lewis acid and water scavenger. 4 The resulting optically pure N-sulfinyl imine intermediate 20 can then undergo a condensation reaction with optically pure tert-butanesulfinamide 19 using NaBH 4 Reduction using an appropriate hydride such as 2-(2-methylphenyl)-2-(2-phenylpropanediol) or L-Selectride can provide the diastereomerically enriched sulfinamide 21. The tert-butanesulfinyl group can then be removed under appropriate acidic conditions to provide the optically pure bicyclic amine of formula 22.

[0435] [ka]

[0436] In some embodiments, the optically pure bicyclic amine of formula 31 can be used as a reagent. Additionally, the amine of formula 31 can be synthesized by the procedure illustrated in Scheme 4 using 5-bromo-2-fluoronicotinaldehyde of formula 23, which is reacted with CuSO as the Lewis acid. 4 The condensation protocol described in Scheme 3 using NaBH can be used to convert the intermediate 25 to optically pure N-sulfinyl imine intermediate. Allylmagnesium bromide can be reacted stereoselectively with the imine functionality of intermediate 25 to afford diastereomerically enriched sulfinamide 26. Subsequent ozonolysis and then NaBH 4 The resulting alcohol 27 can be reacted with, but not limited to, SN-C using potassium tert-butoxide as a base. ArCyclization can be achieved via reaction to provide dihydro-pyranopyridine intermediate 28. The bromo group of intermediate 28 can be coupled with vinylboronic acid, for example, via Suzuki-Miyaura coupling protocols, to provide adduct 29, which can be reduced under hydrogenolysis conditions, conditions routine to those skilled in the art of organic synthesis, to provide intermediate 30. The tert-butanesulfinyl group of intermediate 30 can be removed under acidic conditions to provide chiral amine 31.

[0437] [ka]

[0438] Bicyclic lactones of formula 32 can be prepared from hemiacetal 1 using, but not limited to, NaBH as a reducing agent. 4 Lactone 12 can then be subjected to the reaction sequence illustrated in Scheme 1 for intermediates 3 through 7, followed by reaction sequence for intermediates 8 through 11 to provide intermediate 33. The lactone portion of intermediate 33 can be prepared by, but not limited to, reaction with SOCl in EtOH. 2 Subsequent SN-NMR of the amine of formula 35 in the presence of tert-butylmagnesium chloride as a base gives intermediate 34. 2 Substitution followed by cyclization gives the final compound of formula 36.

[0439] [ka]

[0440] In some embodiments, 4-bromo-naphthyridine 42 can be used as a reagent and prepared by the procedure illustrated in Scheme 6. Heating a mixture of a suitably substituted 3-amino-pyridine 37, Meldrum's acid 38, and triethyl orthoformate 39 can produce intermediate 40, which can subsequently undergo thermal cyclization to give naphthyridin-4-ol 41. 4-Bromo-naphthyridine 42 can be prepared by the procedure illustrated in Scheme 6 using, but not limited to, PBr 3 Alternatively, bromo-naphthyridine 42 may be prepared by triflation of the hydroxyl group of naphthyridin-4-ol 41 followed by bromination using, but not limited to, LiBr.

[0441] [ka]

[0442] Intermediates of formula 44 may be prepared by the reactions depicted in Scheme 7. A suitably substituted cinnolin-4-one 43 can be halogenated using, but not limited to, phosphorus oxybromide to give 4-bromocinnoline 44.

[0443] [ka]

[0444] Alternatively, intermediates of formula 8 can undergo cross-coupling reactions with various aryl or heteroaryl halides of formula 12 under conditions described in Scheme 1 to give intermediates 45. The methyl ester functionality of 45 can be converted to alcohols under various reducing conditions routine to one skilled in the art of organic synthesis. The primary alcohol of intermediate 46 can be oxidized by a suitable reagent to give aldehyde 47 under several conditions routine to one skilled in the art. Various N-substituted imidazolyl Grignard reagents (e.g., 48-50), such as, but not limited to, (1-trityl-1H-imidazol-5-yl)magnesium iodide, (1-trityl-1H-imidazol-2-yl)magnesium iodide, or (1-methyl-1H-imidazol-2-yl)magnesium iodide, can be reacted with aldehyde 47 to give the corresponding secondary alcohols 51-53. Compounds of formula 54-56 can be generated by reduction of the corresponding alcohols 51-53 using, but not limited to, triethylsilane and TFA with heat in a polar aprotic solvent such as 1,2-dichloroethane.

[0445] [ka] In some embodiments, compounds of formula 59 can be synthesized by the procedure illustrated in Scheme 9. Optionally substituted ethyl 4-bromo-1,7-naphthyridine-8-carboxylate 57, produced by the reaction sequence depicted in Scheme 6, can be coupled with lactam 11 to give compounds of formula 58. The ester functionality of 58 can be converted to an amide by a saponification followed by an amide coupling reaction sequence routine to one skilled in the art of organic synthesis to give the product of formula 59. Alternatively, the same reaction sequence can be applied to ester 57 to give intermediate 60, which can be coupled with lactam 11 to form product 59. Starting with ethyl 4-bromo-quinoline-8-carboxylate, a similar sequence can be followed to give G 1 but,

[0446] [ka] and R 10d But -C(O)N(R 1a ) 2 OR -C(O)OR 1a Ethyl 4-bromo-quinoline-8-carboxylate may be prepared starting from the substituted aniline analog of 37 using the process of Scheme 6.

[0447] [ka]

[0448] In some embodiments, compounds of formulae 63-65 can be prepared using the procedures depicted in Scheme 10. The 8-OMe group of compound 60 can be substituted with any of the following: PBr 3 or BBr 3 The tautomeric mixture of intermediates 61a and 61b can be demethylated using POCl 3 with 6-bromoquinolin-4-yl to afford the versatile 8-Cl intermediate 62. Compounds of formula 63 and 64 can be generated by SNAr reactions using alcohols or amines as substrates in the presence of base using conditions well known to those skilled in the art of organic synthesis. Alternatively, intermediate 62 can be subjected to the Buchwald-Hartwig or Suzuki-Miyaura coupling protocols described in Scheme 1 to yield products of formula 64 or 65. Quinolin-4-yl analogs of 63-65 can be prepared using similar processes from 8-bromoquinolin-4-yl intermediates analogous to 62.

[0449] [ka]

[0450] Intermediate 4 can be prepared by the reaction of, but not limited to, bis(pinacolato)diboron 66 and PdCl2 (dppf)·CH 2 Cl 2 may be converted to borate ester 67 using, which can undergo copper(II) bromide mediated bromination to give bromide-containing intermediate 68. The methyl ester functionality of 68 can be subjected to the reaction sequence of intermediates 8 to 11 illustrated in Scheme 1 to give intermediate 69. The substituted pyrazol-1-yl moiety of intermediate 71 can be constructed by introducing BOC-hydrazine under Buchwald-Hartwig coupling conditions, including but not limited to, those described in Scheme 1, followed by deprotection of Boc and heterocyclization using conditions well known to those skilled in the art of organic synthesis to give intermediate 71. Finally, compounds of formula 73 can be produced by removing the dimethoxybenzyl group of 71 and then introducing an Ar-group under Buchwald-Hartwig coupling conditions described in Scheme 1.

[0451] [ka]

[0452] In some embodiments, compounds of formula 76 can be prepared using intermediate 69 by removal of the dimethoxybenzyl group, Buchwald-Hartwig coupling, followed by Suzuki-Miyaura coupling under the reaction conditions described in Scheme 1.

[0453] [ka]

[0454] In some embodiments, substituted 2-alkyl-4-chloro-quinazolines 80 or 84 are used as reagents and can be prepared by the procedure illustrated in Scheme 13. Substituted 2-amino-benzoic acids 77 and ethanethioamides 78 can be heated to generate tautomeric mixtures of 2-methylquinazolin-4(3H)-one intermediates 79a and 79b, which can be further reacted with, but not limited to, POCl. 3 Chlorination using 5-methyl-1,4-dichloro-2-methyl-quinazoline 80 can provide the substituted 4-chloro-2-methyl-quinazoline 80. Alternatively, reaction of methyl amino-benzoate 81 with alkyl-nitrile 82 gives the 2-alkylquinazolin-4(3H)-one intermediate 83, which can subsequently undergo chlorination reaction as described above to give the 2-alkyl-4-chloro-quinazoline 84.

[0455] [ka]

[0456] In some embodiments, substituted 2-amino-4-chloro-quinazoline 87 can be used as a reagent and prepared by the procedure illustrated in Scheme 14. Substituted chloro-quinazolin-4(3H)-one 85 and substituted amine 86 can be reacted to generate substituted 2-amino-quinazolin-4(3H)-one intermediate 87 via an SNAr reaction. Subsequent chlorination reaction using the procedure illustrated in Scheme 13 can provide substituted 2-amino-4-chloro-quinazoline 88.

[0457] Precursor reagents and intermediates for the core aryl or phenyl structures were either commercially available or prepared using methods known in the literature. Procedures to key intermediates are detailed in the designated examples or below.

[0458] Compounds and intermediates can be isolated and purified by methods well known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports such as silica gel, alumina or silica derivatized with alkylsilane groups, recrystallization at high or low temperatures, with optional prior treatment with activated charcoal, thin layer chromatography, distillation at various pressures, sublimation and trituration under vacuum, as described, for example, in "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England.

[0459] The disclosed compounds can have at least one basic nitrogen, which allows the compounds to be treated with an acid to form a desired salt.For example, a compound can be reacted with an acid at room temperature or above room temperature to produce a desired salt, which is deposited and collected by filtration after cooling.Examples of acids suitable for this reaction include, but are not limited to, tartaric acid, lactic acid, succinic acid, as well as mandelic acid, atrolactic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, carbonic acid, fumaric acid, maleic acid, gluconic acid, acetic acid, propionic acid, salicylic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, citric acid, hydroxybutyric acid, camphorsulfonic acid, malic acid, phenylacetic acid, aspartic acid or glutamic acid.

[0460] The reaction conditions and reaction times for each of the individual steps may vary depending on the specific reactants used and the substituents present in the reactants used. Specific procedures are presented in the Examples section. The reactions can be worked up in a conventional manner, for example by removing the solvent from the residue, and can be further purified according to methodologies generally known in the art, such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise stated, starting materials and reagents are commercially available or can be prepared by those skilled in the art from commercially available materials using methods described in the chemical literature. If the starting materials are not commercially available, they can be prepared by procedures selected from standard organic chemistry techniques, techniques similar to the synthesis of known structurally similar compounds, or procedures similar to those described in the Schemes or Synthesis Examples sections above.

[0461] Routine experimentation, including proper manipulation of reaction conditions, sequence of reagents and synthetic routes, protection of any functional groups that are not compatible with the reaction conditions, and deprotection at suitable points in the reaction sequence of the method, are within the scope of the present invention. Suitable protecting groups and methods of protecting and deprotecting various substituents using such suitable protecting groups are well known to those of skill in the art, examples of which can be found in PGM Wuts and TW Greene, in Greene's book titled Protective Groups in Organic Synthesis (4 th ed.), John Wiley & Sons, NY (2006). Synthesis of compounds of the invention can be carried out by methods analogous to those described in the synthetic schemes and specific examples described herein above.

[0462] If an optically active form of a disclosed compound is required, the optically active form may be obtained by carrying out one of the procedures described herein using optically active starting materials (e.g., prepared by asymmetric induction of a suitable reaction step) or by resolution of a stereoisomeric mixture of the compound or intermediate using standard procedures (such as chromatographic separation, recrystallization or enzymatic resolution).

[0463] Similarly, if a pure geometric isomer of a compound is required, the geometric isomer can be obtained by carrying out one of the procedures described above using a pure geometric isomer as a starting material, or by resolution of a mixture of geometric isomers of the compound or intermediate using standard procedures such as chromatographic separation.

[0464] It will be understood that the synthetic schemes and specific examples described are illustrative and should not be read as limiting the scope of the invention, as defined in the appended claims. All alternatives, modifications and equivalents of the synthetic methods and specific examples are included within the scope of the claims. EXAMPLES

[0465] C. Working Example Abbreviation The following abbreviations are used in the examples and elsewhere in the specification: AcOH = acetic acid aq. = aqueous BINAP = 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (Boc) 2 O = di-tert-butyl dicarbonate BrettPhos = 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl CH 2 Cl 2 = Methylene chloride conc.=conc. Cs 2 CO 3 = Cesium carbonate DBU = 1,8-diazabicyclo[5.4.0]undeca-7-ene DCE = dichloroethane DCM = dichloromethane DIPEA / DIEA = N,N-diisopropylethylamine DMA = Dimethylacetamide DMF = Dimethylformamide DMSO = dimethyl sulfoxide Dowtherm A = eutectic mixture of 26.5% diphenyl + 73.5% diphenyl oxide EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide eq. or equiv = equivalent Ether = Diethyl Ether Et 3 N = triethylamine EtOAc = ethyl acetate EtOH = ethanol g = grams h or hr = hours HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HCl = Hydrochloric Acid Hex = Hexane HOBt = hydroxybenzotriazole K 2 CO 3 = Potassium carbonate KOH = Potassium hydroxide LRMS=low resolution mass spectrometry L-selectride = Lithium tri-sec-butylborohydride [M+H] + = the protonated mass of the free base of the compound MeCN = acetonitrile MeOH = methanol MeONa = sodium methoxide mg = milligrams MgSO 4 = Magnesium sulfate min=minutes mL or ml = milliliters mmol = millimolar Na 2 CO 3= Sodium carbonate NaH = sodium hydride NaHCO 3= Sodium bicarbonate NaN 3 = Sodium azide NaOH = Sodium hydroxide NBS = N-bromosuccinimide NIS=N-iodosuccinimide NMP = N-methyl-2-pyrrolidone NMR=nuclear magnetic resonance PdCl 2 (dppf) / Pd(dppf)Cl 2 =[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd 2 (dba) 3 = Tris(dibenzylideneacetone)dipalladium(0) Pd(PPh 3 ) 4 =Tetrakis(triphenylphosphine)palladium(0) Pd(PPh 3 ) 2 Cl 2 Bis(triphenylphosphine)palladium(II) dichloride Pd(OAc) 2 =Palladium(II) acetate Pd(t-Bu 3 P) 2 = Bis(tri-tert-butylphosphine)palladium(0) PPh 3 = Triphenylphosphine p-TSA = para-toluenesulfonic acid RT or rt = room temperature Rt=retention time (min) sat = saturated SPhos = 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl TBAF = Tetra-n-butylammonium fluoride TEA = triethylamine Tf 2 O = Trifluoromethanesulfonic anhydride THF = tetrahydrofuran TFA = trifluoroacetic acid Trityl = Triphenylmethyl wt.=weight Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0466] Microwave assisted reactions are carried out in a single mode reactor: an Emrys™ Optimizer microwave reactor (Personal Chemistry AB, now Biotage).

[0467] The hydrogenation reaction is carried out using a balloon at atmospheric pressure or using a Parr hydrogenation shaker apparatus.

[0468] Progressive flash silica gel-based column chromatography was performed using ISCO ready-to-connect cartridges on non-uniform silica gel (particle size 15-40 μm) on an ISCO Combi-flash Companion chromatography system.

[0469] Low-resolution mass spectra were obtained on an Agilent 1200 series 6130 mass spectrometer. Analytical HPLC was performed using ELSD detection (LC / MS (J-Sphere 80-C18, 3.0x50mm, 4.1 min gradient (5% [0.05% TFA / CH 3 CN]:95% [0.05% TFA / H 2 HO] to 100% [0.05% TFA / CH 3CN]) with UV detection at 214 nm and 254 nm. Preparative RP-HPLC purification is performed on a custom HP1100 automated purification system with mass-activated collection or using a preparative UV-based system from Gilson Inc. using a Phenomenex Luna C18 column (50x30mm ID 5μm) with a custom acetonitrile (unmodified)-water (0.1% TFA) gradient.

[0470] For LC-MS characterization of the compounds of the invention the following methods are used.

[0471] Method 1: HPLC measurements are performed using an Agilent 1200 system equipped with a degasser, autosampler, column oven, diode array detector (DAD), and binary pump equipped with columns as specified in the individual methods below. The flow from the column is split to an SQ mass spectrometer and a Polymer Labs ELSD. The MS detector is configured with an ES ionization source. Nitrogen is used as the nebulizer gas. The source temperature is maintained at 350° C. Data acquisition is performed with Agilent Chemstation software. Reverse phase HPLC is performed on a Kinetex C18 column (2.6 μm, 2.1×30 μm) from Phenomenex at 45° C. with a flow rate of 1.5 mL / min. The gradient conditions used are: 93% A (water + 0.1% TFA), 7% B (acetonitrile) to 95% B in 1.1 min, returning to initial conditions at 1.11 min. Injection volume 1 μL. Low-resolution mass spectra (single quadrupole MSD detector) are acquired in electrospray mode by scanning 100-700 times at 0.25 s, step width 0.1 and peak width 0.03 min. The capillary needle voltage is 3.0 kV and the fragmentor voltage is 100 V.

[0472] Method 2: Use of the equipment and column conditions of method 1. The gradient conditions used are: 95% A (water + 0.1% TFA), 5% B (acetonitrile) to 95% B in 2.0 min, back to initial conditions at 2.11 min. Injection volume 1 μL. Low-resolution mass spectra (single quadrupole MSD detector) are acquired in electrospray mode by scanning 100-700 times at 0.25 s, step width 0.1 and peak width 0.03 min. The capillary needle voltage is 3.0 kV and the fragmentor voltage is 100 V.

[0473] Method 3: Use of the equipment and column conditions of method 1. The gradient conditions used are: 50% A (water + 0.1% TFA), 50% B (acetonitrile) to 95% B in 2.0 min, back to initial conditions at 2.11 min. Injection volume 1 μL. Low-resolution mass spectra (single quadrupole MSD detector) are acquired in electrospray mode by scanning 100-700 times at 0.25 s, step width 0.1 and peak width 0.03 min. The capillary needle voltage is 3.0 kV and the fragmentor voltage is 100 V.

[0474] 1 H NMR spectra were recorded on either a Bruker DPX-400 or Bruker AV-500 spectrometer with standard pulse sequences operating at 400 MHz and 500 MHz, respectively. Chemical shifts (δ) are reported in parts per million (ppm) downfield from tetramethylsilane (TMS), used as the internal standard. Coupling constants (J values) are reported in Hz.

[0475] The following examples are presented as illustrative examples of the scope and specific embodiments of the present invention, and are not intended to be limiting of the scope of the present invention.Abbreviations and chemical symbols have their usual and customary meanings unless otherwise indicated.Unless otherwise indicated, the compounds described herein may be prepared, isolated and characterized using the schemes and other methods disclosed herein, or may be prepared using them.

[0476] [ka] Intermediate 1 Methyl 2-(2,4-dimethoxybenzyl)-5-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate Standard reductive amination procedure: Dimethyl 2-hydroxy-2,3-dihydrobenzofuran-4,6-dicarboxylate (15.0 g, 59.5 mmol, 1 equiv.) and (2,4-dimethoxyphenyl)methanamine (13.4 mL, 89.2 mmol, 1.5 equiv.) were dissolved in CH 2 Cl 2 (200 mL) and stirred at 30° C. for 30 min. Sodium triacetoxyborohydride (25.2 g, 118.9 mmol, 2 eq) was then added and the reaction was stirred at 30° C. for 3 h. The reaction mixture was concentrated, dissolved in 1,4-dioxane (100 mL) and then heated at 110° C. overnight. Saturated aqueous NaHCO 3 This mixture was then mixed with CH 2 Cl 2 (3x30mL). The combined organic phase was extracted with MgSO 4 Drying at rt and concentration in vacuo gave the title compound (22 g, 59.2 mmol, quantitative), which was used without further purification. 1 H NMR (400 MHz, chloroform-d) δ 8.26 (d, J = 1.6 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.39 (d, J = 7.8 Hz, 2H), 4.73 (s, LCMS (ESI): Method 2: R T = 1.965 min, m / z = 372.1 [M+H] + .

[0477] [ka] Intermediate 2 Methyl 2-(2,4-dimethoxybenzyl)-1-oxo-5-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate Standard triflation procedure: THF:CH 2 Cl 2 To a solution of methyl 2-(2,4-dimethoxybenzyl)-5-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (Intermediate 1, 30.0 g, 80.8 mmol, 1 equiv.) and N,N-diisopropylethylamine (35 mL, 201.9 mmol, 2.5 equiv.) in (5:1, 360 mL) was added phenyltriflimide (34.6 g, 96.9 mmol, 1.2 equiv.) at 23 °C and stirred for 14 h. Saturated aqueous NaHCO 3 This mixture was then mixed with CH 2 Cl 2 (3x30mL). The combined organic phase was extracted with MgSO 4 The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc=0-100% gradient) to give the title compound (24.5 g, 48.7 mmol, 82% yield) as an oil. 1 H NMR (400 MHz, chloroform-d) δ 8.80 (d, J = 1.6 Hz, 1H), 8.02 (d, J = 1.6 Hz, 1H), 7.33 - 7.27 (m, 1H), 6.49 - 6.43 (m, 2H), 4.74 (s, 2H), LCMS (ESI): Method 3: R T = 2.546 min, m / z = 504.0 [M+H] + .

[0478] [ka] Intermediate 3 Methyl 2-(2,4-dimethoxybenzyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate Standard Suzuki coupling procedure: Methyl 2-(2,4-dimethoxybenzyl)-1-oxo-5-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (Intermediate 2, 12.3 g, 24.3 mmol, 1 equiv.), (1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (7.1 mg, 36.4 mmol, 1.5 equiv.), potassium carbonate (8.4 g, 60.8 mmol, 2.5 equiv.) and PdCl 2 (dppf) (890 mg, 1.2 mmol, 0.05 equiv) was dissolved in 1,4-dioxane:water (4:1, 5 mL) in a sealed tube under Ar atmosphere. The reaction mixture was stirred at 90° C. for 14 h and then cooled to 23° C. Brine was added to the mixture and then extracted with EtOAc (3×20 mL). The combined organic layers were washed with MgSO 4 The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc=0-100% gradient) to give the title compound (11.0 g, 21.8 mmol, 90% yield). 1H NMR (400 MHz, chloroform-d) δ 8.81 (d, J = 1.9 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.36 (d, J = 1.1 Hz, 1H), 7.31 - 7.27 (m, 1H), 6.45 (dd, J = 6.2, 2.5 Hz, 2H), 4.73 (s, 2H), 4.00 (s, 3H), 3.92 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.46 (t, J = 6.6 Hz, 2H), 2.75 (t, J = 6.5 Hz, 2H); LCMS (ESI): Method 2: R T = 1.072 min, m / z = 504.4 [M+H] + .

[0479] [ka] Intermediate 4 Methyl 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate Standard TFA deprotection procedure: CH 2 Cl 2 To a solution of methyl 2-(2,4-dimethoxybenzyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (Intermediate 3, 22.0 g, 43.7 mmol, 1 equiv.) in 1H-pyrazol-4-yl (50 mL) and TFA (100 mL) was added anisole (24 mL, 218 mmol, 5 equiv.). The reaction was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was dissolved in EtOAc and saturated NaHCO 3 The organic layer was dried (MgSO 4 ) and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, gradient of Hex / EtOAc = 0 to 100%, then MeOH / CH 2 Cl 2= 0 to 10% gradient) to give the title compound (13.5 g, 38.2 mmol, 87% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.77 (d, J = 1.6 Hz, 1H), 8.05 (d, J = 1.6 Hz, 1H), 7.40 (s, 1H), 6.25 (s, 1H), 4.03 (s, 3H), 3.92 (s, 3H), 3.51 (td, J = 6.5, 2.8 Hz, 2H), 2.84 (t, J = 6.5 Hz, 1H); LCMS (ESI): Method 2: R T = 1.363 min, m / z = 354.1 [M+H] + .

[0480] [ka] Intermediate 5 7-(hydroxymethyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one Standard reduction procedure for methyl esters: To a solution of methyl 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (Intermediate 4, 457 mg, 1.3 mmol, 1 equiv.) in THF at 0° C. was added lithium triethylborohydride (4 mL, 3.9 mmol, 3 equiv.) dropwise. The reaction was stirred for 40 min and then the reaction was diluted with saturated aqueous NaHCO 3 The mixture was then extracted with EtOAc. The combined organic layers were washed with MgSO 4 Concentration at 40° C. and drying under reduced pressure gave the title compound (420 mg, 1.3 mmol, quantitative), which was used without further purification. LCMS (ESI): Method 2: R T =1.145 min, m / z=326.1[M+H] + .

[0481] [ka] Intermediate 6 7-(Bromomethyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one Standard bromination procedure: CH of 7-(hydroxymethyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 5, 420 mg, 1.3 mmol, 1 equiv.) 2 Cl 2 (10 mL) solution at 0°C. 3 (0.2 mL, 2.6 mmol, 2 equiv) was added. The reaction was allowed to warm to room temperature and stirred overnight. Saturated aqueous NaHCO 3 was added and the mixture was extracted with EtOAc. The combined organic layers were washed with MgSO 4 Drying at rt and concentration afforded the title compound (440 mg, 1.3 mmol, quantitative), which was used in the next step without further purification. 1 H NMR (400 MHz, chloroform-d) δ 8.15 (d, J = 2.0 Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 1.1 Hz, 1H), 4.51 (s, 2H), 4.02 (s, 3H), 3.48 (td, J = 6.5, 2.7 Hz, 2H), 2.79 (t, J = 6.5 Hz, 2H); LCMS (ESI): m / z = 387.9 [M+H] + .

[0482] [ka] Intermediate 7 7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one Standard bromide displacement procedure: To a solution of 7-(bromomethyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 6, 1.0 g, 2.6 mmol, 1 equiv.) in acetonitrile (15 mL) was added 2-methyl-1H-imidazole (846 mg, 10.3 mmol, 4 equiv.) at 23° C. The reaction mixture was stirred at 50° C. for 12 h, then cooled to ambient temperature, filtered and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM / MeOH=0-10% gradient) to give the title compound (700 mg, 1.8 mmol, 70% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.01 (d, J = 2.0 Hz, 1H), 7.32 (s, 1H), 6.95 (d, J = 1.4 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 1.4 Hz, LCMS (ESI): Method 2: R T = 0.973 min, m / z = 390.0 [M+H] + .

[0483] [ka] Intermediate 8 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one To a solution of 7-(bromomethyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 6, 1.3 g, 3.3 mmol, 1 equiv.) in acetonitrile (15 mL) was added 1H-imidazole (0.91 g, 13 mmol, 4 equiv.) at 23° C. The reaction mixture was stirred at 50° C. for 12 h, then cooled to ambient temperature, filtered and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM / MeOH=0-10% gradient) to give the title compound (750 mg, 2.0 mmol, 60% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.03 (brs, 1H), 8.01 (d, J = 1.1 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 1.2 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.19 - 7.15 LCMS (ESI):Method 2: R T = 0.979 min, m / z = 376.0 [M+H] + .

[0484] [ka] Intermediate 9 4-Bromo-6-methoxycinnoline 6-Methoxycinnoline-4(1H)-one (84.0 mg, 0.477 mmol, 1 equiv) was dissolved in acetonitrile (4 mL) and stirred at room temperature. Potassium carbonate (198 mg, 1.43 mmol, 3 equiv) and phosphorus oxybromide (410 mg, 1.43 mmol, 3 equiv) were added and the reaction was placed in a reaction block preheated to 60° C. The reaction was quenched by adding ice and water. Saturated NaHCO3 The pH of this mixture was adjusted to 7-9 by adding 2 Cl 2 (3x20mL). The combined organic layers were extracted with MgSO 4 The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc=0-100% gradient) to give the title compound (38 mg, 0.16 mmol, 33% yield). 1 LCMS (ESI): Method 2: R T = 1.429 min, m / z = 239.1 [M+H] + .

[0485] [ka] Intermediate 10 Ethyl 6-bromo-4-hydroxyquinoline-8-carboxylate Step A. Preparation of ethyl 5-bromo-2-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)benzoate. To a solution of ethyl 2-amino-5-bromobenzoate (5.0 g, 16.6 mmol) and Meldrum's acid (1.2 equiv) in EtOH (25 mL) was added triethyl orthoformate (1 equiv). The reaction was stirred at 80° C. overnight. The reaction was cooled to 0° C., filtered, and washed with cold EtOH to give the title compound.

[0486] Step B. Preparation of ethyl 6-bromo-4-hydroxyquinoline-8-carboxylate. Ethyl 5-bromo-2-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)benzoate (16.6 mmol) was added in small portions to Dowtherm A (10 mL) at 260° C. and stirred for 30 min. The reaction was cooled to room temperature and hexane was added. The resulting mixture was filtered and the solid was washed with hexane to give the title compound (3.70 g, 12.5 mmol, 79.9% yield for two steps). 1 H NMR (400 MHz, chloroform-d) δ 8.75 (d, J = 2.2 Hz 1H), 8.45 (d, J = 2.3 Hz, 1H), 7.69-7.65 (m, 1H), 6.35 (dd, J = 1.1 Hz, 1H), 4.46 (q, J = 7.0 2H), 1.46 (t, J = 7.1 3H); LCMS (ESI): m / z = 295.9 [M+H] + .

[0487] [ka] Intermediate 11 Ethyl 6-ethyl-4-hydroxyquinoline-8-carboxylate In a sealed tube, ethyl 6-bromo-4-hydroxyquinoline-8-carboxylate (Intermediate 10, 1.49 g, 5.03 mmol) in THF (20 mL), triethylborane (2 equiv., 1 M THF), cesium carbonate (2 equiv.) and Pd(dppf)Cl 2 (0.05 equiv.) was stirred at 60° C. under Ar for 3 h. The reaction was cooled to 0° C. and diluted with 10% aqueous NaOH and 30% aqueous H 2 O 2 The mixture was warmed to 23 °C, brine was added, and the mixture was extracted with EtOAc (3x50 mL). The combined organic layers were washed with MgSO 4The residue was purified by flash chromatography (Combi-flash Rf, gradient of 0-100% Hex / EtOAc, then gradient of 0-10% DCM / MeOH) to give the title compound (700 mg, 2.85 mmol, 57% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.49 (s, 1H), 8.25 (s, 1H), 7.69 (t, J = 7.7 Hz, 1H), 6.35 (d, J = 4.1 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 2.80 (q, J = 7.6 Hz, 2H), 1.47 (t, J = 7.1 3H), 1.35 (t, J = 7.6 3H); LCMS (ESI): m / z = 246.1 [M+H] + .

[0488] [ka] Intermediate 12 Ethyl 4-bromo-6-ethylquinoline-8-carboxylate A solution of ethyl 6-ethyl-4-hydroxyquinoline-8-carboxylate (Intermediate 11, 610 mg, 2.49 mmol) in DMF (15 mL) was added to PBr at 0 °C. 3 (2 equiv.) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with ice and the pH of the mixture was adjusted to 0.05 with NaHCO 3 The mixture was adjusted to 7 by addition of 1.5 mL of 1.25 ml of 10 ... 1H NMR (400 MHz, chloroform-d) δ 8.48 (s, 1H), 8.35 (s, 1H), 8.27 (t, J = 7.0 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 4.50 (q, J = 7.1 Hz, 2H), 2.80 (q, J = 7.6 Hz, 2H), 1.49 (t, J = 7.4 3H), 1.33 (t, J = 7.6 3H); LCMS (ESI): m / z = 309.1 [M+H] + .

[0489] [ka] Intermediate 13 5-Bromo-3-methoxy-7-methylquinoline Step A. Preparation of 2,6-dibromo-4-methylbenzaldehyde. To a solution of 1,3-dibromo-5-methylbenzene (21.0 g, 84 mmol) in anhydrous THF (200 mL) was added dropwise 2.0 M lithium diisopropylamide solution (58.8 mL, 1.4 equiv.) at -78 °C. The reaction mixture was stirred for 30 min, then DMF (7.8 mL, 1.2 equiv.) was added. The reaction was stirred at -78 °C for 1 h, then quenched with 1N HCl and EtOAc. The quenched mixture was extracted with EtOAc (2x200 mL), the organic layer was washed with brine, and MgSO 4 The mixture was dried at 40° C., filtered, and concentrated to give the title compound (23.0 g, 98%). 1 H NMR (400 MHz, chloroform-d) δ 10.26 (s, 1H), 7.49 (s, 2H), 2.39 (s, 3H).

[0490] Step B. Preparation of 2-(2,6-dibromo-4-methylphenyl)-1,3-dioxolane. A mixture of 2,6-dibromo-4-methylbenzaldehyde (23.0 g, 83 mmol), ethane-1,2-diol (11 mL, 2.3 equiv.) and p-toluenesulfonic acid monohydrate (7.9 g, 0.5 equiv.) in anhydrous toluene (200 mL) was refluxed using a Dean-Stark trap until TLC showed no starting material. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in DCM (200 mL), washed with aqueous 1N NaOH (50 mL) and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc=0-5% gradient) to give the title compound (15.7 g, 59%). 1 H NMR (400 MHz, chloroform-d) δ 7.39 (s, 2H), 6.36 (s, 1H), 4.35-4.31 (m, 2H), 4.08-4.05 (m, 2H), 2.29 (s, 3).

[0491] Step C. Preparation of N-(3-bromo-2-(1,3-dioxolan-2-yl)-5-methylphenyl)-1,1-diphenylmethanimine. A mixture of 2-(2,6-dibromo-4-methylphenyl)-1,3-dioxolane (15.7 g, 48.8 mmol), benzophenone imine (8.2 mL, 1.0 equiv), cesium carbonate (31.8 g, 2.0 equiv), BINAP (3.0 g, 0.1 equiv) and palladium(II) acetate (0.55 g, 0.05 equiv) in anhydrous toluene (200 mL) was purged with Ar and then stirred at 80° C. for 16 h. The reaction mixture was cooled to ambient temperature and purified with H. 2 The mixture was quenched with O (200 mL). The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and MgSO 4The mixture was dried at 40° C., filtered and concentrated. The residue was triturated with DCM (200 mL). The solid was filtered to give the title compound. The filtrate was concentrated and the residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc=0-10% gradient) to give additional title compound (17.1 g, 83% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.67-7.62 (m, 2H), 7.57-7.46 (m, 3H), 7.34 (bs, 3H), 7.24 (bs, 2H), 7.00 (s, 1H), 6.16 (s, 1H), 6.14 (s, 1H), 4.02-3.98 (m, 2H), 3.88-3.84 (m, 2H), 2.01 (s, 3H).

[0492] Step D. Preparation of 2-amino-6-bromo-4-methylbenzaldehyde. To a solution of N-(3-bromo-2-(1,3-dioxolan-2-yl)-5-methylphenyl)-1,1-diphenylmethanimine (17.1 g, 40.5 mmol) in THF (100 mL) was added aqueous 1N HCl (100 mL, 2.5 equiv.). The reaction mixture was stirred at 80° C. for 2 h and then cooled to ambient temperature. The mixture was neutralized with aqueous 6N NaOH. The mixture was extracted with EtOAc and the combined organic layers were washed with brine and diluted with MgSO 4 The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc 0-10% gradient) to give the title compound (6.3 g, 73%) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 10.30 (s, 1H), 6.73 (s, 1H), 6.38 (s, 1H), 2.23 (s, 3H); LCMS method 2: >95% purity 254 nm, R T = 1.74 min, MS (ESI) 214.0 [M+H] + .

[0493] Step E. Preparation of 5-bromo-3-methoxy-7-methylquinoline. To a solution of 2-amino-6-bromo-4-methylbenzaldehyde (1.0 mmol) in ethanol was added methoxyacetaldehyde (1.2 equiv.) and 1M aqueous NaOH (2.0 equiv.). The reaction was heated in a microwave at 110° C. for 30 min. The reaction was cooled to room temperature, poured into dichloromethane and washed with brine. The layers were separated and the organic layer was concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc 0-15% gradient) to give the title compound. 1 H NMR (400 MHz, chloroform-d) δ 8.63 (d, J=2.7 Hz, 1H), 7.80 (s, 1H), 7.68-7.66 (m, 2H), 3.99 (s, 3H), 2.51 (s, 3H).

[0494] [ka] Intermediate 14 4-Bromo-6-ethyl-8-methoxy-1,7-naphthyridine Step A: Preparation of 6-ethyl-2-methoxypyridin-3-amine. In a round-bottom flask, 6-bromo-2-methoxypyridin-3-amine (1100 mg, 5.4 mmol, 1 equiv.), PdCl 2 (dppf)-CH 2 Cl 2 The adduct (221 mg, 0.27 mmol, 0.05 equiv) was dissolved in THF (20 mL) and placed at room temperature under an argon atmosphere. Diethylzinc (3.5 mL, 3.5 mmol, 0.65 equiv, 1M hexane) was added dropwise and the reaction mixture was then placed on a preheated heating block and stirred at 65° C. for 4 h. At 23° C., the mixture was diluted with saturated NH 4 Cl was added and extracted with EtOAc (3x20 mL). The combined organic layers were washed with MgSO 4The mixture was dried at 40° C. and concentrated under reduced pressure. After purification by column chromatography (Combi-flash Rf, Hex / EtOAc=0-70%, gradient), the title compound (645 mg, 4.2 mmol, 78% yield) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 7.54 (d, J = 7.5 Hz, 1H), 6.54 (d, J = 7.5 Hz, 1H), 3.97 (s, 3H), 3.61 (brs, 2H), 2.62 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H); LCMS (ESI): Method 2: R T = 1.473 min, m / z = 153.2 [M+H] + .

[0495] Step B: Preparation of 5-(((6-ethyl-2-methoxypyridin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione. In a round bottom flask, 6-ethyl-2-methoxypyridin-3-amine (10.5 g, 69 mmol, 1 equiv) and 2,2-dimethyl-1,3-dioxane-4,6-dione (11.9 g, 83 mmol, 1.2 equiv) were dissolved in EtOH (200 mL). Triethoxymethane (11 mL, 69 mmol, 1 equiv) was then added and the reaction was stirred at 80° C. overnight. The reaction was cooled to 0° C., filtered and washed with cold EtOH to give the title compound (18.0 g, 58.8 mmol, 85% yield). 1 H NMR (400 MHz, chloroform-d) δ 11.33 (d, J = 14.5 Hz, 1H), 8.60 (d, J = 14.6, 1H), 7.47 (d, J = 7.9 Hz, 1H), 6.80 (d, J = 7.9 Hz, 1H), 4.07 (s, 3H), 2.74 (q, J = 7.5 Hz, 2H), 1.75 (s, 6H), 1.29 (t, J = 7.5 Hz, 3H); LCMS (ESI): Method 2: R T = 2.070 min, m / z = 307.0 [M+H] + .

[0496] Step C: Preparation of 6-ethyl-8-methoxy-1,7-naphthyridin-4-ol. Finely powdered 5-(((6-ethyl-2-methoxypyridin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (6.13 g, 20.00 mmol, 1 equiv.) was added in portions over 15 min to vigorously stirred Dowtherm A (80 mL) at 228° C., then stirred for an additional 15 min. The reaction was immediately cooled in a room temperature water bath with constant stirring. Hexane was added to form a precipitate, which was filtered and washed with hexane to give the title compound (2.50 g, 12.2 mmol, 61% yield). The title compound was purified by flash column chromatography (Combi-flash Rf, DCM / MeOH = This was further purified by elution with 0% to 10% gradient. 1 H NMR (400 MHz, chloroform-d) δ 8.87 (brs, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.52 (s, 1H), 6.38 (d, J = 7.5 Hz, 1H), 4.12 (s, 3H), 2.80 (q, J = 7.5 Hz, 2H), 1.31 (t, J = 7.6 Hz, 3H); LCMS (ESI): Method 2: R T = 1.099 min, m / z = 205.2 [M+H] + .

[0497] Step D: Preparation of 6-ethyl-8-methoxy-1,7-naphthyridin-4-yl trifluoromethanesulfonate. 6-Ethyl-8-methoxy-1,7-naphthyridin-4-ol (7.17 g, 35.0 mmol, 1 equiv) was dissolved in DMF (150 mL) and stirred at room temperature. 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (18.83 g, 52.7 mmol, 1.5 equiv) was added followed by N,N-diisoproplyethylamine (15 mL, 87.8 mmol, 2.5 equiv) and DMAP (86 mg, 0.70 mmol, 0.02 equiv) and the reaction was stirred at 50° C. for 4 h. The reaction was diluted with EtOAc and saturated NH 4 The organic layer was extracted with MgSO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure. After purification by column chromatography (Combi-flash Rf, Hex / EtOAc=0-100%, gradient), the title compound (9.89 g, 29.4 mmol, 84% yield) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 8.95 (d, J = 5.2 Hz, 1H), 7.57 (d, J = 4.8 Hz, 1H), 7.22 (s, 1H), 4.22 (s, 3H), 2.90 (q, J = 7.6 Hz, 2H), 1.38 (t, J = 7.5 Hz, 3H); LCMS (ESI): Method 2: R T = 1.861 min, m / z = 337.0 [M+H] + .

[0498] Step E: Preparation of 4-bromo-6-ethyl-8-methoxy-1,7-naphthyridine. 6-Ethyl-8-methoxy-1,7-naphthyridin-4-yl trifluoromethanesulfonate (9.89 g, 29.4 mmol, 1 equiv) was dissolved in acetonitrile (200 mL) and stirred at room temperature. Lithium bromide (25.5 g, 294 mmol, 10 equiv) was added and the reaction was stirred at 80° C. overnight. The reaction was cooled to room temperature and concentrated under reduced pressure. The reaction was diluted with EtOAc and water and extracted with EtOAc. The organic layer was removed using MgSO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure. After purification by column chromatography (Combi-flash Rf, Hex / EtOAc=0-100%, gradient), the title compound (6.51 g, 24.4 mmol, 83% yield) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 8.63 (d, J = 4.7 Hz, 1H), 7.81 (d, J = 4.6 Hz, 1H), 7.31 (s, 1H), 4.22 (s, 3H), 2.87 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.5 Hz, 3H); LCMS (ESI): Method 2: R T = 1.628 min, m / z = 267.0 [M+H] + .

[0499] [ka] Intermediate 15 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-methoxy-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 1.0 equiv.), 4-bromo-6-ethyl-8-methoxy-1,7-naphthyridine (Intermediate 14, 2.0 equiv.), cesium carbonate (2.0 equiv.), Xantphos (0.2 equiv.) and Pd 2 (dba) 3 (0.1 equiv.) was dissolved in 1,4-dioxane under Ar. The reaction mixture was stirred at 110° C. for 14 h and then cooled to 23° C. Brine was added to the mixture and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with MgSO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. 2 O / CH 3 Gradient of CN, 15-85% CH 3 The residue was purified by elution with 100% TFA (CN, 0.1% TFA) and then saturated aqueous NaHCO 3 Neutralization with afforded the title compound. 1 H NMR (400 MHz, chloroform-d) δ 8.93 (d, J=4.6 Hz, 1H), 8.15 (s, 1H), 7.59 (s, 1H), 7.47 (d, J=4.6 Hz, 1H), 7.41 (s, 1H), 7.18 (s, 1H), 7.11 (s, 1H), 6.95 (s, 2H), 5.20 (s, 2H), 4.22 (s, 3H), 4.02 (s, 3H), 4.00-3.96 (m, 1H), 3.84-3.78 (s, 1H), 3.19-3.11 (m, 1H), 3.00-2.94 (m, 1H), 2.81 (q, J=7.5 Hz, 2H), 1.32 (t, J=7.5 Hz, 3H); LCMS method 2: >95%, R T = 1.40 minutes, MS (ESI) 562.0 [M+H] + .

[0500] [ka] Intermediate 16 (S)-6-Ethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine dihydrochloride

[0501] Step A: Preparation of (R,E)-N-((5-bromo-2-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide. A solution of 5-bromo-2-fluoronicotinaldehyde (4.0 g, 20 mmol, 1 equiv.) in dichloromethane (80 mL) was reacted with (R)-2-methylpropane-2-sulfinamide (2.4 g, 20 mmol, 1 equiv.) and Cs 2 CO 3 (9.6 g, 29 mmol, 1.5 equiv.) was added. The resulting mixture was stirred at room temperature for 36 h and then washed with water. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. The residue was purified by silica gel column chromatography (Combi-flash Rf, Hex / EtOAc=0-20%, gradient) to give the title compound (5.1 g, 17 mmol, 85% yield). LCMS (ESI): m / z=349.0 [M+H] + .

[0502] Step B: Preparation of (R)-N-((S)-1-(5-bromo-2-fluoropyridin-3-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide. To a solution of (R,E)-N-((5-bromo-2-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide (1.55 g, 5.05 mmol, 1 equiv) in THF (35 mL) was added 1 M allylzinc bromide (7.57 mL, 7.57 mmol, 1.5 equiv) dropwise at -78 °C. The resulting mixture was stirred for 45 min and then washed with saturated NH 4 The mixture was quenched with aqueous Cl and extracted with EtOAc. The combined organic layers were washed with Na 2 SO 4The residue was purified by silica gel column chromatography (Combi-flash Rf, Hex / EtOAc=0-50%, gradient) to give the title compound (1.7 g, 4.9 mmol, 96% yield, dr=93:7). 1 H NMR (400 MHz, chloroform-d) Main isomer: δ 8.19 (m, 1H), 7.87 (dd, J = 2.4, 4.0 Hz, 1H), 5.71 (m, 1H), 5.22 (m, 2H), 4.71 (m , 1H), 3.68 (d, J = 2.8 minor isomer: δ 8.19 (m, 1H), 7.87 (dd, J = 2.4, 4.0 Hz, 1H), 5.64 (m, 1H), 5.14 (m, 2H), 4.57 (m , 1H), 3.74 (d, J = 7.6 Hz, 1H), 2.69 (m, 1H), 2.54 (m, 1H), 2.05 (s, 1H), 1.23 (s, 9H).

[0503] Step C: Preparation of (R)-N-((S)-1-(5-bromo-2-fluoropyridin-3-yl)-3-hydroxypropyl)-2-methylpropane-2-sulfinamide. A solution of (R)-N-((S)-1-(5-bromo-2-fluoropyridin-3-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (1.76 g, 5.04 mmol, 1 equiv) in MeOH (75 mL) was added with 0.5 mL of 0.5% CO.sub.2O. 3 The reaction was vented and the progress of the reaction was monitored by LCMS. Once the starting material was consumed, KF (351 mg, 6.04 mmol, 1.2 equiv) was added and the acetone / dry ice bath was replaced with an ice bath. The resulting mixture was stirred at 0° C. for 30 min, then added NaBH 4 (381.3 mg, 10.08 mmol, 2 equiv) was added and stirring was continued for an additional hour. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc and washed with brine / water. The organic layer was extracted with Na 2 SO 4The residue was purified by silica gel column chromatography (Combi-flash Rf, Hex / EtOAc=0-80%, gradient) to give the title compound (770 mg, 2.18 mmol, 43% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.18 (s, 1H), 7.91 (d, J = 4.0 Hz, 1H), 4.82 (m, 2H), 3.90 (m, 2H), 2.03 (m, 2H), 1.25 (s, 9H).

[0504] Step D: Preparation of (R)-N-((S)-6-bromo-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)-2-methylpropane-2-sulfinamide. To a solution of (R)-N-((S)-1-(5-bromo-2-fluoropyridin-3-yl)-3-hydroxypropyl)-2-methylpropane-2-sulfinamide (770 mg, 2.18 mmol, 1 equiv) in 1,4-dioxane (22 mL) was added tBuOK (501.4 mg, 4.47 mmol, 2.05 equiv). The resulting mixture was stirred at 53° C. for 1 h, then quenched with brine / water and extracted with EtOAc. The combined organic layers were washed with NaCl and concentrated. 2 SO 4 The residue was purified by silica gel column chromatography (Combi-flash Rf, DCM / MeOH=0-10% gradient) to give the title compound (698 mg, 2.09 mmol, 96% yield). LCMS (ESI): m / z=333.0 [M+H] + .

[0505] Step E: Preparation of (R)-2-methyl-N-((S)-6-vinyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)propane-2-sulfinamide. A solution of (R)-N-((S)-6-bromo-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)-2-methylpropane-2-sulfinamide (227.6 mg, 0.68 mmol, 1 equiv) in EtOH (7 mL) was diluted with potassium vinyltrifluoroborate (137 mg, 1.02 mmol, 1.5 equiv), PdCl 2 (dppf) (25 mg, 34 μmol, 0.05 equiv.) and Et 3 N (237 μL, 1.7 mmol, 2.5 equiv) was added. The resulting mixture was stirred in a sealed tube at 80° C. for 16 h and then concentrated. The residue was dissolved in EtOAc and washed with brine / water. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. The residue was purified by silica gel column chromatography (Combi-flash Rf, Hex / EtOAc=50-100% gradient) to give the title compound (113.4 mg, 0.4 mmol, 59% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.16 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 6.63 (dd, J = 10.8, 17.6 Hz, 1H), 5.64 (d, J = 17.6 Hz, 1H), 5.24 (d, J = 10.8 Hz, 1H), 4.57 (m, 1H), 4.40 (m 2H), 3.53 (d, J = 10.4 Hz, 1H), 2.45 (m, 1H), 2.15 (m, 1H), 1.28 (s, 9H).

[0506] Step F: Preparation of (R)-N-((S)-6-ethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)-2-methylpropane-2-sulfinamide. To a solution of (R)-2-methyl-N-((S)-6-vinyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)propane-2-sulfinamide (113 mg, 0.4 mmol, 1 equiv) in EtOH (6 mL) was added 10% Pd on carbon (42 mg, 40 μmol, 0.1 equiv). The resulting mixture was subjected to H 2 The mixture was stirred under atmosphere for 16 h, then filtered through a plug of Celite. The combined filtrate was concentrated, and the residue was purified by silica gel column chromatography (Combi-flash Rf, Hex / EtOAc=50-100% gradient) to give the title compound (108 mg, 0.38 mmol, 95% yield). 1 H NMR (400 MHz, chloroform-d) δ 7.96 (s, 1H), 7.51 (s, 1H), 4.53 (m, 1H), 4.35 (m, 2H), 3.56 (d, J = 9.2 Hz, 1H), 2.56 (q, J = 7.6 Hz, 2H), 2.41 (m, 1H), 2.12 (m, 1H), 1.25 (s, 9H), 1.19 (t, J = 76 Hz, 3H).

[0507] Step G: Preparation of (S)-6-ethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine hydrochloride. To a solution of (R)-N-((S)-6-ethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)-2-methylpropane-2-sulfinamide (155 mg, 0.55 mmol, 1 equiv) in THF (5.5 mL) at 0° C. was added 4M HCl in 1,4-dioxane (2.74 mL, 10.98 mmol, 20 equiv). The resulting mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated and diethyl ether (2 mL) was added. The resulting suspension was filtered and the solid was dried under vacuum to give the title compound (136 mg, 0.54 mmol, 98% yield). LCMS(ESI): m / z=179.2[M+H] + .

[0508] [ka] Intermediate 17 5-Hydroxy-1-oxoisochroman-7-carboxylate methyl ester Dimethyl 2-hydroxy-2,3-dihydrobenzofuran-4,6-dicarboxylate (110 mg, 0.436 mmol, 1 equiv.) was dissolved in EtOH (4 mL) and then cooled to 20° C. with NaBH 4 (20 mg, 0.523 mmol, 1.2 equiv) was added in small portions. Upon completion, the reaction was concentrated under reduced pressure. The reaction mixture was diluted with EtOAc and saturated NH 4 The mixture was diluted with Cl and extracted with EtOAc. The organic layer was washed with MgSO 4 The mixture was dried at rt and concentrated under reduced pressure, and the title compound (105 mg, 0.473 mmol, quantitative) was used without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.53 (s, 1H), 7.97 (d, J = 1.2 Hz, 1H), 7.65 (d, J = 1.4 Hz, 1H), 4.50 (t, J = 6.1 Hz, 2H), 3.86 (s, 3H), 2.97 (t, J = 6.0 Hz, 2H); LCMS (ESI): Method 2: R T = 1.460 min, m / z = 223.0 [M+H] + .

[0509] [ka] Intermediate 18 1-Oxo-5-(((trifluoromethyl)sulfonyl)oxy)isochroman-7-carboxylate methyl ester THF:CH 2 Cl 2To a solution of methyl 5-hydroxy-1-oxoisochroman-7-carboxylate (Intermediate 17, 100 mg, 0.45 mmol, 1 equiv.) and N,N-diisopropylethylamine (0.2 mL, 1.35 mmol, 3 equiv.) in (5:1, 4.8 mL) was added phenyltriflimide (209 mg, 0.58 mmol, 1.3 equiv.) at 23 °C and stirred for 14 h. Saturated aqueous NaHCO 3 This mixture was then mixed with CH 2 Cl 2 (3x20mL). The combined organic phase was extracted with MgSO 4 The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc=0-100% gradient) to give the title compound (136 mg, 0.38 mmol, 86% yield). 1 LCMS (ESI): Method 2: R T = 1.724 min, m / z = 355.0 [M+H] + .

[0510] [ka] Intermediate 19 Methyl 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxoisochroman-7-carboxylate Methyl 1-oxo-5-(((trifluoromethyl)sulfonyl)oxy)isochroman-7-carboxylate (Intermediate 18, 18.5 g, 52.2 mmol, 1 equiv.), (1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (15.2 g, 78.3 mmol, 1.5 equiv.), potassium carbonate (18.0 g, 131 mmol, 2.5 equiv.) and PdCl 2(dppf) (1.91 g, 2.6 mmol, 0.05 equiv) was dissolved in 1,4-dioxane:water (4:1, 150 mL) in a sealed tube under argon atmosphere. The reaction mixture was stirred at 90° C. for 1 h and then cooled to 23° C. Brine was added to the mixture and then the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with MgSO 4 The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc=0-100% gradient) to give the title compound (16.0 g, 45 mmol, 86% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.80 (d, J = 1.5 Hz, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.42 (s, 1H), 4.48 (t, J = 5.9 Hz, 2H), 4.04 (s, 3H), 3.95 (s, 3H), 2.90 (t, J = 5.9 Hz, 2H); LCMS (ESI): Method 2: R T = 1.588 min, m / z = 355.0 [M+H] + .

[0511] [ka] Intermediate 20 7-(hydroxymethyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)isochroman-1-one Step A: Preparation of 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxoisochroman-7-carboxylic acid. Methyl 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxoisochroman-7-carboxylate (Intermediate 19, 1.027 g, 2.90 mmol, 1 equiv.) was dissolved in THF:water (3:1, 26.7 mL) at room temperature. Lithium hydroxide (139 mg, 5.8 mmol, 2 equiv.) was then added and the reaction was stirred overnight. 2M HCl was added and stirred for 2 h until lactone hydrolysis was detected by LCMS and pH<2. The pH of the mixture was adjusted to 0.5 with saturated NaHCO 3 The pH was adjusted to 4-5 with CH 2 Cl 2 (3x30mL). The organic layer was extracted with MgSO 4 Drying at rt and concentration under reduced pressure gave the title compound (0.972 g, 2.86 mmol, 99% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.49 (d, J = 1.6 Hz, 1H), 8.12 (s, 1H), 8.02 (d, J = 1.4 Hz, 1H), 4.47 (t, J = 5.9 Hz, 2H), 3.99 (s, 3H), 2.93 (t, J = 5.9 Hz, 2H); LCMS (ESI): Method 2: R T = 1.354 min, m / z = 341.0 [M+H] + .

[0512] Step B: Preparation of 7-(hydroxymethyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)isochroman-1-one. 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxoisochroman-7-carboxylic acid (855.3 mg, 1 equiv, 2.514 mmol) was dissolved in CH 2 Cl 2(10 mL) and added CDI (489.1 mg, 1.2 equiv, 3.016 mmol) at 25° C. The slurry dissolved almost immediately and the reaction was stirred for 3 h. The reaction was concentrated under reduced pressure and then redissolved in THF (8 mL) and cooled to 0° C. NaBH 4 (190.2 mg, 2 equiv., 5.0 mmol) was added followed by the dropwise addition of water (2 mL). The reaction was quenched by the addition of MeOH (1 mL) and then CH 2 Cl 2 The organic layer was extracted with saturated NH 4 Wash with Cl and MgSO 4 The residue was purified by flash chromatography (Combi-flash Rf, gradient of 0-100% Hex / EtOAc, then gradient of 0-10% DCM / MeOH) to give the title compound (580.2 mg, 1.78 mmol, 71% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.05 (s, 1H), 7.96 (s, 1H), 7.47 (s, 1H), 5.39 (t, J = 5.7 Hz, 1H), 4.56 (d, J = 5.5 Hz, 2H), 4.42 (t, J = 5.9 Hz, 2H), 3.98 (s, 3H), 2.81 (t, J = 5.9, 2H); LCMS (ESI): Method 2: R T = 1.374 min, m / z = 327.1 [M+H] + .

[0513] [ka] Intermediate 21 7-(Bromomethyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)isochroman-1-one CH of 7-(hydroxymethyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)isochroman-1-one (Intermediate 20, 9.0 g, 28 mmol, 1 equiv.) 2 Cl2 (100 mL) solution at 0°C. 3 (5.2 mL, 55 mmol, 2 equiv.) was added. The reaction was allowed to warm to room temperature and stirred overnight. Saturated aqueous NaHCO 3 was added and the mixture was extracted with EtOAc. The combined organic layers were washed with MgSO 4 The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc=0-100% gradient) to give the title compound (7.57 g, 19.5 mmol, 71% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.17 (d, J = 1.9 Hz, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.42 (s, 1H), 4.50 (s, 2H), 4.45 (t, J = 6.0 Hz, 2H), 4.03 (s, 3H), 2.84 (t, J = 6.0 Hz, 2H); LCMS (ESI): Method 2: R T = 1.983 min, m / z = 388.9 [M+H] + .

[0514] [ka] Intermediate 22 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)isochroman-1-one To a solution of 7-(bromomethyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)isochroman-1-one (Intermediate 21, 7.57 g, 19.5 mmol, 1 equiv.) in acetonitrile (100 mL) was added imidazole (3.97 g, 58.4 mmol, 3 equiv.) at 23° C. The reaction mixture was stirred at 50° C., then cooled to ambient temperature, filtered and concentrated. The residue was purified by HCl distillation. 2 Cl 2 The combined organic layers were then extracted with saturated aqueous NH 4 Wash with Cl and MgSO 4The residue was purified by flash chromatography (Combi-flash Rf, gradient of 0-100% Hex / EtOAc, then gradient of 0-10% DCM / MeOH) to give the title compound (5.83 g, 15.5 mmol, 80% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.05 (d, J = 1.6 Hz, 1H), 7.55 (s, 1H), 7.35 (s, 1H), 7.17 (d, J = 1.7 Hz, 1H), 7.10 (s, 1H), 6.91 (s, 1H), 5.17 (s, 2H), 4.45 (t, J = 6.0 Hz, 2H), 4.01 (s, 3H), 2.84 (t, J = 6.0 Hz, 2H); LCMS (ESI): Method 2: R T = 1.167 min, m / z = 377.0 [M+H] + .

[0515] [ka] Intermediate 23 Ethyl 5-((1H-imidazol-1-yl)methyl)-2-(2-chloroethyl)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)benzoate A solution of 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)isochroman-1-one (Intermediate 22, 254 mg, 0.68 mmol, 1 equiv.) in EtOH (3.5 mL) was added with SOCl at room temperature. 2 (790 μL, 10.8 mmol, 16 equiv.) was added. The resulting mixture was stirred in a sealed tube at room temperature for 24 h, then saturated NaHCO 3 The mixture was quenched with aqueous solution of 1,2-dichloromethane and the mixture was extracted with EtOAc. The combined organic layers were washed with Na 2 SO 4The residue was purified by silica gel column chromatography (Combi-flash Rf, DCM / MeOH=0-10% gradient) to give the title compound (293 mg, 0.67 mmol, 98% yield). 1 H NMR (400 MHz, chloroform-d) δ 7.75 (d, J = 2.0 Hz, 1H), 7.56 (s, 1H), 7.39 (s, 1H), 7.11 (s, 1H), 7.09 (d, J = 2.0 Hz, 1H), 6.90 (m, 1H), 5.14 (s, 2H), 4.40 (q, J = 7.2 Hz, 2H), 4.03 (s, 3H), 3.54 (t, J = 8.0 Hz, 2H), 3.30 (t, J = 8.0 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H).

[0516] [ka] Intermediate 24 4-Bromo-6,8-dimethoxy-1,7-naphthyridine Step A. Preparation of 5-(((2,6-dimethoxypyridin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione. The title compound (8.48 g, 27.5 mmol, 85% yield) was prepared following the procedure described for Step B of Intermediate 15, substituting 2,6-dimethoxypyridin-3-amine (5.00 g, 32.4 mmol, 1 equiv). 1 H NMR (400 MHz, chloroform-d) δ 11.28 (d, J = 14.2 Hz, 1H), 8.52 (d, J = 14.6 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 6.39 (d, J = 8.4 Hz, 1H), 4.06 (s, 3H), 3.94 (s, 3H), 1.75 (s, 6H).

[0517] Step B. Preparation of 6,8-dimethoxy-1,7-naphthyridin-4-ol. The title compound (412 mg, 0.100 mmol, 4% yield) was prepared following the procedure described for Step C of Intermediate 15, substituting 5-(((2,6-dimethoxypyridin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8.48 g, 27.5 mmol, 1 equiv.). LCMS (ESI): Method 2:R T =1.062 min, m / z=207.1[M+H] + .

[0518] Step C. Preparation of 4-bromo-6,8-dimethoxy-1,7-naphthyridine. A solution of 6,8-dimethoxy-1,7-naphthyridin-4-ol (211 mg, 1.02 mmol, 1 equiv) in DMF (4 mL) was added to PBr at 0 °C. 3 (0.19 mL, 2.05 mmol, 2 equiv.) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with ice and saturated aqueous NaHCO 3 The mixture was extracted with EtOAc. The combined organic layers were washed with MgSO 4 The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc=0-100% gradient) to give the title compound (152 mg, 0.566 mmol, 55% yield). 1 LCMS (ESI): Method 2: R T = 1.682 min, m / z = 269.0 [M+H] + .

[0519] [ka] Intermediate 25 4-Bromo-6-ethyl-8-methoxycinnoline Step A. Preparation of 1-(2-amino-5-ethyl-3-methoxyphenyl)ethan-1-one. In a sealed tube, combine 1-(2-amino-5-bromo-3-methoxyphenyl)ethan-1-one (527 mg, 2.16 mmol, 1 equiv.), triethylborane (4.3 mL, 4.3 mmol, 2 equiv., 1 M THF), cesium carbonate (1.41 g, 4.32 mmol, 2 equiv.) and Pd(dppf)Cl in THF (10 mL). 2 A mixture of (79 mg, 108 μmol, 0.05 equiv) was stirred at 60 °C under Ar for 3 h. The reaction was cooled to 23 °C and quenched by adding a solution of 1:1 (v / v) AcOH:water. The mixture was extracted with EtOAc (3x30 mL). The combined organic layers were diluted with MgSO 4 The residue was purified by flash chromatography (Combi-flash Rf, gradient of 0-100% Hex / EtOAc, then gradient of 0-10% DCM / MeOH) to give the title compound (366 mg, 1.89 mmol, 88% yield). 1 H NMR (400 MHz, chloroform-d) δ 7.13 (d, J = 1.5 Hz, 1H), 6.72 (d, J = 1.5 Hz, 1H), 3.87 (s, 3H), 2.57 (q, J = 7.6 Hz, 2H), 2.56 (s, 3H), 1.23 (t, J = 7.6 Hz, 3H); LCMS (ESI): Method 2: R T = 0.643 min, m / z = 194.2 [M+H] + .

[0520] Step B. Preparation of 6-ethyl-8-methoxycinnolin-4-ol. 1-(2-amino-5-ethyl-3-methoxyphenyl)ethan-1-one (352 mg, 1.82 mmol, 1 equiv) was dissolved in concentrated HCl (5 mL) and stirred at 0 °C. A solution of sodium nitrite (188 mg, 2.73 mmol, 1.5 equiv) in water (0.5 mL) was added dropwise at 0 °C. The reaction was stirred at 0 °C for 1 h and allowed to warm to room temperature. Solid NaHCO3 The pH was adjusted to pH 7-9 by adding CH 2 Cl 2 (3x20mL). The combined organic layers were extracted with MgSO 4 The residue was purified by flash chromatography (Combi-flash Rf, gradient of 0-100% Hex / EtOAc, then gradient of 0-10% DCM / MeOH) to give the title compound (271 mg, 1.33 mmol, 73% yield). 1 H NMR (400 MHz, chloroform-d) δ 10.35 (brs, 1H), 7.84 (s, 1H), 7.63 (s, 1H), 6.94 (d, J = 1.4 Hz, 1H), 4.03 (s, 3H), 2.75 (q, J = 7.6 Hz, 2H), 1.30 (t, J = 7.6 Hz, 3H); LCMS (ESI): Method 2: R T = 1.135 min, m / z = 205.2 [M+H] + .

[0521] Step C. Preparation of 4-bromo-6-ethyl-8-methoxycinnoline. Phosphorus oxybromide (1.14 g, 3.98 mmol, 3 equiv.) and 6-ethyl-8-methoxycinnoline-4-ol (271 mg, 1.33 mmol, 1 equiv.) were dissolved in acetonitrile (10 mL). The reaction mixture was stirred at 60° C. until complete. The reaction was quenched with ice and saturated aqueous NaHCO 3 The mixture was extracted with EtOAc. The combined organic layers were washed with MgSO 4 The residue was purified by flash chromatography (Combi-flash Rf, gradient of 0-100% Hex / EtOAc, then gradient of 0-10% DCM / MeOH) to give the title compound (119 mg, 0.445 mmol, 34% yield). 1H NMR (400 MHz, chloroform-d) δ 9.44 (s, 1H), 7.44 (s, 1H), 7.03 (d, J = 1.2 Hz, 1H), 4.18 (s, 3H), 2.90 (q, J = 7.5 Hz, 2H), 1.39 (t, J = 7.6 Hz, 3H); LCMS (ESI): Method 2: R T = 1.696 min, m / z = 267.0 [M+H] + .

[0522] [ka] Intermediate 26 4-Bromo-6-ethyl-1,7-naphthyridine-8-carboxylate ethyl Step A. Preparation of ethyl 3-amino-6-ethylpicolinate. The title compound (2 g, quantitative) was prepared according to the procedure described for Step A of Intermediate 25, substituting ethyl 3-amino-6-bromopicolinate (2.5 g, 10.2 mmol, 1 equiv.). 1 H NMR (400 MHz, chloroform-d) δ 7.13 (d, J = 8.3 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 5.60 (brs, 2H), 4.44 (q, J = 7.1 Hz, 2H), 2.78 (q, J = 7.6 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.5 Hz, 3H).

[0523] Step B. Preparation of ethyl 3-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)-6-ethylpicolinate. The title compound (2.44 g, 7.01 mmol, 62% yield) was prepared following the procedure described for Step B of Intermediate 15, substituting ethyl 3-amino-6-ethylpicolinate (2.2 g, 11.3 mmol, 1 equiv). 1H NMR (400 MHz, chloroform-d) δ 8.67 (d, J = 14.1 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 4.60 (q, J = 7.1 Hz, 2H), 2.94 (q, J = LCMS (ESI): Method 2: R T = 1.833 min, m / z = 349.0 [M+H] + .

[0524] Step C. Preparation of ethyl 6-ethyl-4-hydroxy-1,7-naphthyridine-8-carboxylate. The title compound (641 mg, 2.6 mmol, 37% yield) was prepared following the procedure described for step C of intermediate 15, substituting ethyl 3-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)-6-ethylpicolinate (2.44 g, 7.01 mmol, 1 equiv.). LCMS (ESI): Method 2:R T =1.129 min, m / z=247.2[M+H] + .

[0525] Step D. Preparation of ethyl 4-bromo-6-ethyl-1,7-naphthyridine-8-carboxylate. The title compound (101 mg, 0.327 mmol, 13% yield) was prepared according to the procedure described for step C of intermediate 24, substituting ethyl 6-ethyl-4-hydroxy-1,7-naphthyridine-8-carboxylate (641 mg, 2.6 mmol, 1 equiv). 1H NMR (400 MHz, chloroform-d) δ 8.76 (d, J = 4.6 Hz, 1H), 7.87 - 7.86 (m, 2H), 4.61 (q, J = 7.2 Hz, 2H), 3.09 (q, J = 7.6 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H), 1.43 (t, J = 7.6 Hz, 3H); LCMS (ESI): Method 2: R T = 1.609 min, m / z = 309.0 [M+H] + .

[0526] [ka] Intermediate 27 3-Methoxy-2-methyl-5,6,7,8-tetrahydroquinolin-5-amine dihydrochloride Step A. Preparation of 7,8-dihydro-6H-spiro[quinoline-5,2'-[1,3]dioxolane]. To a solution of 7,8-dihydroquinolin-5(6H)-one (4.1 g, 28 mmol, 1 equiv.) and ethane-1,2-diol (112 mmol, 4 equiv.) in toluene (60 mL) was added p-TSA (6.59 g, 34.7 mmol, 1.25 equiv.). The resulting mixture was refluxed for 24 h with a Dean-Stark trap. The toluene was removed under reduced pressure and the residue was dissolved in EtOAc and washed with 1M NaOH. The organic layer was washed with Na 2 SO 4 The residue was purified by silica gel column chromatography (Combi-flash Rf, Hex / EtOAc=0-50% gradient) to give the title compound (4.9 g, 26 mmol, 91% yield). 1H NMR (400 MHz, chloroform-d) δ 8.49 (dd, J = 1.2, 4.8 Hz, 1H), 7.79 (dd, J = 2.0, 8.0 Hz, 1H), 7.16 (dd, J = 4.8, 8.0 Hz, 1H), 4.17 (m, 4H), 2.97 (t, J = 6.4 Hz, 2H), 2.04 (m, 2H), 1.98 (m, 2H).

[0527] Step B. Preparation of 7,8-dihydro-6H-spiro[quinolin-5,2'-[1,3]dioxolan]-3-ol. To a solution of 7,8-dihydro-6H-spiro[quinoline-5,2'-[1,3]dioxolane] (3.76 g, 19.7 mmol, 1 equiv) in THF (37 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (7.99 g, 31.5 mmol, 1.6 equiv), 4,4'-di-tert-butyl-2,2'-bipyridine (496 mg, 1.85 mmol, 0.094 equiv), and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (613 mg, 0.92 mmol, 0.047 equiv). The resulting mixture was stirred in a sealed tube at 78 °C for 20 h and then cooled to 0 °C. The reaction was quenched with MeOH and concentrated. The residue was dissolved in dichloromethane (100 mL), cooled to 0° C., and 30% hydrogen peroxide (12.9 mL, 126 mmol, 6.4 equiv) was added. The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction was diluted with saturated aqueous Na 2 SO 3 The mixture was quenched with dichloromethane. The resulting mixture was extracted with dichloromethane. The combined organic layers were washed with Na 2 SO 4 The residue was purified by silica gel column chromatography (Combi-flash Rf, Hex / EtOAc=50-100% gradient) to give the title compound (cmpound) (3.01 g, 14.5 mmol, 74% yield). 1H NMR (400 MHz, chloroform-d) δ 8.19 (d, J = 3.2 Hz, 1H), 7.32 (d, J = 2.8 Hz, 1H), 4.16 (m 4H), 2.90 (t, J = 6.4 Hz, 2H), 2.03 (m, 2H), 1.92 (m, 2H).

[0528] Step C. Preparation of 2-iodo-7,8-dihydro-6H-spiro[quinoline-5,2'-[1,3]dioxolan]-3-ol. To a suspension of 7,8-dihydro-6H-spiro[quinoline-5,2'-[1,3]dioxolan]-3-ol (690 mg, 3.3 mmol, 1 equiv.) in water (49 mL) was added Na 2 CO 3 (706 mg, 6.7 mmol, 2 equiv.) was added. The resulting mixture was stirred at room temperature for 30 min to form a homogeneous solution. Once a homogeneous solution was obtained, iodine (845.2 mg, 3.33 mmol, 1 equiv.) was added. The resulting mixture was stirred at room temperature for 16 h and then quenched with 4 M HCl. This mixture was diluted with saturated aqueous NaHCO 3 The mixture was basified with ethyl acetate and extracted with EtOAc. The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated. The residue was purified by silica gel column chromatography (Combi-flash Rf, Hex / EtOAc=0-100% gradient) to give the title compound (985 mg, 2.95 mmol, 88% yield). 1 H NMR (400 MHz, chloroform-d) δ 7.15 (s, 1H), 4.14 (m, 4H), 2.80 (t, J = 6.4 Hz, 2H), 1.97 (m, 4H).

[0529] Step D. Preparation of 2-iodo-3-methoxy-7,8-dihydro-6H-spiro[quinoline-5,2'-[1,3]dioxolane]. To a solution of 2-iodo-7,8-dihydro-6H-spiro[quinoline-5,2'-[1,3]dioxolane]-3-ol (406 mg, 1.22 mmol, 1 equiv) in THF (8 mL) was added 1M NaHMDS (1.6 mL, 1.6 mmol, 1.3 equiv) at 0°C. The ice bath was removed and the mixture was stirred at room temperature for 50 min and then concentrated under reduced pressure. The residue was dissolved in DMF (8 mL) and iodomethane (85 μL, 1.4 mmol, 1.1 equiv) was added. The resulting mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was dissolved in chloroform and washed with brine / water. The organic layer was extracted with Na 2 SO 4 The residue was purified by silica gel column chromatography (Combi-flash Rf, Hex / EtOAc=30-100% gradient) to give the title compound (370 mg, 1.07 mmol, 87% yield). 1 H NMR (400 MHz, chloroform-d) 1 H NMR (400 MHz, chloroform-d) δ 7.06 (s, 1H), 4.15 (m, 4H), 2.91 (t, J = 6.4 Hz, 2H), 1.95 (m, 4H).

[0530] Step E. Preparation of 3-Methoxy-2-methyl-7,8-dihydro-6H-spiro[quinoline-5,2'-[1,3]dioxolane]. To a solution of 2-iodo-3-methoxy-7,8-dihydro-6H-spiro[quinoline-5,2'-[1,3]dioxolane] (145.7 mg, 0.42 mmol, 1 equiv) in THF (4 mL) was added 1.7 M t-BuLi (519 μL, 0.88 mmol, 2.1 equiv) at -78°C. The mixture was stirred for 15 min, then iodomethane (53 μL, 0.84 mmol, 2 equiv) was added. The reaction mixture was warmed to 0°C and stirred for 45 min, then saturated NH 4The mixture was quenched with aqueous Cl. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with Na 2 SO 4 The residue was purified by silica gel column chromatography (Combi-flash Rf, Hex / EtOAc=0-50% gradient) to give the title compound (79 mg, 0.33 mmol, 78% yield). 1 H NMR (400 MHz, chloroform-d) δ 7.16 (s, 1H), 4.15 (m, 4H), 3.84 (s, 3H), 2.86 (t, J = 6.4 Hz, 2H), 2.44 (s, 3H), 1.99 (m, 2H), 1.94 (m, 2H).

[0531] Step F. Preparation of 3-methoxy-2-methyl-7,8-dihydroquinolin-5(6H)-one. To a solution of 3-methoxy-2-methyl-7,8-dihydro-6H-spiro[quinoline-5,2'-[1,3]dioxolane] (135 mg, 574 μmol, 1 equiv.) in acetone (1.5 mL) was added 2 M HCl (1.5 mL, 30 mmol, 5 equiv.). The mixture was stirred at 45°C for 16 h, then saturated aqueous NaHCO 3 The mixture was neutralized with chloroform and extracted with chloroform. The combined organic layer was 2 SO 4 The residue was purified by silica gel column chromatography (Combi-flash Rf, Hex / EtOAc = 0 to 100% gradient) to give the title compound (104.6 mg, 547 μmol, 95% yield). LCMS (ESI): m / z = 192.2 [M + H] + .

[0532] Step G. Preparation of 3-Methoxy-2-methyl-5,6,7,8-tetrahydroquinolin-5-ol. To a solution of 3-methoxy-2-methyl-7,8-dihydroquinolin-5(6H)-one (62 mg, 0.32 mmol, 1 equiv) in THF (3 mL) was added 1M L-selectride (973 μL, 0.97 mmol, 3 equiv) at 0° C. The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction was purified with saturated aqueous NaHCO 3 The mixture was quenched with EtOAc and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with Na 2 SO 4 The residue was purified by silica gel column chromatography (Combi-flash Rf, DCM / MeOH=0-10% gradient) to give the title compound (60.9 mg, 0.32 mmol, 97% yield). LCMS (ESI): m / z=194.3 [M+H] + .

[0533] Step H. Preparation of 5-azido-3-methoxy-2-methyl-5,6,7,8-tetrahydroquinoline. To a solution of 3-methoxy-2-methyl-5,6,7,8-tetrahydroquinolin-5-ol (60.9 mg, 0.32 mmol, 1 equiv.) in THF (4 mL) was added DBU (71 μL, 0.47 mmol, 1.5 equiv.) and diphenylphosphoryl azide (102 μL, 0.47 mmol, 1.5 equiv.) at room temperature. The reaction mixture was stirred at room temperature overnight and then quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with NaCl. 2 SO 4 The residue was purified by silica gel column chromatography (Combi-flash Rf, Hex / EtOAc=0-60% gradient) to give the title compound (69 mg, 0.32 mmol, 100% yield). LCMS (ESI): m / z=219.2 [M+H] + .

[0534] Step I. Preparation of tert-butyl (3-methoxy-2-methyl-5,6,7,8-tetrahydroquinolin-5-yl)carbamate. To a solution of 5-azido-3-methoxy-2-methyl-5,6,7,8-tetrahydroquinoline (69 mg, 0.32 mmol, 1 equiv) in THF (3.5 mL) was added PPh 3 (116 mg, 0.44 mmol, 1.4 equiv) and water (0.35 mL) were added. The mixture was stirred in a sealed tube at 50° C. overnight. Saturated NaHCO 3 Aqueous solution (2.5 mL) and (Boc) 2 2H2O (89.7 mg, 0.41 mmol, 1.3 equiv) was added. The resulting mixture was stirred at room temperature for 5 h and then extracted with EtOAc. The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated. The residue was purified by silica gel column chromatography (Combi-flash Rf, Hex / EtOAc=0-50% gradient) to give the desired product (80 mg, 0.27 mmol, 87% yield). LCMS (ESI): m / z=293.2 [M+H] + .

[0535] Step J. Preparation of 3-methoxy-2-methyl-5,6,7,8-tetrahydroquinolin-5-amine dihydrochloride. To a solution of tert-butyl (3-methoxy-2-methyl-5,6,7,8-tetrahydroquinolin-5-yl)carbamate (80 mg, 0.27 mmol, 1 equiv) in DCM (1 mL) was added 4M HCl in 1,4-dioxane (1.71 mL, 6.84 mmol, 25 equiv) at 0° C. The mixture was allowed to warm to room temperature and stirred for 48 h, then concentrated. The residue was dissolved in Et 2 O and dried under vacuum to give the title compound (73 mg, 0.27 mmol, 100% yield); LCMS (ESI): m / z=193.2 [M+H] + .

[0536] [ka] Intermediate 28 3-Ethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-amine dihydrochloride Step A. Preparation of 3-ethyl-6H-pyrano[3,4-b]pyridin-5(8H)-one. A solution of 2H-pyran-3,5(4H,6H)-dione (308 mg, 2.7 mmol, 1 equiv.) in toluene (5 mL) was added with 2-ethylacrolein (343 μL, 3.5 mmol, 1.3 equiv.), NH 4 OAc (416 mg, 5.4 mmol, 2 equiv.), 4 Å molecular sieves (0.5 g) and acetic acid (1.2 mL) were added. The resulting mixture was stirred in a sealed tube at 115° C. for 16 h. The mixture was cooled to ambient temperature, diluted with EtOAc and filtered. The filtrate was diluted with saturated aqueous NaHCO 3 Wash with Na 2 SO 4 The residue was purified by silica gel column chromatography (Combi-flash Rf, Hex / EtOAc=0-100% gradient) to give the title compound (194 mg, 1.1 mmol, 40% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.59 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H), 4.95 (s, 2H), 4.39 (s, 2H), 2.74 (q, J = 7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H).

[0537] Step B. Preparation of 3-ethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-ol. A solution of 3-ethyl-6H-pyrano[3,4-b]pyridin-5(8H)-one (172 mg, 1.0 mmol, 1 equiv) in EtOH (5 mL) was added with NaBH 4 (80 mg, 2.1 mmol, 2.1 equiv) was added. The resulting mixture was allowed to warm to room temperature and stirred for 1.5 h. The solvent (EtOH) was removed under reduced pressure and the residue was dissolved in EtOAc and saturated aqueous NaHCO 3 The organic layer was washed with Na 2 SO 4The residue was purified by silica gel column chromatography (Combi-flash Rf, Hex / EtOAc = 0 to 60% gradient) to give the title compound (66 mg, 368 μmol, 38% yield). LCMS (ESI): m / z = 180.2 [M + H] + .

[0538] Step C. Preparation of 5-azido-3-ethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridine. To a solution of 3-ethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-ol (66 mg, 368 μmol, 1 equiv.) in THF (4 mL) was added DBU (86 μL, 0.56 mmol, 1.5 equiv.) and diphenylphosphoryl azide (130 μL, 0.56 mmol, 1.5 equiv.) at room temperature. The reaction was stirred at room temperature overnight and then quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with Na 2 SO 4 The residue was purified by silica gel column chromatography (Combi-flash Rf, Hex / EtOAc=0-60% gradient) to give the title compound (70 mg, 340 μmol, 93% yield). LCMS (ESI): m / z=205.2 [M+H] + .

[0539] Step D. Preparation of 3-ethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-amine dihydrochloride. The title compound (101 mg, 0.327 mmol, 13% yield) was prepared following the procedure described for steps I and J of intermediate 27, substituting 5-azido-3-ethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridine (641 mg, 2.6 mmol, 1 equiv). 1H NMR (400 MHz, chloroform-d) δ 8.76 (d, J = 4.6 Hz, 1H), 7.87 - 7.86 (m, 2H), 4.61 (q, J = 7.2 Hz, 2H), 3.09 (q, J = 7.6 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H), 1.43 (t, J = 7.6 Hz, 3H); LCMS (ESI): Method 2: R T = 1.609 min, m / z = 309.0 [M+H] + .

[0540] [ka] Intermediate 29 4-Chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline Triphenylphosphine (polymer-bound, 3 mmol / g) (560 mg, 2.14 mmol, 3 equiv.) and 2-methoxyethan-1-ol (0.06 mL, 0.71 mmol, 1 equiv.) in CH 2 Cl 2 To a stirred suspension of (5 mL / g of resin (3.5 mL)) at 0° C. was added DIAD (0.4 mL, 2.14 mmol, 3 equiv.) followed by 4-chloro-6-methoxyquinazolin-7-ol (150 mg, 0.71 mmol, 1 equiv.). The reaction mixture was stirred and allowed to warm to room temperature. The reaction mixture was filtered and purified by HCl. 2 Cl 2 The mixture was washed with hexanes. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (Combi-flash Rf, Hex / EtOAc = 0 to 100% gradient) to give the title compound (161 mg, 0.599 mmol, 83% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.87 (s, 1H), 7.39 (s, 1H), 7.37 (s, 1H), 4.37 - 4.34 (m, 2H), 4.05 (s, 3H), 3.90 - 3.87 (m, 2H) 3.48 (s, 3H); LCMS (ESI) Method 2: R T= 1.262 min, m / z = 269.1 [M+H] + .

[0541] [ka] Intermediate 30 4-Chloro-6-methoxy-7-((1-methyl-1H-pyrazol-5-yl)methoxy)quinazoline The title compound (49 mg, 0.16 mmol, 23% yield) was prepared following the procedure described for intermediate 29, substituting ethyl(1-methyl-1H-pyrazol-5-yl)methanol (80 mg, 0.71 mmol, 1 equiv). 1 H NMR (400 MHz, chloroform-d) δ 8.89 (s, 1H), 7.47 - 7.46 (m, 2H), 7.42 (s, 1H), 6.44 (d, J = 1.8 Hz, 1H), 5.29 (s, 2H), 4.04 (s, 3H), 3.97 (s, 3H); LCMS (ESI) method 2: R T = 1.304 min, m / z = 305.1 [M+H] + .

[0542] [ka] Intermediate 31 4-Chloro-6-ethyl-8-methoxyquinazoline Step A. Preparation of 6-bromo-8-methoxyquinazolin-4-ol. A mixture of 2-amino-5-bromo-3-methoxybenzoic acid (2.000 g, 8.13 mmol, 1 eq.) and formamidine acetate (8.462 g, 81.28 mmol, 10 eq.) was stirred at 150° C. The cooled mixture was poured into ice water. The solid was collected by filtration, washed with water, and dried to give the title compound (1.83 g, 7.18 mmol, 88% yield). LCMS (ESI) Method 2: R T =1.063 min, m / z=255.0[M+H] + .

[0543] Step B. Preparation of 6-ethyl-8-methoxyquinazolin-4-ol. The title compound (400 mg, 1.96 mmol, quantitative) was prepared following the procedure described for Step A of Intermediate 14, substituting 6-bromo-8-methoxyquinazolin-4-ol (500 mg, 1.96 mmol, 1 equiv.). LCMS (ESI) Method 2:R T =1.025 min, m / z=205.2[M+H] + .

[0544] Step C. Preparation of 4-chloro-6-ethyl-8-methoxyquinazolin-4-ol. To a mixture of 6-ethyl-8-methoxyquinazolin-4-ol (100 mg, 0.458 mmol, 1 equiv.) and N,N-diisopropylethylamine (0.12 mL, 0.687 mmol, 1.5 equiv.) in anisole (4 mL) was added POCl while maintaining the temperature between 0 and 10 °C in an ice-water bath. 3 (0.064 mL, 0.687 mmol, 1.5 equiv) was added dropwise. The mixture was stirred at room temperature for 1 h and then heated to 95° C. The reaction was cooled to room temperature and quenched with ice water. Saturated aqueous NaHCO 3 The pH was adjusted to 7-9 by adding 0.5% NaOH. The mixture was extracted with EtOAc. The combined organic layers were washed with MgSO 4 The residue was purified by flash column chromatography (Combi-flash Rf, Hex / EtOAc=0-100% gradient) to give the title compound (30 mg, 0.13 mmol, 29% yield). 1 H NMR (400 MHz, chloroform-d) δ 9.00 (s, 1H), 7.62 (s, 1H), 7.16 (s, 1H), 4.10 (s, 3H), 2.88 (q, J = 7.6 Hz, 2H), 1.38 (t, J = 7.6 Hz, 3H).

[0545] [ka] Intermediate 32 4-Chloro-6-ethoxy-7-methoxyquinazoline The title compound (80 mg, 0.34 mmol, 47% yield) was prepared following the procedure described for Intermediate 29 using 4-chloro-7-methoxyquinazolin-6-ol (150 mg, 0.71 mmol, 1 equiv.) and ethanol (0.042 mL, 0.71 mmol, 1 equiv.). 1 LCMS (ESI) Method 2: R T = 1.383 min, m / z = 239.1 [M+H] + .

[0546] [ka] Intermediate 33 4-Chloro-7-ethoxy-6-methoxyquinazoline The title compound was prepared following the procedure described for Intermediate 29, substituting ethanol (0.083 mL, 1.42 mmol, 2 equiv). 1 LCMS (ESI) Method 2: R T = 1.367 min, m / z = 239.1 [M+H] + .

[0547] [ka] Intermediate 34 5-Chloro-3-ethyl-1,6-naphthyridine Step A. Preparation of 3-ethyl-1,6-naphthyridin-5-ol. The title compound (150 mg, 0.86 mmol, 97% yield) was prepared following the procedure described for Step A of Intermediate 14, substituting 3-bromo-1,6-naphthyridin-5-ol (200 mg, 0.889 mmol, 1 equiv.). LCMS (ESI) Method 2:R T =0.844 min, m / z=175.2[M+H] + .

[0548] Step B. Preparation of 5-chloro-3-ethyl-1,6-naphthyridine. 3-Ethyl-1,6-naphthyridin-5-ol (200 mg, 1.15 mmol, 1 equiv.) was dissolved in POCl 3 (2 mL) was added dropwise. The mixture was stirred at 90° C. The reaction was cooled to room temperature and quenched with ice water. Saturated aqueous NaHCO 3 The pH was adjusted to 7-9 by adding 0.5% NaOH. The mixture was extracted with EtOAc. The combined organic layers were washed with MgSO 4 The residue was purified by flash column chromatography (Combi-flash Rf, Hex / EtOAc = 0 to 100% gradient) to give the title compound (50 mg, 0.26 mmol, 23% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.99 (d, J = 1.8 Hz, 1H), 8.44 (d, J = 5.8 Hz, 1H), 8.37 (s, 1H), 7.85 (d, J = 5.8 Hz, 1H), 2.92 (q, J = 7.6 Hz, 2H), 1.39 (t, J = 7.6 Hz, 3H); LCMS (ESI) method 2: R T = 1.615 min, m / z = 193.1 [M+H] + .

[0549] [ka] Intermediate 35 Methyl 2-(2,4-dimethoxybenzyl)-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate Methyl 2-(2,4-dimethoxybenzyl)-1-oxo-5-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (Intermediate 2, 500 mg, 0.99 mmol, 1 equiv.), bis(pinacolato)diboron (504 mg, 1.99 mmol, 2 equiv.), KOAc (2.92 mg, 2.98 mmol, 3 equiv.) and PdCl 2 (dppf)·CH 2 Cl 2 (36 mg, 0.05 mmol, 0.05 equiv) was dissolved in 1,4-dioxane (10 mL) and placed under Ar atmosphere. The reaction mixture was stirred at 100 °C overnight. Brine was added to the cold mixture and extracted with EtOAc. The combined organic layers were treated with MgSO 4 The residue was purified by flash chromatography (Combi-flash Rf, EtOAc / Hex=0-50% gradient) to give the title compound (481 mg, 1.0 mmol, quantitative). 1 H NMR (400 MHz, chloroform-d) δ 8.86 (d, J = 2.0 Hz, 1H), 8.55 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 6.45 (s, 1H), 6.44 (dd, J = 7.8, 2.4 Hz, 1H), 4.75 (s, 2H), 3.92 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.50 (t, J = 6.6 Hz, 2H), 3.30 (t, J = 6.6 Hz, 2H), 1.33 (s, 12H); LCMS (ESI) Method 2: R T = 2.200 min, m / z = 482.1 [M+H] + .

[0550] [ka] Intermediate 36 Methyl 5-bromo-2-(2,4-dimethoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate Methyl 2-(2,4-dimethoxybenzyl)-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (Intermediate 35, 479 mg, 0.99 mmol, 1 equiv.), copper(II) bromide (665 mg, 2.98 mmol, 3 equiv.) and MeOH / H 2 A mixture of 2,4-dimethylformamide (DMSO) and 1,2,3-tetrahydrofuran (1:1 v / v, 100 mL) was stirred and refluxed at 80 °C. The mixture was cooled to room temperature and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were diluted with MgSO 4 The residue was purified by flash chromatography (Combi-flash Rf, 0-50% EtOAc / Hex gradient) to give the title compound (373 mg, 0.86 mmol, 87% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.73 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 1.7 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 6.46 (s, 1H), 6.45 (dd, J = 8.2, 2.4 LCMS (ESI) method 2: R T = 2.075 min, m / z = 433.9 [M+H] + .

[0551] [ka] Intermediate 37 5-Bromo-2-(2,4-dimethoxybenzyl)-7-(hydroxymethyl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (2.79 g, 6.87 mmol, 66% yield) was prepared following the procedure described for Intermediate 5 using methyl 5-bromo-2-(2,4-dimethoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (Intermediate 36, 4.5 g, 10 mmol, 1 equiv.). 1 H NMR (400 MHz, chloroform-d) δ 8.03 (s, 1H), 7.69 (d, J = 1.2 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 6.46 (s, 1H), 6.45 (dd, J = 8.2, 2.4 Hz, 1H), LCMS (ESI) method 2: R T = 1.832 min, m / z = 406.0 [M+H] + .

[0552] [ka] Intermediate 38 5-Bromo-7-(chloromethyl)-2-(2,4-dimethoxybenzyl)-3,4-dihydroisoquinolin-1(2H)-one CH of 5-bromo-2-(2,4-dimethoxybenzyl)-7-(hydroxymethyl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 37, 2.79 g, 6.87 mmol, 1 equiv.) 2 Cl 2 (60 mL) was added thionyl chloride (0.8 mL, 10.3 mmol, 1.5 equiv) at 0° C. The reaction was allowed to warm to room temperature and stirred overnight. 3 This mixture was then mixed with CH 2 Cl 2The combined organic layers were extracted with MgSO 4 Drying at rt and concentration afforded the title compound (2.5 g, 5.9 mmol, 86% yield), which was used in the next step without further purification. 1 H NMR (400 MHz, chloroform-d) δ 8.11 (d, J = 1.7 Hz, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 6.46 (s, 1H), 6.45 (dd, J = 8.2, 2.4 LCMS (ESI) method 2: R T = 2.125 min, m / z = 423.9 [M+H] + .

[0553] [ka] Intermediate 39 7-((1H-imidazol-1-yl)methyl)-5-bromo-2-(2,4-dimethoxybenzyl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (1.83 g, 4.0 mmol, 68% yield) was prepared following the procedure described for Intermediate 7 using 5-bromo-7-(chloromethyl)-2-(2,4-dimethoxybenzyl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 38, 2.5 g, 5.9 mmol, 1 equiv.), 1H-imidazole (1.2 g, 17.7 mmol, 4 equiv.) and cesium carbonate (3.84 g, 11.8 mmol, 2 equiv.). 1H NMR (400 MHz, chloroform-d) δ 8.03 (s, 1H), 7.79 - 7.73 (m, 1H), 7.41 (s, 1H), 7.25 (d, J = 6.1 Hz, 1H), 7.14 (s, 1H), 6.93 (s, 1H), 6.46 (s, 1H), 6.45 (dd, J = 8.4, 2.4 Hz, 1H), 5.14 (s, 2H), 4.71 (s, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 3.55 (t, J = 6.7 Hz, 2H), 2.99 (t, J = 6.7 Hz, 2H); LCMS (ESI) method 2: R T = 1.439 min, m / z = 456.0 [M+H] + .

[0554] [ka] Intermediate 40 tert-Butyl 1-(7-((1H-imidazol-1-yl)methyl)-2-(2,4-dimethoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)hydrazine-1-carboxylate The title compound (180 mg, 0.36 mmol, 25% yield) was prepared according to the Buchwald coupling procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-5-bromo-2-(2,4-dimethoxybenzyl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 39, 650 mg, 1.4 mmol, 1 equiv.) and tert-butyl hydrazinecarboxylate (376 mg, 2.85 mmol, 2 equiv.). 1 H NMR (400 MHz, DMSO-d 6) δ 8.82 (s, 1H), 7.68 (s, 1H), 7.41 (s, 1H), 7.24 (s, 1H), 7.09 (s, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.89 (s, 1H), 6.65 (s, 1H), 6.57 (d, J = 2.3 Hz, 1H), 6.47 (dd, J = 8.3, 2.3 Hz, 1H), 5.15 (s, 2H), 4.55 (s, 2H), 3.79 (s, 3H), 3.74 (s, 3H), 3.41 (t, J = 6.6 Hz, 2H), 2.70 (t, J = 6.9 Hz, 2H), 1.41 (s, 9H); LCMS (ESI) Method 2: R T = 1.400 min, m / z = 508.1 [M+H] + .

[0555] [ka] Intermediate 41 7-((1H-imidazol-1-yl)methyl)-2-(2,4-dimethoxybenzyl)-5-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)-3,4-dihydroisoquinolin-1(2H)-one CH of tert-butyl 1-(7-((1H-imidazol-1-yl)methyl)-2-(2,4-dimethoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)hydrazine-1-carboxylate (Intermediate 40, 164 mg, 0.323 mmol, 1 equiv.) 2 Cl 2(2 mL) solution was added dropwise at room temperature to a 4M HCl solution in 1,4-dioxane (1.6 mL, 6.46 mmol, 20 equiv.) and stirred for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOH (1 mL) and DIPEA (0.17 mL, 0.97 mmol, 3 equiv.) was added dropwise at room temperature. The reaction mixture was cooled to 0° C. and (Z)-1,1,1-trifluoro-4-methoxypent-3-en-2-one (0.05 mL, 0.36 mmol, 1.1 equiv.) was added dropwise. The reaction mixture was allowed to warm to room temperature and then refluxed at 80° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (Combi-flash Rf, MeOH / CH 2 Cl 2 = 0-10% gradient) to give the title compound (118 mg, 0.23 mmol, 70% yield). T =1.555 min, m / z=526.0[M+H] + .

[0556] [ka] Intermediate 42 7-((1H-imidazol-1-yl)methyl)-5-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (56 mg, 0.15 mmol, 71% yield) was prepared following the TFA deprotection procedure described for Intermediate 4 using 7-((1H-imidazol-1-yl)methyl)-2-(2,4-dimethoxybenzyl)-5-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 41, 110 mg, 0.21 mmol, 1 equiv.). LCMS (ESI) Method 2: R T =1.165 min, m / z=376.0[M+H] + .

[0557] [ka] Intermediate 43 4-Bromo-6-ethyl-8-methoxy-2-methyl-1,7-naphthyridine Step A: Preparation of 5-(1-((6-ethyl-2-methoxypyridin-3-yl)amino)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione. In a dry flask, Meldrum's acid (30 g, 0.21 mol, 1 eq.) was added followed by pyridine (30 mL) and triethyl orthoacetate (60 mL, 0.32 mol, 1.5 eq.). The reaction mixture was heated at 80° C. for 20 min. The reaction mixture was cooled rapidly to room temperature and the solvent was removed by rotary evaporation with a bath temperature below 42° C. The viscous material was heated with ligroin at 80° C. for 5 min and the ligroin was decanted. This process was repeated two more times. 5-(1-ethoxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione was used without further purification (45 g, 0.21 mol, quantitative). Concentration of the ligroin fraction afforded additional pure material. 1 H NMR (400 MHz, chloroform-d) δ 4.41 (q, J = 6.8 Hz, 2H), 2.74 (s, 3H), 1.72 (s, 6H), 1.53 (t, J = 7.2 Hz, 3H); LCMS (ESI): m / z = 214.3 [M+H] + In a dry flask, 6-ethyl-2-methoxypyridin-3-amine (Step A of Intermediate 14, 15 g, 0.099 mol, 1 equiv.) was dissolved in anhydrous toluene (30 mL). 5-(1-Ethoxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (45 g, 0.21 mol, 2.1 equiv.) was added and the reaction mixture was heated at 110° C. for 4 h. After cooling to room temperature, a solid was formed which was isolated by filtration and washing with cold ethanol to give the title compound (13.85 g, 0.043 mol, 44% yield). 1 H NMR (400 MHz, DMSO-d 6) δ 7.73 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 3.93 (s, 3H), 2.73 (q, J = 7.6 Hz, 2H), 2.45 (s, 3H), 1.66 (s, 6H), 1.25 (t, J = 7.6 Hz, 3H); LCMS (ESI) method 2: R T = 1.906 min, m / z = 321.1 [M+H] + .

[0558] Step B: Preparation of 6-ethyl-8-methoxy-2-methyl-1,7-naphthyridin-4-ol. Finely powdered 5-(1-((6-ethyl-2-methoxypyridin-3-yl)amino)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3.8 g, 12 mmol, 1 equiv.) was added in portions over 15 min to vigorously stirred diphenyl ether (40 mL) at 230° C. and then stirred for an additional 15 min. The reaction was then immediately cooled in a room temperature water bath with constant stirring. After 2 min, the water was replaced with cold water. Hexane was then added and the precipitate was filtered and washed with hexane to give the title compound (2.16 g, 9.9 mmol, 83% yield) as an off-white solid. LCMS (ESI) Method 2:R T =1.386 min, m / z=219.1[M+H] + .

[0559] Step C: Preparation of 6-ethyl-8-methoxy-2-methyl-1,7-naphthyridin-4-yl trifluoromethanesulfonate. 6-Ethyl-8-methoxy-2-methyl-1,7-naphthyridin-4-ol (1.0 g, 4.58 mmol, 1 equiv) was dissolved in DMF (20 mL) and stirred at room temperature. 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (2.46 g, 6.87 mmol, 1.5 equiv) was added followed by N,N-diisopropylethylamine (2 mL, 11.5 mmol, 2.5 equiv) and DMAP (11.2 mg, 0.092 mmol, 0.02 equiv) and the reaction was stirred at 50° C. for 4 h. The reaction was diluted with EtOAc and saturated NH 4 The organic layer was extracted with MgSO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure. After purification by column chromatography (Combi-flash Rf, EtOAc / Hex=0-20%, gradient), the title compound (1.6 g, 1.5 mmol, quantitative) was obtained. 1 LCMS (ESI) Method 2: R T = 2.106 min, m / z = 351.0 [M+H] + .

[0560] Step D: Preparation of 4-bromo-6-ethyl-8-methoxy-2-methyl-1,7-naphthyridine. 6-Ethyl-8-methoxy-2-methyl-1,7-naphthyridin-4-yl trifluoromethanesulfonate (1.6 g, 1.5 mmol, 1 equiv) was dissolved in acetonitrile (40 mL) and stirred at room temperature. Lithium bromide (4.0 g, 46 mmol, 10 equiv) was added and the reaction was stirred at 80° C. until complete after 3 h. The reaction was cooled to room temperature and concentrated under reduced pressure. The reaction was diluted with EtOAc and water and extracted with EtOAc. The organic layer was removed using MgSO4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure. After purification by column chromatography (Combi-flash Rf, EtOAc / Hex=0-50%, gradient), the title compound (1.12 g, 3.97 mmol, 87% yield) was obtained. 1 LCMS (ESI) Method 2: R T = 1.598 min, m / z = 281.1 [M+H] + .

[0561] [ka] Intermediate 44 4-Chloro-6-ethyl-8-methoxy-2-methylquinazoline Step A: Preparation of 6-bromo-8-methoxy-2-methylquinazolin-4(3H)-one. To a solution of 2-amino-5-bromo-3-methoxybenzoic acid (246 mg, 1.0 mmol, 1 equiv) in ethanol (2 mL) was added ethanethioamide (376 mg, 5.0 mmol, 5 equiv). The reaction mixture was stirred at 85° C. under argon atmosphere for 7 h. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. The residue was suspended in water, filtered and dried. The title compound (112 mg, 0.42 mmol, 42% yield) was used without further purification. LCMS (ESI) Method 2:R T =1.384 min, m / z=269.1[M+H] + .

[0562] Step B: Preparation of 6-ethyl-8-methoxy-2-methylquinazolin-4(3H)-one and 6-ethyl-8-methoxy-2-methylquinazolin-4(1H)-one. In a round-bottom flask, 6-bromo-8-methoxy-2-methylquinazolin-4(3H)-one (269 mg, 1.0 mmol, 1 equiv.), PdCl 2(dppf)-CH 2 Cl 2 The adduct (40 mg, 0.05 mmol, 0.05 equiv) was dissolved in THF (5 mL) and placed under argon at room temperature. Diethylzinc (1 mL, 1.0 mmol, 1 equiv, 1M hexane) was added dropwise and the reaction mixture was then placed on a preheated heating block and stirred at 65° C. for 30 min. At 23° C., the mixture was filtered and concentrated. The residue was suspended in EtOAc (10 mL) and then hexane (20 mL) was added. The precipitate was filtered to give the title compound (142 mg, 0.65 mmol, 65% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.70 (d, J = 2.1 Hz, 0.5H), 7.44 (s, 1H), 7.43 (s, 0.5H), 7.17 (d, J = 1.4 Hz, 1H), 3.90 (s, 1.5H), 3.87 (s, 3H), 2.70 (q, J = LCMS (ESI) method 2: R T = 0.263 min, m / z = 219.1 [M+H] + .

[0563] Step C: Preparation of 4-chloro-6-ethyl-8-methoxy-2-methylquinazolin-4(3H)-one. A mixture of 6-ethyl-8-methoxy-2-methylquinazolin-4(1H)-one (300 mg, 1.37 mmol, 1 equiv.) in a reaction vial was treated with POCl 3 (1.5 mL) was added dropwise. The mixture was stirred at 90° C. until completion. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc and saturated NaHCO 3 The combined organic layers were washed with MgSO 4 The mixture was dried at rt and concentrated under reduced pressure, and the title compound (364 mg, 1.54 mmol, quantitative) was used without further purification. 1H NMR (400 MHz, chloroform-d) δ 7.57 (s, 1H), 7.10 (d, J = 1.2 Hz, 1H), 4.08 (s, 3H), 2.88 (s, 3H), 2.84 (q, J = 6.8 Hz, 2H), 1.36 (t, J = 7.6 Hz, 3H); LCMS (ESI) method 2: R T = 1.639 min, m / z = 237.1 [M+H] + .

[0564] [ka] Intermediate 45 4-(4-chloro-6,7-dimethoxyquinazolin-2-yl)morpholine Step A: Preparation of 6,7-dimethoxy-2-morpholinoquinazolin-4(3H)-one. 2-Chloro-6,7-dimethoxyquinazolin-4(3H)-one (100 mg, 0.42 mmol, 1 equiv) and morpholine (0.06 mL, 0.70 mmol, 1.7 equiv) were dissolved in EtOH (2 mL) and stirred at 80° C. until completion. The reaction was cooled to 0° C., filtered and washed with cold EtOH to give 6,7-dimethoxy-2-morpholinoquinazolin-4(3H)-one (112 mg, 0.38 mmol, 92% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.19 (brs, 1H), 7.28 (s, 1H), 6.78 (s, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.66 (t, J = 4.7 Hz, 4H), 3.53 (t, J = 4.8 Hz, 4H); LCMS (ESI) Method 2: R T = 1.056 min, m / z = 292.1 [M+H] + .

[0565] Step B: Preparation of 4-(4-chloro-6,7-dimethoxyquinazolin-2-yl)morpholine. In a reaction vial, 6,7-dimethoxy-2-morpholinoquinazolin-4(3H)-one (50 mg, 0.17 mmol, 1 equiv.) was added with POCl 3 (0.5 mL) was added dropwise. The mixture was stirred at 90° C. until completion. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc and saturated NaHCO 3 The combined organic layers were washed with MgSO 4 The mixture was dried at rt and concentrated under reduced pressure, and the title compound (54 mg, 0.17 mmol, quantitative) was used without further purification. 1 LCMS (ESI) Method 2: R T = 1.529 min, m / z = 310.0 [M+H] + .

[0566] [ka] Intermediate 46 4-Chloro-6,7-dimethoxy-N-methylquinazolin-2-amine Step A: Preparation of 6,7-dimethoxy-2-(methylamino)quinazolin-4(3H)-one. 2-Chloro-6,7-dimethoxyquinazolin-4(3H)-one (300 mg, 1.25 mmol, 1 equiv), potassium carbonate (431 mg, 3.12 mmol, 2.5 equiv) and methylamine hydrochloride (421 mg, 6.23 mmol, 5 equiv) were dissolved in EtOH (2 mL) and stirred at 80° C. until complete. The reaction was cooled to 0° C., filtered and washed with cold EtOH to give 6,7-dimethoxy-2-(methylamino)quinazolin-4(3H)-one (265 mg, 1.13 mmol, 90% yield). LCMS (ESI) Method 2: R T =1.024 min, m / z=236.1[M+H]+ .

[0567] Step B: Preparation of 4-chloro-6,7-dimethoxy-N-methylquinazolin-2-amine. The title compound (55 mg, 0.21 mmol, quantitative) was prepared according to the procedure described for Step C of Intermediate 44, substituting 6,7-dimethoxy-2-(methylamino)quinazolin-4(3H)-one (50 mg, 0.21 mmol, 1 equiv). 1 LCMS (ESI) Method 2: R T = 1.256 min, m / z = 254.1 [M+H] + .

[0568] [ka] Intermediate 47 7-((1H-imidazol-1-yl)methyl)-5-bromo-3,4-dihydroisoquinolin-1(2H)-one The title compound (230 mg, 0.75 mmol, 86% yield) was prepared following the TFA deprotection procedure described for Intermediate 4 using 7-((1H-imidazol-1-yl)methyl)-5-bromo-2-(2,4-dimethoxybenzyl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 39, 400 mg, 0.88 mmol, 1 equiv.). 1 H NMR (400 MHz, DMSO-d 6) δ 8.10 (s, 1H), 7.88 - 7.80 (m, 1H), 7.77 (s, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.31 - 7.20 (m, 1H), 6.99 - 6.89 (m, 1H), 5.24 (s, 2H), 3.37 (td, J = 6.6, 2.7 Hz, 2H), 2.93 (t, J = 6.6 Hz, 2H); LCMS (ESI) method 2: R T = 1.102 min, m / z = 306.0 [M+H] + .

[0569] [ka] Intermediate 48 7-((1H-imidazol-1-yl)methyl)-5-bromo-2-(6,7-dimethoxy-2-methylquinazolin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (280 mg, 0.55 mmol, 75% yield) was prepared following the Buchwald coupling procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-5-bromo-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 47, 244 mg, 0.73 mmol, 1 equiv.) and 4-chloro-6,7-dimethoxy-2-methylquinazoline (210 mg, 0.88 mmol, 1.2 equiv.). LCMS (ESI) Method 2: R T =1.282 min, m / z=508.0[M+H] + .

[0570] [ka] Intermediate 49 (R)-N-((S)-3-chloro-5,6,7,8-tetrahydroisoquinolin-5-yl)-2-methylpropane-2-sulfinamide Step A: Preparation of (S,E)-N-((5-bromo-2-chloropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide. (S)-2-methylpropane-2-sulfinamide (6.60 g, 54.4 mmol, 1.2 equiv.) and Cs in anhydrous dichloromethane (70 mL). 2 CO 3 (14.8 g, 45.4 mmol, 1 equiv) was stirred at room temperature for 10 min, then 5-bromo-2-chloroisonicotinaldehyde (10.0 g, 45.4 mmol, 1 equiv) was added. The mixture was stirred at 42° C. until completion of the reaction. The reaction mixture was filtered. The filtrate was concentrated and purified by flash chromatography (Combi-flash Rf, EtOAc / Hex=0-20% gradient) to give (S,E)-N-((5-bromo-2-chloropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (7.49 g, 23.1 mmol, 51% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.85 (s, 1H), 8.63 (s, 1H), 7.85 (s, 1H), 1.30 (s, 10H); LCMS (ESI): m / z = 323.2 [M+H] + .

[0571] Step B: Preparation of (S,E)-N-((2-chloro-5-vinylpyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide. In an oven-dried 2-dram vial equipped with a magnetic stir bar, add (S,E)-N-((5-bromo-2-chloropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (1.00 g, 3.09 mmol, 1 equiv.), PdCl 2 (dppf)(452mg, 0.62mmol, 0.2eq), K 3 PO 4 (3.28 g, 15.4 mmol, 5 equiv.) and potassium vinyltrifluoroborate (455 mg, 3.40 mmol, 1.1 equiv.) in THF (10 mL) and H 2The resulting suspension was heated to 75° C. and stirred until the reaction was complete. The reaction mixture was cooled to room temperature and then diluted with CH 2 Cl 2 and H 2 The mixture was diluted with O. The layers were separated. The aqueous layer was diluted with CH 2 Cl 2 (2x). The combined organic layers were extracted with anhydrous Na 2 SO 4 The crude material was purified by flash chromatography (Combi-flash Rf, 0-30% EtOAc / Hex gradient) to give (S,E)-N-((2-chloro-5-vinylpyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (452 ​​mg, 3.09 mmol, 54% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.82 (s, 1H), 8.59 (d, J = 0.7 Hz, 1H), 7.77 (s, 1H), 7.21 - 7.06 (m, 1H), 5.75 (dd, J = 17.4, 0.8 Hz, 1H), 5.61 (dd, J = 11.1, 0.7 Hz, 1H), 1.29 (s, 10H); LCMS (ESI): m / z = 271.2 [M+H] + .

[0572] Step C: Preparation of (S)-N-((S)-1-(2-chloro-5-vinylpyridin-4-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide. To a suspension of granular zinc (1.97 g, 30 mmol, 1.2 equiv) in THF (25.5 mL) was added allyl bromide (2.21 mL, 25.5 mmol, 1 equiv) dropwise. The resulting suspension was stirred at 40° C. until most of the zinc was consumed. In a separate oven-dried 200 mL round-bottom flask equipped with a magnetic stir bar, freshly prepared 1 M allylzinc bromide solution (14.7 mL, 14.7 mmol, 1.5 equiv) was added dropwise to a solution of (S,E)-N-((2-chloro-5-vinylpyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (2.66 g, 9.82 mmol, 1 equiv) in anhydrous THF (48 mL) at −78° C. The resulting mixture was stirred at −78° C. for 1 h and then washed with saturated aqueous NH 4 The mixture was allowed to warm to room temperature and then extracted with EtOAc. The combined organic layers were dried (Na 2 SO 4 ) and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, 0-50% EtOAc / Hex gradient) to give (S)-N-((S)-1-(2-chloro-5-vinylpyridin-4-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (2.68 g, 9.82 mmol, 88% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.43 (s, 1H), 7.33 (s, 1H), 6.94 (dd, J = 17.3, 11.1 Hz, 1H), 5.79 - 5.59 (m, 2H), 5.51 (dd, J = 11.0, 1.0 Hz, 1H), 5.36 - 5.15 (m, 2H), 4.90 - 4.72 (m, 1H), 3.79 (s, 1H), 2.60 (dt, J = 14.5, 5.8 Hz, 1H), 2.49 - 2.28 (m, 1H), 1.25 (s, 10H); LCMS (ESI): m / z = 313.3 [M+H] + .

[0573] Step D: Preparation of (S)-N-((S)-3-chloro-5,6-dihydroisoquinolin-5-yl)-2-methylpropane-2-sulfinamide. (S)-N-((S)-1-(2-chloro-5-vinylpyridin-4-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (1.63 g, 5.21 mmol, 1 equiv.) in CH 2 Cl 2 To the (45 mL) solution was added benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(tricyclohexylphosphine)ruthenium (Grubbs II catalyst, 221 mg, 0.26 mmol, 0.05 equiv). The resulting solution was heated to 40° C. with an air needle and stirred until the reaction was complete, which was typically 1 h. The reaction was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by flash chromatography (Combi-flash Rf, EtOAc / Hex=0-100% gradient) to give (S)-N-((S)-3-chloro-5,6-dihydroisoquinolin-5-yl)-2-methylpropane-2-sulfinamide (1.40 g, 5.21 mmol, 94% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.11 (s, 1H), 7.35 (s, 1H), 6.54 (d, J = 9.8 Hz, 1H), 6.15 (dt, J = 9.2, 4.3 Hz, 1H), 4.53 (q, J = 8.3 Hz, 1H), 3.35 (d, J = 9.5 Hz, 1H), 2.88 (dt, J = 16.9, 5.6 Hz, 1H), 2.64 - 2.42 (m, 1H), 1.26 (s, 10H); LCMS (ESI): m / z = 285.2 [M+H] + .

[0574] Step E: Preparation of (S)-N-((S)-3-chloro-5,6,7,8-tetrahydroisoquinolin-5-yl)-2-methylpropane-2-sulfinamide. To a solution of (S)-N-((S)-3-chloro-5,6-dihydroisoquinolin-5-yl)-2-methylpropane-2-sulfinamide (1.40 g, 4.92 mmol, 1 equiv) in MeOH (10 mL) was added platinum(IV) oxide (112 mg, 0.49 mmol, 0.1 equiv). The flask was evacuated and H 2 (3x) was back-charged. The solution was stirred until the reaction was complete. The reaction mixture was filtered over Celite. The filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to give the desired product (1.39 g, 4.85 mmol, 99% yield), which was used without further purification. 1 H NMR (400 MHz, chloroform-d) δ 8.14 (s, 1H), 7.36 (s, 1H), 4.39 (q, J = 8.1 Hz, 1H), 3.33 (d, J = 10.0 Hz, 1H), 2.74 (t, J = 6.1 Hz, 2H), 2.52 - 2.33 (m, 1H), 1.97 (qd, J = 7.2, 3.8 Hz, 1H), 1.91 - 1.75 (m, 2H), 1.30 (s, 9H); LCMS (ESI): m / z = 287.2 [M+H] + .

[0575] [ka] Intermediate 50 (S)-3-Ethyl-5,6,7,8-tetrahydroisoquinolin-5-amine Step A: Preparation of (S)-N-((S)-3-ethyl-5,6,7,8-tetrahydroisoquinolin-5-yl)-2-methylpropane-2-sulfinamide. (S)-N-((S)-3-chloro-5,6,7,8-tetrahydroisoquinolin-5-yl)-2-methylpropane-2-sulfinamide (Intermediate 49, 1.00 g, 3.49 mmol, 1 equiv.) and PdCl in THF (30 mL). 2To a suspension of (dppf) (128 mg, 0.17 mmol, 0.05 equiv.) was added diethylzinc (1 M in hexanes, 4.2 mL, 4.18 mmol, 1.2 equiv.) dropwise at 0° C. The resulting mixture was heated to 60° C. and stirred until the reaction was complete. The reaction mixture was cooled and then diluted with EtOAc and H 2 The mixture was diluted with O. The layers were separated. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was purified by flash chromatography (Combi-flash Rf, MeOH / CH 2 Cl 2 = 0-10% gradient) to give the desired product (980 mg, 3.49 mmol, quantitative). 1 H NMR (400 MHz, chloroform-d) δ 8.28 (s, 1H), 7.21 (s, 1H), 4.39 (s, 1H), 3.36 (d, J = 9.8 Hz, 1H), 2.88 - 2.66 (m, 4H), 2.48 - 2.33 (m, 1H), 2.05 - 1.77 (m, 2H), 1.32 - 1.17 (m, 14H); LCMS (ESI): m / z = 281.3 [M+H] + .

[0576] Step B: Preparation of (S)-3-ethyl-5,6,7,8-tetrahydroisoquinolin-5-amine. To a solution of (S)-N-((S)-3-ethyl-5,6,7,8-tetrahydroisoquinolin-5-yl)-2-methylpropane-2-sulfinamide (100 mg, 0.55 mmol, 1 equiv) in THF (6 mL) was added 4M HCl in 1,4-dioxane (1.8 mL, 7.13 mmol, 20 equiv) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction was concentrated in vacuo. The residue was purified by HCl ...4M in 1,4-dioxane (1.8 mL, 7.13 mmol, 20 equiv) was added to a solution of (S)-N-((S)-3-ethyl-5,6,7,8-tetrahydroisoquinolin-5-yl)-2-methylpropane-2-sulfinamide (100 mg, 0.55 mmol, 1 equiv) in THF (6 mL) at 0° C. 2 Cl 2 Suspended in saturated aqueous Na 2 CO 3 The aqueous layer was washed with CH 2 Cl 2(2x). The combined organic layers were extracted with anhydrous Na 2 SO 4 Drying by FT-IR, filtration, and concentration under reduced pressure gave (S)-3-ethyl-5,6,7,8-tetrahydroisoquinolin-5-amine (41 mg, 0.36 mmol, 65% yield): 1 H NMR (400 MHz, chloroform-d) δ 8.26 (s, 1H), 3.97 (s, 1H), 2.91 - 2.61 (m, 5H), 2.09 (t, J = 6.6 Hz, 1H), 1.94 (d, J = 6.4 Hz, 0H), 1.89 - 1.57 (m, 8H), 1.30 (d, J = 7.6 Hz, 3H); LCMS (ESI): m / z = 177.4 [M+H] + .

[0577] [ka] Intermediate 51 Methyl (S)-3'-ethyl-5-hydroxy-1-oxo-3,4,5',6',7',8'-hexahydro-1H-[2,5'-biisoquinoline]-7-carboxylate The title compound (243 mg, 0.64 mmol, 40% yield) was prepared following the procedure described for Intermediate 1 using dimethyl 2-hydroxy-2,3-dihydrobenzofuran-4,6-dicarboxylate (400 mg, 1.6 mmol, 1 equiv.) and (S)-3-ethyl-5,6,7,8-tetrahydroisoquinolin-5-amine (Intermediate 50, 310 mg, 1.7 mmol, 1.1 equiv.). 1H NMR (400 MHz, chloroform-d) δ 8.41 (d, J = 1.5 Hz, 1H), 8.33 (s, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.04 (s, 1H), 6.05 (dd, J = 10.4, 5.8 Hz, 1H), 4.01 - 3.83 (m, 5H), 3.40 (ddd, J = 12.4, 10.3, 4.7 Hz, 1H), 3.20 (dt, J = 12.0, 5.5 Hz, 1H), 3.04 (dt, J = 16.7, 5.1 Hz, 1H), 2.95 - 2.66 (m, 6H), 2.26 - 2.08 (m, 3H), 1.98 - 1.76 (m, 2H), 1.25 (q, J = 7.3 Hz, 4H); LCMS (ESI): m / z = 381.4 [M+H] + .

[0578] [ka] Intermediate 52 (S)-7-(Chloromethyl)-3'-ethyl-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4,5',6',7',8'-hexahydro-1H-[2,5'-biisoquinolin]-1-one Step A: Preparation of methyl (S)-3'-ethyl-1-oxo-5-(((trifluoromethyl)sulfonyl)oxy)-3,4,5',6',7',8'-hexahydro-1H-[2,5'-biisoquinoline]-7-carboxylate. The title compound (311 mg, 0.63 mmol, 40% yield) was prepared according to the procedure described for Intermediate 2 using methyl (S)-3'-ethyl-5-hydroxy-1-oxo-3,4,5',6',7',8'-hexahydro-1H-[2,5'-biisoquinoline]-7-carboxylate (Intermediate 51, 240 mg, 0.63 mmol, 1 equiv.). 1H NMR (400 MHz, chloroform-d) δ 8.87 (d, J = 1.6 Hz, 1H), 8.34 (s, 1H), 8.08 (d, J = 1.6 Hz, 1H), 6.94 (s, 1H), 6.03 (dd, J = 10.5, 6.0 Hz, 1H), 3.97 (d, J = 12.4 Hz, 4H), 3.42 (ddd, J = 12.6, 9.9, 4.7 Hz, 1H), 3.30 - 3.17 (m, 1H), 3.15 - 2.91 (m, 2H), 2.76 (td, J = 16.0, 6.9 Hz, 5H), 2.25 - 2.07 (m, 2H), 1.97 - 1.72 (m, 2H), 1.25 (dt, J = 9.6, 7.4 Hz, 8H); LCMS (ESI): m / z = 513.3 [M+H] + .

[0579] Step B: Preparation of methyl (S)-3'-ethyl-5-(1-methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl)-1-oxo-3,4,5',6',7',8'-hexahydro-1H-[2,5'-biisoquinoline]-7-carboxylate. The title compound (150 mg, 0.29 mmol, 48% yield) was prepared according to the procedure described for intermediate 3 using methyl (S)-3'-ethyl-1-oxo-5-(((trifluoromethyl)sulfonyl)oxy)-3,4,5',6',7',8'-hexahydro-1H-[2,5'-biisoquinoline]-7-carboxylate (310 mg, 0.61 mmol, 1 equiv.). 1H NMR (400 MHz, chloroform-d) δ 8.86 (d, J = 1.9 Hz, 1H), 8.33 (s, 1H), 8.06 (d, J = 1.9 Hz, 1H), 7.39 (s, 1H), 6.05 (t, J = 8.4 Hz, 1H), 4.02 (s, 3H), 3.95 (s, 3H), 3.32 (s, 1H), 3.10 (dt, J = 12.5, 5.5 Hz, 1H), 2.76 (dd, J = 15.7, 9.3 Hz, 7H), 2.28 - 2.07 (m, 2H), 1.99 - 1.73 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H); LCMS (ESI): m / z = 513.4 [M+H] + .

[0580] Step C: Preparation of (S)-3'-ethyl-7-(hydroxymethyl)-5-(1-methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl)-3,4,5',6',7',8'-hexahydro-1H-[2,5'-biisoquinoline]-1-one. The title compound (109 mg, 0.29 mmol, 77% yield) was prepared according to the procedure described for intermediate 5 using methyl (S)-3'-ethyl-5-(1-methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl)-1-oxo-3,4,5',6',7',8'-hexahydro-1H-[2,5'-biisoquinoline]-7-carboxylate (150 mg, 0.29 mmol, 1 equiv). 1H NMR (400 MHz, chloroform-d) δ 8.31 (s, 1H), 8.20 (d, J = 1.9 Hz, 1H), 7.43 (d, J = 1.9 Hz, 1H), 7.36 (s, 1H), 6.99 (s, 1H), 6.04 (dd, J = 10.6, 6.0 Hz, 1H), 4.78 (d, J = 5.6 Hz, 2H), 4.00 (s, 3H), 3.29 (ddd, J = 12.4, 8.9, 5.7 Hz, 1H), 3.08 (dt, J = 11.9, 5.5 Hz, 1H), 2.89 - 2.56 (m, 7H), 2.23 - 2.00 (m, 2H), 1.98 - 1.67 (m, 3H), 1.23 (t, J = 7.6 Hz, 3H); LCMS (ESI): m / z = 485.4 [M+H] + .

[0581] Step D: Preparation of (S)-7-(chloromethyl)-3'-ethyl-5-(1-methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl)-3,4,5',6',7',8'-hexahydro-1H-[2,5'-biisoquinolin]-1-one. The title compound (84 mg, 0.17 mmol, 96% yield) was prepared according to the procedure described for intermediate 38 using (S)-3'-ethyl-7-(hydroxymethyl)-5-(1-methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl)-3,4,5',6',7',8'-hexahydro-1H-[2,5'-biisoquinolin]-1-one (84 mg, 0.17 mmol, 1 equiv.) and thionyl chloride (0.19 mL, 2.6 mmol, 15 equiv.). LCMS(ESI): m / z=503.3[M+H] + .

[0582] [ka] Intermediate 53 4-Chloro-N-ethyl-6,7-dimethoxy-N-methylquinazolin-2-amine Step A: Preparation of 2-(ethyl(methyl)amino)-6,7-dimethoxyquinazolin-4(3H)-one. Chloro-6,7-dimethoxyquinazolin-4(3H)-one (100 mg, 0.42 mmol, 1 equiv) and N-methylethanamine (0.06 mL, 0.70 mmol, 1.7 equiv) were dissolved in EtOH (2 mL) and stirred at 80° C. until complete. The reaction was cooled to 0° C., filtered and washed with cold EtOH to give 2-(ethyl(methyl)amino)-6,7-dimethoxyquinazolin-4(3H)-one (100 mg, 0.38 mmol, 91% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.93 (s, 1H), 7.25 (s, 1H), 6.71 (s, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.56 (q, J = 7.0 Hz, 2H), 3.02 (s, 3H), 1.08 (t, J = 7.0 Hz, 3H); LCMS (ESI) method 2: R T = 1.096 min, m / z = 264.1 [M+H] + .

[0583] Step B: Preparation of 4-chloro-N-ethyl-6,7-dimethoxy-N-methylquinazolin-2-amine. The title compound (83 mg, 0.29 mmol, 78% yield) was prepared following the procedure described for Step C of Intermediate 44, substituting 2-(ethyl(methyl)amino)-6,7-dimethoxyquinazolin-4(3H)-one (100 mg, 0.38 mmol, 1 equiv.). LCMS (ESI) Method 2:R T =1.425 min, m / z=282.1[M+H] + .

[0584] [ka] Intermediate 54 4-Chloro-2-ethyl-6,7-dimethoxyquinazoline Step A: Preparation of 2-ethyl-6,7-dimethoxyquinazolin-4(3H)-one. To a reaction vial was added methyl 2-amino-4,5-dimethoxybenzoate (100 mg, 0.47 mmol, 1 equiv), propiononitrile (0.11 mL, 1.42 mmol, 3 equiv) and 4M HCl in 1,4-dioxane (1 mL) and the resulting heterogenous mixture was stirred at 115° C. until completion. The reaction mixture was cooled and washed with cold saturated NaHCO 3 The precipitate was filtered, washed with water, and air-dried to give 2-ethyl-6,7-dimethoxyquinazolin-4(3H)-one (100 mg, 0.43 mmol, 90% yield), which was used without purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.40 (s, 1H), 7.07 (s, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 2.59 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz, 3H); LCMS (ESI) method 2: R T = 0.331 min, m / z = 235.2 [M+H] + .

[0585] Step B: Preparation of 4-chloro-2-ethyl-6,7-dimethoxyquinazolin-4(3H)-one. In a reaction vial, 2-ethyl-6,7-dimethoxyquinazolin-4(3H)-one (100 mg, 0.43 mmol, 1 equiv.) was dissolved in POCl. 3 (0.5 mL) was added dropwise. The mixture was stirred at 90° C. until completion. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc and saturated NaHCO 3 The combined organic layers were washed with MgSO 4 The title compound (64 mg, 0.25 mmol, 59% yield) was used without further purification. LCMS (ESI) Method 2: T =1.524 min, m / z=253.0[M+H] + .

[0586] [ka] Intermediate 55 4-Chloro-2-cyclopropyl-6,7-dimethoxyquinazoline Step A: Preparation of 2-cyclopropyl-6,7-dimethoxyquinazolin-4(3H)-one. The title compound (27 mg, 0.11 mmol, 23% yield) was prepared following the procedure described for Step A of Intermediate 54 using methyl 2-amino-4,5-dimethoxybenzoate (100 mg, 0.47 mmol, 1 equiv.) and cyclopropanecarbonitrile (0.11 mL, 1.42 mmol, 3 equiv.). LCMS (ESI) Method 2:R T =0.245 min, m / z=247.1[M+H] + .

[0587] Step B: Preparation of 4-chloro-2-cyclopropyl-6,7-dimethoxyquinazolin. The title compound (17 mg, 0.064 mmol, 63% yield) was prepared following the procedure described for Step C of Intermediate 44, substituting 2-cyclopropyl-6,7-dimethoxyquinazolin-4(3H)-one (25 mg, 0.10 mmol, 1 equiv). LCMS (ESI) Method 2:R T =1.609 min, m / z=265.1[M+H] + .

[0588] [ka] Intermediate 56 4-Chloro-6,7-dimethoxy-2-(tetrahydro-2H-pyran-4-yl)quinazoline Step A: Preparation of 6,7-dimethoxy-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one. To a reaction vial was added methyl 2-amino-4,5-dimethoxybenzoate (400 mg, 1.89 mmol, 1 equiv), tetrahydro-2H-pyran-4-carbonitrile (2.1 mL, 18.9 mmol, 3 equiv) and 4M HCl in 1,4-dioxane (10 mL) and the resulting heterogeneous mixture was stirred at 100° C. until completion. The reaction mixture was cooled and washed with cold saturated NaHCO 3 The precipitate was filtered, washed with water, and air-dried to give 6,7-dimethoxy-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (546 mg, 1.88 mmol, 99% yield), which was used without purification. LCMS (ESI) Method 2: T =1.139 min, m / z=291.1[M+H] + .

[0589] Step B: Preparation of 4-chloro-6,7-dimethoxy-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (300 mg, 1.03 mmol, 1 equiv.) was added to a reaction vial with POCl 3 (1 mL) was added dropwise. The mixture was stirred at 90° C. until completion. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc and saturated NaHCO 3 The combined organic layers were washed with MgSO 4 It was dried at rt and concentrated under reduced pressure, and the title compound (298 mg, 0.93 mmol, 90% yield) was used without further purification. 1H NMR (400 MHz, chloroform-d) δ 7.37 (s, 1H), 7.31 (s, 1H), 4.11 (ddd, J = 11.4, 4.3, 2.0 Hz, 2H), 4.07 (s, 3H), 4.06 (s, 3H), 3.89 (ddd, J = LCMS (ESI) method 2: R T = 1.571 min, m / z = 309.1 [M+H] + .

[0590] [ka] Example 1 7-((1H-imidazol-1-yl)methyl)-2-(3-ethyl-1,6-naphthyridin-5-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (68 mg, 0.13 mmol, 80% yield) was prepared following the procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 60 mg, 0.16 mmol, 1 equiv.) and 5-chloro-3-ethyl-1,6-naphthyridine (Intermediate 34, 46 mg, 0.24 mmol, 1.5 equiv.). 1H NMR (400 MHz, chloroform-d) δ 8.98 (d, J = 2.1 Hz, 1H), 8.58 - 8.47 (m, 2H), 8.19 (s, 1H), 7.96 (s, 1H), 7.90 (d, J = 5.5 Hz, 1H), 7.48 (s, 1H), 7.31 (s, 1H), 7.29 (s, 1H), 7.05 (s, 1H), 5.37 (s, 2H), 4.36 (brs, 1H), 4.04 (s, 3H), 3.90 (brs, 1H), 3.06 (brs, 2H), 2.87 (q, J = 7.6 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H); LCMS (ESI) method 2: >95%, R T = 1.326 min, m / z = 532.0 [M+H] + .

[0591] [ka] Example 2 2-(3-Methoxy-7-methylquinolin-5-yl)-7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (57.9 mg, 103 μmol, 67% yield) was prepared using 7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 7, 60 mg, 0.15 mmol, 1 equiv.) and 5-bromo-3-methoxy-7-methylquinoline (Intermediate 13, 78 mg, 0.31 mmol, 2 equiv.) following the Buchwald coupling procedure described for Intermediate 15. 1H NMR (400 MHz, chloroform-d) δ 8.67 (d, J = 2.7 Hz, 1H), 8.13 (s, 1H), 7.86 (s, 1H), 7.39 (s, 1H), 7.33 (s, 1H), 7.27 (d, J = 2.7 Hz, 1H), 7.01 (s, 1H), 6.97 (s, 1H), 6.89 (s, 1H), 5.13 (s, 2H), 4.02 (s, 3H), 3.99 (td, J = 11.5, 4.5 Hz, 1H), 3.88 (s, 3H), 3.75 (dt, J = 12.5, 5.6 Hz, 1H), 3.15 - 3.06 (m, 1H), 2.97 (dt, J = 16.5, 4.8 Hz, 1H), 2.54 (s, 3H), 2.38 (s, 3H); 19 F NMR (376 MHz, chloroform-d) δ-60.16; LCMS (ESI) Method 2: >95%, R T = 1.437 min, m / z = 561.0 [M+H] + .

[0592] [ka] Example 3 Ethyl 6-ethyl-4-(7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)quinoline-8-carboxylate The title compound (155 mg, 0.252 mmol, 98% yield) was prepared using 7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 7, 100 mg, 0.257 mmol, 1 equiv.) and ethyl 4-bromo-6-ethylquinoline-8-carboxylate (Intermediate 12, 150 mg, 0.488 mmol, 1.9 equiv.) following the Buchwald coupling procedure described for Intermediate 15.1 H NMR (400 MHz, chloroform-d) δ 9.03 (d, J = 4.6 Hz, 1H), 8.12 (d, J = 1.8 Hz, 1H), 7.89 (d, J = 1.9 Hz, 1H), 7.72 - 7.71 (m, 1H), 7.40 (s, 1H), 7.36 (d, J = 4.6 Hz, 1H), 7.03 (d, J = 1.8 Hz, 1H), 6.96 (d, J = 1.3 Hz, 1H), 6.88 (d, J = 1.3 Hz, 1H), 5.13 (s, 2H), 4.54 (q, J = 7.1 Hz, 2H), 4.02 (s, 3H), 4.00 (td, J = 11.2, 4.2 Hz, 1H), 3.78 (dt, J = 12.3, 5.3 Hz, 1H), 3.19 - 3.11 (m, 1H), 2.97 (dt, J = 16.5, 4.7 Hz, 1H), 2.84 (q, J = 7.5 Hz, 2H), 2.37 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H), 1.31 (t, J = 7.6 Hz, 3H); LCMS (ESI) method 2: R T = 1.374 min, m / z = 617.1 [M+H] + .

[0593] [ka] Example 4 6-Ethyl-4-(7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)quinoline-8-carboxylic acid Ethyl 6-ethyl-4-(7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)quinoline-8-carboxylate (140 mg, 0.227 mmol, 1 equiv.) was dissolved in THF (2 mL) at room temperature. Water (0.7 mL) and LiOH (10.9 mg, 0.454 mmol, 2 equiv.) were added and the reaction mixture was stirred overnight. The reaction was concentrated and purified by silica gel chromatography (Combi-flash Rf, DCM / MeOH=0-10%, gradient) to give the title compound (129 mg, 0.220 mmol, 97% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.13 (d, J = 4.9 Hz, 1H), 8.51 (d, J = 1.9 Hz, 1H), 8.10 (s, 1H), 8.08 (d, J = 1.9 Hz, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.87 (d, J = 4.9 Hz, 1H), 7.26 (d, J = 1.4 Hz, 1H), 7.22 (d, J = 1.2 Hz, 1H), 6.85 (d, J = 1.1 Hz, 1H), 5.30 (s, 2H), 4.15 (td, J = 11.6, 4.2 Hz, 1H), 4.00 (s, 3H), 3.86 (dt, J LCMS (ESI) Method 2: R T = 1.385 min, m / z = 589.0 [M + H] + .

[0594] [ka] Example 5 6-Ethyl-N-methyl-4-(7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)quinoline-8-carboxamide To a solution of 6-ethyl-4-(7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)quinoline-8-carboxylic acid (Example 4, 60 mg, 0.10 mmol, 1 equiv.) in DMF (1 mL) was added HATU (58 mg, 0.15 mmol, 1.5 equiv.). After stirring at room temperature for 10 min, the reaction was cooled to 0° C. Methylamine hydrochloride (69 mg, 1.0 mmol, 10 equiv.) and N,N-diisopropylethylamine (0.036 mL, 0.20 mmol, 2 equiv.) were added and then stirred at 0° C. for an additional 2 h and allowed to warm to room temperature. The reaction mixture was diluted with saturated NH 4 Dilute with Cl and CH 2 Cl 2 (3x20mL). The organic layer was then extracted with MgSO 4 The mixture was dried at 40°C, filtered, and concentrated. 2 O / CH 3 Gradient of CN, 15-80% CH 3 The residue was purified by elution with 100% TFA (CN, 0.1% TFA) and then saturated aqueous NaHCO 3 Neutralization with afforded the title compound (16.7 mg, 0.028 mmol, 27% yield). 1H NMR (400 MHz, chloroform-d) δ 11.05 (d, J = 4.5 Hz, 1H), 8.93 (d, J = 4.7 Hz, 1H), 8.81 (d, J = 1.7 Hz, 1H), 8.12 (s, 1H), 7.75 (s, 1H), 7.41 - 7.39 (m, 2H), 7.05 (s, 1H), 6.98 (s, 1H), 6.89 (s, 1H), 5.14 (s, 2H), 4.02 (s, 3H), 4.01 (td, J = 11.3, 4.1 Hz, 1H), 3.82 (dt, J = 12.4, 5.3Hz, 1H), 3.22 - 3.12 (m, 4H), 2.99 (dt, J = 16.5, 4.5 Hz, 1H), 2.87 (q, J = 7.5 Hz, 2H), 2.39 (s, 3H), 1.32 (t, J = 7.6 Hz, 3H); 19 F NMR (376 MHz, chloroform-d) δ -60.10; LCMS (ESI) Method 2: >95%, R T = 1.372 min, m / z = 602.1 [M+H] + .

[0595] [ka] Example 6 6-Ethyl-4-(7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)quinoline-8-carboxamide The title compound (22.5 mg, 0.038 mmol, 38% yield) was prepared following the procedure described for Example 5, substituting ammonium chloride (55 mg, 1.0 mmol, 10 equiv). 1H NMR (400 MHz, chloroform-d) δ 10.90 (d, J = 4.8 Hz, 1H), 8.94 (d, J = 4.6 Hz, 1H), 8.80 (s, 1H), 8.12 (s, 1H), 7.80 (s, 1H), 7.42 - 7.41 (m, 2H), 7.05 (s, 1H), 6.97 (s, 1H), 6.88 (s, 1H), 6.08 (d, J = 4.5 Hz, 1H), 5.14 (s, 2H), 4.06 - 3.99 (m, 4H), 3.82 (dt, J = 12.3, 5.2 Hz, 1H), 3.22 - 3.14 (m, 1H), 2.99 (dt, J = 16.4, 4.3 Hz, 1H), 2.88 (q, J = 7.6 Hz, 2H), 2.38 (s, 3H), 1.32 (t, J = 7.6 Hz, 3H); 19 F NMR (376 MHz, chloroform-d) δ -60.10; LCMS (ESI) Method 2: >95%, R T = 1.361 min, m / z = 588.1 [M+H] + .

[0596] [ka] Example 7 Mixture of 4-(7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-6-ethyl-1,7-naphthyridin-8(7H)-one and 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-hydroxy-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one A solution of 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-methoxy-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 14, 1.00 g, 1.78 mmol, 1 equiv.) in DMF (6 mL) was added to PBr at 25 °C. 3 (0.25 mL, 2.67 mmol, 1.5 equiv) was added. The reaction was stirred overnight. Saturated aqueous NaHCO 3 was added and the mixture was extracted with EtOAc. The combined organic layers were washed with MgSO 4 The residue was purified by flash chromatography (Combi-flash Rf, DCM / MeOH=0-20% gradient) to give an inseparable mixture of the title compounds (661 mg, 1.21 mmol, 68% yield). 1 H NMR (400 MHz, chloroform-d) δ 11.24 - 10.78 (m, 1H), 8.88 (d, J = 4.6 Hz, 1H), 8.15 (s, 1H), 7.63 (s, 1H), 7.47 (d, J = 4.7 Hz, 1H), 7.41 (s, 1H), 7.19 (s, 1H), 7.11 (s, 1H), 6.95 (s, 1H), 6.21 (s, 1H), 5.21 (s, 2H), 4.03 (s, 3H), 3.99 (td, J = 11.6, 4.2 Hz, 1H), 3.76 (dt, J = 12.1, 5.2 Hz, 1H), 3.16 - 3.07 (m, 1H), 2.97 (dt, J = 16.5, 4.6 Hz, 1H), 2.74 (q, J = 7.3 Hz, 2H), 1.30 (t, J =7.5 Hz, 3H); 19 F NMR (376 MHz, chloroform-d) δ -60.11; LCMS (ESI) Method 2: >95%, R T = 1.228 min, m / z = 548.1 [M+H] + .

[0597] [ka] Example 8 7-((1H-imidazol-1-yl)methyl)-2-(8-chloro-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one To a mixture of 4-(7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-6-ethyl-1,7-naphthyridin-8(7H)-one and 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-hydroxy-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Example 7, 150 mg, 274 μmol, 1 equiv.), excess POCl was added. 3 (1.0 mL, 11.0 mmol) was added and the reaction was heated at 80° C. for 2 h. The reaction was cooled to room temperature and ice was added to quench the reaction. The quenched mixture was diluted with saturated aqueous NaHCO 3 Neutralized by CH 2 Cl 2 The organic layer was extracted with MgSO 4 and concentrated under reduced pressure to give the title compound (110 mg, 0.194 mmol, 70.9% yield). 1 H NMR (400 MHz, CDCl 3) δ 9.04 (d, J = 4.2 Hz, 1H), 8.12 (s, 1H), 7.48 (q, J = 6.8 Hz, 2H), 7.31 (q, J = 11.8 Hz, 4H), 7.07 (s, 1H), 5.38 (s, 2H), 3.98 (s, LCMS (ESI) method 2: >95%, R T = 1.650 min, m / z = 566.0 [M+H] + .

[0598] [ka] Example 9 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-(methylamino)-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 7-((1H-imidazol-1-yl)methyl)-2-(8-chloro-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Example 8, 50 mg, 0.088 mmol, 1 equiv.) was dissolved in acetonitrile (1 mL) and stirred at room temperature. Potassium carbonate (0.12 g, 0.88 mmol, 10 equiv.) and methylamine hydrochloride (60 mg, 0.88 mmol, 10 equiv.) were then added and the reaction was stirred until complete. The reaction mixture was diluted with saturated aqueous NH 4 Dilute with Cl and CH 2 Cl 2 (3x20mL). The combined organic layers were extracted with MgSO 4 The mixture was dried at 40°C, filtered, and concentrated. 2 O / CH3 Gradient of CN, 15-80% CH 3 The residue was purified by elution with 100% TFA (CN, 0.1% TFA) and then saturated aqueous NaHCO 3 Neutralization with afforded the title compound (15.3 mg, 0.027 mmol, 31% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.66 (d, J = 4.7 Hz, 1H), 8.16 (d, J = 1.9 Hz, 1H), 7.59 (s, 1H), 7.42 - 7.40 (m, 2H), 7.17 (d, J = 1.7 Hz, 1H), 7.08 (s, 1H), 6.95 (s, 1H), 6.91 (brs, 1H), 6.52 (s, 1H), 5.20 (s, 2H), 4.03 (s, 3H), 3.91 (td, J = 11.2, 4.2 Hz, 1H), 3.83 - 3.78 (m, 1H), 3.22 (d, J = 3.9 Hz, 3H), 3.21 - 3.09 (m, 1H), 2.95 (dt, J = 16.8, 4.6 Hz, 1H), 2.76 (q, J = 7.3 Hz, 2H), 1.31 (t, J = 7.5 Hz, 3H); 19 F NMR (376 MHz, chloroform-d) δ -60.10; LCMS (ESI) Method 2: >95%, R T = 1.332 min, m / z = 561.1 [M+H] + .

[0599] [ka] Example 10 2-(6-ethyl-8-methoxy-1,7-naphthyridin-4-yl)-7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (44 mg, 76 μmol, 74% yield) was prepared using 7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 7, 40 mg, 0.10 mmol, 1 equiv.) and 4-bromo-6-ethyl-8-methoxy-1,7-naphthyridine (Intermediate 14, 44 mg, 0.16 mmol, 1.6 equiv.) following the Buchwald coupling procedure described for Intermediate 15. 1 H NMR (400 MHz, chloroform-d) δ 8.93 (d, J = 4.6 Hz, 1H), 8.12 (d, J = 1.7 Hz, 1H), 7.48 (d, J = 4.6 Hz, 1H), 7.40 (s, 1H), 7.03 (d, J = 1.8 Hz, 1H), 6.97 (s, 1H), 6.95 (s, 1H), 6.89 (s, 1H), 5.14 (s, 2H), 4.22 (s, 3H), 4.02 (s, 3H), 3.99 (td, J = 11.2, 4.2 Hz, 1H), 3.81 (dt, J = 12.2, 5.3 Hz, 1H), 3.19 - 3.11 (m, 1H), 2.97 (dt, J = 16.5, 4.6 Hz, 1H), 2.81 (q, J = 7.5 Hz, 2H), 2.38 (s, 3H), 1.33 (t, J = 7.5 Hz, 3H); 19 F NMR (376 MHz, chloroform-d) δ -60.09; LCMS (ESI) Method 2: >95%, R T = 1.555 min, m / z = 576.0 [M+H] + .

[0600] [ka] Example 11 (S)-7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one To a suspension of (S)-6-ethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine dihydrochloride (Intermediate 16, 56 mg, 222 μmol, 2.0 equiv.) in THF (2.5 mL) at −78° C. was added 1M tert-butylmagnesium chloride (666 μL, 0.66 mmol, 6.0 equiv.). The acetone / dry ice bath was removed and the reaction mixture was allowed to warm to 0° C. and stirred for 20 min. Ethyl 5-((1H-imidazol-1-yl)methyl)-2-(2-chloroethyl)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)benzoate (Intermediate 23, 45 mg, 111 μmol, 1 equiv.) was added as a solution in THF (4 mL). The reaction was allowed to warm to room temperature and stirred for 16 h, then saturated NH 4 The mixture was quenched with aqueous Cl. The mixture was extracted with EtOAc. The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated. 2 O / CH 3 Gradient of CN, 30-90% CH 3 The residue was purified by CN, 0.1% TFA) to give the title compound (30 mg, 56 μmol, 50% yield). 1H NMR (400 MHz, chloroform-d) δ 8.12 (d, J = 2.0 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.57 (s, 1H), 7.32 (s, 2H), 7.12 (d, J = 2.0 Hz, 1H), 7.10 (s, 1H), 6.94 (m, 1H), 6.21 (t, J = 8.4 Hz, 1H), 5.19 (s, 2H), 5.50 (m, 1H), 4.35 (m, 1H), 3.99 (s, 3H), 3.28 (m, 1H), 3.09 (m, 1H), 2.68 (m, 2H), 2.53 (m, 2H), 2.16 (m, 2H), 1.16 (t, J = 7.6 Hz, 3H); LCMS (ESI): >95%, m / z = 537.4 [M + H] + .

[0601] [ka] Example 12 7-((1H-imidazol-1-yl)methyl)-2-(6,8-dimethoxy-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (189 mg, 0.337 mmol, 97% yield) was prepared according to the Buchwald coupling procedure described for Example 1 using 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 130 mg, 0.346 mmol, 1 equiv.) and 4-bromo-6,8-dimethoxy-1,7-naphthyridine (Intermediate 24, 149 mg, 0.554 mmol, 1.6 equiv.). 1H NMR (400 MHz, chloroform-d) δ 8.79 (d, J = 4.5 Hz, 1H), 7.74 (s, 1H), 7.43 (d, J = 4.5 Hz, 1H), 7.41 (s, 1H), 7.20 (s, 1H), 7.15 (s, 1H), 6.98 (s, 1H), 6.43 (s, 1H), 5.19 (s, 2H), 4.24 (s, 3H), 4.03 (s, 3H), 3.99 - 3.93 (m, 4H), 3.80 (dt, J = 12.3, 5.3 Hz, 1H), 3.18 - 3.10 (m, 1H), 2.96 (dt, J = 16.5, 4.5 Hz, 1H); 19 F NMR (376 MHz, chloroform-d) δ -60.08; LCMS (ESI) Method 2: >95%, R T = 1.867 min, m / z = 564.0 [M+H] + .

[0602] [ka] Example 13 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-methoxycinnoline-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (50 mg, 0.089 mmol, 61% yield) was prepared following the Buchwald coupling procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 55 mg, 0.15 mmol, 1 equiv.) and 4-bromo-6-ethyl-8-methoxycinnoline (Intermediate 25, 59 mg, 0.22 mmol, 1.5 equiv.). 1H NMR (400 MHz, chloroform-d) δ 9.24 (s, 1H), 8.16 (d, J = 1.8 Hz, 1H), 7.74 (s, 1H), 7.52 (s, 1H), 7.22 (d, J = 1.9 Hz, 1H), 7.14 (s, 1H), 7.12 (s, 1H), 6.99 (d, J = 1.1 Hz, 1H), 6.98 (s, 1H), 5.23 (s, 2H), 4.18 (s, 3H), 4.09 - 4.00 (m, 4H), 3.89 - 3.83 (m, 1H), 3.18 - 3.10 (m, 1H), 3.01 (dt, J = 16.4, 4.9 Hz, 1H), 2.84 (q, J = 7.6 Hz, 2H), 1.32 (t, J = 7.6 Hz, 3H); 19 F NMR (376 MHz, chloroform-d) δ-60.06; LCMS (ESI) Method 2: >95%, R T = 1.740 min, m / z = 562.0 [M+H] + .

[0603] [ka] Example 14 2-(6-ethyl-8-methoxycinnoline-4-yl)-7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (62.5 mg, 0.109 mmol, 77% yield) was prepared according to the Buchwald coupling procedure described for Intermediate 15 using 7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 7, 55 mg, 0.14 mmol, 1 equiv.) and 4-bromo-6-ethyl-8-methoxycinnoline (Intermediate 25, 57 mg, 0.21 mmol, 1.5 equiv.). 1H NMR (400 MHz, chloroform-d) δ 9.23 (s, 1H), 8.12 (d, J = 1.7 Hz, 1H), 7.40 (s, 1H), 7.12 (s, 1H), 7.04 (d, J = 1.8 Hz, 1H), 6.99 - 6.98 (m, 2H), 6.90 (d, J = 1.3 Hz, 1H), 5.14 (s, 2H), 4.18 (s, 3H), 4.08 - 3.99 (m, 4H), 3.88 - 3.82 (m, 1H), 3.18 - 3.10 (m, 1H), 3.00 (dt, J = 16.8, 4.9 Hz, 1H), 2.84 (q, J = 7.6 Hz, 2H), 2.40 (s, 3H), 1.33 (t, J = 7.6 Hz, 3H); 19 F NMR (376 MHz, chloroform-d) δ -60.06; LCMS (ESI) Method 2: >95%, R T = 1.753 min, m / z = 576.1 [M+H] + .

[0604] [ka] Example 15 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxy-2-methylquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 60 mg, 0.16 mmol, 1 equiv.), 4-chloro-6,7-dimethoxy-2-methylquinazoline (76 mg, 0.32 mmol, 2 equiv.), cesium carbonate (104 mg, 0.32 mmol, 2 equiv.), Xantphos (28 mg, 0.048 mmol, 0.3 equiv.) and Pd 2 (dba) 3(15 mg, 0.016 mmol, 0.1 equiv) was dissolved in 1,4-dioxane (1 mL) under Ar. The reaction mixture was stirred at 115° C. for 14 h and then cooled to 23° C. Brine was added to the mixture and the mixture was diluted with CH 2 Cl 2 (3x20mL). The combined organic layers were extracted with MgSO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. 2 O / CH 3 Gradient of CN, 15-70% CH 3 The residue was purified by elution with 100% TFA (CN, 0.1% TFA) and then saturated aqueous NaHCO 3 Neutralization with afforded the title compound (61.3 mg, 0.106 mmol, 66% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.08 (s, 1H), 7.99 (s, 1H), 7.79 (s, 1H), 7.39 (s, 1H), 7.34 (s, 1H), 7.22 (s, 1H), 7.06 (s, 1H), 6.91 (s, 1H), 5.31 (s, 2H), 3.99 (s, 4H), 3.98 (s, 4H), 3.79 (s, 3H), 3.01 (brs, 2H), 2.67 (s, 3H); 19 F NMR (376 MHz, chloroform-d) δ -58.24; LCMS (ESI) Method 2: >95%, R T = 1.663 min, m / z = 578.1 [M+H] + .

[0605] [ka] Example 16 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxyquinolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (61.4 mg, 0.109 mmol, 68% yield) was prepared following the Buchwald coupling procedure described for Intermediate 15, substituting 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 60 mg, 0.16 mmol, 1 equiv.) and 4-bromo-6,7-dimethoxyquinoline (86 mg, 0.32 mmol, 2 equiv.). 1 H NMR (400 MHz, chloroform-d) δ 8.78 (d, J = 4.8 Hz, 1H), 8.18 (s, 1H), 7.64 (s, 1H), 7.50 (s, 1H), 7.41 (s, 1H), 7.22 (d, J = 4.7 Hz, 1H), 7.19 (s, 1H), 7.12 (s, 1H), 7.00 (s, 1H), 6.96 (s, 1H), 5.21 (s, 2H), 4.05 (s, 3H), 4.02 - 3.97 (m, 4H), 3.94 (s, 3H), 3.83 - 3.77 (m, 1H), 3.18 - 3.10 (m, 1H), 3.01 - 2.94 (m, 1H); 19 F NMR (376 MHz, chloroform-d) δ -60.16; LCMS (ESI) Method 2: >95%, R T = 1.615 min, m / z = 563.1 [M+H] + .

[0606] [ka] Example 17 7-((1H-imidazol-1-yl)methyl)-2-(6-methoxy-1,5-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (67.8 mg, 0.127 mmol, 68% yield) was prepared following the Buchwald coupling procedure described for Intermediate 15, substituting 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 70 mg, 0.186 mmol, 1 equiv.) and 8-bromo-2-methoxy-1,5-naphthyridine (67 mg, 0.28 mmol, 1.5 equiv.). 1 H NMR (400 MHz, chloroform-d) δ 8.84 (d, J = 4.7 Hz, 1H), 8.26 (d, J = 9.1 Hz, 1H), 7.72 (brs, 1H), 7.66 (d, J = 4.7 Hz, 1H), 7.41 (s, 1H), 7.16 (s, 1H), 7.14 (s, 1H), 6.97 (s, 1H), 5.22 (s, 2H), 4.08 (t, J = 6.2 Hz, 2H), 4.03 (s, 3H), 3.95 (s, 3H), 3.08 (t, J = 6.3 Hz, 2H); 19 F NMR (376 MHz, chloroform-d) δ -60.28; LCMS (ESI) Method 2: >95%, R T = 1.421 min, m / z = 534.0 [M+H] + .

[0607] [ka] Example 18 Ethyl 4-(7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-6-ethyl-1,7-naphthyridine-8-carboxylate The title compound (130 mg, 0.214 mmol, 90% yield) was prepared according to the Buchwald coupling procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 90 mg, 0.24 mmol, 1 equiv.) and ethyl 4-bromo-6-ethyl-1,7-naphthyridine-8-carboxylate (Intermediate 26, 111 mg, 0.36 mmol, 1.5 equiv.). 1 H NMR (400 MHz, chloroform-d) δ 9.04 (d, J = 4.6 Hz, 1H), 8.16 (s, 1H), 7.76 (s, 1H), 7.51 - 7.49 (m, 2H), 7.43 (s, 1H), 7.23 (s, 1H), 7.14 (s, 1H), 6.98 (s, 1H), 5.23 (s, 2H), 4.61 (qd, J = 7.2 Hz, 2.4 Hz, 2H), 4.09 - 4.00 (m, 4H), 3.83 - 3.77 (m, 1H), 3.22 - 3.14 (m, 1H), 3.03 - 2.98 (m, 3H), 1.48 (t, J = 7.2 Hz, 3H), 1.36 (t, J = 7.6 Hz, 3H); LCMS (ESI) method 2: >95%, R T = 1.362 min, m / z = 604.0 [M+H] + .

[0608] [ka] Example 19 4-(7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-6-ethyl-1,7-naphthyridine-8-carboxylic acid The title compound (122 mg, 0.213 mmol, quantitative) was prepared according to the procedure described for Example 4 using ethyl 4-(7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-6-ethyl-1,7-naphthyridine-8-carboxylate (Example 18, 128 mg, 0.214 mmol, 1 equiv.). LCMS (ESI) Method 2: >95%, R T =1.637 min, m / z=576.0[M+H] + .

[0609] [ka] Example 20 4-(7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-6-ethyl-N-methyl-1,7-naphthyridine-8-carboxamide The title compound (40 mg, 0.068 mmol, 33% yield) was prepared following the procedure described for Example 5, substituting 4-(7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-6-ethyl-1,7-naphthyridine-8-carboxylic acid (Example 19, 120 mg, 0.208 mmol, 1 equiv.). 1H NMR (400 MHz, chloroform-d) δ 9.18 (d, J = 4.4 Hz, 1H), 9.06 (d, J = 4.6 Hz, 1H), 8.15 (s, 1H), 7.77 (s, 1H), 7.54 - 7.53 (m, 2H), 7.44 (s, 1H), 7.24 (s, 1H), 7.15 (s, 1H), 6.98 (s, 1H), 5.24 (s, 2H), 4.07 (td, J = 11.7, 4.0 Hz, 1H), 4.03 (s, 3H), 3.82 (dt, J = 12.0, 5.2 Hz, 1H), 3.23 - 3.15 (m, 4H), 3.07 (q, J = 7.6 Hz, 2H), 3.00 (dt, J = 16.4, 4.6 Hz, 1H), 1.37 (t, J = 7.6 Hz, 3H); 19 F NMR (376 MHz, chloroform-d) δ -60.08; LCMS (ESI) Method 2: >95%, R T = 1.411 min, m / z = 589.0 [M+H] + .

[0610] [ka] Example 21 7-((1H-imidazol-1-yl)methyl)-2-(3-ethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (16 mg, 30 μmol, 28% yield) was prepared following the procedure described for Example 11 using ethyl 5-((1H-imidazol-1-yl)methyl)-2-(2-chloroethyl)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)benzoate (Intermediate 23, 45 mg, 111 μmol, 1 eq.) and 3-ethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-amine dihydrochloride (Intermediate 28, 54 mg, 215 μmol, 2.0 eq.).1 H NMR (400 MHz, chloroform-d) δ 8.36 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H), 7.86 (s, 1H), 7.45 (s, 1H), 7.31 (s, 1H), 7.17 (s, 1H), 7.15 (d, J = 2.0 Hz, 1H), 7.00 (s, 1H), 5.96 (brs, 1H), 5.24 (s, 2H), 4.87 (d, J = 16.0 Hz, 1H), 4.71 (d, J = 16.0 Hz, 1H), 4.18 (dd, J = 2.4, 12.4 Hz, 1H), 4.05 (dd, LCMS (ESI): >95%, m / z = 537.4 [M+H] + .

[0611] [ka] Example 22 7-((1H-imidazol-1-yl)methyl)-2-(3-methoxy-2-methyl-5,6,7,8-tetrahydroquinolin-5-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one Step A. Preparation of methyl 5-hydroxy-2-(3-methoxy-2-methyl-5,6,7,8-tetrahydroquinolin-5-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate. To a suspension of 3-methoxy-2-methyl-5,6,7,8-tetrahydroquinolin-5-amine dihydrochloride (Intermediate 27, 20 mg, 75 μmol, 1 equiv.) in dichloromethane (1 mL) was added DIPEA (0.037 mL, 21 μmol, 3 equiv.) at 30° C. The mixture was stirred for 15 min, then dimethyl 2-hydroxy-2,3-dihydrobenzofuran-4,6-dicarboxylate (19 mg, 75 μmol, 1 equiv.) and NaBH(OAc) 3 (24 mg, 113 μmol, 1.5 equiv) was added stepwise. The reaction was stirred at 30° C. for 2 h and then concentrated. The residue was dissolved in 1,4-dioxane (10 mL) and heated at 90° C. for 1 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried (Na 2 SO 4 ) and concentration to give the title compound, which was used without further purification.

[0612] Step B. Preparation of methyl 2-(3-methoxy-2-methyl-5,6,7,8-tetrahydroquinolin-5-yl)-1-oxo-5-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate. The title compound (28.3 mg, 53.5 μmol, 71% yield over two steps) was prepared following the procedure described for Intermediate 2 using methyl 5-hydroxy-2-(3-methoxy-2-methyl-5,6,7,8-tetrahydroquinolin-5-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (30 mg, 75 μmol, 1 equiv.). 1H NMR (400 MHz, chloroform-d) δ 8.87 (s, 1H), 8.07 (s, 1H), 6.85 (s, 1H), 6.08 (dd, J = 6.0, 9.6 Hz, 1H), 3.99 (s, 3H), 3.72 (s, 3H), 3.45 (m, 1H), 3.24 (m, 1H), 3.06 (m, 1H), 2.92 (m, 3H), 2.45 (s, 3H), 2.15 (m, 2H), 1.87 (m, 1H), 1.75 (m, 1H).

[0613] Step C. Preparation of methyl 2-(3-methoxy-2-methyl-5,6,7,8-tetrahydroquinolin-5-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate. The title compound (33 mg, 53.5 μmol, 100% yield) was prepared according to the procedure described for intermediate 3 using methyl 2-(3-methoxy-2-methyl-5,6,7,8-tetrahydroquinolin-5-yl)-1-oxo-5-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (28.3 mg, 53.5 μmol, 1 equiv.). LCMS (ESI): m / z=529.2 [M+H] + .

[0614] Step D. Preparation of 7-(hydroxymethyl)-2-(3-methoxy-2-methyl-5,6,7,8-tetrahydroquinolin-5-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one. The title compound (25.8 mg, 51.5 μmol, 96% yield) was prepared according to the procedure described for Intermediate 5 using methyl 2-(3-methoxy-2-methyl-5,6,7,8-tetrahydroquinolin-5-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (28.3 mg, 53.5 μmol, 1 equiv.). 1 H NMR (400 MHz, chloroform-d) δ 8.21 (s, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.35 (s, 1H), 6.91 (s, 1H), 6.09 (dd, J = 6.0, 9.6 Hz, 1H), 4.78 (s, 2H), 4.00 (s, 3H), 3.72 (s, 3H), 3.29 (m, 1H), 3.06 (m, 1H), 2.90 (m, 2H), 2.65 (m, 2H), 2.45 (s, 3H), 2.09 (m, 2H), 1.89 (m, 1H), 1.78 (m, 1H).

[0615] Step E. Preparation of 7-(chloromethyl)-2-(3-methoxy-2-methyl-5,6,7,8-tetrahydroquinolin-5-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one. The title compound (26.8 mg, 51.5 μmol, 100% yield) was prepared following the procedure described for Intermediate 6 using 7-(hydroxymethyl)-2-(3-methoxy-2-methyl-5,6,7,8-tetrahydroquinolin-5-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (25.8 mg, 51.5 μmol, 1 equiv.) and thionyl chloride (2.0 equiv.). LCMS(ESI):m / z=519.2[M+H] + .

[0616] Step F. Preparation of 7-((1H-imidazol-1-yl)methyl)-2-(3-methoxy-2-methyl-5,6,7,8-tetrahydroquinolin-5-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one. The title compound (23.5 mg, 42.7 μmol, 82% yield) was prepared following the procedure described for Intermediate 7 using 7-(chloromethyl)-2-(3-methoxy-2-methyl-5,6,7,8-tetrahydroquinolin-5-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (26.7 mg, 51.5 μmol, 1 equiv.) and 1H-imidazole (206 μmol, 4 equiv.). 1H NMR (400 MHz, chloroform-d) δ 8.14 (d, J = 2.0 Hz, 1H), 7.65 (s, 1H), 7.32 (s, 1H), 7.12 (m, 2H), 7.00 (s, 1H), 6.91 (s, 1H), 6.07 (m, 1H), 5.20 (s, 2H), 3.99 (s, 3H), 3.73 (s, 3H), 3.30 (m, 1H), 3.06 (m, 1H), 2.89 (m, 2H), 2.65 (m, 2H), 2.46 (s, 3H), 2.11 (m, 2H), 1.89 (m, 1H), 1.76 (m, 1H); LCMS (ESI): >95%, m / z = 551.5 [M+H] + .

[0617] [ka] Example 23 7-((1H-imidazol-1-yl)methyl)-2-(7-hydroxy-6-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (9 mg, 0.02 mmol, 10% yield) was prepared according to the Buchwald coupling procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 60 mg, 0.16 mmol, 1 equiv.) and 4-chloro-6-methoxyquinazolin-7-ol (51 mg, 0.24 mmol, 1.5 equiv.). 1 H NMR (400 MHz, DMSO-d 6) δ 10.92 (s, 1H), 8.93 (s, 1H), 8.09 (s, 1H), 8.02 (d, J = 1.4 Hz, 1H), 7.99 (brs, 1H), 7.42 (s, 1H), 7.30 (brs, 1H), 7.26 (s, 1H), 7.10 (s, 1H), 7.02 (brs, 1H), 5.35 (s, 2H), 4.05 - 3.96 (m, 5H), 3.82 (s, 3H), 3.02 (brs, 2H); 19 F NMR (376 MHz, DMSO-d 6 ) δ-58.21; LCMS (ESI) method 2: >95%, R T = 1.125 min, m / z = 550.0 [M+H] + .

[0618] [ka] Example 24 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (61 mg, 0.11 mmol, 68% yield) was prepared following the Buchwald coupling procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 60 mg, 0.16 mmol, 1 equiv.) and 4-chloro-6,7-dimethoxyquinazoline (54 mg, 0.24 mmol, 1.5 equiv.). 1H NMR (400 MHz, chloroform-d) δ 9.03 (s, 1H), 8.18 (d, J = 1.7 Hz, 1H), 7.93 - 7.91 (m, 1H), 7.44 (s, 1H), 7.36 (s, 1H), 7.23 (s, 1H), 7.17 (s, 1H), 7.00 - 6.99 (m, 2H), 5.19 (s, 2H), 4.15 (brs, 2H), 4.07 (s, 3H), 4.04 (s, 3H), 3.94 (s, 3H), 3.06 (t, J = 6.2 Hz, 2H); 19 F NMR (376 MHz, chloroform-d) δ -60.09; LCMS (ESI) Method 2: >95%, R T = 1.212 min, m / z = 564.0 [M+H] + .

[0619] [ka] Example 25 7-((1H-imidazol-1-yl)methyl)-2-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (61 mg, 0.10 mmol, 63% yield) was prepared following the Buchwald coupling procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 60 mg, 0.16 mmol, 1 equiv.) and 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (Intermediate 29, 65 mg, 0.24 mmol, 1.5 equiv.). 1H NMR (400 MHz, chloroform-d) δ 9.02 (s, 1H), 8.18 (d, J = 1.5 Hz, 1H), 7.99 (s, 1H), 7.44 (s, 1H), 7.36 (s, 1H), 7.23 (d, J = 1.6 Hz, 1H), 7.19 (s, 1H), 7.02 (s, 1H), 6.98 (s, 1H), 5.27 (s, 2H), 4.36 (t, J = 4.7 Hz, 2H), 4.15 (brs, 2H), 4.04 (s, 3H), 3.91 (s, 3H), 3.89 (t, J = 4.7 Hz, 2H), 3.48 (s, 3H), 3.06 (t, J = 6.0 Hz, 2H); LCMS (ESI) method 2: >95%, R T = 1.225 min, m / z = 608.1 [M+H] + .

[0620] [ka] Example 26 7-((1H-imidazol-1-yl)methyl)-2-(6-methoxy-7-((1-methyl-1H-pyrazol-5-yl)methoxy)quinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (42 mg, 0.11 mmol, 61% yield) was prepared according to the Buchwald coupling procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 40 mg, 0.11 mmol, 1 equiv.) and 4-chloro-6-methoxy-7-((1-methyl-1H-pyrazol-5-yl)methoxy)quinazoline (Intermediate 30, 49 mg, 0.16 mmol, 1.5 equiv.). 1H NMR (400 MHz, chloroform-d) δ 9.03 (s, 1H), 8.17 (s, 1H), 8.06 - 7.93 (m, 1H), 7.46 (s, 2H), 7.44 (s, 1H), 7.24 (s, 1H), 7.20 - 7.17 (m, 1H), 7.02 - 6.99 (m, 2H), 6.44 (d, J = 1.6 Hz, 1H), 5.29 - 5.16 (m, 4H), 4.16 (brs, 2H), 4.04 (s, 3H), 3.96 (s, 3H), 3.90 (s, 3H), 3.06 (t, J = 6.0 Hz, 2H); LCMS (ESI) Method 2: >95%, R T = 1.249 min, m / z = 644.1 [M+H] + .

[0621] [ka] Example 27 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (25 mg, 0.045 mmol, 56% yield) was prepared following the Buchwald coupling procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 30 mg, 0.08 mmol, 1 equiv.) and 4-chloro-6-ethyl-8-methoxyquinazoline (Intermediate 31, 27 mg, 0.12 mmol, 1.5 equiv.). 1H NMR (400 MHz, chloroform-d) δ 9.16 (s, 1H), 8.19 (d, J = 1.7 Hz, 1H), 7.89 (s, 1H), 7.44 (s, 1H), 7.23 (d, J = 1.5 Hz, 1H), 7.20 (s, 1H), 7.17 (s, 1H), 7.09 (d, J = 1.1 Hz, 1H), 7.00 (s, 1H), 5.25 (s, 2H), 4.13 (brs, 2H), 4.10 (s, 3H), 4.04 (s, 3H), 3.07 (brs, 2H), 2.81 (q, J = 7.5 Hz, 2H), 1.30 (t, J = 7.6 Hz, 3H); LCMS (ESI) method 2: >95%, R T = 1.333 min, m / z = 562.0 [M+H] + .

[0622] [ka] Example 28 7-((1H-imidazol-1-yl)methyl)-2-(6-ethoxy-7-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (25 mg, 0.043 mmol, 27% yield) was prepared following the Buchwald coupling procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 60 mg, 0.16 mmol, 1 equiv.) and 4-chloro-6-ethoxy-7-methoxyquinazoline (Intermediate 32, 57 mg, 0.24 mmol, 1.5 equiv.). 1H NMR (400 MHz, chloroform-d) δ 9.01 (s, 1H), 8.18 (s, 1H), 8.11 - 7.94 (m, 1H), 7.44 (s, 1H), 7.35 (s, 1H), 7.23 (s, 1H), 7.21 - 7.17 (m, 1H), 7.03 - 7.00 (m, 1H), 6.98 (s, 1H), 5.27 (s, 2H), 4.16 - 4.11 (m, 4H), 4.06 (s, 3H), 4.04 (s, 3H), 3.05 (t, J = 5.9 Hz, 2H), 1.51 (t, J = 7.0 Hz, 3H); LCMS (ESI) Method 2: >95%, R T = 1.490 min, m / z = 578.1 [M+H] + .

[0623] [ka] Example 29 7-((1H-imidazol-1-yl)methyl)-2-(7-ethoxy-6-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (37 mg, 0.064 mmol, 40% yield) was prepared following the Buchwald coupling procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 60 mg, 0.16 mmol, 1 equiv.) and 4-chloro-7-ethoxy-6-methoxyquinazoline (Intermediate 33, 76 mg, 0.32 mmol, 2 equiv.). 1H NMR (400 MHz, chloroform-d) δ 9.01 (s, 1H), 8.18 (s, 1H), 7.91 - 7.81 (m, 1H), 7.43 (s, 1H), 7.34 (s, 1H), 7.22 (s, 1H), 7.16 (s, 1H), 6.99 (s, 1H), 6.98 (s, 1H), 5.25 (s, 2H), 4.31 (q, J = 7.0 Hz, 2H), 4.14 (brs, 2H), 4.03 (s, 3H), 3.93 (s, 3H), 3.05 (t, J = 6.2 Hz, 2H), 1.58 (t, J = 7.0 Hz, 3H); LCMS (ESI) Method 2: >95%, R T = 1.283 min, m / z = 578.1 [M+H] + .

[0624] [ka] Example 30 7-((1H-imidazol-1-yl)methyl)-2-(6,7-diethoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (68 mg, 0.11 mmol, 72% yield) was prepared following the Buchwald coupling procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 60 mg, 0.16 mmol, 1 equiv.) and 4-chloro-6,7-diethoxyquinazoline (61 mg, 0.24 mmol, 1.5 equiv.). 1 H NMR (400 MHz, DMSO-d 6) δ 8.99 (s, 1H), 8.09 (s, 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.79 (s, 1H), 7.40 (d, J = 1.4 Hz, 1H), 7.39 (s, 1H), 7.22 (s, 1H), 7.09 (s, 1H), 6.91 (s, 1H), 5.32 (s, 2H), 4.29 (q, J = 7.0 Hz, 2H), 4.10 - 4.01 (m, 4H), 3.99 (s, 3H), 3.00 (brs, 2H), 1.44 (t, J = 7.0 Hz, 3H), 1.35 (t, J = 6.9 Hz, 3H); LCMS (ESI) method 2: >95%, R T = 1.502 min, m / z = 592.0 [M+H] + .

[0625] [ka] Example 31 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxyphthalazin-1-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (65 mg, 0.12 mmol, 72% yield) was prepared according to the Buchwald coupling procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 60 mg, 0.16 mmol, 1 equiv.) and 1-chloro-6,7-dimethoxyphthalazine (54 mg, 0.24 mmol, 1.5 equiv.). 1 H NMR (400 MHz, DMSO-d 6) δ 9.46 (s, 1H), 8.10 (s, 1H), 7.98 (d, J = 1.4 Hz, 1H), 7.79 (s, 1H), 7.66 (s, 1H), 7.40 (s, 1H), 7.22 (s, 1H), 7.19 (s, 1H), 6.91 (s, 1H), 5.32 (s, 2H), 4.20 - 4.05 (m, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.94 - 3.84 (m, 4H), 3.16 (brs, 1H), 2.95 (brs, 1H); LCMS (ESI) Method 2: >95%, R T = 1.108 min, m / z = 564.0 [M+H] + .

[0626] [ka] Example 32 7-((1H-imidazol-1-yl)methyl)-2-(7-fluoro-6-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (28 mg, 0.051 mmol, 32% yield) was prepared according to the Buchwald coupling procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 60 mg, 0.16 mmol, 1 equiv.) and 4-chloro-7-fluoro-6-methoxyquinazoline (51 mg, 0.24 mmol, 1.5 equiv.). 1H NMR (400 MHz, chloroform-d) δ 9.08 (s, 1H), 8.17 (d, J = 1.7 Hz, 1H), 7.91 (s, 1H), 7.70 (d, J = 11.2 Hz, 1H), 7.44 (s, 1H), 7.25 (d, J = 1.7 Hz, 1H), 7.17 (s, 1H), 7.12 (d, J = 8.8 Hz, 1H), 7.00 (s, 1H), 5.27 (s, 2H), 4.17 (brs, 2H), 4.04 (s, 3H), 3.95 (s, 3H), 3.07 (t, J = 6.2 Hz, 2H); 19 F NMR (376 MHz, chloroform-d) δ-60.08, -120.25; LCMS (ESI) Method 2: >95%, R T = 1.314 min, m / z = 552.0 [M+H] + .

[0627] [ka] Example 33 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-(2-methoxyethoxy)-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one To a solution of 2-methoxyethanol (1 mL) at 0° C., sodium hydride (9.4 mg, 90% w / w, 0.35 mmol, 4 equiv.) was added and stirred for 15 min. 7-((1H-imidazol-1-yl)methyl)-2-(8-chloro-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Example 8, 50 mg, 0.088 mmol, 1 equiv.) was added. The reaction mixture was then allowed to warm to room temperature and stirred overnight. Saturated aqueous NaHCO 3 was added and the mixture was extracted with EtOAc. The combined organic layers were washed with MgSO 4The mixture was dried at 40° C. and concentrated under reduced pressure. 2 Cl 2 / MeOH = 0-10% gradient) and reversed-phase HPLC (Phenomenex Gemini C18, H 2 O / CH 3 Gradient of CN, 15-80% CH 3 The residue was purified by elution with 100% TFA (CN, 0.1% TFA) and then saturated aqueous NaHCO 3 Neutralization with afforded the title compound (23 mg, 0.038 mmol, 43% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.95 (d, J = 4.6 Hz, 1H), 8.18 (s, 1H), 8.01 (brs, 1H), 7.47 (d, J = 4.5 Hz, 1H), 7.45 (s, 1H), 7.24 - 7.21 (m, 2H), 7.04 (brs, 1H), 6.95 (s, 1H), 5.28 (s, 2H), 4.81 (t, J = 5.2 Hz, 2H), 4.04 (s, 3H), 4.01 - 3.90 (m, 3H), 3.84 - 3.78 (m, 1H), 3.47 (s, 3H), 3.21 - 3.12 (m, 1H), 3.01 - 2.95 (m, 1H), 2.79 (q, J = 7.4 Hz, 2H), 1.31 (t, J = 7.5 Hz, 3H); 19 F NMR (376 MHz, chloroform-d) δ -60.06; LCMS (ESI) Method 2: >95%, R T = 1.500 min, m / z = 606.1 [M+H] + .

[0628] [ka] Example 34 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-(pyrrolidin-1-yl)-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (22 mg, 37 μmol, 49% yield) was prepared according to the Buchwald coupling procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-2-(8-chloro-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Example 8, 42.4 mg, 0.075 mmol, 1 equiv.) and pyrrolidine (8.00 mg, 11 μL, 113 μmol, 1.5 equiv.). 1 H NMR (400 MHz, CDCl 3 ) δ 8.77 (d, J = 4.6 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.77 (s, 1H), 7.44 (t, J = 4.1 Hz, 2H), 7.22 (d, J = 1.6 Hz, 1H), 7.15 (s, 1H), 6.99 (d, J = 2.9 Hz, 1H), 6.54 (s, 1H), 5.24 (s, 2H), 4.33 (d, J = 38.6 Hz, 4H), 4.03 (s, 3H), 3.96 (m, 1H), 3.76 (m, 1H), 3.04 (m, 4H), 2.07 (t, J = 6.1 Hz, 4H), 1.32 (t, J = 7.5 Hz, 3H); LCMS (ESI) method 2: >95%, R T = 1.40 min, m / z = 601.1 [M+H] + .

[0629] [ka] Example 35 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-(1H-pyrrol-1-yl)-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (24 mg, 40 μmol, 54% yield) was prepared according to the Buchwald coupling procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-2-(8-chloro-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Example 8, 42.4 mg, 0.075 mmol, 1 equiv.) and 1H-pyrrole (7.5 mg, 7.8 μL, 112.5 μmol, 1.5 equiv.). 1 H NMR (400 MHz, CDCl 3 ) δ 9.01 (d, J = 4.5 Hz, 1H), 8.64 (s, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.15 (t, J = 2.3 Hz, 2H), 7.51 (t, J = 3.9 Hz, 2H), 7.35 (d, J = 1.5 Hz, 1H), 7.29 (s, 1H), 7.24 (s, 1H), 7.10 (s, 1H), 6.41 (t, J = 2.3 Hz, 2H), 5.39 (s, 2H), 4.04 (m, 4H), 3.85 (m, 1H), 3.21 (m, 1H), 3.03 (m, 1H), 2.92 (q, J = 7.5 Hz, 2H), 1.36 (t, J = 7.5 Hz, 3H); LCMS (ESI) method 2: >95%, R T = 1.74 min, m / z = 597.0 [M+H] + .

[0630] [ka] Example 36 7-((1H-imidazol-1-yl)methyl)-2-(8-ethoxy-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (20 mg, 0.035 mmol, 39% yield) was prepared following the procedure described for Example 33 using 7-((1H-imidazol-1-yl)methyl)-2-(8-chloro-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Example 8, 50 mg, 0.088 mmol, 1 equiv.) and ethanol (1 mL). 1 H NMR (400 MHz, chloroform-d) δ 9.01 - 8.96 (m, 1H), 8.19 (s, 1H), 7.93 - 7.80 (m, 1H), 7.50 - 7.48 (m, 1H), 7.46 (s, 1H), 7.25 (s, 1H), 7.19 (s, 1H), 7.02 (s, 1H), 6.90 (s, 1H), 5.27 (s, 2H), 4.76 - 4.68 (m, 2H), 4.06 (s, 3H), 4.05 - 3.99 (m, 1H), 3.86 - 3.82 (m, 1H), 3.22 - 3.11 (m, 1H), 3.04 - 2.96 (m, 1H), 2.85 - 2.78 (m, 2H), 1.61 - 1.58 (m, 3H), 1.37 - 1.31 (m, 3H); 19 F NMR (376 MHz, chloroform-d) δ-60.08; LCMS (ESI) Method 2: >95%, R T = 1.573 min, m / z = 576.0 [M+H] + .

[0631] [ka] Example 37 7-((1H-imidazol-1-yl)methyl)-2-(6,8-diethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (28.00 mg, 50.04 μmol, 67% yield) was prepared following the procedure described for Step A of Intermediate 14 using 7-((1H-imidazol-1-yl)methyl)-2-(8-chloro-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Example 8, 42.4 mg, 0.075 mmol, 1 equiv.) and diethylzinc (75.0 μL, 1.0 M, 75.0 μmol, 1 equiv.). 1 H NMR (400 MHz, CDCl 3 ) δ 9.01 (d, J = 4.5 Hz, 1H), 8.55 (s, 1H), 8.19 (s, 1H), 7.50 (d, J = 4.2 Hz, 2H), 7.34 (s, 1H), 7.29 (d, J = 8.1 Hz, 2H), 7.09 (s, 1H), 5.38 (s, 2H), 4.04 (s, 4H), 3.83 (t, J = 6.0 Hz, 1H), 3.60 (m, 2H), 3.20 (q, J = 7.2 Hz, 1H), 3.00 (m, 3H), 1.46 (t, J = 7.5 Hz, 3H), 1.36 (t, J = 7.5 Hz, 3H); LCMS (ESI) method 2: >95%, R T = 1.377 min, m / z = 560.1 [M+H] + .

[0632] [ka] Example 38 7-((1H-imidazol-1-yl)methyl)-2-(8-cyclopropyl-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (25 mg, 44 μmol, 58% yield) was prepared following the Suzuki reaction described for Intermediate 3 using 7-((1H-imidazol-1-yl)methyl)-2-(8-chloro-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Example 8, 42.4 mg, 0.075 mmol, 1 equiv.) and cyclopropylboronic acid (7.1 mg, 83 μmol, 1.1 equiv.). 1 H NMR (400 MHz, CDCl 3 ) δ 8.99 (d, J = 4.5 Hz, 1H), 8.92 (s, 1H), 8.21 (s, 1H), 7.52 (s, 1H), 7.48 (d, J = 4.5 Hz, 1H), 7.38 (s, 1H), 7.33 (s, 1H), 7.13 (s, 2H), 5.42 (s, 2H), 4.04 (m, 4H), 3.82 (m, 1H), 3.57 (m, 1H), 3.19 (m, 1H), 3.02 (q, J = 7.2 Hz, 1H), 2.86 (q, J = 7.4 Hz, 2H), 1.30 (q, J = 11.2 Hz, 5H), 1.18 (t, J = 6.3 Hz, 2H); LCMS (ESI) method 2: >95%, R T = 1.588 min, m / z = 572.1 [M+H] + .

[0633] [ka] Example 39 7-((1H-imidazol-1-yl)methyl)-2-(8-(2,2-difluoroethoxy)-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (27 mg, 0.044 mmol, 50% yield) was prepared following the procedure described for Example 33 using 7-((1H-imidazol-1-yl)methyl)-2-(8-chloro-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Example 8, 50 mg, 0.088 mmol, 1 equiv.) and 2,2-difluoroethan-1-ol (1 mL). 1 H NMR (400 MHz, chloroform-d) δ 8.99 (d, J = 4.6 Hz, 1H), 8.16 (d, J = 1.3 Hz, 1H), 7.83 (brs, 1H), 7.50 (d, J = 4.6 Hz, 1H), 7.43 (s, 1H), 7.23 (s, 1H), 7.16 (s, 1H), 7.03 (s, 1H), 7.00 (s, 1H), 6.37 (tt, J = 55.8, 4.4 Hz, 1H), 5.25 (s, 2H), 4.90 - 4.81 (m, 2H), 4.06 - 3.99 (m, 4H), 3.81 (dt, J = 12.2, 5.1 Hz, 1H), 3.21 - 3.12 (m, 1H), 2.99 (dt, J = 16.4, 4.5 Hz, 1H), 2.81 (q, J = 7.5 Hz, 2H), 1.32 (t, J = 7.5 Hz, 3H); 19 F NMR (376 MHz, chloroform-d) δ -60.08, -124.98 (d, J = 30.5 Hz); LCMS (ESI) Method 2: >95%, R T = 1.569 min, m / z = 612.0 [M+H] + .

[0634] [ka] Example 40 7-((1H-imidazol-1-yl)methyl)-2-(6-(benzyloxy)-7-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (735 mg, 1.15 mmol, 94% yield) was prepared following the Buchwald coupling procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 460 mg, 1.23 mmol, 1 equiv.) and 6-(benzyloxy)-4-chloro-7-methoxyquinazoline (553 mg, 1.84 mmol, 1.5 equiv.). 1 H NMR (400 MHz, chloroform-d) δ 9.00 (s, 1H), 8.17 (d, J = 1.3 Hz, 1H), 7.79 (brs, 1H), 4.43 (s, 1H), 7.37 - 7.34 (m, 4H), 7.25 - 7.17 (m, LCMS (ESI) method 2: >95%, R T = 1.545 min, m / z = 640.0 [M+H] + .

[0635] [ka] Example 41 7-((1H-imidazol-1-yl)methyl)-2-(6-hydroxy-7-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one To a solution of 7-((1H-imidazol-1-yl)methyl)-2-(6-(benzyloxy)-7-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Example 40, 706 mg, 1.10 mmol, 1 equiv) in MeOH (30 mL) was added Pd / C (210 mg, 10% w / w, 197 μmol, 0.18 equiv) at room temperature. The reaction was degassed and placed under a hydrogen atmosphere. The reaction was heated to 50° C. and stirred until completion. The reaction mixture was filtered through celite and concentrated under reduced pressure to give the title compound (510 mg, 0.928 mmol, 84% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.22 (s, 1H), 8.95 (s, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 7.80 (s, 1H), 7.44 (s, 1H), 7.39 (s, 1H), 7.23 (s, 1H), 7.05 (s, 1H), 6.92 (s, 1H), 5.32 (s, 2H), 4.05 - 3.96 (m, 8H), 2.98 (brs, 2H); LCMS (ESI) method 2: >95%, R T = 1.392 min, m / z = 550.0 [M+H] + .

[0636] [ka] Example 42 4-(7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-7-methoxyquinazolin-6-yl trifluoromethanesulfonate CH of 7-((1H-imidazol-1-yl)methyl)-2-(6-hydroxy-7-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Example 41, 300 mg, 546 μmol, 1 equiv.) and pyridine (0.2 mL, 2.18 mmol, 4 equiv.). 2 Cl 2 (3 mL) solution at 0°C. 2 O(1.64mL, 1.64mmol, 3eq, 1M CH 2 Cl 2 The reaction mixture was stirred at 0° C. for 1 h and then diluted with CH 2 Cl 2 The reaction was diluted with saturated aqueous NaHCO 3 Quench with CH 2 Cl 2 The combined organic layers were extracted with MgSO 4 The residue was purified by column chromatography (Combi-flash Rf, CH 2 Cl 2 / MeOH=0-10% gradient) to give the title compound (370 mg, 0.542 mmol, 99% yield). 1 H NMR (400 MHz, chloroform-d) δ 9.17 (s, 1H), 8.34 - 8.08 (m, 2H), 7.73 (s, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 7.30 - 7.20 (m, 2H), 7.05 - LCMS (ESI) method 2: >95%, R T = 1.636 min, m / z = 681.9 [M+H] + .

[0637] [ka] Example 43 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-7-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (31 mg, 0.055 mmol, 63% yield) was prepared following the procedure described for Intermediate 11 using 4-(7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-7-methoxyquinazolin-6-yl trifluoromethanesulfonate (Example 42, 60 mg, 0.088 mmol, 1 equiv.), triethylborane (0.18 mmol, 2 equiv., 1M THF) and cesium acetate (34 mg, 0.18 mmol, 2 equiv.). 1 H NMR (400 MHz, chloroform-d) δ 9.05 (s, 1H), 8.18 (s, 1H), 7.78 (brs, 1H), 7.56 (s, 1H), 7.42 (s, 1H), 7.31, (s, 1H), 7.21 - 7.14 (m, 2H), 7.00 (brs, 1H), 5.23 (s, 2H), 4.14 (brs, 2H), 4.03 (s, 3H), 4.02 (s, 3H), 3.05 (t, J = 6.0 Hz, 2H), 2.78 (q, J = 7.4 Hz, 2H), 1.23 (t, J = 7.5 Hz, 3H); LCMS (ESI) method 2: >95%, R T = 1.487 min, m / z = 562.0 [M+H] + .

[0638] [ka] Example 44 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-morpholino-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (27.0 mg, 44 μmol, 58% yield) was prepared according to the Buchwald coupling procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-2-(8-chloro-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Example 8, 42.5 mg, 0.075 mmol, 1 equiv.) and morpholine (9.8 mg, 9.7 μL, 113 μmol, 1.5 equiv.). 1 H NMR (400 MHz, CDCl 3 ) δ 9.14 (s, 1H), 8.81 (t, J = 4.5 Hz, 1H), 8.21 (s, 1H), 7.54 (t, J = 7.3 Hz, 1H), 7.47 (s, 1H), 7.42 (s, 1H), 7.39 (s, 1H), 7.18 (d, J = 6.2 Hz, 1H), 6.80 (s, 1H), 5.47 (s, 2H), 4.22 (s, 3H), 4.05 (s, 4H), 3.97 (m, 6H), 3.81 (t, J = 6.0 Hz, 1H), 3.19 (q, J = 9.0 Hz, 1H), 2.99 (m, 2H), 1.29 (q, J = 7.9 Hz, 3H); LCMS (ESI) method 2: >95%, R T = 1.387 min, m / z = 617.1 [M+H] + .

[0639] [ka] Example 45 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-(pyridin-4-yl)-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (28 mg, 46 μmol, 61% yield) was prepared following the Suzuki reaction described for Intermediate 3 using 7-((1H-imidazol-1-yl)methyl)-2-(8-chloro-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Example 8, 42.4 mg, 0.075 mmol, 1 equiv.) and pyridin-4-ylboronic acid (14 mg, 113 μmol, 1.5 equiv.). 1 H NMR (400 MHz, CDCl 3 ) δ 9.04 (d, J = 4.5 Hz, 1H), 8.80 (q, J = 2.1 Hz, 2H), 8.45 (s, 1H), 8.21 (q, J = 3.7 Hz, 3H), 7.54 (t, J = 4.1 Hz, 1H), 7.51 (d, J = 5.0 Hz, 2H), 7.35 (d, J = 1.6 Hz, 1H), 7.26 (s, 1H), 7.09 (s, 1H), 5.38 (s, 2H), 4.13 (m, 1H), 4.05 (s, 3H), 3.87 (m, 1H), 3.23 (m, 1H), 3.06 (q, J = 7.5 Hz, 3H), 1.41 (t, J = 7.5 Hz, 3H); LCMS (ESI) method 2: >95%, R T = 1.315 min, m / z = 609.0 [M+H] + .

[0640] [ka] Example 46 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-(4-methylpiperazin-1-yl)-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (28 mg, 44 μmol, 59% yield) was prepared according to the Buchwald coupling procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-2-(8-chloro-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Example 8, 42.5 mg, 0.075 mmol, 1 equiv.) and 1-methylpiperazine (11 mg, 13 μL, 113 μmol, 1.5 equiv.). 1 H NMR (400 MHz, CDCl 3 ) δ 8.80 (d, J = 4.6 Hz, 1H), 8.13 (d, J = 1.8 Hz, 1H), 7.62 (s, 1H), 7.43 (t, J = 4.6 Hz, 2H), 7.20 (d, J = 1.8 Hz, 1H), 7.12 (s, 1H), 6.96 (s, 1H), 6.92 (s, 1H), 5.21 (s, 2H), 4.03 (s, 4H), 3.97 (m, J = 5.5 Hz, 2H), 3.80 (m, 1H), 3.50 (t, J = 16.8 Hz, 2H), 3.17 (m, 3H), 2.98 (q, J = 7.3 Hz, 2H), 2.83 (s, 3H), 2.76 (q, J = 7.5 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H); LCMS (ESI) method 2: >95%, R T = 1.267 min, m / z = 630.1 [M+H] + .

[0641] [ka] Example 47 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-methoxy-1,7-naphthyridin-4-yl)-5-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (25 mg, 0.045 mmol, 33% yield) was prepared according to the Buchwald coupling procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-5-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 42, 50 mg, 0.13 mmol, 1 equiv.) and 4-bromo-6-ethyl-8-methoxy-1,7-naphthyridine (Intermediate 14, 39 mg, 0.15 mmol, 1.1 equiv.). 1 H NMR (400 MHz, chloroform-d) δ 9.07 (brs, 1H), 8.94 (d, J = 4.6 Hz, 1H), 8.33 (s, 1H), 7.48 (d, J = 4.5 Hz, 1H), 7.47 (s, 1H), 7.35 (brs, 1H), 7.06 (brs, 1H), 6.91 (s, 1H), 6.67 (s, 1H), 5.53 (s, 2H), 4.23 (s, 3H), 4.04 (td, J = 11.6, 3.6 Hz, 1H), 3.83 (dt, J = 12.4, 5.4 Hz, 1H), 3.18 - 3.08 (m, 1H), 2.81 (q, J = 7.5 Hz, 2H), 2.77 - 2.70 (m, 1H), 2.38 (s, 3H), 1.32 (t, J = 7.5 Hz, 3H); 19 F NMR (376 MHz, chloroform-d) δ -58.57; LCMS (ESI) Method 2: >95%, R T = 1.472 min, m / z = 562.0 [M+H] + .

[0642] [ka] Example 48 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-methoxy-2-methyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 50 mg, 0.13 mmol, 1.0 equiv.), 4-bromo-6-ethyl-8-methoxy-2-methyl-1,7-naphthyridine (Intermediate 43, 41 mg, 0.15 mmol, 2.0 equiv.), cesium carbonate (87 mg, 0.27 mmol, 2 equiv.), Xantphos (12 mg, 0.02 mmol, 0.15 equiv.) and Pd 2 (dba) 3 (6 mg, 0.007 mmol, 0.05 equiv) was dissolved in 1,4-dioxane under Ar. The reaction mixture was stirred at 115° C. for 14 h and then cooled to 23° C. Brine was added to the mixture and the mixture was diluted with CH 2 Cl 2 (3x20mL). The combined organic layers were extracted with MgSO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. 2 O / CH 3 Gradient of CN, 15-70% CH 3 The residue was purified by elution with 100% TFA (CN, 0.1% TFA) and then saturated aqueous NaHCO 3 Neutralization with afforded the title compound (65 mg, 0.11 mmol, 85% yield). 1 H NMR (400 MHz, DMSO-d 6) δ 8.08 (s, 1H), 7.95 (s, 1H), 7.78 (s, 1H), 7.67 (s, 1H), 7.41 (s, 1H) 7.21 (s, 1H), 7.05 (s, 1H), 6.91 (s, 1H), 5.31 (s, 2H), 4.06 (s, 3H), 4.03 - 3.95 (m, 4H), 3.78 - 3.72 (m, 1H), 3.18 - 3.09 (m, 1H), 2.87 (dt, J = 16.4, 4.5 Hz, 1H), 2.73 (q, J = 7.5 Hz, 2H), 2.65 (s, 3H), 1.24 (t, J = 7.5 Hz, 3H); 19 F NMR (376 MHz, DMSO-d 6 ) δ -58.21; LCMS (ESI) Method 2: >95%, R T = 1.256 min, m / z = 576.0 [M+H] + .

[0643] [ka] Example 49 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxycinnoline-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (47 mg, 0.084 mmol, 63% yield) was prepared following the Buchwald coupling procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 50 mg, 0.13 mmol, 1 equiv.) and 4-chloro-6,7-dimethoxycinnoline (45 mg, 0.20 mmol, 1.5 equiv.). 1H NMR (400 MHz, chloroform-d) δ 9.07 (s, 1H), 8.17 (d, J = 1.5 Hz, 1H), 8.08 (s, 1H), 7.80 (s, 1H), 7.46 (s, 1H), 7.27 (s, 1H), 7.19 (s, 1H), 7.03 (s, 1H), 6.89 (s, 1H), 5.29 (s, 2H), 4.15 - 4.08 (m, 1H), 4.11 (s, 3H), 4.03 (s, 3H), 3.99 (s, 3H), 3.88 - 3.81 (m, 1H), 3.19 - 3.10 (m, 1H), 3.03 (dt, J = 16.4, 4.4 Hz, 1H); 19 F NMR (376 MHz, chloroform-d) δ -60.07; LCMS (ESI) Method 2: >95%, R T = 1.123 min, m / z = 564.0 [M+H] + .

[0644] [ka] Example 50 7-((1H-imidazol-1-yl)methyl)-2-(6,8-dimethoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (55 mg, 0.097 mmol, 73% yield) was prepared following the Buchwald coupling procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 50 mg, 0.13 mmol, 1 equiv.) and 4-chloro-6,8-dimethoxyquinazoline (45 mg, 0.20 mmol, 1.5 equiv.). 1 H NMR (400 MHz, DMSO-d 6) δ 9.03 (s, 1H), 8.09 (s, 1H), 7.99 (d, J = 1.7 Hz, 1H), 7.78 (s, 1H), 7.40 (d, J = 1.4 Hz, 1H), 7.22 (s, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.91 (s, 1H), 6.71 (d, J = 2.4 Hz, 1H), 5.32 (s, 2H), 4.00 (brs, 2H), 3.99 (s, 6H), 3.80 (s, 3H), 3.00 (brs, 2H); 19 F NMR (376 MHz, DMSO-d 6 ) δ -58.22; LCMS (ESI) method 2: >95%, R T = 1.327 min, m / z = 564.0 [M+H] + .

[0645] [ka] Example 51 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-methoxy-2-methylquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 400 mg, 1.07 mmol, 1.0 equiv.), 4-chloro-6-ethyl-8-methoxy-2-methylquinazoline (Intermediate 44, 328 mg, 1.39 mmol, 1.3 equiv.), cesium carbonate (694 mg, 2.13 mmol, 2 equiv.), Xantphos (93 mg, 0.16 mmol, 0.15 equiv.) and Pd 2 (dba) 3 (49 mg, 0.053 mmol, 0.05 equiv) was dissolved in 1,4-dioxane (6 mL) under Ar. The reaction mixture was stirred at 115° C. for 14 h and then cooled to 23° C. Brine was added to the mixture and the mixture was diluted with CH2 Cl 2 (3x50mL). The combined organic layers were extracted with MgSO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. 2 O / CH 3 Gradient of CN, 15-70% CH 3 The residue was purified by elution with 100% TFA (CN, 0.1% TFA) and then saturated aqueous NaHCO 3 Neutralization with afforded the title compound (215 mg, 0.37 mmol, 35% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.10 (s, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.78 (s, 1H), 7.40 (d, J = 1.7 Hz, 1H), 7.28 (d, J = 1.5 Hz, 1H), 7.22 (s, 1H), 7.19 (d, J = 1.3 Hz, 1H), 6.91 (s, 1H), 5.32 (s, 2H), 3.99 (brs, 8H), 3.00 (brs, 2H), 2.720 (q, J = 7.6 Hz, 2H), 2.719 (s, 3H), 1.21 (t, J = 7.6 Hz, 3H); 19 F NMR (376 MHz, DMSO-d 6 ) δ -58.25; LCMS (ESI) Method 2: >95%, R T = 1.391 min, m / z = 576.1 [M+H] + .

[0646] [ka] Example 52 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-(methoxymethyl)-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one In a sealed tube, 7-((1H-imidazol-1-yl)methyl)-2-(8-chloro-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Example 8, 30 mg, 0.053 mmol, 1 equiv.), tributyl(methoxymethyl)stannane (0.03 mL, 0.098 mmol, 1.9 equiv.) and Pd(PPh 3 ) 4 (7.1 mg, 0.008 mmol, 0.1 equiv) was dissolved in DMF (0.5 mL) and placed under an argon atmosphere. The reaction mixture was then placed in a preheated heating block and stirred at 115° C. At 23° C., brine was added to the mixture and CH 2 Cl 2 The combined organic layers were extracted with MgSO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. 2 The residue was purified by elution with a 15-70% HO gradient (0.1% TFA) followed by elution with saturated aqueous NaHCO 3 Neutralization with afforded the title compound (16 mg, 0.028 mmol, 52% yield). 1 H NMR (400 MHz, chloroform-d) δ 9.00 (d, J = 4.6 Hz, 1H), 8.24 - 8.15 (m, 2H), 7.50 (d, J = 4.6 Hz, 1H), 7.47 (s, 1H), 7.37 (s, 1H), 7.29 (d, J = 2.0 Hz, 1H), 7.22 (s, 1H), 7.04 (s, 1H), 5.34 (dd, J = 60.0, 12.8 Hz, 1H), 5.30 (s, 2H), 4.07 - 4.01 (m, 1H), 4.04 (m, 3H), 3.87 - 3.76 (m, 1H), 3.61 (s, 3H), 3.19 (ddd, J = 16.2, 10.8, 5.1 Hz, 1H), 3.02 (q, J = 7.6 Hz, 2H), 3.01 - 2.97 (m, 1H), 1.36 (t, J = 7.5 Hz, 3H); 19F NMR (376 MHz, chloroform-d) δ -60.05; LCMS (ESI) Method 2: >95%, R T = 1.226 min, m / z = 576.0 [M+H] + .

[0647] [ka] Example 53 7-((1H-imidazol-1-yl)methyl)-2-(7-fluoro-6-methoxy-2-methylquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound (450 mg, 0.8 mmol, quantitative) was prepared according to the Buchwald coupling procedure described for Intermediate 15 using 7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-p...

Claims

1. A compound of formula (I) 【Chemistry 1】 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, G1 is 【Chemistry 2】 and R 10a is hydrogen, fluoro, chloro, C 1-3 alkyl, or C 1-3 fluoroalkyl; R 10b is hydrogen, fluoro, chloro, C 1-3 alkyl, or C 1-3 fluoroalkyl; R 10d is X 1 , hydrogen, halogen, C 1-4 alkyl, C 1-4 fluoroalkyl, or G 1a ; R 10e is halogen, cyano, C 1-4 alkyl, C 1-4 fluoroalkyl, OH, —OC 1-4 alkyl, —OC 1-4 fluoroalkyl, —OG 1c , —OC 1-3 alkylene-G 1c , or —O—C 2-3 alkylene-Y; R 10f is independently at each occurrence halogen, cyano, C 1-4 alkyl, C 1-4 fluoroalkyl, OH, -OC 1-4 alkyl, -OC 1-4 fluoroalkyl, -OC 3-4 cycloalkyl, -OC 1-3 alkylene-C 3-4 cycloalkyl, -OPG or -OSO 2 CF 3 ; m is 0 or 1; n is 0, 1 or 2; PG is a hydroxy protecting group; X 1 is —C(O)N(R 1a ) 2 , —OR 1a , —N(R 1a ) 2 , cyano, —C(O)OR 1a , —C(O)R 1b , —SO 2 R 1b , —SO 2 N(R 1a ) 2 , —NR 1a C(O)H or —NR 1a C(O)R 1b ; R 1a is independently at each occurrence hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, -C 2-3 alkylene-OR 1e , -C 2-3 alkylene-N(R 1e ) 2 , -C 2-3 alkylene-N(R 1e )C(O)R 1e , G 1a or -C 1-3 alkylene-G 1a ; R 1b is independently at each occurrence C 1-4 alkyl, C 1-4 fluoroalkyl, -C 1-3 alkylene-OR 1e , -C 1-3 alkylene-N(R 1e ) 2 , -C 1-3 alkylene-N(R 1e )C(O)R 1e , G 1a or -C 1-3 alkylene-G 1a ; G 1a is independently at each occurrence C 3-8 cycloalkyl, 5-6 membered heteroaryl, or 4-8 membered heterocyclyl, G 1a is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 fluoroalkyl, oxo, -L 2 -X 2 and -L 2 -G 1b ; L 2 is, independently at each occurrence, a bond or C 1-3 alkylene; X 2 is, independently at each occurrence, —OR 1c , —N(R 1c ) 2 , —SR 1c , cyano, —C(O)OR 1c , —C(O)N(R 1c ) 2 , —C(O)R 1c , —SOR 1d , —SO 2 R 1d , —SO 2 N(R 1c ) 2 , —NR 1c C(O)R 1c , —NR 1c C(O)OR 1c , —NR 1c C(O)N(R 1c ) 2 , —NR 1c S(O) 2 R 1d or —NR 1c S(O) 2 N(R 1c ) 2 ; R 1c is independently at each occurrence hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, G 1b or -C 1-3 alkylene-G 1b , alternatively two R 1c together with the common nitrogen atom to which they are attached form a 4-8 membered saturated or partially unsaturated heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 fluoroalkyl, oxo, -OH and -OC 1-4 alkyl; R 1d is, independently at each occurrence, C 1-4 alkyl, C 1-4 fluoroalkyl, G 1b or -C 1-3 alkylene-G 1b ; R 1e is independently at each occurrence hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, G 1b or -C 1-3 alkylene-G 1b , alternatively two R 1e together with the common nitrogen atom to which they are attached form a 4-8 membered saturated or partially unsaturated heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 fluoroalkyl, oxo, -OH and -OC 1-4 alkyl; G 1b is independently at each occurrence C 3-6 cycloalkyl, 4-6 membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from O, N and S, 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, or phenyl, G 1b is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 fluoroalkyl, oxo, -OH and -OC 1-4 alkyl; Y is OH, -OC1-4alkyl, -OC1-4fluoroalkyl, -OC3-4cycloalkyl or -OC1-3alkylene-C3-4cycloalkyl; G 1c is C 3-6 cycloalkyl, 4-7 membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from O, N and S, or 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S; G 1c is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 fluoroalkyl, oxo, -OH, -OC 1-4 alkyl, C 3-4 cycloalkyl and -C 1-3 alkylene-C 3-4 cycloalkyl; G 2 is a 5-6 membered heteroaryl, G 2 is optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, halogen, —OR 4c , —N(R 4c ) 2 , cyano, —C(O)OR 4c , —C(O)N(R 4c ) 2 , —C(O)R 4c , —SO 2 R 4d , —SO 2 N(R 4c ) 2 , —NR 4c C(O)R 4c , C 3-8 cycloalkyl, and —C 1-3 alkylene-C 3-8 cycloalkyl, each C 3-8 cycloalkyl being optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 1-4 alkyl and halogen; R 4c is independently at each occurrence hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, C 3-8 cycloalkyl or -C 1-6 alkylene-C 3-8 cycloalkyl, each C 3-8 cycloalkyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 1-4 alkyl and halogen; alternatively, two R 4c together with the common nitrogen atom to which they are attached form a 4-8 membered saturated or partially unsaturated heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 fluoroalkyl, oxo, -OH and -OC 1-4 alkyl; R 4d is independently at each occurrence C 1-4 alkyl, C 1-4 fluoroalkyl, C 3-8 cycloalkyl, or -C 1-6 alkylene-C 3-8 cycloalkyl, each C 3-8 cycloalkyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 1-4 alkyl and halogen; R 5 and R 6 are each independently hydrogen, halogen, C 1-4 alkyl, C 1-4 fluoroalkyl or —OC 1-4 alkyl; and R 8 is unsubstituted imidazolyl or imidazolyl substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 fluoroalkyl, NO 2 , NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , C 3-8 cycloalkyl and —C 1-3 alkylene-C 3-8 cycloalkyl, each C 3-8 cycloalkyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 fluoroalkyl, OH and —OC 1-4 alkyl. with the proviso that the compound is 7-((1H-imidazol-1-yl)methyl)-2-(6-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; or 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-methoxy-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one A compound of formula (I) or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, provided that:

2. Compounds of formula (I) 【Chemistry 1】 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, G １ teeth, 【Chemistry 2】 and R １０ｂ is C １～３ Alkyl, 4-8 membered monocyclic heterocyclyl, hydrogen, fluoro, chloro, C １～３ Fluoroalkyl, C ３～６ Cycloalkyl, NH ２ , -NHC １～４ Alkyl or -N(C １～４ Alkyl) ２ wherein the heterocyclyl contains 1 to 2 heteroatoms independently selected from the group consisting of O, N and S, and is selected from halogen, cyano, oxo, C １～４ Alkyl, C １～４ Fluoroalkyl, OH, —OC １～４ Alkyl, -OC １～４ Fluoroalkyl, NH ２ , -NHC １～４ Alkyl and -N(C １～４ Alkyl) ２ and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: R １０ｅ is -OC １～４ Alkyl, halogen, cyano, C １～４ Alkyl, C １～４ Fluoroalkyl, OH, —OC １～４ Fluoroalkyl, -OG １ｃ , -OC １～３ Alkylene-G １ｃ , -O-C ２～３ Alkylene-Y, NH ２ , -NHC １～４ Alkyl, -N(C １～４ Alkyl) ２ or a 4-8 membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of N, O and S, said heterocyclyl being selected from halogen, cyano, oxo, C １～４ Alkyl, C １～４ Fluoroalkyl, OH, —OC １～４ Alkyl, -OC １～４ Fluoroalkyl, NH ２ , -NHC １～４ Alkyl and -N(C １～４ Alkyl) ２ and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: R １０ｆ is independently for each occurrence -OC １～４ Alkyl, C １～４ Alkyl, halogen, cyano, C １～４ Fluoroalkyl, OH, —OC １～４ Fluoroalkyl, -OC ３～４ Cycloalkyl, -OC １～３ Alkylene-C ３～４ Cycloalkyl, -OPG or -OSO ２ CF ３ and m is 0 or 1; n is 0, 1 or 2; PG is a hydroxy protecting group; Y is OH, -OC １～４ Alkyl, -OC １～４ Fluoroalkyl, -OC ３～４ Cycloalkyl or -OC １～３ Alkylene-C ３～４ is cycloalkyl, G １ｃ is C ３～６ cycloalkyl, 4-7 membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from O, N and S, or 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S; １ｃ is halogen, cyano, C １～４ Alkyl, C １～４ Fluoroalkyl, oxo, -OH, -OC １～４ Alkyl, C ３～４ Cycloalkyl and -C １～３ Alkylene-C ３～４ optionally substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyl; G ２ is a 5-6 membered heteroaryl or phenyl; G ２ is C １～４ Alkyl, C １～４ Fluoroalkyl, halogen, -OR ４ｃ , -N(R ４ｃ ) ２ , cyano, -C(O)OR ４ｃ , -C(O)N(R ４ｃ ) ２ , -C(O)R ４ｃ , -SO ２ R ４ｄ , -SO ２ N (R ４ｃ ) ２ , -NR ４ｃ C(O)R ４ｃ , C ３～８ Cycloalkyl and -C １～３ Alkylene-C ３～８ Optionally substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyl, C ３～８ Each cycloalkyl is C １～４ optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl and halogen; R ４ｃ is independently for each occurrence hydrogen, C １～４ Alkyl, C １～４ Fluoroalkyl, C ３～８ Cycloalkyl or -C １～６ Alkylene-C ３～８ cycloalkyl, C ３～８ Each cycloalkyl is C １～４ Optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl and halogen, alternatively, two R ４ｃ is the above R ４ｃ Together with the common nitrogen atom to which it is attached, C １～４ Alkyl, C １～４ Fluoroalkyl, oxo, -OH and -OC １～４ forming a 4-8 membered saturated or partially unsaturated heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; R ４ｄ is expressed independently for each occurrence as C １～４ Alkyl, C １～４ Fluoroalkyl, C ３～８ Cycloalkyl or -C １～６ Alkylene-C ３～８ cycloalkyl, C ３～８ Each cycloalkyl is C １～４ optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl and halogen; R ５ and R ６ are each independently hydrogen, halogen, or C １～４ Alkyl, C １～４ Fluoroalkyl or -OC １～４ is alkyl, R ８ is unsubstituted imidazolyl, or halogen, C １～４ Alkyl, C １～４ Fluoroalkyl, NO ２ , N.H. ２ , -NH(C １～４ Alkyl), -N(C １～４ Alkyl) ２ , C ３～８ Cycloalkyl and -C １～３ Alkylene-C ３～８ imidazolyl substituted by 1 to 3 substituents independently selected from the group consisting of cycloalkyl, ３～８ Cycloalkyl is halogen, C １～４ Alkyl, C １～４ Fluoroalkyl, OH and -OC １～４ and optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl. with the proviso that the compound is A compound of formula (I) or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, provided that the compound is not 7-((1H-imidazol-1-yl)methyl)-2-(6-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one.

3. R ８ but, 【Chemistry 3】 and R ２０ａ is hydrogen, C １～４ Alkyl, NH ２ , -NH(C １～４ Alkyl), -N(C １～４ Alkyl) ２ Or C ３～８ is cycloalkyl, R ２０ｂ , R ２０ｃ , R ２０ｄ , R ２０ｅ , R ２０ｆ , R ２０ｇ , R ２０ｈ and R ２０ｉ are each independently hydrogen, C １～４ Alkyl or C ３～８ is cycloalkyl, 3. A compound according to claim 1 or 2, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

4. R ８ but, 【Chemistry 4】 4. The compound of claim 3, wherein:

5. R 8 is 5. The compound of claim 4, wherein:

6. G 1 is and R 10d is X 1 ; X 1 is —OR 1a ; R 1a is, independently at each occurrence, C 1-4 alkyl, e.g., methyl or ethyl; R 10f is, independently at each occurrence, C 1-4 alkyl, and said C 1-4 alkyl in R 10f is, independently at each occurrence, ethyl; n is 0 or 1; R 5 is hydrogen; R 6 is hydrogen, and G2 is 6. The compound of claim 5, wherein:

7. G 1 is 7. The compound of claim 6, wherein:

8. G １ but, 【Chemistry 5】 3. The compound of claim 1 or 2, wherein:

9. G １ but, 【Chemistry 6】 3. The compound of claim 1 or 2, wherein:

10. R １０ｂ But, C １～３ 7. The compound of claim 6, wherein R is an alkyl group; or a tautomer thereof; or a pharma- ceutically acceptable salt of said compound or tautomer.

11. The compound of claim 8, wherein R 10b is C 1-3 alkyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

12. The compound of claim 10, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, wherein R10b is methyl.

13. R １０ｂ is said optionally substituted 4-8 membered monocyclic heterocyclyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

14. (a) R １０ｅ But, -OC １～４ Alkyl, halogen, OH, -OC １～３ Alkylene-G １ｃ Or -O-C ２～３ alkylene-Y; or (b) R １０ｅ But NH ２ , -NHC １～４ Alkyl, -N(C １～４ Alkyl) ２ or a 4-8 membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of N, O and S, said heterocyclyl being selected from halogen, cyano, oxo, C １～４ Alkyl, C １～４ Fluoroalkyl, OH, OC １～４ Alkyl, O.C. １～４ Fluoroalkyl, NH ２ , -NHC １～４ Alkyl and -N(C １～４ Alkyl) ２ or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

15. R １０ｅ But, -OC １～４ 15. The compound of claim 14, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, wherein R is 0, 1 or 2;

16. R １０ｆ But, independently for each occurrence, -OC １～４ Alkyl, C １～４ Alkyl, OH, -OPG or -OSO ２ CF ３ 3. The compound of claim 1 or 2, wherein:

17. R １０ｆ But, C １～４ Alkyl or -OC １～４ 17. The compound of claim 16, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, wherein:

18. G １ but, 【Chemistry 9】 3. The compound of claim 2, wherein:

19. G １ but, 【Chemistry 10】 3. The compound of claim 1 or 2, wherein:

20. G １ but, 【Chemistry 11】 3. The compound of claim 1 or 2, wherein:

21. G １ but, 【Chemistry 12】 3. The compound of claim 1 or 2, wherein:

22. G ２ is said optionally substituted 5-6 membered heteroaryl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

23. G ２ 23. The compound of claim 22, wherein said optionally substituted 5-6 membered heteroaryl ring system in is pyrazolyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer.

24. G ２ But halogen, C １～４ Alkyl and C １～４ 24. The compound of claim 23, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, optionally substituted with 1 to 4 substituents independently selected from the group consisting of fluoroalkyl.

25. G ２ but, 【Chemistry 13】 25. The compound of claim 24, wherein:

26. G2 is 26. The compound of claim 25, wherein:

27. R ５ 3. The compound of claim 1 or 2, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, wherein is hydrogen.

28. R ６ 3. The compound of claim 1 or 2, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, wherein is hydrogen.

29. below: 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxy-2-methylquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(7-hydroxy-6-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-methoxy-7-((1-methyl-1H-pyrazol-5-yl)methoxy)quinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethoxy-7-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(7-ethoxy-6-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-diethoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(7-fluoro-6-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-(benzyloxy)-7-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-hydroxy-7-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 4-(7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-7-methoxyquinazolin-6-yl trifluoromethanesulfonate; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-7-methoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,8-dimethoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-methoxy-2-methylquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(7-fluoro-6-methoxy-2-methylquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(7-(azetidin-1-yl)-6-methoxy-2-methylquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-methoxy-2-methyl-7-(methylamino)quinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxy-2-morpholinoquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxy-2-(methylamino)quinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxy-2-methylquinazolin-4-yl)-5-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxy-2-methylquinazolin-4-yl)-5-(1,3-dimethyl-1H-pyrazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxy-2-methylquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(2-(ethyl(methyl)amino)-6,7-dimethoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(2-ethyl-6,7-dimethoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(2-cyclopropyl-6,7-dimethoxyquinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxy-2-methylquinazolin-4-yl)-5-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxy-2-methylquinazolin-4-yl)-5-(4-fluoro-2-methylphenyl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,7-dimethoxy-2-(tetrahydro-2H-pyran-4-yl)quinazolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; or a pharma- ceutically acceptable salt thereof.

30. The following: 7-((1H-imidazol-1-yl)methyl)-2-(8-chloro-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-(methylamino)-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 2-(6-ethyl-8-methoxy-1,7-naphthyridin-4-yl)-7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,8-dimethoxy-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; Ethyl 4-(7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-6-ethyl-1,7-naphthyridine-8-carboxylate; 4-(7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-6-ethyl-1,7-naphthyridine-8-carboxylic acid; 4-(7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-6-ethyl-N-methyl-1,7-naphthyridine-8-carboxamide; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-(2-methoxyethoxy)-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-(pyrrolidin-1-yl)-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-(1H-pyrrol-1-yl)-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(8-ethoxy-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6,8-diethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(8-cyclopropyl-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(8-(2,2-difluoroethoxy)-6-ethyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-morpholino-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-(pyridin-4-yl)-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-(4-methylpiperazin-1-yl)-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one; 2. The compound of claim 1, selected from the group consisting of:

31. The compound of claim 1, wherein the compound is 7-((1H-imidazol-1-yl)methyl)-2-(6-ethyl-8-methoxy-2-methyl-1,7-naphthyridin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharma- ceutically acceptable salt thereof.

32. 32. A pharmaceutical composition comprising a compound according to any one of claims 1, 2, 29, 30 and 31 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, and a pharma- ceutically acceptable carrier.

33. 40. A pharmaceutical composition comprising a compound or a tautomer thereof according to any one of claims 1, 2, 29, 30 and 31, or a pharma- ceutically acceptable salt of said compound or tautomer, for use in the treatment of cancer.

34. 40. A pharmaceutical composition comprising a compound according to any one of claims 1, 2, 29, 30 and 31 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, for use in inhibiting the proliferation of cancer cells.

35. 40. Use of a compound according to any one of claims 1, 2, 29, 30 and 31, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, in the manufacture of a medicament for treating cancer.

36. 40. Use of a compound according to any one of claims 1, 2, 29, 30 and 31, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or tautomer, in the manufacture of a medicament for inhibiting the proliferation of cancer cells.

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