Macrocyclic BCL6 degradation agent

Abstract

Compounds, compositions, and methods for treating diseases and conditions involving aberrant B cell lymphoma 6 (BCL6) activity are described.

Description

[0001] Related Applications

[0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 396,381 filed on August 9, 2022, U.S. Provisional Application No. 63 / 432,580 filed on December 14, 2022, and U.S. Provisional Application No. 63 / 465,584 filed on May 11, 2023, each of which is incorporated herein by reference in its entirety. Background Art

[0003] The clinical efficacy of thalidomide analogs in the treatment of hematological malignancies indicates that small molecule-induced protein degradation has become a powerful therapeutic strategy. Thalidomide analogs (including lenalidomide and pomalidomide) regulate Cullin Really Interesting New Gene (RING) ligase 4-cereblon (CRBN) (CRL4 CRBN ) E3 ubiquitin ligase activity to recruit and ubiquitinate new substrates, including Ikaros family zinc finger 1 (IKZF1), IKZF3, and casein kinase 1-α (CK1α), which leads to their degradation by the proteasome (Kronke et al., Science 343:301-305 (2014); Lu et al., Science 343:305-309 (2014); Kronke et al., Nature 523:183-188 (2015)). Other small molecules that induce protein degradation include aryl sulfonamides, which bind to CRL4-DNA damage binding protein 1 (DDB1) and CUL4-associated factor 15 (DCAF15) (CRL4 DCAF15 )-dependent manner to promote the destruction of RNA-binding motif protein 39 (RBM39) (Han et al., Science 356:eaal3755 (2017)).

[0004] Other types of small molecules include heterobifunctional degraders (also known as PROTACs) (Toure et al., Angew. Chem. Int. Ed. Engl. 55: 1966-1973 (2016)), which have been developed for a wide range of targets, including kinases (Huang et al., Cell Chem. Biol. 25: 88-99 (2018)), nuclear receptors (Bondeson et al., Nat. Chem. Biol. 11: 611-617 (2015)), and epigenetic enzymes (Winter et al., Science 348: 1376-1381 (2015)). These small molecule degraders bind E3 ligases and target protein substrates, promoting the formation of a substrate-drug-ligase ternary complex (Nowak et al., Nat. Chem. Biol. 14:706-714 (2018); Petzold et al., Nature 532:127-130 (2016); Sievers et al., Science 362:aat0572 (2018)).

[0005] While degraders have shown significant efficacy and sustained depletion for some target proteins, this approach has been shown to be ineffective for other proteins. One such example is the B-cell lymphoma 6 (BCL6) protein, for which heterobifunctional degraders have been shown to be insufficient for target modulation to induce growth inhibition (McCoull et al., ACS Chem. Biol. 13: 3131-3141 (2018)).

[0006] BCL6 was originally identified as a locus affected by chromosomal translocation in diffuse large B-cell lymphoma (DLBCL). It is currently known that it is widely expressed in many lymphomas. Its role in lymphoma formation stems from its function in the humoral immune system, where the upregulation of BCL6 is necessary for the formation of germinal centers (GC) during humoral immune response (Ye et al., Nat. Genet. 16: 161-170 (1997); Dent et al., Science 276: 89-92 (1997)). GC is a transient structure formed in response to antigenic stimulation. In GC, B cells tolerate the mutagenesis of a large number of proliferation and DNA editing enzyme AICDA to perform immunoglobulin affinity maturation (Klein et al., Nat. Rev. Immunol. 8: 22-33 (2008)). These activities are coordinated by BCL6 and depend on BCL6, which is a strong transcriptional repressor that silences hundreds of genes. Some of these target genes control DNA damage perception (i.e., ATR, CHEK1, TP53, ARF) and proliferation checkpoints (i.e., CDKN1A, CDKN1B, CDKN2A, CDKN2B, PTEN) (Hatzi et al., Trends Mol. Med. 20:343-352 (2014)). BCL6 also inhibits genes required for exiting GC reactions and plasma cell differentiation (e.g., IRF4, PRDM1). This ensures that GC B cells have enough time to acquire somatic hypermutations of their immunoglobulin genes. Therefore, dysregulated inhibition of these target genes can lead to malignant transformation of B cells.

[0007] BCL6 also inhibits many oncogenes in GC B cells, including MYC, BCL2, BMI1 and CCND1 (Ci et al., Blood 113: 5536-5548 (2009)). Through this function, BCL6 can alleviate its own cancer-promoting checkpoint inhibition, thereby reducing the possibility of malignant transformation of GC B cells. This effect is eliminated in the presence of BCL2 or MYC translocation, which drives the expression of these oncogenes through abnormal regulatory elements. The presence of MYC and / or BCL2 with BCL6 (regardless of whether translocation occurs) is obviously harmful because it provides simultaneous inhibition of checkpoints for B cells through BCL6, as well as the growth-promoting and survival effects of MYC and BCL6 (Cardenas et al., Clin. Cancer Res. 23: 885-893 (2017)). In normal immune responses, BCL6 function is terminated by CD40-induced ERK signaling, which disrupts the BCL6 transcription complex and downregulates BCL6 mRNA by IRF4 and PRDM1 (Polo et al., Blood 112: 644-651 (2008)). Termination of BCL6 function is required for B cells to exit the GC response.

[0008] BCL6 is a promising drug target for non-Hodgkin lymphomas such as diffuse large B-cell lymphoma (DLBCL) (Cerchietti et al., Cancer Cell 17:400-411 (2010); Cardenas et al., J. Clin. Invest. 126:3351-3362 (2016)) and follicular lymphoma (Bosga-Bouwer et al., Genes Chromosomes Cancer 44:301-304 (2005)). Pathological increase in BCL6 expression due to somatic BCL6 translocation, exon mutation, promoter mutation or regulatory pathway mutation is a common driver of B cell malignancies (Hatzi et al., Trends Mol. Med. 20:343-352 (2014)). In genetically engineered mice, overexpression of BCL6 is sufficient to drive lymphoma development (Cattoretti et al., Cancer Cell 7:445-455 (2005)). BCL6 acts as a master transcriptional repressor, allowing germinal center (GC) B cells to rapidly express and tolerate genomic instability caused by immunoglobulin gene hypermutation and class switch recombination (Hatzi et al., Trends Mol. Med. 20:343-352 (2014)). BCL6 inhibits a wide range of genes involved in DNA damage response (Ranuncolo et al., Blood Cells Mol. Dis. 41:95-99 (2008)), cell cycle checkpoints (Tunyaplin et al., J. Immunol. 173:1158-1165 (2004)) and differentiation (Phan et al., Nat. Immunol. 6:1054-1060 (2005)). As expected, knockout of BCL6 in lymphoma cells leads to tumor stasis (Schlager et al., Oncotarget 11:875-890 (2020)). Several peptide and small molecule inhibitors targeting BCL6 have shown efficacy in vivo, but only at high concentrations, which limits their translation into clinical therapeutics (Cerchietti et al., Cancer Cell 17:400-411 (2010); Cardenas et al., J. Clin. Invest. 126:3351-3362 (2016)).

[0009] Broad complex / Tramtrack / Bric-a-brac (BTB) proteins are a diverse family of proteins characterized by the presence of a common protein-protein interaction domain, called the BTB domain. BTB proteins have a variety of functions ranging from transcriptional regulation and chromatin remodeling to protein degradation and cytoskeletal regulation. Functional specificity is determined in part by additional domains and interaction partners present in a given BTB protein. Studies of BTB proteins in Drosophila and mammalian systems have revealed the importance of these proteins in a variety of developmental contexts and in cancer and nervous system and musculoskeletal diseases. BTB proteins play a key role in transcriptional regulation and chromatin remodeling (Chaharbakhshi et al., Genesis 54: 505-518 (2016)).

[0010] The BTB domain mediates multiple functions of BCL6, such as homodimerization and interaction with co-repressors (Ghetu et al., Mol. Cell 29:384-391 (2008); Ahmad et al., Mol. Cell 12:1551-1564 (2003)). Technologies that disrupt the protein-protein interaction between the BTB domain of BCL6 and its co-repressors may help combat BCL6-related diseases. Summary of the invention

[0011] The first aspect of the present disclosure relates to a compound having a structure shown in formula (I):

[0012] or a pharmaceutically acceptable salt or stereoisomer thereof,

[0013] in:

[0014] X 1 is N, CH, CCl, CF or CCN;

[0015] X 2 Is N or CR 4 ;

[0016] R 4 is H, (C 1 -C 4 )Alkyl, halogen, OH, NH 2 , (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, (C 2 -C 4 ) alkenyl, (C2 -C 4 )Alkynyl, NO 2 、CN、NH(C 1 -C 4 )alkyl or N(C 1 -C 4 alkyl) 2 ;

[0017] R 1 is H, OH or halogen;

[0018] R 2 is H, OH or halogen;

[0019] R 3 is H, halogen or CN;

[0020] Y is CH 2 , NH or O;

[0021] Z is CH 2 , NH, S or O;

[0022] n is 0, 1, or 2;

[0023]

[0024]

[0025] X 3 is CH or N;

[0026] R 5 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) hydroxyalkyl, (C 1 -C 6 )aminoalkyl, (C 3 -C 6 ) carbocyclic group, 4 to 7 membered heterocyclic group, (C 1 -C 6 )alkyl-(C 3 -C 7 )Carbocyclic or (C 3 -C 7 ) carbocyclyl-4 to 7 membered heterocyclyl; wherein the alkyl, carbocyclyl or heterocyclyl is further optionally substituted by one or more identical or different R 13 Group substitution, where R 13 Yes (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen, NH 2OH, (C 1 -C 6 ) haloalkyl, NH(C 1 -C 6 )alkyl or N((C 1 -C 6 )alkyl) 2 , (C 3 -C 6 ) a carbocyclic group, a 4- to 7-membered heterocyclic group, or

[0027] R 5 Yes – LY 1 -Z 1 ,in

[0028] L does not exist or (C 1 -C 5 ) alkylene, which is optionally selected from (C 1 -C 2 ) alkyl and oxo are substituted with one or more substituents;

[0029] Y 1 Does not exist, it is O, S, S(O), S(O) 2 , NR', C(O), C(O)O, OC(O), C(O)N(R'), N(R')C(O), N(R')C(O)N(R'), N(R')C(O)O, OC(O)N(R'), S(O) 2 N(R') or N(R')S(O) 2 ;

[0030] Each R' is independently H or (C 1 -C 4 )alkyl;

[0031] Z 1 is H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 3 -C 10 ) a carbocyclic group or a 3- to 10-membered heterocyclic group, wherein Z 1 Optionally substituted with one or more substituents independently selected from the following: 1 -C 4 ) alkyl, halogen, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 )Haloalkoxy, NH 2 , (C1 -C 4 )aminoalkyl, CN, OH, carboxyl, carbamoyl, aminosulfonyl, mercapto, urea, NR r R s , OR r 、C(O)R r 、C(O)OR r 、OC(O)R r 、C(O)NR r R s 、N(R r )C(O)R r 、S(O) 0-2 R r 、S(O) 2 NR r R s 、N(R r )SO 2 R r 、Si(R r )(R s )R t and (CH 2 ) 1-3 NR r R s ; where R r , R s and R t Each independently is H, (C 1 -C 6 ) alkyl or (C 3 -C 6 ) cycloalkyl; or R r and R s Together with the nitrogen atom to which they are attached, they form a 4- to 9-membered heterocyclic group, which is optionally selected from (C 1 -C 4 ) alkyl, halogen, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) alkylamino, NH 2 , CN and OH are substituted with one or more substituents;

[0032] R 6 Yes – L 1 CR 14 R 15 R 16 or –CH=CH–R 16 ,in

[0033] L 1 Does not exist, is O, S, (C 1 -C 4 )alkylene, -O-(C 1 -C 4 )alkylene or -S-(C 1 -C 4 ) alkylene;

[0034] R 14 is H or (C 1 -C 4 )alkyl;

[0035] R 15 is H or (C 1 -C 4 ) alkyl, or

[0036] R 14 and R 15 Together with the carbon atom to which they are attached, they form (C 3 -C 5 ) carbocyclyl, 4- to 7-membered heterocyclyl or C=O;

[0037] R 16 Yes (C 1 -C 6 )alkyl, –NR 17 R 18 ,–OR 17 , –C(O)R 17 , –C(O)OR 17 , –N(R 18 )C(O)R 17 , –C(O)NR 17 R 18 , –S(O)-(C 1 -C 6 )alkyl, –S(O) 2 -(C 1 -C 6 )alkyl, –P(O)-(C 1 -C 6 alkyl) 2 , –C(NH)NH 2 ,–(C 1 -C 4 )alkyl-NR 18 C(O)R 17 or a 4- to 7-membered heterocyclic group, wherein

[0038] R 17 is H, a 3- to 6-membered heterocyclic group or (C 1 -C 4) alkyl, which is optionally substituted by one or more identical or different groups selected from the group consisting of OH, Cl, F, CF 3 、N(C 1 -C 4 alkyl) 2 , (C 3 -C 6 ) carbocyclic group, 3 to 6 membered heterocyclic group, (C 2 -C 4 ) alkenyl and (C 2 -C 4 ) alkynyl;

[0039] R 18 is H or (C 1 -C 4 )alkyl;

[0040] R 7 is H, methyl, –(CH 2 ) 1-3 W 1 W 2 or in

[0041] W 1 Yes CR 19 R19' or C(O);

[0042] R 19 and R 19’ are independently H, (C 1 -C 2 )alkyl, F, OH, CN, NO 2 , (C 1 -C 2 ) alkoxy, (C 1 -C 2 ) haloalkyl, (C 1 -C 2 )Haloalkoxy, NH 2 NH(C 1 -C 2 )alkyl or N(C 1 -C 2 alkyl) 2 ,or

[0043] R 19 and R 19’ Together with the carbon atoms to which they are attached, they form C(O), (C 3 -C 6 ) a carbocyclyl or a 3- to 6-membered heterocyclyl, which is optionally substituted by one or more substituents independently selected from the following: (C 1 -C 2 ) alkyl, halogen, (C 1-C 2 ) haloalkyl, (C 1 -C 2 ) haloalkoxy, (C 1 -C 2 ) alkoxy, (C 1 -C 2 ) alkylamino, NH 2 , CN and OH;

[0044] W 2 is CN, OH, 5- or 6-membered heteroaryl, phenyl, C(O)-(C 1 -C 2 )alkyl, S(O) 2 -(C 1 -C 2 )alkyl, S(O)(NH)-(C 1 -C 2 )alkyl, C(O)OCH 3 、C(O)NHCH 3 , CR 20 R 21 R 22 NH 2 NH(C 1 -C 2 )alkyl or N(C 1 -C 2 alkyl) 2 ,in

[0045] R 20 is H, (C 1 -C 2 )alkyl, F, Cl, Br, OH, NH 2 、CN、NO 2 , (C 1 -

[0046] C 2 ) alkoxy, (C 1 -C 2 ) haloalkyl or (C 1 -C 2 ) haloalkoxy;

[0047] R 21 is H, (C 1 -C 2 )Alkyl, F, Cl, Br, OH, CN, NO 2 , (C 1 -C 2 ) alkoxy, (C 1 -C 2 ) haloalkyl, (C 1 -C 2) haloalkoxy or –Y 2 -L 2 -Z 2 ,in

[0048] Y 2 Does not exist, it is O, S, S(O), S(O) 2 ,NR',C(O),C(O)O,OC(O),C(O)N(R'),N(R')C(O),S(O) 2 N(R') or N(R')SO 2 ;

[0049] L 2 Does not exist or (C 1 -C 2 ) alkylene;

[0050] Z 2 is H, (C 1 -C 6 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, phenyl, (C 3 -C 6 ) a carbocyclic group or a 4- to 6-membered heterocyclic group, wherein Z 2 Optionally substituted with one or more substituents independently selected from the following: 1 -C 4 ) alkyl, halogen, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) alkylamino, NH 2 , CN, OH, C(O)R', C(O)OR', OC(O)R', C(O)NR'R' and N(R')C(O)R', wherein each R' is independently H or (C 1 -C 4 )alkyl;

[0051] or R 20 and R 21 Together with the carbon atom to which they are attached, they form (C 3 -C 6 ) a carbocyclic group or a 3- to 6-membered heterocyclic group, which is optionally substituted by one or more substituents selected from the following: (C 1 -C 2 ) alkyl, halogen, (C1 -C 2 ) haloalkyl, (C 1 -C 2 ) haloalkoxy, (C 1 -C 2 ) alkoxy, (C 1 -C 2 ) alkylamino, NH 2 , CN and OH;

[0052] R 22 Yes (C 1 -C 2 )alkyl, -C(O)OR", OR", -C(O)NR", NR"R", phenyl or 5-membered heteroaryl, wherein each R" is independently H or (C 1 -C 2 )alkyl;

[0053] A” is (C 4 -C 6 ) a carbocyclyl or a 4- to 6-membered heterocyclyl, which is optionally substituted by one or more substituents independently selected from the following: (C 1 -C 2 ) alkyl, halogen, OH, oxo, CN and (C 1 -C 2 ) alkoxy;

[0054] W 3 YesNR 23 or CR 24 R24', where

[0055] R 23 is H, (C 1 -C 2 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 )hydroxyalkyl, -C(O)CH 3 or –C(O)O-(C 1 -C 4 )alkyl;

[0056] R 24 and R 24’ are independently H, (C 1 -C 2 )alkyl, cyclopropyl, F, Cl, Br, OH, NH 2 、CN、NO 2 , (C 1 -C 2 ) haloalkyl, (C 1 -C 2) haloalkoxy, (C 1 -C 2 )alkoxy, -C(O)OR", NR"R", phenyl or 5-membered heteroaryl;

[0057] R 8 is H, (C 1 -C4) alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 4 ) haloalkyl or CN, wherein the alkyl or cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of: (C 1 -C 4 ) alkyl, (C 3 -C 6 )cycloalkyl, OH, (C 1 -C 2 ) alkoxy, NH 2 NH(C 1 -C 2 ) alkyl, N((C 1 -C 2 )alkyl) 2 , (C 1 -C 2 )aminoalkyl and halogen;

[0058] R 8 ' is H, (C 1 -C 4 )alkyl, CN, (C 1 -C 4 ) haloalkyl or –Y 3 -L 3 -Z 3 ,in

[0059] Y 3 Does not exist, is C(O)O or C(O)N(R”);

[0060] L 3 Does not exist or (C 1 -C 2 ) alkylene;

[0061] Z 3 is H, (C 1 -C 6 ) alkyl, phenyl, (C 3 -C 6 ) cycloalkyl or 4 to 6 membered heterocyclic group, wherein Z 3 Optionally substituted with one or more substituents independently selected from the following: 1 -C 2 ) alkyl, halogen, (C1 -C 2 ) haloalkyl, (C 1 -C 2 ) haloalkoxy, (C 1 -C 2 ) alkoxy, NH 2 、NO 2 , CN and OH, or

[0062] R 8 and R 8 'Together with the carbon atoms to which they are attached, they form (C 4 -C 6 ) a carbocyclic group or a 4- to 6-membered heterocyclic group;

[0063] A' is a 6- or 7-membered heterocyclic group, except R 8 and R 8 ', which is optionally further substituted by one or more substituents independently selected from the following: oxo, (C 1 -C 2 )alkyl, cyclopropyl, spirocyclopropyl, halogen, (C 1 -C 2 ) haloalkyl, (C 1 -C 2 ) haloalkoxy, (C 1 -C 2 ) alkoxy, NH 2 , CN and OH;

[0064] X 4 Yes CR 25 or N, where

[0065] R 25 is H, F, Cl or methyl;

[0066] R 9 is H, (C 1 -C 2 ) alkyl, (C 3 -C 4 )cycloalkyl, (C 1 -C 2 ) haloalkyl, CN, (C 2 -C 4 ) alkenyl or (C 2 -C 4 ) alkynyl;

[0067] R 9 'Yes(C 1 -C 4 )alkyl, CN, (C 1 -C 4 ) haloalkyl or –Y 4 -L4 -Z 4 ,in

[0068] Y 4 Does not exist, is C(O), C(O)O, OC(O), C(O)N(R") or S(O) 2 N(R”);

[0069] L 4 Does not exist or (C 1 -C 2 ) alkylene, which is optionally selected from (C 1 -C 2 ) alkyl and oxo are substituted with one or more substituents;

[0070] Z 4 is H, (C 1 -C 6 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, phenyl, (C 3 -C 6 )Carbocyclic group, (C 3 -C 6 )cycloalkenyl or 4 to 6 membered heterocyclic group, wherein Z 4 Optionally substituted with one or more substituents independently selected from the group consisting of oxo, (C 1 -C 4 ) alkyl, (C 3 -C 6 )cycloalkyl, halogen, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) alkylamino, NH 2 、NO 2 、CN、OH、C(O)R u 、C(O)OR u 、OC(O)R u 、C(O)NR u R u and N(R u )C(O)R u , where each R u are independently H, (C 1 -C 4 ) alkyl, (C 3 -C 6) cycloalkyl, or

[0071] Z 4 Yes – QL 5 -W 4 ,in

[0072] Q does not exist and is O, NH, or N(C 1 -C 2 )alkyl;

[0073] L 5 Does not exist or (C 1 -C 2 ) alkylene, which is optionally selected from oxo and (C 1 -C 2 ) is substituted with one or more substituents on the alkyl group;

[0074] W 4 Yes (C 1 -C 4 ) alkyl, phenyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 ) cycloalkenyl or 5 or 6 membered heterocyclic group, wherein W 4 Optionally substituted with one or more substituents independently selected from the following: 1 -C 4 ) alkyl, halogen, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy,

[0075] (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) alkylamino, NH 2 、NO 2 , CN or OH; or

[0076] R 9 and R 9 'Together with the carbon atoms to which they are attached, they form (C 3 -C 10 ) carbocyclyl or 4 to 10 membered heterocyclyl, which is optionally substituted by one or more substituents independently selected from the following: oxo, (C 1 -C 2 ) alkyl, halogen, (C 1 -C 2 ) haloalkyl, (C 1 -C 2 ) haloalkoxy, (C 1-C 2 ) alkoxy, (C 1 -C 2 ) alkylamino, NH 2 、NO 2 , CN or OH; or said (C 3 -C 10 ) carbocyclic group or 4 to 10 membered heterocyclic group is optionally fused with 5 or 6 membered heteroaryl or benzene ring, and the 5 or 6 membered heteroaryl or benzene ring is optionally fused with (C 1 -C 2 ) alkyl, halogen, (C 1 -C 2 ) haloalkyl, (C 1 -C 2 ) haloalkoxy, (C 1 -C 2 ) alkoxy, (C 1 -C 2 ) alkylamino, NH 2 、NO 2 , CN or OH substitution;

[0077] R 9 " is H, (C 1 -C 4 ) alkyl, (C 1 -C 2 ) haloalkyl, (C 1 -C 2 ) alkoxy, (C 1 -C 2 )Haloalkoxy, CN, NO 2 , ethynyl, phenyl, or 5 or 6 membered heteroaryl, wherein the alkyl, phenyl or heteroaryl is optionally independently selected from halogen, OH, and NH 2 is substituted with one or more substituents;

[0078] X 5 Does not exist, yes (C 3 -C 6 )Carbocyclic ring, (C 3 -C 6 )Carbocyclic (C=O) or SO 2 ;

[0079] R 10 and R 10 ' are independently H, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) hydroxyalkyl, (C 1 -C 3 )aminoalkyl, or

[0080] R 10 and R 10 'Together with the same carbon atom to which they are attached, they form (C 3 -C 6 ) carbocyclyl or 4 to 6 membered heterocyclyl, wherein the alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl or heterocyclyl is optionally substituted by one or more identical or different R 10a Group substitution, where R 10a Yes (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )alkyl-(C 1 -C 3 ) alkoxy, halogen, NH 2 OH, (C 1 -C 6 ) haloalkyl, NH-(C 1 -C 6 ) alkyl, N((C 1 -C 6 )alkyl) 2 , (C 3 -C 6 ) a carbocyclic group, a 4- to 6-membered heterocyclic group, or

[0081] R 10 ' and R 11 'Together with the carbon atoms to which they are attached, they form (C 3 -C 6 ) a carbocyclic group or a 4- to 6-membered heterocyclic group;

[0082] R 11 and R 11 ' are independently H, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) hydroxyalkyl, (C 1 -C 3 )aminoalkyl, or

[0083] R 11 and R 11 'Together with the same carbon atom to which they are attached, they form C=O, (C 3 -C 6 ) carbocyclic or 4 to 6 membered heterocyclic, wherein the carbocyclic or heterocyclic is optionally substituted by one or more identical or different R 11a group substituted, where each R 11a Independently (C 1 -C 6) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )alkyl-(C 1 -C 3 ) alkoxy, halogen, NH 2 OH, (C 1 -C 6 ) haloalkyl, NH-(C 1 -C 6 ) alkyl, N((C 1 -C 6 )alkyl) 2 , (C 3 -C 6 ) a carbocyclic group or a 4- to 6-membered heterocyclic group, or two of which R 11a The groups, together with the same carbon atom to which they are attached, form C=O;

[0084] R 12 It is H, OH, NH-(C 1 -C 6 ) alkyl, NH-(C 1 -C 6 ) hydroxyalkyl, NH-(C 1 -C 6 )aminoalkyl, NH-(C 3 -C 6 ) carbocyclic group, NH-4 to 6 membered heterocyclic group, NH-(C 1 -C 6 )alkyl-(C 3 -C 6 )Carbocyclic or NH-(C 1 -C 6 )alkyl-4 to 6 membered heterocyclyl, wherein the alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl or heterocyclyl is further optionally substituted by one or more identical or different R 12a group substituted, where each R 12a Independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )alkyl-(C 1 -C 3 ) alkoxy, halogen, NH 2 OH, (C 1 -C 6 ) haloalkyl, NH-(C 1 -C 6 ) alkyl, N((C 1 -C6 )alkyl) 2 , (C 3 -C 6 ) a carbocyclic group or a 4- to 6-membered heterocyclic group;

[0085] m is 0, 1, or 2; and

[0086] o is either 0 or 1.

[0087] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0088] Another aspect of the present disclosure relates to a method for treating a disease or condition involving abnormal BCL6 activity, which requires administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof to a subject in need thereof. In some embodiments, the disease or condition is cancer. In some embodiments, the disease or condition is an inflammatory disease.

[0089] In some embodiments, the cancer is a lymphoid malignancy. In some embodiments, the lymphoid malignancy is peripheral T-cell lymphoma (PTCL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia / lymphoma (ALL), cutaneous T-cell lymphoma, chronic myeloid leukemia, or B-cell non-Hodgkin's lymphoma. DETAILED DESCRIPTION

[0090] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the subject matter herein belongs. As used in the specification and the appended claims, unless otherwise specified, the following terms have the indicated meanings to facilitate understanding of the present disclosure.

[0091] As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a composition" includes mixtures of two or more such compositions, reference to "an inhibitor" includes mixtures of two or more such inhibitors, and so forth.

[0092] Unless otherwise indicated, the term "about" means within 10% (eg, within 5%, 2%, or 1%) of the particular value that the term "about" modifies.

[0093] The transitional term "comprising," which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. When used in the context of the number of heteroatoms in a heterocyclic structure, it means the heterocyclic group having that minimum number of heteroatoms. Conversely, the transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional phrase "consisting essentially of" limits the scope of the claim to the specified materials or steps "and those materials or steps that do not materially affect the basic and novel characteristics of the present disclosure."

[0094] With respect to the compounds of the present disclosure, and to the extent that the following terminology is used herein to further describe them, the following definitions apply.

[0095] As used herein, the term "alkyl" refers to a saturated straight or branched chain monovalent hydrocarbon radical. In some embodiments, the alkyl radical is C 1 -C 6 In some embodiments, and to the extent not otherwise disclosed for any one or more groups of the compounds of formula (I), the alkyl radical is C 0 -C 6 , C 0 -C 5 , C 0 -C 3 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 or C 1 -C 3 Group (where C 0 Alkyl refers to a bond). Examples of alkyl groups include methyl, ethyl, 1-propyl, 2-propyl, isopropyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 1-pentyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl. In some embodiments, the alkyl group is C 1 -C 3 In some embodiments, the alkyl group is C 1 -C 2 Alkyl Group. In some embodiments, the alkyl group is a methyl group.

[0096] As used herein, the term "alkylene" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a radical group, consisting only of carbon and hydrogen, containing no unsaturation, and having one to six carbon atoms, for example, methylene, ethylene, propylene, n-butylene, etc. The alkylene chain can be attached to the rest of the molecule and to the radical group by a single bond. In some embodiments, and to the extent not otherwise disclosed for any one or more groups of the compounds of Formula (I), the alkylene group contains one to four carbon atoms (C 1 -C 4 In other embodiments, the alkylene group contains from one to three carbon atoms (C 1 -C 3 In other embodiments, the alkylene group contains one to two carbon atoms (C 1 -C 2 In other embodiments, the alkylene group contains one carbon atom (C 1 alkylene).

[0097] As used herein, the term "alkenyl" refers to a straight or branched monovalent hydrocarbon radical having at least one carbon-carbon double bond. Alkenyl includes radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. In some embodiments, the alkenyl radical is C 2 -C 15 In some embodiments, and to the extent not otherwise disclosed for any one or more groups of the compounds of formula (I), the alkenyl radical is C 2 -C 12 , C 2 -C 10 , C 2 -C 8 , C 2 -C 6 or C 2 -C 3 Examples include ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, 2-methylbut-1,3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hex-1,3-dienyl.

[0098] As used herein, the term "alkynyl" refers to a straight or branched monovalent hydrocarbon radical having at least one carbon-carbon triple bond. 2 -C 15In some embodiments, and to the extent not otherwise disclosed for any one or more groups of the compounds of formula (I), the alkynyl radical is C 2 -C 12 , C 2 -C 10 , C 2 -C 8 , C 2 -C 6 or C 2 -C 3 Examples include ethynylprop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl and but-3-ynyl.

[0099] As used herein, the term "alkoxy" or "alkoxy" refers to an alkyl group as defined above, having an oxygen radical attached thereto, and the oxygen radical is the point of attachment. In some embodiments, the alkoxy group is a methoxy, ethoxy, propoxy, or tert-butoxy group. An "ether" is two hydrocarbon groups covalently linked by oxygen. Thus, the alkyl substituent that makes an alkyl an ether is an alkoxy or is similar to an alkoxy, such as can be represented by one of -O-alkyl, -O-alkenyl, and -O-alkynyl.

[0100] As used herein, the term "halogen" (or "halo" or "halide") refers to fluorine, chlorine, bromine or iodine.

[0101] As used herein, the term "cyclic group" broadly refers to any group used alone or as part of a larger portion, which contains a saturated, partially saturated or aromatic ring system, for example, carbocyclic (cycloalkyl, cycloalkenyl), heterocyclic (heterocyclic alkyl, heterocyclic alkenyl), aryl and heteroaryl groups. The cyclic group can have one or more (e.g., fused) ring systems. Thus, for example, the cyclic group can contain one or more carbocyclic, heterocyclic, aryl or heteroaryl groups.

[0102] As used herein, the term "carbocycle" (also referred to as "carbocyclyl") refers to a group used alone or as part of a larger moiety that contains a saturated, partially unsaturated and or aromatic ring system having 3 to 12 carbon atoms, alone or as part of a larger moiety (e.g., an alkyl carbocyclic group). The term carbocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged and spirocyclic systems and combinations thereof. In one embodiment, a carbocyclyl includes 3 to 10 carbon atoms (C 3 -C 10 In one embodiment, the carbocyclyl group comprises 3 to 6 carbon atoms (C 3 -C 6 In one embodiment, the carbocyclyl group comprises 5 to 6 carbon atoms (C 5 -C 6In some embodiments, the carbocyclyl group is a bicyclic ring including C 6 -C 10 In another embodiment, the carbocyclyl group as a spirocyclic ring system includes C 5 -C 11 Representative examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and phenyl; bicyclic carbocyclyls having 7 to 11 ring atoms include [4,3], [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, naphthalene, and bicyclo[3.2.2]nonane. Representative examples of spiro carbocyclyl include spiro [2.2] pentane, spiro [2.3] hexane, spiro [2.4] heptane, spiro [2.5] octane and spiro [4.5] decane. The term carbocyclyl includes aromatic ring systems as defined herein. The term carbocyclyl also includes cycloalkyl rings (e.g., saturated or partially unsaturated monocarbocycles, dicarbocycles or spirocarbocycles). The term carbocyclic group also includes carbocycles fused to one or more (e.g., 1, 2 or 3) different cyclic groups (e.g., aryl or heterocycle), wherein the free radical or point of attachment is on the carbocycle.

[0103] Thus, the term carbocycle also encompasses carbocyclylalkyl groups, which, as used herein, refer to groups of the formula --R c -Carbocyclic group, where R c is an alkylene chain. The term carbocycle also encompasses carbocyclylalkoxy groups, as used herein, which refer to a carbocyclylalkoxy group of the formula --O--R c - a group bonded to the oxygen atom of a carbocyclic group, wherein R c It is an alkylene chain.

[0104] As used herein, the term "aryl" is used alone or as part of a larger moiety (e.g., "aralkyl", where the terminal carbon atom on the alkyl group is the point of attachment, e.g., a benzyl group), "aralkyloxy", where the oxygen atom is the point of attachment, or "aryloxyalkyl", where the point of attachment is on the aryl group), and refers to a group including a monocyclic, bicyclic or tricyclic ring, a carbocyclic ring system including a fused ring, where at least one ring in the system is aromatic. In some embodiments, the aralkyloxy group is a benzyloxy group. The term "aryl" can be used interchangeably with the term "aromatic ring". In one embodiment, the aryl group includes a group having 6-12 carbon atoms. In another embodiment, the aryl group includes a group having 6-10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, biphenyl, 1,2,3,4-tetrahydronaphthyl, etc., which can be substituted or independently substituted by one or more substituents described herein. A specific aryl group is phenyl. In some embodiments, an aryl group includes an aromatic ring fused to one or more (eg, 1, 2, or 3) different ring groups (eg, carbocyclic or heterocyclic) wherein the radical or point of attachment is on the aromatic ring.

[0105] Thus, the term aryl encompasses aralkyl groups (eg, benzyl), which, as disclosed above, refer to groups of the formula: c -aryl radical, wherein R c is an alkylene chain, such as methylene or ethylene. In some embodiments, the aralkyl group is an optionally substituted benzyl group. The term aryl also encompasses aralkyloxy groups, as used herein, which refer to groups of the formula --O--R c -- a group bonded to the oxygen atom of an aromatic group, wherein R c is an alkylene chain, such as methylene or ethylene.

[0106] As used herein, the term "heterocyclyl" refers to a "carbocyclyl" used alone or as part of a larger moiety, containing a saturated, partially unsaturated and or aromatic ring system in which one or more (e.g., 1, 2, 3, 4 or 5) of the carbon atoms have been replaced by a heteroatom or a heteroatom-containing group (e.g., O, N, N(O), S, S(O) or S(O)). 2 ) replacement. The term heterocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged and spirocyclic systems and combinations thereof. In some embodiments, heterocyclyl refers to a 3 to 12 membered heterocyclyl ring system. In some embodiments, heterocyclyl refers to a saturated ring system, such as a 3 to 12 membered saturated heterocyclyl ring system. In some embodiments, heterocyclyl refers to a heteroaromatic ring system, such as a 5 to 12 membered heteroaromatic ring system. The term heterocyclyl also includes C 2 -C 8 Heterocycloalkyl, which is a saturated or partially unsaturated monocyclic, bicyclic or spirocyclic ring system, contains 2-8 carbons and one or more (eg 1, 2 or 3) heteroatoms.

[0107] In some embodiments, the heterocyclic radical group includes 3-12 ring atoms, and includes monocyclic, bicyclic, tricyclic and spirocyclic systems, wherein the ring atoms are carbon, and one to 5 ring atoms are heteroatoms, such as nitrogen, sulfur or oxygen. In some embodiments, the heterocyclic radical includes 3 to 7-membered monocycles with one or more heteroatoms selected from O, N and S. In some embodiments, the heterocyclic radical includes 4 to 6-membered monocycles with one or more heteroatoms selected from O, N and S. In some embodiments, the heterocyclic radical includes 3-membered monocycles. In some embodiments, the heterocyclic radical includes 4-membered monocycles. In some embodiments, the heterocyclic radical includes 5 to 6-membered monocycles. In some embodiments, the heterocyclic radical group includes 0 to 3 double bonds. In any of the aforementioned embodiments, the heterocyclic radical includes 1, 2, 3 or 4 heteroatoms. Any nitrogen or sulfur heteroatom can be optionally oxidized (for example, NO, SO, SO 2 ), and any nitrogen heteroatom may be optionally substituted (e.g., methyl, isopropyl) and / or quaternized (e.g., [NR 4 ] + Cl - , [NR 4 ] + OH -Representative examples of heterocyclyl include oxirane, aziridinyl, thiirane, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydropyranyl, dihydrothiophenyl, tetrahydrothiophenyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinyl, thiazinyl, thioalkyl (thioxanyl), homopiperazinyl, homopiperidinyl, azepanyl, oxepinyl, thioheptyl (thi epanyl, oxazepinyl, diazepinyl, 1,4-diazepinyl, diazepinyl, thiazepinyl, thiazepinyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinone, oxazolidinone, imidazolidinone, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, thienyl, oxazinyl, thiadiazinyl , oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolyl, thiopyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrimidinyl, pyrimidinedione, pyrimidine-2,4-dione, piperazinone, piperazinedionyl, pyrazolidinimidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl , 3-azabicyclo[3.1.1]heptyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl, 8-azabicyclo[2.2.2]octyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonyl, azaspiro[2.5]octyl, azaspiro[4.5]decyl, 1-azaspiro[4.5]dec-2-ene, azaspiro[5.5]undecyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl.Examples of 5-membered heterocyclic groups containing sulfur or oxygen atoms and one to three nitrogen atoms are thiazolyl (e.g., thiazol-2-yl), thiadiazolyl (e.g., 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl), oxazolyl (e.g., oxazol-2-yl) and oxadiazolyl (e.g., 1,3,4-oxadiazol-5-yl and 1,2,4-oxadiazol-5-yl). Examples of 5-membered heterocyclic groups containing 2 to 4 nitrogen atoms include imidazolyl (e.g., imidazol-2-yl), triazolyl (e.g., 1,3,4-triazol-5-yl, 1,2,3-triazol-5-yl and 1,2,4-triazol-5-yl) and tetrazolyl (e.g., 1H-tetrazolyl). Representative examples of benzo-fused 5-membered heterocyclic groups include benzoxazole-2-yl, benzothiazol-2-yl and benzimidazole-2-yl. Examples of 6-membered heterocyclic groups containing one to three nitrogen atoms and optional sulfur or oxygen atoms are pyridyl (e.g., pyridyl-2-yl, pyridyl-3-yl and pyridyl-4-yl), pyrimidyl (e.g., pyrimidine-2-yl and pyrimidine-4-yl), triazine (e.g., 1,3,4-triazine-2-yl and 1,3,5-triazine-4-yl), pyridazine (e.g., pyridazine-3-yl) and pyrazinyl. In some embodiments, the heterocyclic group includes a heterocycle fused to one or more (e.g., 1 or 2) different ring groups (e.g., carbocycle or heterocycle), wherein the free radical or attachment point is on the heterocycle, and in some embodiments, wherein the attachment point is a heteroatom contained in the heterocycle.

[0108] Thus, the term heterocycle encompasses N-heterocyclyl groups, as used herein, which refer to heterocyclyl groups containing at least one nitrogen atom, and wherein the attachment point of the heterocyclyl group to the rest of the molecule is through the nitrogen atom in the heterocyclyl group. Representative examples of N-heterocyclyl groups include 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, 1-pyrazolidinyl, 1-imidazolinyl and 1-imidazolidinyl. The term heterocycle also encompasses C-heterocyclyl groups, as used herein, C-heterocyclyl refers to heterocyclyl groups containing at least one heteroatom, and wherein the attachment point of the heterocyclyl group to the rest of the molecule is through the carbon atom in the heterocyclyl group. Representative examples of C-heterocyclyl radicals include 2- or 3-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl and 2- or 3-pyrrolidinyl. The term heterocycle also encompasses heterocycloalkyl groups, as disclosed above, which refer to a formula of--R c -heterocyclic group, wherein R c is an alkylene chain. The term heterocycle also encompasses heterocyclylalkoxy groups, as used herein, which refer to heterocyclylalkoxy groups of the formula --O--R c - a free radical bonded to the oxygen atom of a heterocyclic group, wherein R c It is an alkylene chain.

[0109] As used herein, the term "heteroaryl" used alone or as part of a larger moiety (e.g., "heteroarylalkyl" (also referred to as "heteroaralkyl") or "heteroarylalkoxy" (also referred to as "heteroaralkoxy")) refers to a monocyclic, bicyclic, or tricyclic ring system having 5 to 12 ring atoms, wherein at least one ring is aromatic and contains at least one heteroatom. In one embodiment, heteroaryl includes 5 to 6 membered monocyclic aromatic groups wherein one or more of the ring atoms is O, N, or S. Representative examples of heteroaryl groups include thienyl, furanyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridinyl, pyrimidinyl, imidazopyridinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazo[1,5-b]pyridazinyl, purinyl, deazapurinyl, benzoxazolyl , benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indolyl, 1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl, and 1,2,3-triazol-5-yl. The term "heteroaryl" also includes groups in which a heteroaryl is fused to one or more cyclic (e.g., carbocyclyl or heterocyclyl) rings, wherein the radical or point of attachment is on the heteroaryl ring. Non-limiting examples include indolyl, indolizinyl, isoindolyl, benzothienyl, benzothienyl, methylenedioxyphenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzodioxazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. The heteroaryl group can be monocyclic, bicyclic or tricyclic. In some embodiments, a heteroaryl group includes a heteroaromatic ring fused to one or more (e.g., 1 or 2) different ring groups (e.g., carbocyclic or heterocyclic), wherein the radical or point of attachment is on the heteroaromatic ring, and in some embodiments, the point of attachment is a heteroatom contained in the heterocyclic ring.

[0110] Thus, the term heteroaryl encompasses N-heteroaryl, as used herein, which refers to a heteroaryl group as defined above containing at least one nitrogen, and wherein the point of attachment of the heteroaryl group to the rest of the molecule is through a nitrogen atom in the heteroaryl group. The term heteroaryl also encompasses C-heteroaryl, as used herein, which refers to a heteroaryl group as defined above, and wherein the point of attachment of the heteroaryl group to the rest of the molecule is through a carbon atom in the heteroaryl group. The term heteroaryl also encompasses heteroaralkyl groups as disclosed above, which refer to heteroaryl groups of the formula—R c-heteroaryl radical, wherein R c is an alkylene chain as defined above. The term heteroaryl also encompasses heteroaralkoxy (or heteroarylalkoxy) groups, as used herein, which refers to a heteroarylalkyl group of the formula --O--R c - a group bonded to the oxygen atom of a heteroaryl group, wherein R c is an alkylene group as defined above.

[0111] Unless otherwise indicated, and to the extent that no specific group in the compounds of formula (I) is further defined, any group described herein may be substituted or unsubstituted. To the extent that no specific group is otherwise disclosed, representative examples of substituents may include alkyl (e.g., C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 1 ), substituted alkyl (e.g., substituted C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 1 ), alkoxy (e.g., C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 1 ), substituted alkoxy (e.g., substituted C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 1 ), haloalkyl (e.g., CF 3 ), alkenyl (e.g., C 2 -C6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 2 ), substituted alkenyl (e.g., substituted C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 2 ), alkynyl (e.g., C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 2 ), substituted alkynyl (e.g., substituted C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 2 ), ring (e.g., C 3 -C 12 , C 5 -C 6 ), substituted rings (e.g., substituted C 3 -C 12 , C 5 -C 6 ), carbocyclic rings (e.g., C 3 -C 12 , C 5 -C 6 ), substituted carbocyclic rings (e.g., substituted C 3 -C 12 , C 5 -C 6 ), heterocyclic (e.g., 3-12 membered, 5-6 membered), substituted heterocyclic (e.g., substituted 3-12 membered, 5-6 membered), aryl (e.g., benzyl and phenyl), substituted aryl (e.g., substituted benzyl or substituted phenyl), heteroaryl (e.g., pyridyl or pyrimidinyl), substituted heteroaryl (e.g., substituted pyridyl or substituted pyrimidinyl), aralkyl (e.g., benzyl), substituted aralkyl (e.g., substituted benzyl), halogen, hydroxy, aryloxy (e.g., C6 -C 12 , C 6 ), substituted aryloxy (e.g., substituted C 6 -C 12 , C 6 ), alkylthio (e.g., C 1 -C 6 ), substituted alkylthio (e.g., substituted C 1 -C 6 ), arylthio (e.g., C 6 -C 12 , C 6 ), substituted arylthio (e.g., substituted C 6 -C 12 , C 6 ), cyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amide, substituted amide, thio, substituted thio, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfinamide, substituted sulfinamide, sulfonamide, substituted sulfonamide, urea, substituted urea, carbamate, carbamate, amino acid, and peptide groups.

[0112] In a broad sense, the compounds of the present disclosure are represented by formula (I):

[0113] or a pharmaceutically acceptable salt or stereoisomer thereof,

[0114] in:

[0115] X 1 is N, CH, CCl, CF or CCN;

[0116] X 2 Is N or CR 4 ;

[0117] R 4 is H, (C 1 -C 4 )Alkyl, halogen, OH, NH 2 , (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, (C 2 -C 4 ) alkenyl, (C 2 -C 4 )Alkynyl, NO 2 、CN、NH(C 1 -

[0118] C 4 )alkyl or N(C 1 -C 4 alkyl) 2 ;

[0119] R 1 is H, OH or halogen;

[0120] R 2 is H, OH or halogen;

[0121] R 3 is H, halogen or CN;

[0122] Y is CH 2 , NH or O;

[0123] Z is CH 2 , NH, S or O;

[0124] n is 0, 1, or 2;

[0125] A is

[0126] X 3 is CH or N;

[0127] R 5 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) hydroxyalkyl, (C 1 -C 6 )aminoalkyl, (C 3 -C 6 ) carbocyclic group, 4 to 7 membered heterocyclic group, (C 1 -C 6 )alkyl-(C 3 -C 7 )Carbocyclic or (C 3 -C 7 ) carbocyclyl-4 to 7 membered heterocyclyl; wherein the alkyl, carbocyclyl or heterocyclyl is further optionally substituted by one or more identical or different R 13 Group substitution, where R 13 Yes (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen, NH 2 OH, (C 1 -C 6 ) haloalkyl, NH(C 1 -C 6 )alkyl or N((C1 -C 6 )alkyl) 2 , (C 3 -C 6 ) a carbocyclic group, a 4- to 7-membered heterocyclic group, or

[0128] R 5 Yes – LY 1 -Z 1 ,in

[0129] L does not exist or (C 1 -C 5 ) alkylene, which is optionally selected from (C 1 -C 2 ) alkyl and oxo are substituted with one or more substituents;

[0130] Y 1 Does not exist, it is O, S, S(O), S(O) 2 , NR', C(O), C(O)O, OC(O), C(O)N(R'), N(R')C(O), N(R')C(O)N(R'), N(R')C(O)O, OC(O)N(R'), S(O) 2 N(R') or N(R')S(O) 2 ;

[0131] Each R' is independently H or (C 1 -C 4 )alkyl;

[0132] Z 1 is H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 3 -C 10 ) a carbocyclic group or a 3- to 10-membered heterocyclic group, wherein Z 1 Optionally substituted with one or more substituents independently selected from the following: 1 -C 4 ) alkyl, halogen, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 )Haloalkoxy, NH 2 , (C 1 -C 4 )aminoalkyl, CN, OH, carboxyl, carbamoyl, aminosulfonyl, mercapto, urea, NR r R s, OR r 、C(O)R r 、C(O)OR r 、OC(O)R r 、C(O)NR r R s 、N(R r )C(O)R r 、S(O) 0-2 R r 、S(O) 2 NR r R s 、N(R r )SO 2 R r 、Si(R r )(R s )R t and (CH 2 ) 1-3 NR r R s ; where R r , R s and R t Each independently is H, (C 1 -C 6 ) alkyl or (C 3 -C 6 ) cycloalkyl; or R r and R s Together with the nitrogen atom to which they are attached, they form a 4- to 9-membered heterocyclic group, which is optionally selected from (C 1 -C 4 ) alkyl, halogen, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) alkylamino, NH 2 , CN and OH are substituted with one or more substituents;

[0133] R 6 Yes – L 1 CR 14 R 15 R 16 or –CH=CH–R 16 ,in

[0134] L 1 Does not exist, is O, S, (C 1 -C 4 )alkylene, -O-(C1 -C 4 )alkylene or -S-(C 1 -C 4 ) alkylene;

[0135] R 14 is H or (C 1 -C 4 )alkyl;

[0136] R 15 is H or (C 1 -C 4 ) alkyl, or

[0137] R 14 and R 15 Together with the carbon atom to which they are attached, they form (C 3 -C 5 ) carbocyclyl, 4- to 7-membered heterocyclyl or C=O;

[0138] R 16 Yes (C 1 -C 6 )alkyl, –NR 17 R 18 ,–OR 17 , –C(O)R 17 , –C(O)OR 17 , –N(R 18 )C(O)R 17 , –C(O)NR 17 R 18 , –S(O)-(C 1 -C 6 )alkyl, –S(O) 2 -(C 1 -C 6 )alkyl, –P(O)-(C 1 -C 6 alkyl) 2 , –C(NH)NH 2 ,–(C 1 -C 4 )alkyl-NR 18 C(O)R 17 or a 4- to 7-membered heterocyclic group, wherein

[0139] R 17 is H, a 3- to 6-membered heterocyclic group or (C 1 -C 4 ) alkyl, which is optionally substituted by one or more identical or different groups selected from the group consisting of OH, Cl, F, CF 3 、N(C 1 -

[0140] C 4 alkyl) 2 , (C 3 -C 6 ) carbocyclic group, 3 to 6 membered heterocyclic group, (C 2 -C 4 ) alkenyl and (C 2 -C 4 ) alkynyl;

[0141] R 18 is H or (C 1 -C 4 )alkyl;

[0142] R 7 is H, methyl, –(CH 2 ) 1-3 W 1 W 2 or in

[0143] W 1 Yes CR 19 R19' or C(O);

[0144] R 19 and R 19’ are independently H, (C 1 -C 2 )Alkyl, F, OH, CN, NO 2 , (C 1 -

[0145] C 2 ) alkoxy, (C 1 -C 2 ) haloalkyl, (C 1 -C 2 )Haloalkoxy, NH 2 NH(C 1 -C 2 )alkyl or N(C 1 -C 2 alkyl) 2 ,or

[0146] R 19 and R 19’ Together with the carbon atoms to which they are attached, they form C(O), (C 3 -C 6 ) a carbocyclyl or a 3- to 6-membered heterocyclyl, which is optionally substituted by one or more substituents independently selected from the following: (C 1 -C 2 ) alkyl, halogen, (C 1 -C 2 ) haloalkyl, (C 1 -C2 ) haloalkoxy, (C 1 -C 2 ) alkoxy, (C 1 -C 2 ) alkylamino, NH 2 , CN and OH;

[0147] W 2 is CN, OH, 5- or 6-membered heteroaryl, phenyl, C(O)-(C 1 -C 2 )alkyl, S(O) 2 -(C 1 -C 2 )alkyl, S(O)(NH)-(C 1 -C 2 )alkyl, C(O)OCH 3 、C(O)NHCH 3 , CR 20 R 21 R 22 NH 2 NH(C 1 -C 2 )alkyl or N(C 1 -C 2 alkyl) 2 ,in

[0148] R 20 is H, (C 1 -C 2 )alkyl, F, Cl, Br, OH, NH 2 、CN、NO 2 , (C 1 -

[0149] C 2 ) alkoxy, (C 1 -C 2 ) haloalkyl or (C 1 -C 2 ) haloalkoxy;

[0150] R 21 is H, (C 1 -C 2 )Alkyl, F, Cl, Br, OH, CN, NO 2 , (C 1 -C 2 ) alkoxy, (C 1 -C 2 ) haloalkyl, (C 1 -C 2 ) haloalkoxy or –Y 2 -L 2 -Z2 ,in

[0151] Y 2 Does not exist, it is O, S, S(O), S(O) 2 ,NR',C(O),C(O)O,OC(O),C(O)N(R'),N(R')C(O),S(O) 2 N(R') or N(R')SO 2 ;

[0152] L 2 Does not exist or (C 1 -C 2 ) alkylene;

[0153] Z 2 is H, (C 1 -C 6 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, phenyl, (C 3 -

[0154] C 6 ) a carbocyclic group or a 4- to 6-membered heterocyclic group, wherein Z 2 Optionally substituted with one or more substituents independently selected from the following: 1 -C 4 ) alkyl, halogen, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) alkylamino, NH 2 ,

[0155] CN, OH, C(O)R', C(O)OR', OC(O)R', C(O)NR'R' and N(R')C(O)R', wherein each R' is independently H or (C 1 -C 4 )alkyl;

[0156] or R 20 and R 21 Together with the carbon atom to which they are attached, they form (C 3 -C 6 ) a carbocyclyl or a 3- to 6-membered heterocyclyl, which is optionally substituted by one or more substituents selected from the following:

[0157] (C1 -C 2 ) alkyl, halogen, (C 1 -C 2 ) haloalkyl, (C 1 -C 2 ) haloalkoxy, (C 1 -C 2 ) alkoxy, (C 1 -C 2 ) alkylamino, NH 2 , CN and OH;

[0158] R 22 Yes (C 1 -C 2 )alkyl, -C(O)OR", OR", -C(O)NR", NR"R", phenyl or 5-membered heteroaryl, wherein each R" is independently H or (C 1 -C 2 )alkyl;

[0159] A” is (C 4 -C 6 ) a carbocyclyl or a 4- to 6-membered heterocyclyl, which is optionally substituted by one or more substituents independently selected from the following: (C 1 -C 2 ) alkyl, halogen, OH, oxo, CN and (C 1 -C 2 ) alkoxy;

[0160] W 3 YesNR 23 or CR 24 R24', where

[0161] R 23 is H, (C 1 -C 2 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) hydroxyalkyl, -

[0162] C(O)CH 3 or –C(O)O-(C 1 -C 4 )alkyl;

[0163] R 24 and R 24’ are independently H, (C 1 -C 2 )alkyl, cyclopropyl, F, Cl, Br, OH, NH 2 、CN、NO 2 , (C1 -C 2 ) haloalkyl, (C 1 -C 2 ) haloalkoxy, (C 1 -C 2 )alkoxy, -C(O)OR", NR"R", phenyl or 5-membered heteroaryl;

[0164] R 8 is H, (C 1 -C4) alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 4 ) haloalkyl or CN, wherein the alkyl or cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of: (C 1 -C 4 ) alkyl, (C 3 -C 6 )cycloalkyl, OH, (C 1 -C 2 ) alkoxy, NH 2 NH(C 1 -C 2 ) alkyl, N((C 1 -C 2 )alkyl) 2 , (C 1 -C 2 )aminoalkyl and halogen;

[0165] R 8 ' is H, (C 1 -C 4 )alkyl, CN, (C 1 -C 4 ) haloalkyl or –Y 3 -L 3 -Z 3 ,in

[0166] Y 3 Does not exist, is C(O)O or C(O)N(R”);

[0167] L 3 Does not exist or (C 1 -C 2 ) alkylene;

[0168] Z 3 is H, (C 1 -C 6 ) alkyl, phenyl, (C 3 -C 6 ) cycloalkyl or 4 to 6 membered heterocyclic group, wherein Z 3Optionally substituted with one or more substituents independently selected from the following: 1 -C 2 ) alkyl, halogen, (C 1 -C 2 ) haloalkyl, (C 1 -C 2 ) haloalkoxy, (C 1 -C 2 ) alkoxy, NH 2 、NO 2 , CN and OH, or

[0169] R 8 and R 8 'Together with the carbon atoms to which they are attached, they form (C 4 -C 6 ) a carbocyclic group or a 4- to 6-membered heterocyclic group;

[0170] A' is a 6- or 7-membered heterocyclic group, except R 8 and R 8 ', which is optionally further substituted by one or more substituents independently selected from the following: oxo, (C 1 -C 2 )alkyl, cyclopropyl, spirocyclopropyl, halogen, (C 1 -C 2 ) haloalkyl, (C 1 -C 2 ) haloalkoxy, (C 1 -C 2 ) alkoxy, NH 2 , CN and OH;

[0171] X 4 Yes CR 25 or N, where

[0172] R 25 is H, F, Cl or methyl;

[0173] R 9 is H, (C 1 -C 2 ) alkyl, (C 3 -C 4 )cycloalkyl, (C 1 -C 2 ) haloalkyl, CN, (C 2 -C 4 ) alkenyl or (C 2 -C 4 ) alkynyl;

[0174] R 9 'Yes(C 1 -C 4)alkyl, CN, (C 1 -C 4 ) haloalkyl or –Y 4 -L 4 -Z 4 ,in

[0175] Y 4 Does not exist, is C(O), C(O)O, OC(O), C(O)N(R") or S(O) 2 N(R”);

[0176] L 4 Does not exist or (C 1 -C 2 ) alkylene, which is optionally selected from (C 1 -C 2 ) alkyl and oxo are substituted with one or more substituents;

[0177] Z 4 is H, (C 1 -C 6 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, phenyl, (C 3 -C 6 )Carbocyclic group, (C 3 -C 6 )cycloalkenyl or 4 to 6 membered heterocyclic group, wherein Z 4 Optionally substituted with one or more substituents independently selected from the group consisting of oxo, (C 1 -C 4 ) alkyl, (C 3 -C 6 )cycloalkyl, halogen, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) alkylamino, NH 2 、NO 2 、CN、OH、C(O)R u 、C(O)OR u 、OC(O)R u 、C(O)NR u R u and N(R u )C(O)R u , where each R u are independently H, (C1 -C 4 ) alkyl, (C 3 -C 6 ) cycloalkyl, or

[0178] Z 4 Yes – QL 5 -W 4 ,in

[0179] Q does not exist and is O, NH, or N(C 1 -C 2 )alkyl;

[0180] L 5 Does not exist or (C 1 -C 2 ) alkylene, which is optionally selected from oxo and (C 1 -C 2 ) is substituted with one or more substituents on the alkyl group;

[0181] W 4 Yes (C 1 -C 4 ) alkyl, phenyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 ) cycloalkenyl or 5 or 6 membered heterocyclic group, wherein W 4 Optionally substituted with one or more substituents independently selected from the following: 1 -C 4 ) alkyl, halogen, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy,

[0182] (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) alkylamino, NH 2 、NO 2 , CN or OH; or

[0183] R 9 and R 9 'Together with the carbon atoms to which they are attached, they form (C 3 -C 10 ) carbocyclyl or 4 to 10 membered heterocyclyl, which is optionally substituted by one or more substituents independently selected from the following: oxo, (C 1 -C 2 ) alkyl, halogen, (C 1 -C 2) haloalkyl, (C 1 -C 2 ) haloalkoxy, (C 1 -C 2 ) alkoxy, (C 1 -C 2 ) alkylamino, NH 2 、NO 2 , CN or OH; or said (C 3 -C 10 ) carbocyclic group or 4 to 10 membered heterocyclic group is optionally fused with 5 or 6 membered heteroaryl or benzene ring, and the 5 or 6 membered heteroaryl or benzene ring is optionally fused with (C 1 -C 2 ) alkyl, halogen, (C 1 -C 2 ) haloalkyl, (C 1 -C 2 ) haloalkoxy, (C 1 -C 2 ) alkoxy, (C 1 -C 2 ) alkylamino, NH 2 、NO 2 , CN or OH substitution;

[0184] R 9 " is H, (C 1 -C 4 ) alkyl, (C 1 -C 2 ) haloalkyl, (C 1 -C 2 ) alkoxy, (C 1 -C 2 )Haloalkoxy, CN, NO 2 , ethynyl, phenyl, or 5 or 6 membered heteroaryl, wherein the alkyl, phenyl or heteroaryl is optionally independently selected from halogen, OH, and NH 2 is substituted with one or more substituents;

[0185] X 5 Does not exist, yes (C 3 -C 6 )Carbocyclic ring, (C 3 -C 6 )Carbocyclic (C=O) or SO 2 ;

[0186] R 10 and R 10 ' are independently H, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) hydroxyalkyl, (C1 -C 3 )aminoalkyl, or

[0187] R 10 and R 10 'Together with the same carbon atom to which they are attached, they form (C 3 -C 6 ) carbocyclyl or 4 to 6 membered heterocyclyl, wherein the alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl or heterocyclyl is optionally substituted by one or more identical or different R 10a Group substitution, where R 10a Yes (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )alkyl-(C 1 -C 3 ) alkoxy, halogen, NH 2 OH, (C 1 -C 6 ) haloalkyl, NH-(C 1 -C 6 ) alkyl, N((C 1 -C 6 )alkyl) 2 , (C 3 -C 6 ) a carbocyclic group, a 4- to 6-membered heterocyclic group, or

[0188] R 10 ' and R 11 'Together with the carbon atoms to which they are attached, they form (C 3 -C 6 ) a carbocyclic group or a 4- to 6-membered heterocyclic group;

[0189] R 11 and R 11 ' are independently H, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) hydroxyalkyl, (C 1 -C 3 )aminoalkyl, or

[0190] R 11 and R 11 'Together with the same carbon atom to which they are attached, they form C=O, (C 3 -C 6 ) carbocyclic or 4 to 6 membered heterocyclic, wherein the carbocyclic or heterocyclic is optionally substituted by one or more identical or different R 11agroup substituted, where each R 11a Independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )alkyl-(C 1 -C 3 ) alkoxy, halogen, NH 2 OH, (C 1 -C 6 ) haloalkyl, NH-(C 1 -C 6 ) alkyl, N((C 1 -C 6 )alkyl) 2 , (C 3 -C 6 ) a carbocyclic group or a 4- to 6-membered heterocyclic group, or two of which R 11a The groups, together with the same carbon atom to which they are attached, form C=O;

[0191] R 12 It is H, OH, NH-(C 1 -C 6 ) alkyl, NH-(C 1 -C 6 ) hydroxyalkyl, NH-(C 1 -C 6 )aminoalkyl, NH-(C 3 -C 6 ) carbocyclic group, NH-4 to 6 membered heterocyclic group, NH-(C 1 -C 6 )alkyl-(C 3 -C 6 )Carbocyclic or NH-(C 1 -C 6 )alkyl-4 to 6 membered heterocyclyl, wherein the alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl or heterocyclyl is further optionally substituted by one or more identical or different R 12a group substituted, where each R 12a Independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )alkyl-(C 1 -C 3 ) alkoxy, halogen, NH 2 OH, (C 1 -C 6) haloalkyl, NH-(C 1 -C 6 ) alkyl, N((C 1 -C 6 )alkyl) 2 , (C 3 -C 6 ) a carbocyclic group or a 4- to 6-membered heterocyclic group;

[0192] m is 0, 1, or 2; and

[0193] o is either 0 or 1.

[0194] In some embodiments, Z is O. In some embodiments, Z is CH 2 .

[0195] In some embodiments, Y is CH 2 In some embodiments, Y is O. In some embodiments, Y is NH.

[0196] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0197] In some embodiments, R 1 and R 2 Each is H. In some embodiments, R 1 and R 2 In some embodiments, R 1 and R 2 Each is F.

[0198] In some embodiments, R 3 In some embodiments, R 3 It is Cl.

[0199] In some embodiments, X 1 It is N.

[0200] In some embodiments, X 2 It is CH.

[0201] In some embodiments, Z is O and Y is CH 2 In some embodiments, Z is O and Y is O. In some embodiments, Z is O and Y is NH. In some embodiments, Z is CH 2 , and Y is CH 2 In some embodiments, Z is CH 2 , and Y is O. In some embodiments, Z is CH 2 , and Y is NH.

[0202] In some embodiments, Z is O and Y is CH 2 , and n is 1. In some embodiments, Z is O, Y is O, and n is 1. In some embodiments, Z is O, Y is NH, and n is 1. In some embodiments, Z is CH 2 , Y is CH 2 , and n is 1. In some embodiments, Z is CH 2 , Y is O, and n is 1. In some embodiments, Z is CH 2 , Y is NH, and n is 1.

[0203] In some embodiments, Z is O and Y is CH 2 , n is 1, and R 1 and R 2 are each H or F. In some embodiments, Z is O, Y is O, n is 1, and R 1 and R 2 are each H or F. In some embodiments, Z is O, Y is NH, n is 1, and R 1 and R 2 Each is H or F. In some embodiments, Z is CH 2 , Y is CH 2 , n is 1, and R 1 and R 2 Each is H or F. In some embodiments, Z is CH 2 , Y is O, n is 1, and R 1 and R 2 Each is H or F. In some embodiments, Z is CH 2 , Y is NH, n is 1, and R 1 and R 2 Each is H or F.

[0204] In some embodiments, Z is O and Y is CH 2 , n is 1, R 1 and R 2 Each is H or F, and R 3 In some embodiments, Z is O, Y is O, n is 1, R 1 and R 2 Each is H or F, and R 3 In some embodiments, Z is O, Y is NH, n is 1, R 1 and R 2 Each is H or F, and R 3 In some embodiments, Z is CH 2 , Y is CH 2 , n is 1, R 1 and R2 Each is H or F, and R 3 In some embodiments, Z is CH 2 , Y is O, n is 1, R 1 and R 2 Each is H or F, and R 3 In some embodiments, Z is CH 2 , Y is NH, n is 1, R 1 and R 2 Each is H or F, and R 3 It is Cl.

[0205] In some embodiments, Z is O and Y is CH 2 , n is 1, R 1 and R 2 Each is H or F, R 3 is Cl, and X 1 and X 2 are independently N or CH. In some embodiments, Z is O, Y is O, n is 1, R 1 and R 2 Each is H or F, R 3 is Cl, and X 1 and X 2 are independently N or CH. In some embodiments, Z is O, Y is NH, n is 1, R 1 and R 2 Each is H or F, R 3 is Cl, and X 1 and X 2 is independently N or CH. In some embodiments, Z is CH 2 , Y is CH 2 , n is 1, R 1 and R 2 Each is H or F, R 3 is Cl, and X 1 and X 2 is independently N or CH. In some embodiments, Z is CH 2 , Y is O, n is 1, R 1 and R 2 Each is H or F, R 3 is Cl, and X 1 and X 2 is independently N or CH. In some embodiments, Z is CH 2 , Y is NH, n is 1, R 1 and R 2 Each is H or F, R 3 is Cl, and X 1 and X 2are independently N or CH.

[0206] In some embodiments, the compounds of the present disclosure are represented by any of Formulas (Ia-If):

[0207]

[0208] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0209] In some embodiments, the compounds of the present disclosure are represented by any of the following formulas:

[0210]

[0211]

[0212] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0213] In some embodiments, A is And the compound of formula (I) has the structure of formula I-1, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0214] In some embodiments of Formula I-1, R 5 is optionally substituted (C 1 -C 6 In some embodiments of Formula I-1, R 5 It's methyl.

[0215] In some embodiments of Formula I-1, X 3 It is CH.

[0216] In some embodiments of Formula I-1, R 6 Yes – L 1 CR 14 R 15 R 16 In some embodiments of Formula I-1, L 1 Yes-O-(C 1 -C 4 ) alkylene. In some embodiments of Formula I-1, L 1 Yes-O-(C 1 ) alkylene. In some embodiments of Formula I-1, R 14 and R 15 Together with the same carbon atom to which they are attached, they form C=O. In some embodiments of Formula I-1, R 16 It is methyl, OH, NH 2 Or NHMe. In some embodiments of Formula I-1, R16 It's NHMe.

[0217] In some embodiments of Formula I-1, R 5 Yes (C 1 -C 6 ) alkyl, X 3 is CH, and R 6 Yes – L 1 CR 14 R 15 R 16 , where L 1 Yes-O-(C 1 -C 4 ) alkylene, R 14 and R 15 Together with the same carbon atom to which they are attached, they form C=O, and R 16 It is methyl, OH, NH 2 or NHMe.

[0218] In some embodiments, the compound of formula I-1 is a compound of formula I-1a,

[0219] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0220] In some embodiments, the compound of formula I-1a is a compound of formula I-1a1 or I-1ab,

[0221]

[0222] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0223] In some embodiments, A is And the compound of formula (I) has the structure of formula I-2, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0224] In some embodiments of Formula I-2, R 5 is optionally substituted (C 1 -C 6 ) alkyl. In some embodiments of Formula I-2, R 5 It's methyl.

[0225] In some embodiments of Formula I-2, R 7 Yes – (CH 2 ) 1-3 W 1 W 2 In some embodiments of Formula I-2, R 7 Yes – (CH 2 ) 2W 1 W 2 In some embodiments of Formula I-2, W 1 Yes CR 19 R19'. In some embodiments of Formula I-2, R 19 and R 19’ In some embodiments of Formula I-2, W 2 is CN, OH or NH 2 In some embodiments of Formula I-2, W 2 is OH. In some embodiments of Formula I-2, R 7 is H. In some embodiments of Formula I-2, R 7 It's methyl.

[0226] In some embodiments of Formula I-2, R 7 Yes – (CH 2 ) 1-2 W 1 W 2 In some embodiments of Formula I-2, W 1 Yes CR 19 R 19’ In some embodiments of Formula I-2, R 19 and R 19’ is independently H, OH or methyl. In some embodiments of Formula I-2, W 2 Yes CR 20 R 21 R 22 In some embodiments of Formula I-2, R 20 and R 21 Both are H, and R 22 is OH. In some embodiments of Formula I-2, R 20 and R 21 are methyl groups, and R 22 is OH. In some embodiments of Formula I-2, R 20 and R 21 Both are H, and R 22 It is S(O)(NH)-(C 1 -C 2 ) alkyl. In some embodiments of Formula I-2, R 20 and R 21 Together with the carbon atom to which they are attached, they form a 4- to 6-membered heterocyclic group, optionally substituted by one or more substituents selected from the group consisting of: (C 1 -C 2 ) alkyl, halogen, (C 1 -C 2 ) haloalkyl, (C 1 -C2 ) haloalkoxy, (C 1 -C 2 ) alkoxy, (C 1 -C 2 ) alkylamino, NH 2 , CN and OH, and R 22 It's OH.

[0227] In some embodiments of Formula I-2, R 5 Yes (C 1 -C 6) Alkyl, and R 7 Yes – (CH 2 ) 1-3 W 1 W 2 In some embodiments of Formula I-2, R 5 is a methyl group, and R 7 Yes – (CH 2 ) 2 W 1 W 2 , where W 1 Yes CR 19 R 19’ , where R 19 and R 19’ are all methyl groups, and W 2 is CN, OH or NH 2 .

[0228] In some embodiments of Formula I-2, R 5 Yes (C 1 -C 6 ) alkyl, and R 7 is H. In some embodiments of Formula I-2, R 5 is a methyl group, and R 7 It's H.

[0229] In some embodiments of Formula I-2, R 5 Yes (C 1 -C 6 ) alkyl, and R 7 In some embodiments of Formula I-2, R 5 is a methyl group, and R 7 It's methyl.

[0230] In some embodiments of Formula I-2, R 5 Yes (C 1 -C 6 ) alkyl, and R 7 Yes – (CH 2 ) 1-2 W 1 W2 , where W 1 Yes CR 19 R 19’ , and W 2 Yes CR 20 R 21 R 22 In some embodiments of Formula I-2, R 19 and R 19’ is independently H, OH or methyl. In some embodiments of Formula I-2, R 20 and R 21 Both are H, and R 22 is OH. In some embodiments of Formula I-2, R 20 and R 21 are methyl groups, and R 22 is OH. In some embodiments of Formula I-2, R 20 and R 21 Both are H, and R 22 It is S(O)(NH)-(C 1 -C 2 ) alkyl. In some embodiments of Formula I-2, R 20 and R 21 Together with the carbon atom to which they are attached, they form a 4- to 6-membered heterocyclic group, optionally substituted by one or more substituents selected from the group consisting of: (C 1 -C 2 ) alkyl, halogen, (C 1 -C 2 ) haloalkyl, (C 1 -C 2 ) haloalkoxy, (C 1 -C 2 ) alkoxy, (C 1 -C 2 ) alkylamino, NH 2 , CN and OH, and R 22 It's OH.

[0231] In some embodiments, the compound of formula I-2 is a compound of formula I-2a,

[0232] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0233] In some embodiments, the compound of formula I-2a is a compound of formula I-2a1 or I-2a2,

[0234]

[0235] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0236] In some embodiments, the compound of formula I-2 is a compound of formula I-2b,

[0237] or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound of formula I-2b is a compound of formula I-2b1 or I-2b2,

[0238] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0239] In some embodiments, the compound of formula I-2 is a compound of formula I-2c,

[0240] or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound of formula I-2c is a compound of formula I-2c1 or I-2c2,

[0241] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0242] In some embodiments, A is And the compound of formula (I) has the structure of formula I-3, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0243] In some embodiments of Formula I-3, R 5 is optionally substituted (C 1 -C 6 ) alkyl. In some embodiments of Formula I-3, R 5 It's methyl.

[0244] In some embodiments of Formula I-3, R 8 Yes (C 3 -C 6 )cycloalkyl, and R 8’ is H. In some embodiments of Formula I-3, R 8 is cyclopropyl, and R 8’ It's H.

[0245] In some embodiments of formula I-3, A' is a 7-membered heterocyclyl, wherein the heterocyclyl contains 2 heteroatoms selected from N and O, and in addition to R 8 and R 8 ', which is further substituted by one or more substituents independently selected from the following: oxo, (C 1 -C 2 )alkyl, cyclopropyl, spirocyclopropyl, halogen, (C 1 -C 2 ) haloalkyl, (C1 -C 2 ) alkoxy, NH 2 , CN and OH.

[0246] In some embodiments of Formula I-3, R 5 Yes (C 1 -C 6 ) alkyl, R 8 Yes (C 3 -C 6 ) cycloalkyl, R 8 ' is H, and A' is a 7-membered heterocyclic group, wherein the heterocyclic group contains 2 heteroatoms selected from N and O, and except for R 8 and R 8 ', which is optionally further substituted by one or more substituents independently selected from the following: oxo, (C 1 -C 2 )alkyl, cyclopropyl, spirocyclopropyl, halogen, (C 1 -C 2 ) haloalkyl, (C 1 -C 2 ) alkoxy, NH 2 , CN and OH.

[0247] In some embodiments, the compound of formula I-3 is a compound of formula I-3a,

[0248] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0249] In some embodiments, the compound of formula I-3a is a compound of formula I-3a1 or I-3a2,

[0250]

[0251] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0252] In some embodiments, A is And the compound of formula (I) has the structure of formula I-4, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0253] In some embodiments of Formula I-4, R 5 is optionally substituted (C 1 -C 6 In some embodiments of Formula I-4, R 5 It's methyl.

[0254] In some embodiments of Formula I-4, X 4 In some embodiments of Formula I-4, X4 It's NH.

[0255] In some embodiments, A is And the compound of formula (I) has the structure of formula I-5, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0256] In some embodiments of Formula I-5, R 5 is a 4-membered heterocyclic group or a 4-membered heterocyclic group (C 2 ) alkyl; wherein the alkyl, carbocyclic or heterocyclic group is further optionally substituted by one or more identical or different R 13 In some embodiments of Formula I-5, R 2 is a 4-membered heterocyclic group or a 4-membered heterocyclic group (C 2 )alkyl, wherein the heterocyclic group contains 1 heteroatom selected from N and O.

[0257] In some embodiments of Formula I-5, R 2 Yes (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl-OH, (C 1 -C 6 )alkyl-NH(C 1 -C 6 ) alkyl or (C 1 -C 6 )alkyl-N((C 1 -C 6 )alkyl) 2 .

[0258] In some embodiments of Formula I-5, R 6 Yes – L 1 CR 14 R 15 R 16 In some embodiments of Formula I-5, L 1 Yes-O-(C 1 -C 4 ) alkylene. In some embodiments of Formula I-5, L 1 Yes-O-(C 1 ) alkylene. In some embodiments of Formula I-5, R 14 and R 15 Together with the same carbon atom to which they are attached, they form C=O. In some embodiments of Formula I-5, R 16 It is methyl, OH, NH 2 Or NHMe. In some embodiments of Formula I-5, R 16 It's NHMe.

[0259] In some embodiments, A is And the compound of formula (I) has the structure of formula I-6, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0260] In some embodiments of Formula I-6, R 5 is optionally substituted (C 1 -C 6 ) alkyl. In some embodiments of Formula I-6, R 5 It's methyl.

[0261] In some embodiments of Formula 1-6, m is 0.

[0262] In some embodiments of Formula 1-6, m is 1.

[0263] In some embodiments of Formula I-6, X 5 Does not exist.

[0264] In some embodiments of Formula 1-6, o is 0.

[0265] In some embodiments of Formula 1-6, o is 1.

[0266] In some embodiments of Formula I-6, R 10 and R 11 Each is H, and R 10 ' and R 11 'Together with the carbon atom to which they are attached, they form a cyclobutyl group.

[0267] In some embodiments of Formula I-6, R 12 It's OH.

[0268] In some embodiments of Formula I-6, R 5 Yes (C 1 -C 6 ) alkyl, m is 1, X 5 does not exist, o is 1, R 10 and R 11 Each is H, and R 10 ' and R 11 ' together with the carbon atom to which they are attached form a cyclobutyl group, and R 12 It's OH.

[0269] In some embodiments of Formula I-6, R 5 Yes (C 1 -C 6 ) alkyl, m is 0, X 5 does not exist, o is 0, and R 12 It's H.

[0270] In some embodiments, the compound of formula I-6 is a compound of formula I-6a,

[0271] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0272] In some embodiments, the compound of formula I-6a is a compound of formula I-6a1 or I-6a2,

[0273]

[0274] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0275] In some embodiments, the compound of formula I-6 is a compound of formula I-6b,

[0276] or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound of formula I-6b is a compound of formula I-6b1 or I-6b2,

[0277] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0278] In some embodiments of formula I-1a to I-6b, Z is O. In some embodiments of formula I-1a to I-6b, Z is CH 2 .

[0279] In some embodiments of Formulas I-1a to I-6b, Y is CH 2 In some embodiments of formulae I-1a to I-6b, Y is O. In some embodiments, Y is NH.

[0280] In some embodiments of formulas 1-1a to 1-6b, n is 0. In some embodiments of formulas 1-1a to 1-6b, n is 1. In some embodiments of formulas 1-1a to 1-6b, n is 2.

[0281] In some embodiments of Formulas I-1a to I-6b, R 1 and R 2 Each is H. In some embodiments of Formulas I-1a to I-6b, R 1 and R 2 In some embodiments of Formulas I-1a to I-6b, R 1 and R 2 Each is F.

[0282] In some embodiments of Formulas I-1a to I-6b, R 3In some embodiments of Formulas I-1a to I-6b, R 3 is Cl. In some embodiments of Formulas I-1a to I-6b, R 3 It's F.

[0283] In some embodiments of Formulas I-1a to I-6b, X 1 It is N.

[0284] In some embodiments of Formulas I-1a to I-6b, X 2 It is CH.

[0285] In some embodiments of Formulae I-1a to I-6b, Z is O, and Y is CH 2 In some embodiments of formulas I-1a to I-6b, Z is O and Y is O. In some embodiments of formulas I-1a to I-6b, Z is O and Y is NH. In some embodiments of formulas I-1a to I-6b, Z is CH 2 , and Y is CH 2 In some embodiments of Formulae I-1a to I-6b, Z is CH 2 , and Y is O. In some embodiments of Formulas I-1a to I-6b, Z is CH 2 , and Y is NH.

[0286] In some embodiments of Formulae I-1a to I-6b, Z is O, Y is CH 2 , and n is 1. In some embodiments of formulas I-1a to I-6b, Z is O, Y is O, and n is 1. In some embodiments of formulas I-1a to I-6b, Z is O, Y is NH, and n is 1. In some embodiments of formulas I-1a to I-6b, Z is CH 2 , Y is CH 2 , and n is 1. In some embodiments of Formulas I-1a to I-6b, Z is CH 2 , Y is O, and n is 1. In some embodiments of Formulas I-1a to I-6b, Z is CH 2 , Y is NH, and n is 1.

[0287] In some embodiments of Formulae I-1a to I-6b, Z is O, Y is CH 2 , n is 1, and R 1 and R 2 are each H or F. In some embodiments of Formulas I-1a to I-6b, Z is O, Y is O, n is 1, and R 1 and R 2are each H or F. In some embodiments of Formulas I-1a to I-6b, Z is O, Y is NH, n is 1, and R 1 and R 2 Each is H or F. In some embodiments of Formulas I-1a to I-6b, Z is CH 2 , Y is CH 2 , n is 1, and R 1 and R 2 Each is H or F. In some embodiments of Formulas I-1a to I-6b, Z is CH 2 , Y is O, n is 1, and R 1 and R 2 Each is H or F. In some embodiments of Formulas I-1a to I-6b, Z is CH 2 , Y is O, n is 1, and R 1 and R 2 Each is H or F. In some embodiments of Formulas I-1a to I-6b, Z is CH 2 , Y is NH, n is 1, and R 1 and R 2 Each is H or F.

[0288] In some embodiments of Formulae I-1a to I-6b, Z is O, Y is CH 2 , n is 1, R 1 and R 2 Each is H or F, and R 3 is Cl or F. In some embodiments of Formulas I-1a to I-6b, Z is O, Y is O, n is 1, R 1 and R 2 Each is H or F, and R 3 is Cl or F. In some embodiments of Formulas I-1a to I-6b, Z is O, Y is NH, n is 1, R 1 and R 2 Each is H or F, and R 3 is Cl or F. In some embodiments of Formulas I-1a to I-6b, Z is CH 2 , Y is CH 2 , n is 1, R 1 and R 2 Each is H or F, and R 3 is Cl or F. In some embodiments of Formulas I-1a to I-6b, Z is CH 2 , Y is O, n is 1, R 1 and R 2 Each is H or F, and R 3 is Cl or F. In some embodiments of Formulas I-1a to I-6b, Z is CH 2, Y is NH, n is 1, R 1 and R 2 Each is H or F, and R 3 It is Cl or F.

[0289] In some embodiments of Formulae I-1a to I-6b, Z is O, Y is CH 2 , n is 1, R 1 and R 2 Each is H or F, R 3 is Cl or F, and X 1 and X 2 are independently N or CH. In some embodiments of Formulas I-1a to I-6b, Z is O, Y is O, n is 1, R 1 and R 2 Each is H or F, R 3 is Cl or F, and X 1 and X 2 are independently N or CH. In some embodiments of Formulas I-1a to I-6b, Z is O, Y is NH, n is 1, R 1 and R 2 Each is H or F, R 3 is Cl or F, and X 1 and X 2 is independently N or CH. In some embodiments of Formulas I-1a to I-6b, Z is CH 2 , Y is CH 2 , n is 1, R 1 and R 2 Each is H or F, R 3 is Cl or F, and X 1 and X 2 is independently N or CH. In some embodiments of Formulas I-1a to I-6b, Z is CH 2 , Y is O, n is 1, R 1 and R 2 Each is H or F, R 3 is Cl or F, and X 1 and X 2 is independently N or CH. In some embodiments of Formulas I-1a to I-6b, Z is CH 2 , Y is NH, n is 1, R 1 and R 2 Each is H or F, R 3 is Cl or F, and X 1 and X 2 are independently N or CH.

[0290] In some embodiments, the compounds of the present disclosure are represented by any of the following structures:

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0298] The compounds of the present disclosure may be free acids or free bases, or pharmaceutically acceptable salt forms. Pharmaceutically acceptable salts of compounds of the present disclosure may be formed, for example, by reacting the appropriate free base of the compounds of the present invention with an appropriate pharmaceutically acceptable acid in a suitable solvent under standard conditions well known in the art. See, for example, Gould, PL, "Salt selection for basic drugs," International Journal of Pharmaceutics, 33: 201-217 (1986); Bastin, RJ, et al., "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4: 427-435 (2000); and Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66: 1-19 (1977).

[0299] The compounds of the present disclosure may have at least one chiral center and may therefore be in the form of stereoisomers, which, as used herein, encompass all isomers of a single compound that differ only in the orientation of its atoms in space. The term stereoisomer includes mirror image isomers (including enantiomers of the (R-) or (S-) configuration of the compound), mirror image isomer mixtures of the compound (physical mixtures of enantiomers, as well as racemates or racemic mixtures), geometric (cis / trans or E / Z, R / S) isomers of the compound, and isomers (diastereomers) of compounds that are not mirror images of each other and have more than one chiral center. The chiral center of the compound may undergo epimerization in vivo; therefore, for these compounds, administering the compound in its (R-) form is considered equivalent to administering the compound in its (S-) form. Therefore, the compounds of the present disclosure may be prepared and used in the form of a single isomer and substantially free of other isomers, or in the form of a mixture of various isomers (e.g., a racemic mixture of stereoisomers) and used.

[0300] In some embodiments, the compound of formula (I) is an isotopic derivative because it has at least one desired atomic isotope substituted in an amount greater than the natural abundance of the isotope, i.e., enriched. In one embodiment, the compound includes one or more deuterium atoms. As used herein, the term "hydrogen", i.e., H, refers to all isotopes of hydrogen, including protium ( 1 H) and deuterium ( 2 H). As used herein, the term "compound" encompasses isotopic derivatives.

[0301] The compound of formula (I) may also be in the form of N-oxides, crystalline forms (also referred to as polymorphs), co-crystals, active metabolites of compounds having the same type of activity, prodrugs, tautomers, and non-solvated forms of the compound and solvated forms (e.g., hydrates) with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.). As used herein, the term "compound" encompasses all of these forms.

[0302] The compound of formula (I) can be prepared by crystallization under different conditions, and can exist in the form of a polymorph or a combination of multiple polymorphs of the compound. For example, different solvents or different solvent mixtures can be used for recrystallization, by crystallization at different temperatures, or by using various cooling modes (from very fast to very slow cooling during the crystallization process), to identify and / or prepare different polymorphs. It is also possible to obtain polymorphs by heating or melting the compound, followed by gradual or rapid cooling. The presence of polymorphs can be determined by solid probe NMR spectrum, IR spectrum, differential scanning calorimetry, powder X-ray diffraction pattern and / or other known technologies.

[0303] In some embodiments, the pharmaceutical composition comprises a co-crystal of a compound of formula (I). As used herein, the term "co-crystal" refers to a stoichiometric multi-component system comprising a compound of formula (I) and a co-crystal former, wherein the compound of formula (I) and the co-crystal former are linked by non-covalent interactions. As used herein, the term "co-crystal former" refers to a compound that is capable of forming intermolecular interactions with a compound of formula (I) and co-crystalizing therewith. Representative examples of co-crystal formers include benzoic acid, succinic acid, fumaric acid, glutaric acid, trans-cinnamic acid, 2,5-dihydroxybenzoic acid, glycolic acid, trans-2-hexanoic acid, 2-hydroxyhexanoic acid, lactic acid, sorbic acid, tartaric acid, ferulic acid, suberic acid, picolinic acid, salicylic acid, maleic acid, saccharin, 4,4'-bipyridyl para-aminosalicylic acid, nicotinamide, urea, isonicotinamide, methyl 4-hydroxybenzoate, adipic acid, terephthalic acid, resorcinol, pyrogallol, phloroglucinol, hydroxyquinoline, isoniazid, theophylline, adenine, theobromine, phenacetin, phenazone, ethoylline, and phenobarbital.

[0304] Synthesis method

[0305] On the other hand, the present disclosure relates to a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof. In a broad sense, a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof can be prepared by any method known to be suitable for preparing chemically related compounds. The compound of formula (I) will be better understood in conjunction with the synthetic schemes described in the various working examples, which illustrate non-limiting methods for preparing compounds of formula (I).

[0306] Pharmaceutical composition

[0307] Another aspect of the present disclosure relates to a pharmaceutical composition, which includes a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier. As known in the art, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or solvent suitable for administering a compound of the present disclosure to a mammal. Suitable carriers may include, for example, liquids (aqueous and non-aqueous, and combinations thereof), solids, encapsulating materials, gases and combinations thereof (e.g., semisolids) and gases, the function of which is to carry or transport a compound from one organ or body part to another organ or body part. Carriers are "acceptable" in the sense that they are physiologically inert and compatible with other ingredients in the preparation and harmless to a subject or patient. Depending on the type of preparation, the composition may also include one or more pharmaceutically acceptable excipients.

[0308] In a broad sense, the compounds of formula (I) and pharmaceutically acceptable salts and stereoisomers thereof can be formulated into a given type of composition according to conventional pharmaceutical practice, such as conventional mixing, dissolving, granulating, dragee making, levigating, emulsifying, encapsulating, entrapping and compression processes (see, for example, Remington: The Science and Practice of Pharmacy (20th ed.), ed. A. R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York). The type of formulation depends on the mode of administration, which can include enteral (e.g., oral, buccal, sublingual, and rectal), parenteral (e.g., subcutaneous (sc), intravenous (iv), intramuscular (im), and intrasternal injection, or infusion techniques, intraocular, intraarterial, intramedullary, intrathecal, intraventricular, transdermal, intradermal, intravaginal, intraperitoneal, mucosal, nasal, intratracheal instillation, bronchial instillation, and inhalation), and topical (e.g., transdermal). In general, the most appropriate route of administration will depend on a variety of factors, including, for example, the nature of the agent (e.g., its stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). For example, parenteral (e.g., intravenous) administration may also have advantages because the compound can be administered relatively quickly, such as in the case of single-dose treatment and / or acute conditions.

[0309] In some embodiments, the compounds of Formula (I) are formulated for oral or intravenous administration (eg, systemic intravenous injection).

[0310] Thus, the compounds of formula (I) can be formulated into solid compositions (e.g., powders, tablets, dispersible particles, capsules, cachets, and suppositories), liquid compositions (e.g., solutions of dissolved compounds, suspensions of dispersed solid particles of compounds, emulsions, and solutions containing liposomes, micelles or nanoparticles, syrups, and elixirs); semisolid compositions (e.g., gels, suspensions, and creams); and gases (e.g., propellants for aerosol compositions). The compounds can also be formulated for rapid, intermediate, or extended release.

[0311] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with a carrier (e.g., sodium citrate or dicalcium phosphate) and additional carriers or excipients such as a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrants such as cross-linked polymers (e.g., cross-linked polyvinylpyrrolidone (crospovidone), cross-linked carboxymethylcellulose sodium (croscarmellose sodium (croscarmellose sodium (croscarmellose sodium (croscarmellose sodium (croscarmellose sodium (croscarmellose sodium (croscarmellose sodium (croscarmellose sodium (croscarmellose sodium (croscarmellose sodium (croscarmellose sodium (croscarmellose sodium (croscarmellose sodium ( The invention relates to a pharmaceutical composition comprising a pharmaceutical composition comprising a pharmaceutically acceptable salt of a pharmaceutically acceptable salt and a pharmaceutically acceptable salt thereof. The pharmaceutical composition comprises a pharmaceutically acceptable salt of a pharmaceutically acceptable salt and a pharmaceutically acceptable salt thereof. The pharmaceutical composition comprises a pharmaceutically acceptable salt of a pharmaceutically acceptable salt and a pharmaceutically acceptable salt thereof. The pharmaceutical composition comprises a pharmaceutically acceptable salt and a pharmaceutically acceptable salt thereof. The pharmaceutical composition comprises a pharmaceutically acceptable salt and a pharmaceutically acceptable salt thereof. The pharmaceutical composition comprises a pharmaceutically acceptable salt and a pharmaceutically acceptable salt thereof. The pharmaceutical composition comprises a pharmaceutically acceptable salt and a pharmaceutically acceptable salt thereof. The pharmaceutical composition comprises a pharmaceutically acceptable salt and a pharmaceutically acceptable salt thereof. The pharmaceutical composition comprises a pharmaceutically acceptable salt and a pharmaceutically acceptable salt thereof. The pharmaceutical composition comprises a pharmaceutically acceptable salt and a pharmaceutically acceptable salt thereof.

[0312] In some embodiments, the compound of formula (I) can be formulated in a hard or soft gelatin capsule. Representative excipients that can be used include pregelatinized starch, magnesium stearate, mannitol, sodium stearyl fumarate, anhydrous lactose, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose. The gelatin shell can include gelatin, titanium dioxide, iron oxide, and a colorant.

[0313] Liquid dosage forms for oral administration include solutions, suspensions, emulsions, microemulsions, syrups and elixirs. In addition to compounds, liquid dosage forms can contain aqueous or non-aqueous carriers commonly used in the art (depending on the solubility of the compound), such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oil (especially, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitol and mixtures thereof. Oral compositions can also include adjuvants, such as wetting agents, suspending agents, coloring agents, sweeteners, flavoring agents and aromatics.

[0314] Injectable preparations for parenteral administration may include sterile aqueous solutions or oily suspensions. They may be formulated using suitable dispersants or wetting agents and suspending agents according to standard techniques. Sterile injectable preparations may also be sterile injectable solutions, suspensions or emulsions in nontoxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile fixed oils are generally used as solvents or suspension media. For this purpose, any mild fixed oil may be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids (e.g., oleic acid) are used to prepare injections. Injectable preparations may be sterilized, for example, by filtration through a bacterial retention filter, or by incorporation of a sterilizing agent in the form of a sterile solid composition that may be dissolved or dispersed in sterile water or other sterile injection media prior to use. The effect of the compound may be prolonged by slowing absorption, which may be achieved by using a liquid suspension or a crystalline or amorphous material with poor water solubility. Prolonged absorption of a compound from a parenterally administered formulation may also be accomplished by suspending the compound in an oil vehicle.

[0315] In certain embodiments, the compound of formula (I) can be applied in a local manner rather than a systemic manner, for example, by injecting the conjugate directly into an organ, usually in the form of a depot preparation or a sustained-release preparation. In a specific embodiment, the long-acting preparation is applied by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. The injectable depot form is prepared by forming a microcapsule matrix of the compound in a biodegradable polymer (e.g., polylactic acid-polyglycolic acid, poly (orthoester) and poly (anhydride)). The release rate of the compound can be controlled by changing the ratio of the compound to the polymer and the properties of the specific polymer used. Depot injection preparations can also be prepared by encapsulating the compound in a liposome or microemulsion compatible with body tissues. In addition, in other embodiments, the compound is delivered with a targeted drug delivery system, for example, delivered with a liposome coated with an organ-specific antibody. In such embodiments, the liposome is targeted by the organ and selectively absorbed by the organ.

[0316] The composition may be formulated for buccal or sublingual administration, examples of which include tablets, lozenges, and gels.

[0317] The compound of formula (I) can be formulated for inhalation administration. Various forms suitable for inhalation administration include aerosols, sprays or powders. The pharmaceutical composition can be delivered from a pressurized package or atomizer in the form of an aerosol spray, using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In some embodiments, the dosage unit of a pressurized aerosol can be determined by providing a valve to deliver a metered amount. In some embodiments, capsules and cartridges (e.g., for inhalers or insufflators) comprising gelatin can be formulated, containing a powder mixture of the compound and a suitable powder base (e.g., lactose or starch).

[0318] The compounds of formula (I) may be formulated for topical administration, which as used herein means administration of the formulation intradermally to the epidermis. These types of compositions are typically in the form of ointments, pastes, creams, lotions, gels, solutions and sprays.

[0319] Representative examples of carriers for preparing compounds for topical use include solvents (e.g., alcohols, polyols, water), creams, lotions, ointments, oils, unguents, liposomes, powders, emulsions, microemulsions, and buffered solutions (e.g., hypotonic or buffered saline). For example, creams can be prepared using saturated or unsaturated fatty acids (e.g., stearic acid, palmitic acid, oleic acid, palmitoleic acid, hexadecyl or oleyl alcohol). Creams can also contain nonionic surfactants, such as polyoxy-40-stearate.

[0320] In some embodiments, topical preparations may also include adjuvants, examples of which are penetration enhancers. These agents can transport pharmacologically active compounds through the stratum corneum and into the epidermis or dermis, preferably with little or no systemic absorption. The effectiveness of various compounds in improving the permeability of drugs through the skin has been evaluated. See, for example, Percutaneous Penetration Enhancers, Maibach HI and Smith HE (eds.), CRC Press, Inc., Boca Raton, Fla. (1995), which studies the uses and tests of various skin penetration enhancers, and Buyuktimkin et al., Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal and Topical Drug Delivery Systems, Gosh TK, Pfister WR, Yum S.I. (Eds.), Interpharm Press Inc., Buffalo Grove, Ill. (1997). Representative examples of penetration enhancers include triglycerides (e.g., soybean oil), aloe compositions (e.g., aloe vera gel), ethanol, isopropyl alcohol, octylphenyl polyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decyl methyl sulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate), and N-methylpyrrolidone.

[0321] Representative examples of other adjuvants that can be included in topical and other types of preparations (to the extent that they are compatible) include preservatives, antioxidants, humectants, emollients, buffers, solubilizers, skin protectants and surfactants. Suitable preservatives include alcohols, quaternary amines, organic acids, parabens and phenol. Suitable antioxidants include ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol and chelating agents (such as EDTA and citric acid). Suitable humectants include glycerol, sorbitol, polyethylene glycol, urea and propylene glycol. Suitable buffers include citric acid, hydrochloric acid and lactic acid buffers. Suitable solubilizers include quaternary ammonium salts, cyclodextrins, benzyl benzoate, lecithin and polysorbate. Suitable skin protectants include vitamin E oil, allatoin, polydimethylsiloxane, glycerol, vaseline and zinc oxide.

[0322] Transdermal preparations usually adopt transdermal delivery devices and transdermal delivery patches, wherein the compound is prepared in a lipophilic emulsion or a buffered aqueous solution, dissolved and / or dispersed in a polymer or an adhesive. The patch can be used for continuous, pulsed or on-demand delivery of medicaments. The transdermal delivery of the compound can be achieved by the mode of an iontophoresis patch. The transdermal patch can provide the controlled delivery of the compound, wherein by using a rate-controlled membrane or by slowing down the absorption rate by trapping the compound in a polymer matrix or a gel. Absorption enhancers can be used to increase absorption, and examples thereof include absorbable pharmaceutically acceptable solvents that help to pass through the skin.

[0323] Ophthalmic preparations include eye drops.

[0324] Formulations for rectal administration include enemas, rectal gels, rectal foams, rectal aerosols and retention enemas, which may contain conventional suppository bases (e.g., cocoa butter or other glycerides), as well as synthetic polymers (e.g., polyvinyl pyrrolidone, PEG, etc.). Compositions for rectal or vaginal administration may also be formulated as suppositories, which may be prepared by mixing the compound with suitable non-irritating carriers and excipients, such as cocoa butter, fatty acid glyceride mixtures, polyethylene glycol, suppository waxes, and combinations thereof, all of which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compound.

[0325] dose

[0326] As used herein, the term "therapeutically effective amount" refers to an amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof that is effective in producing a desired therapeutic response in a specific patient suffering from a disease or condition mediated by abnormal BCL6 activity. Thus, the term "therapeutically effective amount" includes an amount of a compound or a pharmaceutically acceptable salt or stereoisomer thereof that, when administered, induces a positive change in the disease or condition to be treated, or is sufficient to prevent the development or progression of the disease or condition, or alleviates one or more symptoms of the disease or condition being treated by the subject to a certain extent, or simply kills or inhibits the growth of diseased (e.g., cancer) cells, or reduces the amount of BCL6 in diseased cells.

[0327] The total daily dose of the compound and its usage can be determined according to standard medical practice, for example, by the attending physician using reasonable medical judgment. The specific therapeutically effective dose for any particular subject can depend on a variety of factors, including the disease or condition being treated and its severity (e.g., its current state); the subject's age, weight, general health, sex and diet; the time of administration, route of administration and the excretion rate of the specific compound used; the duration of treatment; drugs used in combination or concomitantly with the compound; and similar factors well known in the medical field (see, for example, Goodman and Gilman's, The Pharmacological Basis of Therapeutics, 10th Edition, A. Gilman, J. Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173 (2001)).

[0328] How to use

[0329] In some aspects, the present disclosure relates to treating diseases or conditions involving (e.g., characterized by or mediated by) abnormal (e.g., elevated BCL6 levels or otherwise dysfunctional, e.g., dysregulated BCL6 levels) BCL6 activity relative to a non-pathological state. Such diseases and conditions include cancer and inflammatory diseases and conditions. The method requires administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof to a subject in need thereof.

[0330] As used herein, the term "subject" (or "patient") includes all members of the animal kingdom susceptible to or suffering from cancer. In some embodiments, the subject is a mammal, e.g., a human or non-human mammal. The method is also applicable to companion animals, such as dogs and cats. According to the present disclosure, a subject "in need of" treatment may "suffer or be suspected of having" a specific cancer, which may have been diagnosed, or otherwise exhibit a sufficient number of risk factors or a sufficient number or combination of signs or symptoms that a medical professional can diagnose or suspect that the subject has cancer. Therefore, subjects suffering from a specific disease or condition and subjects suspected of having a specific disease or condition are not necessarily two different groups.

[0331] In some embodiments, the method relates to treating a subject with cancer. The method includes treating adult tumors / cancers and pediatric tumors / cancers. The cancer can be a vascularized, or not substantially vascularized, or a non-vascularized tumor.

[0332] In some embodiments, the cancer is a lymphoid malignancy.

[0333] In some embodiments, the lymphoid malignancy is peripheral T-cell lymphoma (PTCL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia / lymphoma (ALL), or cutaneous T-cell lymphoma.

[0334] In some embodiments, the methods of the present disclosure entail treating a subject suffering from a cell proliferative disease or a hematological disorder.

[0335] In some embodiments, the method relates to treating a subject having an inflammatory disease or disorder.

[0336] In some embodiments, the inflammatory disease or condition is inflammatory bowel disease, myocarditis, endometriosis, atherosclerosis, an allergic disease or condition, or an autoimmune disease or condition. In some embodiments, the allergic disease or condition is asthma or hay fever. In some embodiments, the autoimmune disease is noninfectious meningitis, autoimmune encephalitis, transverse myelitis, or acute disseminated encephalomyelitis.

[0337] The compound of formula (I) can be used as a monotherapy or by a combination therapy to a cancer patient. Therapy can be a "frontline / first-line" therapy, that is, as the initial treatment for patients who have not received previous anticancer treatment regimens, used alone or in combination with other treatments; or "second-line" therapy, that is, as the treatment of patients who have received previous anticancer treatment regimens, used alone or in combination with other treatments; or as "third line", "fourth line" and other treatments, used alone or in combination with other treatments. Therapy can also be given to patients who have received previous treatments but have not been successful or partially successful but have become unresponsive or intolerant to a particular treatment. Therapy can also be given as an adjuvant therapy, i.e., for preventing the recurrence of cancer in patients who currently have no detectable disease or after surgical removal of the tumor. Therefore, in some embodiments, the compound can be administered to patients who have received another therapy (e.g., chemotherapy, radioimmunotherapy, surgical therapy, immunotherapy, radiotherapy, targeted therapy, or any combination thereof).

[0338] The method of the present disclosure may need to administer a compound of formula (I) or its pharmaceutical composition to a patient in a single dose or multiple doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 20 or more doses). For example, the frequency of administration may range from once a day to about once every eight weeks. In some embodiments, the frequency of administration ranges from about once a day for 1, 2, 3, 4, 5 or 6 weeks, and in other embodiments, at least one 28-day cycle is required, including daily administration for 3 weeks (21 days), followed by a 7-day "drug withdrawal" period. In other embodiments, the compound may be administered twice a day (BID) (a total of 5 doses) within a two-day time course, or administered once a day (QD) (a total of 2 doses) within a two-day time course. In other embodiments, the compound may be administered once a day (QD) within a 5-day time course.

[0339] Combination therapy

[0340] The compounds of formula (I) and pharmaceutically acceptable salts and stereoisomers thereof can be used in combination or simultaneously with at least one other active agent (e.g., an anticancer agent or regimen) to treat cancer. The terms "combined" and "simultaneously" herein mean co-administered agents, which include substantially simultaneous administration, in the same or separate dosage forms, and in the same or different modes of administration, or sequential administration, for example, as part of the same treatment regimen, or by a continuous treatment regimen. Thus, if sequential administration is used, at the start of administration of the second compound, in some cases, the first of the two compounds can still be detected at an effective concentration at the treatment site. The order and time interval can be determined so that they can act together (e.g., synergistically) to provide an increased benefit than if administered in other ways. For example, therapeutic agents can be administered sequentially in any order, simultaneously or at different time points; however, if not administered simultaneously, they can be administered at sufficiently close times to provide the desired therapeutic effect, which can be a synergistic manner. Therefore, these terms are not limited to administering the active agents at exactly the same time.

[0341] In some embodiments, the treatment regimen may include administering a compound of formula (I) in combination with one or more additional therapeutic agents known to treat cancer. The dosage of the additional therapeutic agent may be the same as or even lower than the known or suggested dosage. See, Hardman et al., eds., Goodman & Gilman's the Pharmacological Basis of Basis of Therapeutics, 10th ed., McGraw-Hill, New York, 2001; Physician's Desk Reference 60th ed., 2006. Anticancer agents suitable for use in combination with the compound are known in the art. See, for example, U.S. Pat. No. 9,101,622 (Section 5.2 thereof) and U.S. Pat. No. 9,345,705 B2 (Columns 12-18 thereof). Representative examples of additional anti-cancer agents and treatment regimens include radiation therapy, chemotherapy (e.g., mitotic inhibitors, angiogenesis inhibitors, anti-hormones, autophagy inhibitors, alkylating agents, intercalating antibiotics, growth factor inhibitors, anti-androgens, signal transduction pathway inhibitors, anti-microtubule agents, platinum coordination complexes, HDAC inhibitors, proteasome inhibitors, and topoisomerase inhibitors), immunomodulators, therapeutic antibodies (e.g., monospecific and bispecific antibodies), and CAR-T therapy.

[0342] In some embodiments, the compound of Formula (I) and the additional (e.g., anticancer) therapeutic agent can be taken at intervals of less than 5 minutes, less than 30 minutes, less than 1 hour, about 1 hour, about 1 to about 2 hours, about 2 hours to about 3 hours, about 3 hours to about 4 hours, about 4 hours to about 5 hours, about 5 hours to about 6 hours, about 6 hours to about 7 hours, about 7 hours to about 8 hours, about 8 hours to about 9 hours, about 9 hours to about 10 hours, about 10 hours to about 15 hours, about 15 hours to about 16 hours, about 17 hours to about 18 hours, about 19 hours to about 20 hours, about 21 hours to about 24 hours, about 25 hours to about 26 hours, about 27 hours to about 28 hours, about 29 hours to about 30 hours, about 31 hours to about 32 hours, about 30 hours to about 34 hours, about 31 hours to about 35 hours, about 31 hours to about 36 hours, about 31 hours to about 37 hours, about 31 hours to about 38 hours, about 31 hours to about 39 hours, about 32 hours to about 39 hours, about 33 hours to about 31 hours At about 10 hours intervals, at about 10 hours to about 11 hours intervals, at about 11 hours to about 12 hours intervals, at about 12 hours to 18 hours intervals, at 18 hours to 24 hours intervals, at 24 hours to 36 hours intervals, at 36 hours to 48 hours intervals, at 48 hours to 52 hours intervals, at 52 hours to 60 hours intervals, at 60 hours to 72 hours intervals, at 72 hours to 84 hours intervals, at 84 hours to 96 hours intervals, or at 96 hours to 120 hours intervals. Two or more (e.g., anticancer) therapeutic agents can be administered within the same patient visit.

[0343] When the active components in the combination are not administered in the same pharmaceutical composition, it will be understood that they can be administered to a subject in need thereof in any order. For example, a compound of the present disclosure can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior to), concurrently with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) administering an additional therapeutic agent to a subject in need thereof. In various aspects, the therapeutic agents are administered at 1 minute intervals, 10 minute intervals, 30 minute intervals, less than 1 hour intervals, 1 hour intervals, 1 to 2 hours intervals, 2 to 3 hours intervals, 3 to 4 hours intervals, 4 to 5 hours intervals, 5 to 6 hours intervals, 6 to 7 hours intervals, 7 to 8 hours intervals, 8 to 9 hours intervals, 9 to 10 hours intervals, 10 to 11 hours intervals, 11 to 12 hours intervals, no more than 24 hours intervals, or no more than 48 hours intervals. In one example, the (e.g., anticancer) therapeutic agents are administered within the same visit. In another example, the combination anticancer therapeutic agent can be administered at 1 minute to 24 hours intervals.

[0344] In some embodiments, the compound of formula (I) and the additional anticancer agent or therapeutic agent are administered in cycles. Cyclic therapy involves administering an anticancer therapy over a period of time, followed by administering a second anticancer therapy over a period of time and repeating this sequential administration, i.e., cycles, to reduce resistance to one or both anticancer therapies, avoid or reduce the side effects of one or both anticancer therapies, and / or improve the efficacy of the therapy. In one example, cyclic therapy involves administering a first anticancer therapeutic agent for a period of time, followed by administering a second anticancer therapeutic agent for a period of time, optionally, followed by administering a third anticancer therapeutic agent for a period of time, etc., and repeating this sequential administration, i.e., cycles, to reduce resistance to one of the anticancer therapeutic agents, avoid or reduce the side effects of one of the anticancer therapeutic agents, and / or improve the efficacy of the anticancer therapeutic agent.

[0345] In some embodiments, the compounds of the present disclosure can be used in combination with other anticancer agents, examples of which include etoposide (e.g., lymphoma and non-lymphocytic leukemia), vincristine (e.g., leukemia), daunorubicin (e.g., acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), and Kaposi's sarcoma), rituximab (e.g., non-Hodgkin's lymphoma), alemtuzumab (e.g., chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL), and T-cell lymphoma), bortezomib (e.g., multiple myeloma and mantle cell lymphoma), pegaspargase (e.g., acute lymphoblastic leukemia), (e.g., Hodgkin lymphoma) and dexamethasone (e.g., acute multiple myeloma).

[0346] In some embodiments, the additional anticancer agent is an enhancer of zeste homolog 2 (EZH2) inhibitor, examples of which include tazemetostat, GSK126, lirametostat (CPI-1205), CPI-0209, PF-06821497, SHR2554, HH2853, valemetostat (DS3201), MAK-683, and FTX-6058.

[0347] These and other aspects of the present disclosure will be further understood in consideration of the following examples, which are intended to illustrate certain specific embodiments of the disclosure but are not intended to limit the scope thereof, as defined by the claims.

[0348] Example

[0349] Example 1: 2-(((1 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -Difluoro-1 5 ,4 1 -Dimethyl-4 2 -Oxo-4 1 ,4 2 -Dihydro- 5-Oxa-3-aza-4(6,8)-quinoline-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 3 -yl)oxy)-N-methylethyl Synthesis of amide (4)

[0350]

[0351] 2-(1-Benzyl-4,4-difluoro-5-methyl-3-piperidinyl)ethyl-4-methylbenzenesulfonate

[0352] To a solution of 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidinyl)ethanol (10 g, 37.13 mmol, 1 eq) in DCM (210 mL) was added 4-methylbenzenesulfonyl chloride (8.49 g, 44.56 mmol, 1.2 eq), DMAP (453.60 mg, 3.71 mmol, 0.1 eq) and TEA (7.51 g, 74.26 mmol, 10.34 mL, 2 eq). The mixture was stirred at 15 °C for 12 hours. After adding water (200 mL), the solution was extracted with DCM (300 mL×3) (combined with another batch of the same scale). The combined organic phase was washed with brine (300 mL) and dried over anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate in vacuo. Purify the residue by flash silica gel chromatography (silica gel flash column, 0-50% ethyl acetate / petroleum ether gradient eluent) to give the title compound as a yellow oil (22 g, 47.27 mmol, 64% yield, 91% purity). 1 H NMR (400 MHz, DMSO-d 6 )δppm 7.75(d,J=8.11Hz,2H),7.47(br d,J=7.87Hz,2H),7.24-7.37(m,5H),3.98-4.13(m,2H),3.37-3.54(m,2H),2.65-2.81(m,2H),2.39(s,3 H),1.97-2.03(m,1H),1.76-1.94(m,3H),1.38-1.49(m,1H),1.14-1.22(m,1H),0.84(d,J=6.68Hz,3H).

[0353] 3-(1-Benzyl-4,4-difluoro-5-methyl-3-piperidinyl)propionitrile

[0354] In N 2 To a mixture of 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidinyl)ethyl-4-methylbenzenesulfonate (22 g, 51.95 mmol, 1 eq) in DMSO (450 mL) was added NaCN (11.55 g, 235.68 mmol, 4.54 eq). The mixture was stirred at 50 °C for 4 h. The reaction mixture was cooled to 15 °C and heated with H 2 O (1000 mL), extracted with EtOAc (1000 mL×2), the combined organic phases were washed with brine (1000 mL), 2 SO 4Dry, filter and concentrate in vacuo. Purify the residue by flash silica gel chromatography (silica gel flash column, 0-50% ethyl acetate / petroleum ether gradient eluent) to give the title compound as a yellow oil (8 g, 25.29 mmol, 49% yield, 88% purity). 1 H NMR (400 MHz, DMSO-d 6 )δppm 7.21-7.40(m,5H),3.56-3.70(m,1H),3.41-3.52(m,1H),2.90-3.11(m,1H),2.67-2.79(m,1H),2.52-2. 63(m,2H),2.02-2.20(m,2H),1.78-1.98(m,3H),1.47(dq,J=14.38,7.37Hz,1H),0.88(d,J=6.79Hz,3H).

[0355] Methyl 3-(1-benzyl-4,4-difluoro-5-methyl-3-piperidinyl)propanoate

[0356] A mixture of 3-(1-benzyl-4,4-difluoro-5-methyl-3-piperidinyl)propionitrile (8 g, 28.74 mmol, 1 eq) in HCl / MeOH (160 mL) was stirred at 80 °C for 12 h. The mixture was concentrated in vacuo. To the residue was added saturated NaHCO 3 The aqueous solution (100 mL) was added to pH = 8, and then extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine (100 mL) and dried over anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate in vacuo. Purify the residue by flash silica gel chromatography (silica gel flash column, 0-50% ethyl acetate / petroleum ether gradient elution) to give the title compound as a yellow oil (4.9 g, 15.74 mmol, 55% yield). 1 H NMR (400 MHz, CDCl 3 )δppm 7.25-7.38(m,5H),3.66(s,3H),3.45-3.60(m,2H),2.82-2.91(m,1H),2.69-2.80(m,1H ),2.39(t,J=7.70Hz,2H),1.90-2.19(m,5H),1.48-1.61(m,1H),0.97(d,J=6.72Hz,3H).

[0357] 3-(1-Benzyl-4,4-difluoro-5-methyl-3-piperidinyl)propan-1-ol

[0358] In N 2To a mixture of methyl 3-(1-benzyl-4,4-difluoro-5-methyl-3-piperidinyl)propanoate (7.07 g, 22.71 mmol, 1 eq) in THF (70 mL) was slowly added LiAlH 4 (1.03 g, 27.25 mmol, 1.2 eq). The mixture was stirred at 15°C for 1 hour. Water (~1 mL) was added dropwise to the mixture at 15°C until no bubbles were generated. The mixture was washed with anhydrous Na 2 SO 4 (-20 g) was dried and stirred at 15° C. for 10 min. The mixture was then filtered and the filtrate was concentrated in vacuo to give the title compound as a colorless oil (4.9 g, 15.04 mmol, 66% yield, 87% purity). 1 H NMR (400 MHz, CDCl 3 )δppm 7.27-7.19(m,5H),3.56-3.38(m,4H),2.84-2.82(m,1H),2.65-2.62(m,1H),1.96-1.87( m,4H),1.75-1.65(m,1H),1.53-1.49(m,3H),1.20-1.16(m,1H),0.88(d,J=6.80Hz,3H).

[0359] 4,4-Difluoro-3-(3-hydroxypropyl)-5-methyl-piperidine-1-carboxylic acid tert-butyl ester

[0360] To a solution of 3-(1-benzyl-4,4-difluoro-5-methyl-3-piperidinyl)propan-1-ol (4.9 g, 17.29 mmol, 1 eq) in EtOH (50 mL) was added Pd / C (1 g, 10% purity) and Boc 2 O (7.55 g, 34.59 mmol, 7.95 mL, 2 eq). The suspension was degassed under vacuum and heated to 40 % by volume. 2 Purge several times. 2 The mixture was stirred at 60° C. under pressure (50 psi) for 12 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a grey oil (6.6 g, crude). 1 H NMR (400 MHz, CDCl 3 )δppm 4.22-3.95(m,3H),3.67-3.63(m,2H),2.57(s,2H),1.86-1.82(m,2H),1.66 -1.60(m,2H),1.47-1.45(m,9H),1.29-1.25(m,2H),1.00(d,J=6.40Hz,3H).

[0361] tert-Butyl 4,4-difluoro-3-methyl-5-[3-(p-toluenesulfonyloxy)propyl]piperidine-1-carboxylate

[0362] To a solution of tert-butyl 4,4-difluoro-3-(3-hydroxypropyl)-5-methyl-piperidine-1-carboxylate (6.6 g, 22.50 mmol, 1 eq) in DCM (70 mL) was added TEA (4.55 g, 45.00 mmol, 6.26 mL, 2 eq) and TsCl (4.29 g, 22.50 mmol, 1 eq) at 15 °C. The mixture was stirred at 15 °C for 12 hours. Water (100 mL) was added to the mixture, followed by extraction with DCM (100 mL×2). The combined organic phases were washed with brine (120 mL) and purified by anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate in vacuo. Purify the residue by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, petroleum ether / ethyl acetate = 10 / 1, 3 / 1) to give the title compound as a yellow oil (5.6 g, 12.30 mmol, 55% yield, 98% purity). 1 HNMR (400MHz, CDCl 3 )δppm 7.79(d,J=8.40Hz,2H),7.36(d,J=8.00Hz,2H),4.13-4.02(m,4H),2.56(br s,2H),2.46(s,3H),1.86-1.83(m,1H),1.75-1.70(m,4H),1.46(s,9H),1.28-1.23(m,1H),1.00(d,J=6.80Hz,3H).

[0363] (3R,5S)-4,4-difluoro-3-methyl-5-[3-(p-tolylsulfonyloxy)propyl]piperidine-1-carboxylic acid tert-butyl ester (10C) and (3S,5R)-4,4-difluoro-3-methyl-5-[3-(p-tolylsulfonyloxy)propyl]piperidine-1-carboxylic acid tert-butyl ester

[0364] Separation by SFC (column: DAICEL CHIRALPAKIC (250 mm*50 mm, 10 μm); mobile phase: [0.1% NH 3 H 2O IPA]; B%: 35%-35%, 4.5min) to separate tert-butyl 4,4-difluoro-3-methyl-5-[3-(toluenesulfonyloxy)propyl]piperidine-1-carboxylate (3 g, 6.70mmol, 1eq) to give tert-butyl (3R,5S)-4,4-difluoro-3-methyl-5-[3-(toluenesulfonyloxy)propyl]piperidine-1-carboxylate (1.3 g, 2.87mmol, 43% yield, 99% purity) as a colorless oil, and tert-butyl (3S,5R)-4,4-difluoro-3-methyl-5-[3-(toluenesulfonyloxy)propyl]piperidine-1-carboxylate (1.3 g, 2.84mmol, 42% yield, 98% purity) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 )δppm 7.79(d,J=8.11Hz,2H),7.35(br d,J=7.99Hz,2H),3.85-4.19(m,4H),2.35-2.75(m,5H),1.67-1.97(m,5H),1.46(s,9H),1.20-1.32(m,1H),0.96-1.04(m,3H). 1 H NMR (400 MHz, CDCl 3 )δppm 7.79(d,J=8.34Hz,2H),7.36(d,J=7.99Hz,2H),3.88-4.17(m,4H),2.48-2.68(m,2H),2.46(s,3H),1.85(br s,1H),1.63-1.80(m,4H),1.46(s,9H),1.18-1.32(m,1H),1.00(d,J=6.68Hz,3H).

[0365] (3R,5S)-4,4-difluoro-3-methyl-5-[3-[[1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-6-nitro-2-oxo-8-quinolyl]oxy]propyl]piperidine-1-carboxylic acid tert-butyl ester

[0366] To a mixture of 2-[(8-hydroxy-1-methyl-6-nitro-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide (100 mg, 325.46 mmol, 1 eq) and (3R,5S)-4,4-difluoro-3-methyl-5-[3-(p-toluenesulfonyloxy)propyl]piperidine-1-carboxylic acid tert-butyl ester (218.48 mg, 488.19 μmol, 1.5 eq) in DMF (1 mL) was added K 2 CO 3(89.96 mg, 650.92 mmol, 2 eq). Then, the reaction mixture was stirred at 60 °C for 12 h. 2 O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate in vacuo. Triturate the residue with (petroleum ether / ethyl acetate=1:1, 5 mL) at 15°C for 30 min to give the title compound as a white solid (200 mg, 83% purity). 1 H NMR (400 MHz, DMSO-d 6 )δppm 8.22(br s,1H),7.90(br d,J=2.45Hz,1H),7.77(br s,1H),7.46(s,1H),4.57(s,2H),4.23(br s,2H),4.00-4.15(m,1H),3.90(s,4H),2.56-2.69(m,5H),1.83-2.08(m,5H),1.40(s,10H),0.94(br d,J=6.48Hz,3H).LCMS:[M+H] + =583.4.

[0367] (3S,5R)-3-[3-[[6-amino-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolyl]oxy]propyl]-4,4-difluoro-5-methyl-piperidine-1-carboxylic acid tert-butyl ester

[0368] To a solution of (3R,5S)-4,4-difluoro-3-methyl-5-[3-[[1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-6-nitro-2-oxo-8-quinolinyl]oxy]propyl]piperidine-1-carboxylic acid tert-butyl ester (150.00 mg, 257.47 mmol, 1 eq) in DMF (3 mL) under Ar was added Pd / C (0.1 g, 10% purity). The suspension was degassed under vacuum and heated to 40°C. 2 Purge 3 times. 2 The mixture was stirred at 15° C. for 12 h under 4% CO (15 psi). The reaction mixture was filtered (combined with another batch on a 50 mg scale) and the filtrate was concentrated in vacuo to afford the title compound as a yellow oil (160 mg, crude). 1 HNMR (400MHz, CDCl 3)δppm 7.36-7.46(m,1H),6.76(s,1H),6.39(d,J=2.27Hz,1H),6.34(d,J=2.27Hz,1H),4.51(s,2H),4.16-4.35(m,1H),4.01(br t,J=5.84Hz,2H),3.97(s,3H),3.65-3.84(m,1H),2.89(br s,2H),2.51-2.71(m,2H),1.75-2.08(m,6H),1.47(s,9H),1.37-1.45(m,1H),1.03(d,J=6.68Hz,3H).LCMS:[M+H] + =553.2.

[0369] (3S,5R)-3-[3-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolinyl]oxy]propyl]-4,4-difluoro-5-methyl-piperidine-1-carboxylic acid tert-butyl ester

[0370] To a mixture of (3S,5R)-3-[3-[[6-amino-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolyl]oxy]propyl]-4,4-difluoro-5-methyl-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 180.96 mmol, 1 eq) and 2,4,5-trichloropyrimidine (66.38 mg, 361.92 mmol, 2 eq) in DMF (1 mL) was added DIPEA (58.47 mg, 452.40 mmol, 78.80 mL, 2.5 eq). The reaction mixture was then stirred at 15 °C for 12 h. The mixture was heated to 40 °C with H 2 O (2 mL) to treat the reaction mixture (mixed with another batch of 30 mg scale), then filter the suspension and collect the solid and dry in vacuo. 2 , petroleum ether / THF=1 / 1 to 0 / 1) to give the title compound as a white solid (130 mg, 73% purity). 1 H NMR (400 MHz, DMSO-d 6)δppm 9.57(br s,1H),8.39(br s,1H),7.92(br s,1H),7.44(br d,J=7.63Hz,2H),7.13(br s,1H),4.57(br s,2H),4.09(br s,3H),3.89(br s,4H),2.58-2.73(m,5H),1.81-2.02(m,5H),1.39(br s,10H),0.94(br d,J=5.75Hz,3H).LCMS:[M+H] + =699.4.

[0371] 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-8-[3-[(3S,5R)-4,4-difluoro-5-methyl-3-piperidinyl]propoxy]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide

[0372] A solution of (3S,5R)-3-[3-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolinyl]oxy]propyl]-4,4-difluoro-5-methyl-piperidine-1-carboxylic acid tert-butyl ester (130 mg, 185.83 mmol, 1 eq) in DCM (4 mL) and TFA (1.0 mL) was stirred at 15 °C for 1 hour. The reaction mixture was concentrated in vacuo to give the title compound as a yellow oil (150 mg, crude, TFA salt). LCMS: [M+H] + =599.2.

[0373] 2-(((1 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -Difluoro-1 5 ,4 1 -Dimethyl-4 2 -Oxo-4 1 ,4 2 -Dihydro-5-oxa-3-aza-4(6,8)-quinoline-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 3 -yl)oxy)-N-methylacetamide (4)

[0374] To a solution of 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-8-[3-[(3S,5R)-4,4-difluoro-5-methyl-3-piperidinyl]propoxy]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (150 mg, 210.24 mmol, 1 eq, TFA) in DMF (1.5 mL) was added DIPEA (271.71 mg, 2.10 mmol, 366.19 mL, 10 eq). The reaction mixture was then stirred at 80° C. for 12 hours. The reaction mixture was concentrated in vacuo to give a residue, which was purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 45%-75%, 8 min) to purify the residue to give the title compound as a white solid (15 mg, 25.84 mmol, 12% yield, 97% purity). 1 H NMR (400 MHz, DMSO-d 6 )δppm8.99(s,1H),8.10(s,1H),7.95(br d,J=4.29Hz,1H),7.86(d,J=1.55Hz,1H),7.06(s,2H),4.45-4.72(m,5H),4.14-4.24(m,1H),3.84(s,3H),2.74(br t,J=12.64Hz,1H),2.66(d,J=4.53Hz,3H),2.53-2.60(m,1H),2.29-2.42(m,1H),1.84- 2.02(m,2H),1.59-1.81(m,2H),1.32-1.42(m,1H),0.97(d,J=6.68Hz,3H).LCMS:[M+H] + =563.3.

[0375] Example 2: 2-(((1 3 R,1 5 S)-2 5 -Chloro-1 4 ,1 4 -Difluoro-1 5 ,4 1 -Dimethyl-4 2 -Oxo-4 1 ,4 2 -Dihydro- 5-Oxa-3-aza-4(6,8)-quinoline-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 3 -yl)oxy)-N-methylethyl Synthesis of amide (5)

[0376]

[0377] (3S,5R)-4,4-difluoro-3-methyl-5-[3-[[1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-6-nitro-2-oxo-8-quinolyl]oxy]propyl]piperidine-1-carboxylic acid tert-butyl ester

[0378] To a solution of 2-[(8-hydroxy-1-methyl-6-nitro-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide (120 mg, 390.55 mmol, 1 eq) in DMF (2 mL) was added K 2 CO 3 (107.96 mg, 781.10 mmol, 2 eq) and (3S, 5R) -4,4- difluoro-3-methyl-5- [3- (tosyloxy) propyl] piperidine -1- carboxylic acid tert-butyl ester (262.18 mg, 585.83 μmol, 1.5 eq). The mixture was stirred at 60 ° C for 12 hours. The reaction mixture (mixed with another batch of 30 mg scale) was cooled to 20 ° C and water (2 mL) was added. The mixture was filtered and the filter cake was washed with water (5 mL), and then the filter cake was dried in vacuo. At 20 ° C, the crude product was ground with petroleum ether: ethyl acetate = 1 / 1 (~ 2 mL) for 5 min. The mixture was filtered and the filter cake was dried in vacuo to obtain the title compound as a white solid (130 mg). 1 H NMR (400 MHz, DMSO-d 6 )δppm 8.23(d,J=2.20Hz,1H),7.93(br d,J=4.16Hz,1H),7.76(d,J=2.20Hz,1H),7.46(s,1H),4.57(s,2H),4.23(br t,J=5.20Hz,2H),3.99-4.17(m,1H),3.90(s,4H),2.66(d,J=4.52Hz,5H),1.79-2.11(m,5H),1.40(s,10H),0.94(d,J=6.60Hz,3H).

[0379] (3R,5S)-3-[3-[[6-amino-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolyl]oxy]propyl]-4,4-difluoro-5-methyl-piperidine-1-carboxylic acid tert-butyl ester

[0380] To a solution of (3S,5R)-4,4-difluoro-3-methyl-5-[3-[[1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-6-nitro-2-oxo-8-quinolinyl]oxy]propyl]piperidine-1-carboxylic acid tert-butyl ester (100 mg, 171.65 mmol, 1 eq) in DMF (2 mL) under Ar was added Pd / C (40 mg, 10% purity). The suspension was degassed in vacuo and heated to 40 % with H 2 Purge 3 times. 2 The mixture was stirred at 15°C for 12 hours under 15 psi. The reaction mixture was filtered through a pad of Celite (combined with another batch on a 30 mg scale) and the filtrate was concentrated in vacuo to give the title compound as a yellow solid (120 mg, crude). 1 H NMR (400 MHz, DMSO-d 6 )δppm 7.85-7.98(m,2H),6.94(s,1H),6.45(d,J=2.13Hz,1H),6.26(d,J=2.25Hz,1H),4.49(s,1H),3.75-3.83(m ,3H),3.26-3.33(m,4H),2.89(s,4H),2.73(s,4H),1.79-2.05(m,5H),1.40(s,9H),0.94(d,J=6.75Hz,3H).

[0381] (3R,5S)-3-[3-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolinyl]oxy]propyl]-4,4-difluoro-5-methyl-piperidine-1-carboxylic acid tert-butyl ester

[0382] To a mixture of (3R,5S)-3-[3-[[6-amino-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolyl]oxy]propyl]-4,4-difluoro-5-methyl-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 180.96 mmol, 1 eq) and 2,4,5-trichloropyrimidine (66.38 mg, 361.92 mmol, 2 eq) in DMF (1 mL) was added DIEA (58.47 mg, 452.40 μmol, 78.80 μL, 2.5 eq). The reaction mixture was then stirred at 15 °C for 12 h. The mixture was heated to 40 °C with H 2 O (2 mL) was added to the reaction mixture (combined with another batch of 20 mg scale). The suspension was then filtered and the solid was collected and dried under vacuum. The mixture was purified by column chromatography (SiO 2 , petroleum ether / THF=1 / 1 to 0 / 1) to give the title compound as a black solid (110 mg, 94% purity). 1 H NMR (400 MHz, DMSO-d 6)δppm 9.58(s,1H),8.40(s,1H),7.93(br d,J=4.50Hz,1H),7.44(br d,J=7.63Hz,2H),7.13(s,1H),4.57(s,2H),4.09(br t,J=5.57Hz,2H),3.89(s,4H),3.30(s,2H),2.55-2.71(m,5H),1.81-2.08(m,5H),1.39(s,9H),0.94(d,J=6.75Hz,3H).

[0383] 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-8-[3-[(3R,5S)-4,4-difluoro-5-methyl-3-piperidinyl]propoxy]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methylacetamide

[0384] A solution of (3R,5S)-3-[3-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolinyl]oxy]propyl]-4,4-difluoro-5-methyl-piperidine-1-carboxylic acid tert-butyl ester (80 mg, 114.36 mmol, 1 eq) in TFA (800.00 mL) and DCM (2.4 mL) was stirred at 15 °C for 1 hour. The solution was concentrated in vacuo to give the title compound as a yellow oil (80 mg, crude, TFA salt). LCMS: [M+H] + =599.3.

[0385] 2-(((1 3 R,1 5 S)-2 5 -Chloro-1 4 ,1 4 -Difluoro-1 5 ,4 1 -Dimethyl-4 2 -Oxo-4 1 ,4 2 -Dihydro-5-oxa-3-aza-4(6,8)-quinoline-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 3 -yl)oxy)-N-methylacetamide (5)

[0386] A mixture of 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-8-[3-[(3R,5S)-4,4-difluoro-5-methyl-3-piperidinyl]propoxy]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (80 mg, 112.13 mmol, 1 eq, TFA), DIEA (144.92 mg, 1.12 mmol, 195.30 mL, 10 eq) in DMF (1 mL) was stirred at 80 °C for 12 hours. The solution was concentrated in vacuo (combined with another batch of 30 mg). The product was purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 30%-60%, 8 min) to give the title compound as a white solid (10 mg, 96% purity). 1 H NMR (400 MHz, DMSO-d 6 )δppm 8.99(s,1H),8.11(s,1H),7.91-7.98(m,1H),7.86(d,J=1.83Hz,1H),7.01-7.09(m,2H),4.64 -4.72(m,1H),4.54-4.63(m,3H),4.49-4.54(m,1H),4.14-4.24(m,1H),3.85(s,3H),2.74(br t,J=12.53Hz,1H),2.66(d,J=4.65Hz,3H),2.55(br s,1H),2.29-2.44(m,1H),1.82-2.05(m,2H),1.59-1.82(m,2H),1.28-1.42(m,1H),0.97(d,J=6.72Hz,3H).LCMS:[M+H] + =563.3.

[0387] Example 3: 2-(((1 3 R,1 5 S)-25-chloro-1 5 ,4 1 -Dimethyl-4 2 -Oxo-4 1 ,4 2 -Dihydro-5,8-dioxa- 3-Aza-4(6,8)-quinoline-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 3 -yl)oxy)-N-methylacetamide (6) Synthesis

[0388]

[0389] 5-Methylpyridin-3-ol hydrochloride

[0390] To a solution of 5-methylpyridin-3-ol (10 g, 91.64 mmol, 1 eq) in EtOAc (30 mL) and MeOH (10 mL) was added HCl / EtOAc (4 M, 160 mL) in one portion at 15° C. The mixture was stirred at 15° C. for 4 hours. The mixture was filtered and the filter cake was dried under vacuum to give the title compound as a white solid (26.68 g, crude, HCl salt). 1 H NMR (400 MHz, DMSO-d 6 )δppm 11.97(b,1H),8.19-8.42(m,2H),7.88(s,1H),2.40(s,3H).

[0391] 5-Methylpiperidin-3-ol

[0392] To a solution of 5-methylpyridin-3-ol (13 g, 89.29 mmol, 1 eq, HCl) in AcOH (110 mL) was added PtO under Ar. 2 (1.30 g, 8.93 mmol, 0.1 eq). The suspension was degassed under vacuum and heated to 40 ℃. 2 Purge several times. 2 The mixture was stirred at 50°C for 16 hours under a pressure of 200 psi. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (33 g, crude, HOAc). 1 H NMR (400 MHz, DMSO-d 6 )δppm 8.94-9.58(m,2H),3.67-3.83(m,1H),2.94-3.22(m,2H),2.67(br t,J=10.01Hz,1H),2.24-2.48(m,2H),1.58-1.85(m,2H),0.96-1.17(m,1H),0.87(dd,J=8.38,6.75Hz,3H).

[0393] 3-Hydroxy-5-methyl-piperidine-1-carboxylic acid tert-butyl ester

[0394] In N 2 5-Methylpiperidin-3-ol (11 g, 62.78 mmol, 1 eq, HOAc) and Na 2 CO 3 (13.31 g, 125.55 mmol, 2 eq) in EtOAc (100 mL) and H 2 Boc 2O (13.70 g, 62.78 mmol, 14.42 mL, 1 eq). Then, the mixture was stirred at 15 °C for 12 hours. The mixture was extracted with ethyl acetate (200 mL x 2) (combined with the other 2 batches of the same scale). The combined organic phase was washed with brine (500 mL) and washed with anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate in vacuo. Purify the residue by flash silica gel chromatography (silica gel flash column, 0-50% ethyl acetate / petroleum ether gradient elution) to give the title compound as a white solid (10 g, 46.45 mmol, 25% yield). 1 H NMR (400 MHz, CDCl 3 )δppm 4.23(br s,1H)3.82-4.09(m,1H)3.62(br d,J=4.05Hz,1H)2.38(brt,J=10.67Hz,1H)2.17(br s,1H)1.78-2.10(m,2H)1.53-1.72(m,1H)1.45(s,9H)1.00(q,J=11.92Hz,1H)0.92(d,J=6.68Hz,3H).

[0395] 3-(2-Benzyloxyethoxy)-5-methyl-piperidine-1-carboxylic acid tert-butyl ester

[0396] In N 2 To a solution of tert-butyl 3-hydroxy-5-methyl-piperidine-1-carboxylate (10 g, 46.45 mmol, 1 eq) in DMF (100 mL) was added NaH (3.72 g, 92.90 mmol, 60% purity, 2 eq) in portions at 0°C. The mixture was stirred at 0°C for 30 min, then 2-bromoethoxymethylbenzene (11.99 g, 55.74 mmol, 8.82 mL, 1.2 eq) was added at 0°C, and the mixture was heated to 90°C and stirred for 11.5 hours. At 15°C, saturated NH 4 The mixture was quenched with aqueous Cl solution (200 mL), and the mixture was extracted with ethyl acetate (200 mL×2). The combined organic phase was washed with brine (500 mL) and dried over anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate in vacuo. Purify the residue by flash silica gel chromatography (silica gel flash column, 5-40% ethyl acetate / petroleum ether gradient eluent) to give the title compound as a yellow oil (4.2 g, 9.98 mmol, 44% yield, 83% purity). 1 HNMR (400MHz, CDCl 3)δppm 7.27-7.38(m,5H),4.58(s,2H),4.22-4.46(m,1H),3.88-4.11(m,1H),3.70(br d,J=4.63Hz,2H),3.59-3.64(m,2H),3.26-3.36(m,1H),2.40(br s,1H),2.09-2.25(m,2H),1.53-1.64(m,1H),1.46(s,9H),1.01(q,J=12.09Hz,1H),0.92(d,J=6.63Hz,3H).

[0397] tert-Butyl 3-(2-hydroxyethoxy)-5-methylpiperidine-1-carboxylate

[0398] In N 2 To a solution of tert-butyl 3-(2-benzyloxyethoxy)-5-methyl-piperidine-1-carboxylate (4.2 g, 12.02 mmol, 1 eq) in MeOH (50 mL) was added Pd / C (2 g, 10% purity). The suspension was degassed under vacuum and heated to 40 ℃ for 1 h. 2 Purge several times. 2 The mixture was stirred at 60° C. for 12 h under pressure (50 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound as a black oil (3.3 g, 9.29 mmol, 77% yield, 73% purity). 1 H NMR (400 MHz, CDCl 3 )δppm 4.17-4.43(m,1H),3.86-4.07(m,1H),3.69-3.75(m,2H),3.60-3.66(m,2H),3.26-3.36(m,1H),2.41(br t,J=11.25Hz,1H),2.04-2.30(m,3H),1.54-1.67(m,1H),1.46(s,9H),0.99(q,J=11.98Hz,1H),0.92(d,J=6.60Hz,3H).

[0399] tert-Butyl 3-methyl-5-[2-(p-toluenesulfonyloxy)ethoxy]piperidine-1-carboxylate

[0400] To a mixture of 3-(2-hydroxyethoxy)-5-methyl-piperidine-1-carboxylic acid tert-butyl ester (3.3 g, 12.72 mmol, 1 eq) in DCM (30 mL) were added DMAP (155.45 mg, 1.27 mmol, 0.1 eq) and TEA (1.42 g, 14.00 mmol, 1.95 mL, 1.1 eq). 2TsCl (2.67 g, 14.00 mmol, 1.1 eq) was added to the mixture at 0°C. The mixture was stirred at 15°C for 12 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (80 mL×3). The combined organic phase was washed with brine (200 mL) and dried over anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate in vacuo. 2 , petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give the title compound as a yellow oil (3.5 g, 8.32 mmol, 65% yield, 98% purity). 1 H NMR (400 MHz, CDCl 3 )δppm 7.80(d,J=8.34Hz,2H)7.34(d,J=8.11Hz,2H)4.07-4.34(m,3H)3.80-4.06(m,1H)3.61-3.73(m,2H)3.12-3 .30(m,1H)2.45(s,3H)2.09-2.38(m,2H)1.95-2.04(m,1H)1.48-1.60(m,1H)1.45(s,9H)0.80-0.95(m,4H).

[0401] (3S,5R)-3-methyl-5-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylic acid tert-butyl ester (8C) and (3R,5S)-3-methyl-5-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylic acid tert-butyl ester

[0402] By SFC (column: DAICEL CHIRALPAK IG (250mm*30mm,10μm); mobile phase: [Neu-ETOH]; B%: 20%-20%, 6min) was used to separate tert-butyl 3-methyl-5-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate (900mg, 2.18mmol, 1eq) to obtain tert-butyl (3S,5R)-3-methyl-5-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate (380mg, 909.74μmol, 42% yield, 99% purity) as a colorless oil, and tert-butyl (3R,5S)-3-methyl-5-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate (380mg, 900.55μmol, 41% yield, 98% purity), a colorless oil. 1 H NMR (400 MHz, CDCl 3)δppm 7.81(d,J=8.25Hz,2H),7.35(d,J=8.13Hz,2H),4.14(t,J=4.82Hz,2H),3.66-3.72(m,2H),3.18-3.26(m,1 H),2.46(s,4H),2.10-2.35(m,2H),1.96-2.06(m,1H),1.50-1.61(m,2H),1.46(s,9H),0.83-0.93(m,4H). 1 HNMR (400MHz, CDCl 3 )δppm 7.81(d,J=8.25Hz,2H),7.35(d,J=8.13Hz,2H),4.12-4.17(m,2H),3.66-3.71(m,2H),3.16-3.28(m,1H) ,2.46(s,3H),2.10-2.32(m,2H),1.97-2.06(m,1H),1.53-1.61(m,2H),1.46(s,9H),0.83-0.94(m,5H).

[0403] 7-Methoxy-1-methyl-indole-2,3-dione

[0404] To a solution of 7-methoxyindole-2,3-dione (50 g, 56.45 mmol, 1 eq) in DMF (600 mL) was added K 2 CO 3 (58.5g, 84.67mmol, 1.5eq). The reaction mixture was stirred at 20°C for 30min. Then, MeI (52.08g, 73.38mmol, 22.85mL, 1.3eq) was added to the reaction mixture. The mixture was stirred at 20°C for 11.5 hours. Then, the reaction mixture was poured into water (2000mL), slowly acidified with 2N HCl (aqueous solution) until pH=3 and stirred for 45min. The resulting precipitate was collected by filtration, washed with water (500mL) and dried in vacuo to give the title compound as a red solid (50g, 215.76mmol, 73% yield). 1 H NMR (400 MHz, DMSO-d 6 )δppm 7.41(dd,J=8.17,0.89Hz,1H),7.14-7.18(m,1H),7.06-7.12(m,1H),3.88(s,3H),3.35(s,3H).

[0405] 7-Methoxy-1-methyl-5-nitroindole-2,3-dione

[0406] At 0°C, NaNO 3 (22.23 g, 261.53 mmol, 2 eq) in H 2 SO 4 7-methoxy-1-methyl-indole-2,3-dione (25 g, 130.76 mmol, 1 eq) was quickly added to a solution of 150 mL in H 2 SO 4 (150 mL). The reaction was stirred at 15 ° C for 12 hours. Then, the reaction mixture (combined with another batch of the same scale) was slowly poured into an ice / water mixture while maintaining the temperature at 0 ° C. The resulting aqueous solution was then washed with EtOAc (1 L × 3). The combined organic extracts were purified by Na 2 SO 4 Dry, filter, and concentrate the filtrate in vacuo to afford the title compound as a red solid (60 g, crude). 1 H NMR (400 MHz, DMSO-d 6 )δppm 8.10(d,J=1.88Hz,1H),7.90(d,J=2.13Hz,1H),4.02(s,3H),3.41(s,3H).

[0407] 7-Hydroxy-1-methyl-5-nitroindole-2,3-dione

[0408] A solution of 7-methoxy-1-methyl-5-nitro-indoline-2,3-dione (33 g, 139.72 mmol, 1 eq) in HBr (500 mL, 48% purity) was stirred at 120°C for 12 hours. The reaction mixture (combined with another batch of the same scale) was then slowly poured into ice / water while keeping the temperature at 0°C. The resulting aqueous solution was then washed with EtOAc (2 L x 3). The combined organics were purified by Na 2 SO 4 Dry, filter, and concentrate the filtrate in vacuo. Purify the residue by silica gel flash chromatography (silica gel flash column, 10-50% ethyl acetate / petroleum ether gradient elution) to give the title compound as a red solid (20 g). 1 HNMR (400 MHz, DMSO-d 6 )δppm 11.16(br s,1H),7.90(d,J=2.20Hz,1H),7.75(d,J=2.20Hz,1H),3.41(s,3H).

[0409] 7-Benzyloxy-1-methyl-5-nitroindole-2,3-dione

[0410] To a solution of 7-hydroxy-1-methyl-5-nitro-indoline-2,3-dione (9 g, 40.51 mmol, 1 eq) in DMF (90 mL) was added K 2 CO 3 (6.72 g, 48.61 mmol, 1.2 eq), stirred at 15 ° C for 30 min, then BnBr (7.62 g, 44.56 mmol, 5.29 mL, 1.1 eq) was added dropwise, and the mixture was stirred at 15 ° C for 11.5 hours. Water (200 mL) and brine (200 mL) were added to the mixture (combined with another batch of the same scale), followed by extraction with ethyl acetate (300 mL×3). The combined organic phase was washed with brine (1000 mL) and dried over anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate in vacuo. Purify the residue by flash silica gel chromatography (silica gel flash column, 10-50% ethyl acetate / petroleum ether gradient eluent) to give the title compound as a red solid (12 g, 23.63 mmol, 29% yield, 61% purity). 1 H NMR (400 MHz, DMSO-d 6 )δppm8.23(d,J=2.0Hz,1H),7.91(d,J=2.0Hz,1H),7.55-7.50(m,2H),7.45(t,J=7.3Hz,2H),7.40-7.36(m,1H),5.40(s,2H),3.39(s,3H).

[0411] 8-Benzyloxy-3-hydroxy-1-methyl-6-nitroquinolin-2-one

[0412] To a solution of 7-benzyloxy-1-methyl-5-nitro-indoline-2,3-dione (4.2 g, 13.45 mmol, 1 eq) in DCM (80 mL) was added TMSCHN dropwise at 0 °C. 2 (2M, 13.45 mL, 2 eq) and then stirred the reaction mixture at 15 °C for 1.5 h. The reaction mixture was quenched with HOAc (combined with another batch of the same scale) until no bubbles were generated. 2 O (250 mL) was added to the mixture. The resulting mixture was extracted with DCM (300 mL×3). The combined organic phase was washed with brine (500 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. Triturate the residue with DCM (20 mL) at 15°C for 30 min. Then, filter the suspension and wash the solid with DCM (8 mL x 2) to give the title compound as a brown solid (2.2 g, 6.61 mmol, 25% yield, 98% purity).1 H NMR (400 MHz, DMSO-d 6 )δppm 10.03(s,1H),8.19(d,J=2.26Hz,1H),7.84(d,J=2.27Hz,1H),7.55(br d,J=7.15Hz,2H),7.35-7.47(m,3H),7.29(s,1H),5.33(s,2H),3.88(s,3H).

[0413] 2-[(8-Benzyloxy-1-methyl-6-nitro-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide

[0414] 2-Bromo-N-methyl-acetamide (1.35 g, 8.90 mmol, 1.2 eq) and Cs 2 CO 3 (4.83 g, 14.83 mmol, 2 eq) was added to a solution of 8-benzyloxy-3-hydroxy-1-methyl-6-nitro-quinolin-2-one (2.42 g, 7.42 mmol, 1 eq) in DMF (70 mL). The reaction mixture was stirred at 15 °C for 12 hours. Then, H 2 The reaction mixture was treated with 1% O (100 mL) and filtered. The filter cake was collected and dried in vacuo to afford the title compound as a light brown solid (2.5 g, crude). 1 H NMR (400 MHz, DMSO-d 6 )δppm 8.26(br s,1H),7.92(br s,2H),7.55(br d,J=6.20Hz,2H),7.41-7.49(m,3H),7.39(br d,J=5.60Hz,1H),5.29-5.39(m,2H),4.50-4.65(m,2H),3.86(br s,3H),2.60-2.71(m,3H).

[0415] 2-[(8-Hydroxy-1-methyl-6-nitro-2-oxo-3-quinolinyl)oxy]-N-methyl-acetamide

[0416] To a solution of 2-[(8-benzyloxy-1-methyl-6-nitro-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide (2.5 g, 6.29 mmol, 1 eq) in DCM (150 mL) was added BCl at -70 °C. 3 (1 m, 12.58 mL, 2 eq). The reaction mixture was then stirred at 15 °C for 12 h. 3The reaction mixture was quenched with a mixture of 4-(4-(4-(4-piperidin-2-yl)-1H-butyl)-2-nitropropene (MeOH=10:1, 750 mL) (combined with another batch of 50 mg scale). The reaction mixture was then warmed to 15°C and stirred for 20 min. The mixture was concentrated in vacuo to give the title compound as a yellow solid (1.9 g, 5.44 mmol, 86% yield, 88% purity). 1 HNMR (400 MHz, DMSO-d 6 )δppm 11.07(s,1H),8.04(d,J=2.50Hz,1H),7.90(br d,J=4.38Hz,1H),7.69(d,J=2.63Hz,1H),7.40(s,1H),4.56(s,2H),3.94(s,3H),2.66(d,J=4.75Hz,3H).

[0417] (3S,5R)-3-Methyl-5-[2-[[1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-6-nitro-2-oxo-8-quinolyl]oxy]ethoxy]piperidine-1-carboxylic acid tert-butyl ester

[0418] To a solution of 2-[(8-hydroxy-1-methyl-6-nitro-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide (250 mg, 813.65 μmol, 1 eq) and (3S,5R)-3-methyl-5-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylic acid tert-butyl ester (336.47 mg, 813.65 μmol, 1 eq) in DMF (3 mL) was added K 2 CO 3 The mixture was stirred at 60 ° C for 3 hours. The mixture was cooled to 20 ° C and water (3 mL) was added, which resulted in the formation of a precipitate. The mixture was filtered and the filter cake was washed with water (5 mL × 2) and then washed with an organic solution (petroleum ether: ethyl acetate = 1 / 1, 10 mL). The filter cake was dried in vacuo to give the title compound as a yellow solid (350 mg, 548.69 mmol, 67% yield, 86% purity). 1 H NMR (400 MHz, DMSO-d 6)δppm 8.22(d,J=2.25Hz,1H),7.91(br d,J=2.25Hz,1H),7.80(d,J=2.38Hz,1H),7.45(s,1H),4.57(s,2H),4.33(br t,J=3.94Hz,2H),4.03-4.19(m,1H),3.92-3.95(m,3H),3.73-3.92(m,4H),2.67(d,J=4.50Hz,3H),2.14-2.44(m,2H),2.09(br d,J=12.26Hz,1H),1.43-1.56(m,1H),1.38(s,9H),0.89-0.98(m,1H),0.87(d,J=6.63Hz,3H).

[0419] (3R,5S)-3-[2-[[6-amino-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolyl]oxy]ethoxy]-5-methyl-piperidine-1-carboxylic acid tert-butyl ester

[0420] To a solution of (3S,5R)-3-methyl-5-[2-[[1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-6-nitro-2-oxo-8-quinolinyl]oxy]ethoxy]piperidine-1-carboxylic acid tert-butyl ester (350 mg, 638.01 mmol, 1 eq) in DMF (5 mL) under Ar was added Pd / C (0.1 g, 10% purity). The suspension was degassed under vacuum and heated to 40°C. 2 Purge several times. 2 The mixture was stirred at 20°C for 12 hours under a pressure of 15 psi. The mixture was filtered and the filter cake was washed with DMF (-15 mL). The filtrate was concentrated in vacuo to afford the title compound as a yellow solid (340 mg, crude). LCMS: [M+H] + =519.4.

[0421] (3R,5S)-3-[2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolinyl]oxy]ethoxy]-5-methyl-piperidine-1-carboxylic acid tert-butyl ester

[0422] To a solution of (3R,5S)-3-[2-[[6-amino-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolinyl]oxy]ethoxy]-5-methyl-piperidine-1-carboxylic acid tert-ester (340 mg, 655.61 mmol, 1 eq) and 2,4,5-trichloropyrimidine (240.51 mg, 1.31 mmol, 2 eq) in DMF (3.5 mL) was added DIPEA (169.46 mg, 1.31 mmol, 228.39 mL, 2 eq). The mixture was stirred at 20°C for 12 hours. The reaction mixture was purified by flash silica gel chromatography (silica gel flash column, 10-100% ethanol / ethyl acetate eluent) to give ~300 mg of crude product. The crude product was further triturated with (PE / EtOAc = 1 / 1, 3 mL) at 20 °C for 5 min to afford the title compound as a yellow solid (200 mg, 283.67 mmol, 43% yield, 94% purity). 1 H NMR (400 MHz, DMSO-d 6 )δppm 9.58(s,1H),8.39(s,1H),7.94(br d,J=4.50Hz,1H),7.42(s,2H),7.14(s,1H),4.57(s,2H),4.18(br t,J=4.06Hz,3H),3.85-3.95(m,5H),3.79(dt,J=7.63,3.69Hz,1H),2.66(d,J=4.63Hz,3H),2.14-2.46(m,2H),2.07(br d,J=11.51Hz,1H),1.43-1.57(m,1H),1.38m 1.34(m,10H),0.93(q,J=11.84Hz,1H),0.86(d,J=6.63Hz,3H).

[0423] 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-8-[2-[[(3R,5S)-5-methyl-3-piperidinyl]oxy]ethoxy]-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide

[0424] A solution of (3R,5S)-3-[2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolinyl]oxy]ethoxy]-5-methyl-piperidine-1-carboxylic acid tert-butyl ester (200.00 mg, 300.50 mmol, 1 eq) in DCM (2 mL) and TFA (0.5 mL) was stirred at 20 °C for 1 hour. The mixture was concentrated in vacuo to give the title compound as a yellow oil (220 mg, crude, TFA). LCMS: [M+H] + =565.2.

[0425] 2-(((1 3 R,1 5 S)-2 5 -Chloro-1 5 ,4 1 -Dimethyl-4 2 -Oxo-4 1 ,4 2 -Dihydro-5,8-dioxa-3-aza-4(6,8)-quinoline-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 3 -yl)oxy)-N-methylacetamide (6)

[0426] To a solution of 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-8-[2-[[(3R,5S)-5-methyl-3-piperidinyl]oxy]ethoxy]-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (220 mg, 323.78 mmol, 1 eq, TFA) in DMSO (9 mL) was added DIPEA (418.46 mg, 3.24 mmol, 563.96 mL, 10 eq). The mixture was stirred at 80 ° C for 12 hours. The mixture was filtered and the filtrate was purified without treatment. The product was purified by p-HPLC (column: Waters Xbridge TM BEH C18 100*30mm*10μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 40%-60%, 8 min) to purify the filtrate to give the title compound as a yellow solid (21 mg, 37.48 μmol, 12% yield, 94% purity). 1 H NMR (400 MHz, DMSO-d 6)δppm 8.99(s,1H),8.02-8.11(m,2H),7.94(br d,J=4.05Hz,1H),7.08(d,J=1.79Hz,1H),7.06(s,1H),4.65-4.77(m,1H),4.50-4.62(m,3H),4.32-4.41(m,1H),4.13-4.26(m,1H),3. 68-3.91(m,6H),2.66(d,J=4.53Hz,3H),2.52-2.59(m,2H),1.98(brd,J=11.68Hz,1H),1.55-1.70(m,1H),1.09-1.19(m,1H),0.89(br d, J = 6.56 Hz, 3H). LCMS: [M+H] + =529.3.

[0427] Example 4: 2-(((1 3 S,1 5 R)-25-chloro-1 5 ,4 1 -Dimethyl-4 2 -Oxo-4 1 ,4 2 -Dihydro-5,8-dioxa- 3-Aza-4(6,8)-quinoline-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-43-yl)oxy)-N-methylacetamide (7) Synthesis

[0428]

[0429] (3R,5S)-3-Methyl-5-[2-[[1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-6-nitro-2-oxo-8-quinolyl]oxy]ethoxy]piperidine-1-carboxylic acid tert-butyl ester

[0430] To a solution of 2-[(8-hydroxy-1-methyl-6-nitro-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide (200 mg, 650.92 mmol, 1 eq) and (3R,5S)-3-methyl-5-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylic acid tert-butyl ester (269.17 mg, 650.92 mmol, 1 eq) in DMF (3 mL) was added K 2 CO 3 (224.91 mg, 1.63 mmol, 2.5 eq). The mixture was stirred at 60 ° C for 3 hours. The mixture (combined with another batch of 50 mg scale) was cooled to 20 ° C and ~ 3 mL of water was added. A precipitate appeared. The mixture was filtered and the filter cake was washed with water (5 mL × 2) and an organic solution (petroleum ether: ethyl acetate = 1 / 1, 10 mL), and then the mixture was dried in vacuo to give the title compound as a yellow solid (350 mg, 93.4% purity). 1 H NMR (400 MHz, DMSO-d 6)δppm 8.23(d,J=2.50Hz,1H),7.92(br d,J=4.25Hz,1H),7.81(d,J=2.50Hz,1H),7.46(s,1H),4.57(s,2H),4.33(t,J=4.13Hz,2H),4.01-4.21(m,1H),3.94(s,3H),3.71-3.93(m,4 H),2.66(d,J=4.50Hz,3H),2.15-2.40(m,2H),2.03-2.13(m,1H),1.45-1.57(m,1H),1.38(s,9H),0.89-0.98(m,1H),0.87(d,J=6.63Hz,3H).

[0431] (3S,5R)-3-[2-[[6-amino-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolyl]oxy]ethoxy]-5-methyl-piperidine-1-carboxylic acid tert-butyl ester

[0432] To a solution of (3R,5S)-3-methyl-5-[2-[[1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-6-nitro-2-oxo-8-quinolinyl]oxy]ethoxy]piperidine-1-carboxylic acid tert-butyl ester (350 mg, 638.01 mmol, 1 eq) in DMF (5 mL) under Ar was added Pd / C (0.1 g, 10% purity). The suspension was degassed under vacuum and heated to 40°C. 2 Purge several times. 2 The mixture was stirred at 20°C for 12 hours under a pressure of 15 psi. The mixture was filtered and the filter cake was washed with DMF (-15 mL), then the filtrate was concentrated in vacuo to afford the title compound as a yellow solid (340 mg, crude). LCMS: [M+H] + =519.4.

[0433] (3S,5R)-3-[2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolinyl]oxy]ethoxy]-5-methyl-piperidine-1-carboxylic acid tert-butyl ester

[0434] To a solution of (3S,5R)-3-[2-[[6-amino-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolyl]oxy]ethoxy]-5-methyl-piperidine-1-carboxylic acid tert-butyl ester (340 mg, 655.61 mmol, 1 eq) and 2,4,5-trichloropyrimidine (240.51 mg, 1.31 mmol, 2 eq) in DMF (3.5 mL) was added DIPEA (169.46 mg, 1.31 mmol, 228.39 mL, 2 eq). The mixture was stirred at 20 °C for 12 hours. The mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (silica gel flash column, 10-100% EtOH / ethyl acetate eluent) to give ~300 mg of crude product. The crude product was further triturated with (PE / EtOAc = 1 / 1, 3 mL) at 20 °C for 5 min to afford the title compound as a yellow solid (220 mg, 324.93 mmol, 50% yield, 98% purity). 1 H NMR (400 MHz, DMSO-d 6 )δppm 9.60(s,1H),8.40(s,1H),7.93(br d,J=4.40Hz,1H),7.42(br s,2H),7.14(s,1H),4.57(s,2H),4.05-4.22(m,3H),3.85-3.97(m,5H),3.72-3.84(m,1H),2.66(d,J=4.52Hz,3 H),2.55-2.59(m,2H),2.16-2.42(m,1H),1.42-1.58(m,2H),1.38(s,9H),0.88-0.98(m,1H),0.82-0.88(m,3H).

[0435] 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-8-[2-[[(3S,5R)-5-methyl-3-piperidinyl]oxy]ethoxy]-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide

[0436] A solution of (3S,5R)-3-[2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolinyl]oxy]ethoxy]-5-methyl-piperidine-1-carboxylic acid tert-butyl ester (180 mg, 270.45 mmol, 1 eq) in DCM (2 mL) and TFA (0.5 mL) was stirred at 20 °C for 1 hour. The mixture was concentrated in vacuo to give the title compound as a yellow oil (200 mg, crude, TFA salt). LCMS: [M+H] +=565.6.

[0437] 2-(((1 3 S,1 5 R)-2 5 -Chloro-1 5 ,4 1 -Dimethyl-4 2 -Oxo-4 1 ,4 2 -Dihydro-5,8-dioxa-3-aza-4(6,8)-quinoline-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 3 -yl)oxy)-N-methylacetamide (7)

[0438] To a solution of 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-8-[2-[[(3S,5R)-5-methyl-3-piperidinyl]oxy]ethoxy]-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (200 mg, 294.35 mmol, 1 eq, TFA) in DMSO (8 mL) was added DIPEA (380.42 mg, 2.94 mmol, 512.70 mL, 10 eq). The mixture was stirred at 80 ° C for 12 hours. The mixture was filtered and the filtrate was directly purified without further treatment. The product was purified by p-HPLC (column: Waters Xbridge TM BEH C18 100*30mm*10μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 35%-65%, 8 min) to purify the filtrate (combined with another batch of 25 mg) to give the title compound as a yellow solid (25 mg, 95% purity). 1 H NMR (400 MHz, DMSO-d 6)δppm 8.66-9.21(m,1H),8.06(s,1H),7.99(br d,J=1.63Hz,1H),7.88(s,1H),7.05(s,1H),6.91(br s,1H),4.63(br d,J=10.01Hz,2H),4.54(s,2H),4.36(brd,J=9.38Hz,1H),4.11-4.24(m,1H),3.84-3.92(m,1H),3.67-3.84(m,5H),2.66(br d,J=4.13Hz,3H),2.32-2.47(m,2H),1.96(br d,J=10.38Hz,1H),1.54-1.67(m,1H),1.10(q,J=11.51Hz,1H),0.87(br d,J=6.38Hz,3H).LCMS:[M+H] + =529.3

[0439] Example 5: (1 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -Difluoro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl- 4 2 ,4 3 -Dihydro-4 1 H-5-oxa-3-aza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane- 4 2 Synthesis of -ketone (10)

[0440]

[0441] tert-Butyl (3S,5R)-3-(3-((6-benzylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)propyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0442] To a solution of 5-(benzylamino)-7-hydroxy-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (660 mg, 2.45 mmol, 1 eq) in DMSO (7 mL) was added tert-butyl (3R,5S)-4,4-difluoro-3-methyl-5-(3-(tosyloxy)propyl)piperidine-1-carboxylate (1.1 g, 2.45 mmol, 1 eq) and Cs 2 CO 3 (1.60 g, 4.90 mmol, 2 eq). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture (combined with another batch of 500 mg scale) was treated with water (20 mL) and then extracted with EtOAc (25 mL x 3). The combined organic phases were washed with brine (50 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to give a residue which was purified by preparative HPLC (column: Welch C18 180*70mm*10μm; mobile phase: [water (NH 4 HCO3 )-ACN]; B%: 50%-80%, 15 min) to purify the residue to give the title compound as a white solid (1 g, 1.82 mmol, 66% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=10.35(br s,1H),7.37-7.27(m,4H),7.23-7.18(m,1H),6.03(d,J=1.6Hz,1H),5.93(t,J=6.0Hz,1H),5.82(d,J=1.6Hz,1H),4.22(d,J=6.0Hz,2H),4.15- 3.99(m,1H),3.95(t,J=5.4Hz,3H),3.33(s,3H),2.68-2.52(m,2H),2. 06-1.69(m,5H),1.40(s,9H),1.35-1.26(m,1H),0.94(d,J=6.4Hz,3H).

[0443] (3S,5R)-tert-butyl 3-(3-((6-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)propyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0444] To a solution of tert-butyl (3S,5R)-3-(3-((6-(benzylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)propyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate (1 g, 1.84 mmol, 1 eq) in THF (10 mL) under Ar was added Pd / C (300 mg, 10% purity). The suspension was degassed in vacuo and heated with H 2 Purge several times. 2 The reaction mixture was stirred at 25° C. for 12 h under 4% CO (15 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound as a brown solid (800 mg, 1.60 mmol, 87% yield, 91% purity). 1 H NMR (400 MHz, DMSO-d 6)δ=9.13(s,1H),7.99(s,1H),7.98-7.92(d,J=4.4Hz,2H),7.80-7.74(d,J=2.4 Hz,2H),7.64-7.58(m,1H),7.57-7.51(m,1H),7.22(m,1H),4.66(d,J=7.0Hz,2 H),4.62-4.56(m,2H),4.55-4.49(m,4H),4.17-4.08(m,2H),3.43(m,1H),2.86 -2.72(m,2H),2.67(d,J=4.8Hz,3H),2.15-1.97(m,2H),0.84(d,J=6.4Hz,6H).

[0445] tert-Butyl (3S,5R)-3-(3-((6-((2,5-dichloropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)propyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0446] To a solution of (3S,5R)-3-(3-((6-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)propyl)-4,4-difluoro-5-methylpiperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.10 mmol, 1 eq) in DMF (5 mL) was added 2,4,5-trichloropyrimidine (403.56 mg, 2.20 mmol, 2 eq) and DIPEA (355.45 mg, 2.75 mmol, 479.04 μL, 2.5 eq). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was treated with water (8 mL) and the suspension was filtered. The precipitate was filtered and purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to give the title compound as a yellow solid (530 mg, 793.05 μmol, 72% yield, 90% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=10.90(s,1H),9.39(s,1H),8.34(s,1H),6.97(s,2H),4.06(t,J=4.8Hz,2H),3.97-3.88(m ,1H),3.45(s,3H),2.70-2.54(m,2H),2.02-1.81(m,5H),1.39(s,10H),0.94(d,J=6.8Hz,3H).

[0447] 5-((2,5-dichloropyrimidin-4-yl)amino)-7-(3-((3S,5R)-4,4-difluoro-5-methylpiperidin-3-yl)propoxy)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0448] A solution of (3S,5R)-tert-butyl 3-(3-((6-((2,5-dichloropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)propyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate (500 mg, 831.29 μmol, 1 eq) in DCM (1.5 mL) and TFA (0.5 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated in vacuo to give the title compound as a yellow oil (500 mg, crude, TFA). LCMS: [M+H] + =501.1.

[0449] (1 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -Difluoro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-Oxa-3-aza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-42-one (26)

[0450] To a solution of 5-((2,5-dichloropyrimidin-4-yl)amino)-7-(3-((3S,5R)-4,4-difluoro-5-methylpiperidin-3-yl)propoxy)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (500 mg, 812.51 μmol, 1 eq, TFA) in DMSO (30 mL) was added DIPEA (1.05 g, 8.13 mmol, 1.42 mL, 10 eq). The reaction mixture was stirred at 80 °C for 12 hours. The suspension was treated with water (30 mL) and then filtered to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 1 to 0 / 1) to give the title compound as a yellow solid (250 mg, 516.25 μmol, 64% yield, 96% purity) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6)δ=10.80(s,1H),8.75(s,1H),8.06(s,1H),7.49(s,1H),6.63(s,1H),4.70(d,J=12.6Hz,1H),4.58(d,J=12.8Hz,1H),4.41(t,J=11 .6Hz,1H),3.42(s,3H),2.76-2.68(m,2H),2.40-2.24(m,1H),2.17(t,J=6.8Hz,1H),2.04-1.81(m,3H),1.70-1.57(m,2H),0.97(br d,J=6.0Hz,3H).LCMS:[M+H] + =465.2. 30 mg of the yellow solid was further purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water(NH4HCO3)-ACN]; B%: 40%-70%, 8 min) to give the title compound as a white solid (10 mg, 21.30 μmol, 33% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=10.80(s,1H),8.76(s,1H),8.06(s,1H),7.49(s,1H),6.63(d,J=1.0Hz,1H),4.70(d,J=13 .0Hz,1H),4.59(d,J=12.5Hz,1H),4.46-4.36(m,1H),4.14-4.00(m,1H),3.42(s,3H),2.73(br t,J=12.7Hz,1H),2.59-2.53(m,1H),2.39-2.25(m,1H),2.05-1.57(m,4H),1.35(dt,J=5.2,12.6Hz,1H),0.97(d,J=6.7Hz,3H).LCMS:[M+H] + =465.3.

[0451] (1 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -Difluoro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1H-5-Oxa-3-aza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -Keto (10)

[0452] To a mixture of (13S,15R)-25-chloro-14,14-difluoro-15,43-dimethyl-42,43-dihydro-41H-5-oxa-3-aza-4(6,4)-benzo[d]imidazol-2(2,4)-pyrimidin-1(1,3)-piperidinylcyclooctan-42-one (150 mg, 322.65 μmol, 1 eq) and (3-hydroxy-3-methyl-butyl) 4-methylbenzenesulfonate (166.70 mg, 645.31 μmol, 2 eq) in DMSO (2 mL) were added KI (26.78 mg, 161.33 μmol, 0.5 eq) and Cs 2 CO 3 (210.25 mg, 645.31 μmol, 2 eq). The reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was treated with water and the suspension was filtered. The product was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 60%-90%, 8 min) to give the title compound as a white solid (30 mg, 53.90 μmol, 17% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=8.84(s,1H),8.07(s,1H),7.54(s,1H),6.76(s,1H),4.70(br d,J=12.0Hz,1H),4.59(d,J=12.0Hz,1H),4.49-4.37(m,2H),4.14-4.04(m,1H),3.82(dd,J=6.0,9.6Hz,2H),3.46(s,3H),2.79-2.67 (m,1H),2.59-2.52(m,1H),2.42-2.23(m,1H),2.01-1.57(m,6H),1.41-1.29(m,1H),1.18(s,6H),0.97(d,J=6.8Hz,3H).LCMS:[M+H] + =551.4.

[0453] Example 6: (1 3 R,1 5 S)-2 5 -Chloro-1 4 ,1 4 -Difluoro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl- 4 2 ,4 3 -Dihydro-4 1 H-5-oxa-3-aza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane- 4 2 Synthesis of -ketone (11)

[0454]

[0455] tert-Butyl (3R,5S)-3-(3-((6-benzylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)propyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0456] To a solution of 5-(benzylamino)-7-methoxy-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (500 mg, 1.86 mmol, 1 eq) in DMSO (5 mL) was added tert-butyl (3S,5R)-4,4-difluoro-3-methyl-5-(3-(tosyloxy)propyl)piperidine-1-carboxylate (830.93 mg, 1.86 mmol, 1 eq) and Cs 2 CO 3 (1.21 g, 3.71 mmol, 2 eq). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was treated with water (20 mL) (combined with another batch of the same scale) and then extracted with EtOAc (25 mL x 3). The combined organic phases were washed with brine (50 mL) and dried over anhydrous Na 2 SO 4 Drying, filtration and concentration in vacuo gave a residue which was purified by preparative HPLC (column: Welch C18 180*70mm#10μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 50%-80%, 15 min) residue to afford the title compound as a white solid (850 mg, 1.51 mmol, 59% yield, 97% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=10.35(s,1H),7.38-7.26(m,4H),7.24-7.17(m,1H),6.03(d,J=1.6Hz,1H),5.93(t,J=6.0Hz,1H),5.82(d,J=1.6Hz,1H),4.21 (d,J=6.0Hz,2H),4.16-3.85(m,4H),3.33(s,3H),2.69-2.53(m,2H),2.04-1.69(m,5H),1.35-1.22(m,1H),0.94(d,J=6.8Hz,3H).

[0457] (3R,5S)-tert-butyl 3-(3-((6-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)propyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0458] To a solution of tert-butyl (3R,5S)-3-(3-((6-(benzylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)propyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate (850.00 mg, 1.56 mmol, 1 eq) in THF (10 mL) under Ar was added Pd / C (300 mg, 10% purity). The suspension was degassed in vacuo and heated with H 2 Purge several times. 2 The mixture was stirred at 25° C. under 4% CO (15 psi) for 12 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound as a brown solid (680 mg, crude). 1 H NMR (400 MHz, DMSO-d 6 )δ=10.37(s,1H),5.96(d,J=1.6Hz,1H),5.90(d,J=1.6Hz,1H),4.74(s,2H),4.18-3.84( m,4H),3.35(s,3H),2.58(s,2H),2.06-1.72(m,6H),1.40(s,9H),0.93(d,J=6.6Hz,3H).

[0459] tert-Butyl (3R,5S)-3-(3-((6-((2,5-dichloropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)propyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0460] To a solution of (3R,5S)-3-(3-((6-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)propyl)-4,4-difluoro-5-methylpiperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.10 mmol, 1 eq) in DMF (8 mL) was added 2,4,5-trichloropyrimidine (403.56 mg, 2.20 mmol, 2 eq) and DIPEA (355.44 mg, 2.75 mmol, 479.03 μL, 2.5 eq). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was treated with water (8 mL). The suspension was filtered and purified by column chromatography (SiO 2, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to give the title compound as a yellow solid (500 mg, 656.72 μmol, 60% yield). 1 H NMR (400 MHz, DMSO-d 6 )δ=10.90(s,1H),9.39(s,1H),8.34(s,1H),6.97(s,2H),4.17-4.01(m,3H),3.99-3.85(m,1 H),3.45(s,3H),2.66-2.52(m,2H),2.03-1.80(m,5H),1.39(s,10H),0.94(d,J=6.8Hz,3H).

[0461] 5-((2,5-dichloropyrimidin-4-yl)amino)-7-(3-((3R,5S)-4,4-difluoro-5-methylpiperidin-3-yl)propoxy)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0462] A solution of (3R,5S)-tert-butyl 3-(3-((6-((2,5-dichloropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)propyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate (500.00 mg, 831.29 μmol, 1 eq) in DCM (5 mL) and TFA (1 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated in vacuo to give the title compound as a yellow oil (500 mg, crude, TFA salt). LCMS: [M+H] + =501.2.

[0463] (1 3 R,1 5 S)-2 5 -Chloro-1 4 ,1 4 -Difluoro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-Oxa-3-aza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -Keto (27)

[0464] To a solution of 5-((2,5-dichloropyrimidin-4-yl)amino)-7-(3-((3R,5S)-4,4-difluoro-5-methylpiperidin-3-yl)propoxy)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (500 mg, 812.51 μmol, 1 eq, TFA) in DMSO (20 mL) was added DIPEA (1.05 g, 8.13 mmol, 1.42 mL, 10 eq). The reaction mixture was stirred at 80 °C for 12 hours. Then, the reaction mixture was treated with water (30 mL). The suspension was filtered to give a residue which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to give the title compound as a yellow solid (250 mg, 510.87 μmol, 63% yield, 95% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=10.80(s,1H),8.75(s,1H),8.05(s,1H),7.56-7.41(m,1H),6.63(s,1H),4.81-4.51(m,2H),4.48-4.33(m,1H),4.17-3.99(m, 1H),3.41(s,3H),2.79-2.64(m,2H),2.41-2.14(m,2H),2.05-1.86(m,2H),1.70-1.54(m,2H),0.96(d,J=6.0Hz,3H).LCMS:[M+H] + =465.2. Preparative HPLC (column: Waters XbridgeBEH C18 100*30mm*10μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 40%-70%, 8 min) to further purify 30 mg of the residue to give the title compound as a white solid (10 mg, 99% purity). 1 H NMR (400 MHz, DMSO-d 6)δ=10.81(s,1H),8.77(s,1H),8.06(s,1H),7.49(d,J=1.2Hz,1H),6.63(d,J=1.3Hz,1H),4.70(br d,J=12.8Hz,1H),4.58(br d,J=11.4Hz,1H),4.48-4.35(m,1H),4.07(dt,J=7.0,11.4Hz,1H),3.41(s,3H),2.73(br t,J=12.6Hz,1H),2.59-2.54(m,1H),2.35-2.25(m,1H),2.03-1.90(m,1H),1.87-1.77(m ,1H),1.74-1.58(m,2H),1.35(dt,J=5.2,12.8Hz,1H),0.97(d,J=6.7Hz,3H).LCMS:[M+H] + =465.3.

[0465] (1 3 R,1 5 S)-2 5 -Chloro-1 4 ,1 4 -Difluoro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-Oxa-3-aza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-42-one (11)

[0466] To(1 3 R,1 5 S)-2 5 -Chloro-1 4 ,1 4 -Difluoro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-Oxa-3-aza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2To a mixture of 2-nitro-1-ketone (150 mg, 322.65 μmol, 1 eq) and 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (166.70 mg, 645.31 μmol, 2 eq) in DMSO (5 mL) was added KI (26.78 mg, 161.33 μmol, 0.5 eq) and Cs 2 CO 3 (210.25 mg, 645.31 μmol, 2 eq). 2 The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was treated with water and the suspension was filtered. TM Prep OBD C18 150*40mm*10μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 45%-75%, 8 min) to give the title compound as a white solid (65 mg, 115.60 μmol, 36% yield, 98% purity). 1 HNMR (400 MHz, DMSO-d 6 )δ=8.84(s,1H),8.07(s,1H),7.53(s,1H),6.76(s,1H),4.69(d,J=12.4Hz,1H),4.58(d,J=1 2.6Hz,1H),4.47-4.37(m,2H),4.13-4.03(m,1H),3.82(dd,J=6.4,9.2Hz,2H),3.46(s,3H),2 .72(t,J=12.4Hz,1H),2.57-2.51(m,1H),2.42-2.23(m,1H),2.03-1.89(m,1H),1.86-1.76( m,1H),1.75-1.56(m,4H),1.38-1.29(m,1H),1.18(s,6H),0.96(d,J=6.4Hz,3H).LCMS:[M+H] + =551.4.

[0467] Example 7: (1 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -Difluoro-1 5 ,4 1 ,4 3 -Trimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-oxa- Synthesis of 3-aza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidin-1(1,3)-piperidinylcyclooctane-42-one(29)

[0468]

[0469] (1 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -Difluoro-1 5 ,4 3-Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-oxa-3-aza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidin-1(1,3)-piperidinylcyclooctan-42-one (70 mg, 150.57 μmol, 1 eq), MeI (23.51 mg, 165.63 μmol, 10.31 μL, 1.1 eq) and Cs 2 CO 3 A mixture of (73.59 mg, 225.86 μmol, 1.5 eq) in DMSO (1 mL) was stirred at 15° C. for 2 hours. The mixture was filtered and purified by preparative HPLC (column: Waters Xbridge TM Prep OBD C18 150*40mm*10μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 45%-75%, 8 min) to purify the filtrate to give the title compound as a white solid (30 mg, 62.01 μmol, 41% yield, 99% purity). 1 HNMR (400 MHz, DMSO-d 6 )δ=8.82(s,1H),8.07(s,1H),7.55(s,1H),6.75(s,1H),4.68(br d,J=12.5Hz,1H),4.58(br d,J=13.4Hz,1H),4.42(br t,J=11.8Hz,1H),4.15-4.04(m,1H),3.46(s,3H),3.26(s,3H),2.72(br t,J=12.6Hz,1H),2.57-2.52(m,1H),2.40-2.24(m,1H),2.02-1.77(m,2H),1.76-1.57(m,2H) ,1.38-1.26(m,1H),0.96(d,J=6.7Hz,3H),1.00-0.91(m,1H),0.60-0.35(m,1H).LCMS:[M+H] + =479.2.

[0470] Embodiment 8: (1 3 R,1 5 S)-2 5 -Chloro-1 4 ,1 4 -Difluoro-1 5 ,4 1 ,4 3 -Trimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-oxa- Synthesis of 3-Aza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-42-one(30)

[0471]

[0472] To(1 3 R,1 5 S)-2 5 -Chloro-1 4 ,14 -Difluoro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-Oxa-3-aza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 To a solution of -ketone (30 mg, 64.53 μmol, 1 eq) in DMSO (0.5 mL) was added Cs 2 CO 3 (31.54 mg, 96.80 μmol, 1.5 eq) and iodomethane (10.08 mg, 70.98 μmol, 4.42 μL, 1.1 eq). The reaction mixture was stirred at 15 ° C for 2 hours. The reaction mixture was filtered (10 mg scale and 30 mg scale combined), and the filtrate was concentrated in vacuo to give a residue, which was analyzed by p-HPLC (column: Waters Xbridge TM Prep OBDC18 150*40mm*10μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 50%-80%, 8 min) to purify the residue to give the title compound as a white solid (20 mg, 41.59 μmol, 99% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=8.82(s,1H),8.07(s,1H),7.55(d,J=1.1Hz,1H),6.75(d,J=1.3Hz,1H),4.69(br d,J=13.4Hz,1H),4.59(br d,J=13.1Hz,1H),4.43(br t,J=11.8Hz,1H),4.09(dt,J=7.5,11.3Hz,1H),3.47(s,3H),3.26(s,3H),2.73(br t,J=12.6Hz,1H),2.60-2.52(m,1H),2.41-2.25(m,1H),2.01-1.58(m,4H),1.40-1.29(m,1H),0.97(d,J=6.8Hz,3H).LCMS:[M+H] + =479.3.

[0473] Embodiment 9: (1 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -Difluoro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl- 4 2 ,4 3 -Dihydro-4 1 H-5-Oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinyl ring Octane-4 2 Synthesis of -ketone (14)

[0474]

[0475] Ethyl 2-((6-benzylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetate

[0476] A mixture containing 6-(benzylamino)-4-hydroxy-3-methyl-1H-benzimidazol-2-one (15 g, 55.71 mmol, 1 eq), ethyl 2-bromoacetate (8.35 g, 50.15 mmol, 5.55 mL, 0.9 eq) and Cs 2 CO 3 A flask containing a mixture of (36.32 g, 111.43 mmol, 2 eq) in DMSO (100 mL) was degassed and heated with N 2 Purge 3 times. 2 The reaction mixture was stirred at 20 °C for 12 hours under a 4% CO atmosphere. Water (100 mL) was added to the reaction mixture and the solid was filtered. The filter cake was dried under reduced pressure. The solid was washed with MeOH (50 mL) and then dried under reduced pressure to give the title compound as a white solid (8 g, 22.51 mmol, 40% yield). 1 H NMR (400 MHz, DMSO-d 6 )δppm 10.41(s,1H),7.35-7.29(m,3H),7.23-7.22(m,1H),5.97-5.94(m,2H),5.88-5.87(m,1H), 4.72(s,2H),4.21(d,J=6.0Hz,2H),4.18-4.13(m,2H),3.38(s,3H),1.21(t,J=7.2Hz,3H).

[0477] Ethyl 2-((6-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetate

[0478] A flask containing a mixture of ethyl 2-((6-(benzylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetate (8 g, 22.52 mmol, 1 eq) and Pd / C (300 mg, 10% purity) in THF (100 mL) was degassed and heated with H 2 Purge 3 times. 2 The reaction mixture was stirred at 20°C for 12 hours under atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a white solid (4.5 g, 16.96 mmol, 75% yield). LCMS: [M+H] + =266.3.

[0479] Ethyl 2-((6-((2,5-dichloropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetate

[0480] A flask containing a mixture of ethyl 2-((6-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetate (4.5 g, 16.96 mmol, 1 eq), 2,4,5-trichloropyrimidine (6.22 g, 33.93 mmol, 2 eq) and DIPEA (4.38 g, 33.93 mmol, 5.91 mL, 2 eq) in DMF (30 mL) was degassed and heated with N 2 Purge 3 times. 2 Atmosphere, the reaction mixture was stirred at 20 ° C for 12 hours. Water (30 mL) was added to the reaction mixture, and the pink solid was filtered. The filter cake was dried under reduced pressure and then washed with EtOAc (40 mL). The solid was filtered and the filter cake was dried under reduced pressure to obtain the title compound as a pink solid (4 g, 9.70 mmol, 57% yield). 1 H NMR (400 MHz, DMSO-d 6 )δppm 10.96(s,1H),9.38(s,1H),8.35(s,1H),7.02(s,1H),6.95(s,1H),4.84(s,2H),4.22-4.16(m,2H),3.51(s,3H),1.22(t,J=7.2Hz,3H).

[0481] Ethyl 2-((6-((2-((3S,5R)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetate

[0482] A flask containing a mixture of ethyl 2-((6-((2,5-dichloropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetate (1.5 g, 3.64 mmol, 1 eq) and (3S,5R)-4,4-difluoro-5-methyl-piperidin-3-amine (1.65 g, 6.26 mmol, 1.72 eq, TFA) in DMSO (30 mL) and DIPEA (6 mL) was degassed and heated with N 2 Purge 3 times. 2 The reaction mixture was stirred at 130°C for 12 hours under a C atmosphere. The reaction mixture was poured into water and filtered. The solid was washed with water to give the title compound as a yellow solid (1.2 g, 2.28 mmol, 63% yield).1 H NMR (400 MHz, DMSO-d 6 )δppm 10.90(s,1H),8.63(s,1H),8.04(s,1H),7.05(s,1H),7.02(s,1H),4.83(s,2H),4.58-4.43(m,2H),4.21-4.15(m,2H),3.50(s,3H) ,2.94-2.86(m,1H),2.67-2.59(m,2H),2.54(s,1H),2.09-1.95(m,2H),1.68(s,2H),1.21(t,J=7.2Hz,3H),0.97(d,J=6.8Hz,3H).

[0483] 2-((6-((2-((3S,5R)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetic acid

[0484] A mixture of ethyl 2-((6-((2-((3S,5R)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetate (1.2 g, 2.28 mmol, 1 eq) and LiOH.H 2 O (191.49 mg, 4.56 mmol, 2 eq) in EtOH (10 mL) and H 2 The flask was degassed with a mixture of N 2 Purge 3 times. 2 The reaction mixture was stirred at 20°C for 2 hours under a 4% CO atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was adjusted to pH = 4 with 1N HCl, filtered, and washed with water to give the title compound as a yellow solid (700 mg, 1.41 mmol, 62% yield). LCMS: [M+H] + =498.3.

[0485] (1 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -Difluoro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidin-4-cyclooctane 2 ,7-dione

[0486] A flask containing a mixture of 2-((6-((2-((3S,5R)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetic acid (700 mg, 1.41 mmol, 1 eq), HATU (534.59 mg, 1.41 mmol, 1 eq) and DIPEA (363.42 mg, 2.81 mmol, 489.78 μL, 2 eq) in DMF (10 mL) was degassed and heated with N 2 Purge 3 times. 2 The reaction mixture was stirred at 20°C for 2 hours under atmosphere. The reaction mixture was poured into water and filtered. The precipitate was washed with water, then with MeOH (10 mL), and filtered to give the title compound as a yellow solid (400 mg, 833.56 μmol, 59% yield). 1 H NMR (400 MHz, DMSO-d 6 )δppm10.82(s,1H),8.69(s,1H),8.45(d,J=8.4Hz,1H),8.00(s,1H),7.08(s,1H),6.57(s,1H),4.95(d,J=14.8Hz,1H),4.61(d,J=14. 4Hz,1H),4.42-4.27(m,2H),4.03-3.98(m,1H),3.46(s,3H),3.29-3.26(m,2H),2.67-2.54(m,1H),1.09(d,J=6.8Hz,3H).LCMS:[M+H] + =480.1.

[0487] (1 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -Difluoro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -Keto (31)

[0488] In N 2 At 0℃, 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -Difluoro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 To a solution of H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-42,7-dione in THF (5 mL) was added BH 3 ·THF (1M, 3.33 mL, 4 eq). The reaction mixture was stirred at 60°C for 12 hours. 2 Saturated NH 4 Cl aqueous solution (40 mL), and the reaction mixture was stirred for 20 min after addition. The reaction mixture was poured into water (40 mL) and extracted with EtOAc (40 mL×2). The organic phase was concentrated in vacuo to give a residue, which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give the title compound as a light yellow solid (200 mg, 429.29 μmol, 52% yield). 1 H NMR (400 MHz, DMSO-d 6 )δppm 10.80(s,1H),8.78(s,1H),8.06(s,1H),7.55(s,1H),6.64(s,1H),4.71(d ,J=12.4Hz,1H),4.53-4.39(m,2H),4.07-3.99(m,1H),3.41(s,3H),3.30- 3.20(m,1H),2.98-2.92(m,2H),2.73(t,J=12.6Hz,1H),2.58-2.52(m,1H) ,2.25-2.15(m,1H),2.05-1.88(m,1H),0.96(d,J=6.8Hz,3H).LCMS:[M+H] + =466.3.

[0489] (1 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -Difluoro-4 1 -(3-Hydroxy-3-methylbutyl)-15 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -Keto (14)

[0490] Will be equipped with (1 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -Difluoro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -ketone (100 mg, 214.65 μmol, 1 eq), (3-hydroxy-3-methylbutyl) 4-methylbenzenesulfonate (83.18 mg, 321.97 μmol, 1.5 eq), KI (17.82 mg, 107.32 μmol, 0.5 eq) and Cs 2 CO 3 The flask of a mixture of (139.87 mg, 429.29 μmol, 2 eq) in DMSO (5 mL) was degassed and heated with N 2 Purge 3 times. 2 The reaction mixture was stirred at 80°C for 3 hours under a vacuum atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue (combined with the other 2 batches), which was analyzed by preparative HPLC (column: Waters Xbridge TM PrepOBD C18 150*40mm*10μm; mobile phase: [H 2 O (10 mM NH 4 HCO 3 )-ACN]; gradient: 35%-60% B in 8.0 min) to purify the residue to give 80 mg of product. The product was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm*10 μm); mobile phase: [CO 2 -MeOH (0.1% NH 3 H 2O)]; B%: 46%, isocratic elution mode) to further purify the product (80 mg) to give the title compound as a white solid (47.7 mg, 86.41 μmol). 1 H NMR (400 MHz, DMSO-d 6 )δppm 8.87(s,1H),8.08(s,1H),7.60(s,1H),6.76(s,1H),4.71(d,J=12.4Hz,1H),4.52(d,J= 13.6Hz,1H),4.45-4.39(m,2H),4.08-4.01(m,1H),3.84-3.80(m,2H),3.46(s,3H),3.30 -3.24(m,1H),2.99-2.92(m,2H),2.74(t,J=12.8Hz,1H),2.54(s,1H),2.25-2.15(m,1H ),2.05-1.88(m,1H),1.73-1.65(m,2H),1.18(s,6H),0.97(d,J=6.4Hz,3H).LCMS:[M+H] + =552.3. The stereochemistry of compound 14 was confirmed by the crystal structure of BCL6 / compound 14.

[0491] Embodiment 10: (1 3 R,1 5 S)-2 5 -Chloro-1 4 ,1 4 -Difluoro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl- 4 2 ,4 3 -Dihydro-4 1 H-5-Oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinyl ring Octane-4 2 Synthesis of -ketone (15)

[0492]

[0493] 4-Bromo-2-methoxy-6-nitroaniline

[0494] To a solution of 2-methoxy-6-nitroaniline (100 g, 594.71 mmol, 100 mL, 1 eq) in DCM (2 L) was added NBS (137.60 g, 773.12 mmol, 1.3 eq). The reaction mixture was stirred at 25 ° C for 12 hours. The reaction mixture was concentrated in vacuo (combined with 4 other batches of equal scale), and the residue was ground with water (1 L) at 25 ° C for 30 min and filtered. The filter cake was dried and then ground with petroleum ether / ethyl acetate = 4 / 1 (500 mL) at 25 ° C for 30 min. The solution was filtered and the filter cake was dried to give the title compound as a yellow solid (500 g, 95% purity, 68% yield). 1 H NMR (400 MHz, MeCN-d 3 )δ=7.77(d,J=2.1Hz,1H),7.06(d,J=2.0Hz,1H),6.64(br s,2H),3.90(s,3H).

[0495] 4-Bromo-2-methoxy-N-methyl-6-nitroaniline

[0496] A solution of 4-bromo-2-methoxy-6-nitroaniline (50 g, 202.39 mmol, 1 eq) in DMF (2 L) was stirred at 0°C for 10 min. Cs 2 CO 3 To the reaction mixture was added 4-[4-[( ... 1 H NMR (400 MHz, CDCl 3 )δ=7.59(d,J=1.6Hz,1H),7.24(d,J=5.2Hz,1H),7.18(s,1H),3.87(s,3H),2.86(d,J=5.2Hz,3H).LCMS:[M+H] + =261.1.

[0497] 4-Bromo-6-methoxy-N1-methylbenzene-1,2-diamine

[0498] In N 2 Under atmosphere, 4-bromo-2-methoxy-N-methyl-6-nitroaniline (75 g, 287.28 mmol, 1 eq) and SnCl 2 A mixture of (259.30 g, 1.15 mol, 4 eq) in EtOH (1.5 L) was stirred at 75 ° C for 2 hours. The reaction mixture was concentrated in vacuo (combined with four other batches of the same scale). The residue was treated with water (2 L) and the pH was adjusted to 14 with NaOH. The solid was filtered, the filter cake was washed with EtOAc (4 L), and the filtrate was extracted with EtOAc (1 L×3). The combined organic phases were washed with brine (3 L) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to obtain a residue which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 50 / 1 to 2 / 1) to give the title compound as a colorless oil (260 g, 1.08 mol, 75% yield, 96% purity). 1 HNMR (400MHz, CDCl 3)δ=6.54(d,J=1.8Hz,1H),6.45(d,J=2.0Hz,1H),4.11-3.83(m,2H),3.79(s,3H),3.45-2.85(m,1H),2.63(s,3H).LCMS:[M+H] + =231.0.

[0499] 5-Bromo-7-methoxy-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0500] To a solution of 4-bromo-6-methoxy-N1-methylbenzene-1,2-diamine (45g, 194.73mmol, 1eq) in DMF (450mL) was added CDI (63.15g, 389.46mmol, 2eq). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (500mL) and then filtered. The filter cake was washed with water (500mL) and then with EtOAc (500mL). The solid was dried in vacuo to give the title compound as a white solid (64g, 221.56mmol, 57% yield, 89% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=11.95(br s,1H),7.00(s,1H),6.93(d,J=1.9Hz,1H),3.86(d,J=1.8Hz,3H),3.63(d,J=1.9Hz,3H).

[0501] 5-(Benzylamino)-7-methoxy-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0502] To a mixture of 5-bromo-7-methoxy-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (32 g, 124.47 mmol, 1 eq) and benzylamine (16.01 g, 149.37 mmol, 16.28 mL, 1.2 eq) in THF (320 mL) was added LiHMDS (1 M, 298.74 mL, 2.4 eq) dropwise at 15°C. The reaction mixture was degassed and heated with N 2 BrettPhos (2.67 g, 4.98 mmol, 0.04 eq) and BrettPhos Pd G3 (2.26 g, 2.49 mmol, 0.02 eq) were added to the reaction mixture under N 2 The mixture was stirred at 80°C for 2 hours. 4 The reaction mixture was quenched with aqueous Cl (50 mL) (combined with another batch of the same scale), filtered, and washed with anhydrous Na 2SO 4 The filtrate was concentrated in vacuo and purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 50 / 1 to 2 / 1) to give 65 g of -90% pure product, which was triturated with EtOAc (150 mL) at 15 °C for 30 min to give the title compound as a brown solid (58 g, 192.43 mmol, 77% yield, 94% purity). 1 HNMR (400 MHz, DMSO-d 6 )δ=10.37(s,1H),7.37-7.29(m,4H),7.24-7.18(m,1H),6.06(d,J=1.8Hz,1H),5.96(t ,J=6.0Hz,1H),5.83(d,J=2.0Hz,1H),4.23(d,J=6.0Hz,2H),3.73(s,3H),3.32(s,3H).

[0503] 5-(Benzylamino)-7-hydroxy-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0504] To a solution of 5-(benzylamino)-7-methoxy-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (58 g, 204.71 mmol, 1 eq) in DCM (1.1 L) was added BBr at -70 °C. 3 (153.86 g, 614.14 mmol, 59.18 mL, 3 eq) in DCM (100 mL). The reaction mixture was warmed to 40 °C and stirred at 40 °C for 2 hours. 3 The reaction mixture was quenched with Cl:MeOH=10:1 (1.1 L), and then concentrated in vacuo to give a residue. The residue was treated with 4N HCl (150 mL) and stirred at 40°C for 30 min. 2 CO 3 The resulting mixture was treated with aqueous solution to pH = 9 and then filtered. The filter cake was triturated with EtOAc (150 mL) at 15 °C for 30 min to afford the title compound as a white solid (44 g, 158.49 mmol, 77% yield, 97% purity). 1 H NMR (400 MHz, DMSO-d 6)δ=10.23(s,1H),9.26(s,1H),7.36-7.27(m,4H),7.23-7.17(m,1H),5.89-5.8 3(m,2H),5.72(d,J=2.0Hz,1H),4.17(d,J=6.0Hz,2H),3.33(s,3H).LCMS:[M+H] + =270.2.

[0505] tert-Butyl (7-hydroxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate

[0506] To a solution of 5-(benzylamino)-7-hydroxy-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (15 g, 55.70 mmol, 1 eq) in MeOH (300 mL) was added Pd / C (5 g, 10% purity) under Ar. The suspension was degassed and heated with H 2 The reaction mixture was stirred at 50°C for 12 hours under hydrogen (50 psi). Then, Boc 2 O (9.74 g, 44.65 mmol, 10.26 mL, 1 eq) and the reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue which was triturated with ethyl acetate (30 mL) at 15° C. for 10 min to give the title compound as a red solid (12 g). 1 H NMR (400 MHz, DMSO-d 6 )δ=10.60(s,1H),9.66(s,1H),9.16(br s,1H),6.77(s,2H),3.45(s,3H),1.52(s,9H).LCMS:[M+H] + =280.1.

[0507] tert-Butyl (7-(2-chloroethoxy)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate

[0508] To a solution of tert-butyl (7-hydroxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate (10.00 g, 35.80 mmol, 1 eq) and 2-chloroethyl 4-methylbenzenesulfonate (8.40 g, 35.80 mmol, 1 eq) in ACN (20 mL) and DMF (20 mL) was added K 2 CO 3 (12.37 g, 89.51 mmol, 2.5 eq). 2The reaction mixture was stirred at 70 ° C for 12 hours. The reaction was quenched with water (100 mL), then extracted with ethyl acetate (80 mL × 3). The organic phase was separated and washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was ground with petroleum ether: ethyl acetate = 1: 1 (20 mL) at 25 ° C for 5 min, filtered, and the filter cake was dried in vacuo to obtain the title compound as a white solid (7.8 g, 19.63 mmol, 55% yield, 86% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=10.73(s,1H),9.19(s,1H),6.89(s,1H),6.84(s,1H),4.24(t,J=4.8Hz,2H),4.00(t,J=4.8Hz,2H),3.43(s,3H),1.46(s,9H).

[0509] 5-Amino-7-(2-chloroethoxy)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0510] A solution of tert-butyl (7-(2-chloroethoxy)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate (7.8 g, 22.82 mmol, 1 eq) in TFA (16 mL) and DCM (80 mL) was stirred at 25 °C for 30 min. The reaction mixture was concentrated in vacuo to give the title compound as a brown oil (12 g, crude, TFA). LCMS: [M+H] + =242.2.

[0511] 7-(2-Chloroethoxy)-5-((2,5-dichloropyrimidin-4-yl)amino)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0512] A mixture of 5-amino-7-(2-chloroethoxy)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (9 g, 19.16 mmol, 1 eq, TFA), 2,4,5-trichloropyrimidine (7.03 g, 38.32 mmol, 2 eq) and DIEA (7.43 g, 57.48 mmol, 10.01 mL, 3 eq) in DMF (90 mL) was degassed and heated to 40 ℃ for 2 h. 2 Purge 3 times. 2Under atmosphere, the reaction mixture was stirred at 25 ° C for 2 hours. Water (30 mL) was added and a solid precipitate was formed. The mixture was filtered, and the filter cake was washed with petroleum ether: ethyl acetate = 1: 1 (50 mL) and vacuum dried to give the title compound as a yellow solid (5.7 g, 13.93 mmol, 73% yield, 95% purity). It can be used directly in the next step without further purification. 1 H NMR (400 MHz, DMSO-d 6 )δ=10.94(s,1H),9.40(s,1H),8.34(s,1H),6.98(br d,J=14.8Hz,2H),4.36-4.28(m,2H),4.07-3.99(m,2H),3.49(s,3H).LCMS:[M+H] + =388.1.

[0513] 5-((2-((3R,5S)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-7-(2-chloroethoxy)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0514] A flask containing a mixture of 7-(2-chloroethoxy)-5-((2,5-dichloropyrimidin-4-yl)amino)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (1 g, 2.57 mmol, 1 eq), (3R,5S)-4,4-difluoro-5-methylpiperidin-3-amine (1.95 g, 5.15 mmol, 2 eq, TFA) and DIEA (3.33 g, 25.73 mmol, 4.48 mL, 10 eq) in DMSO (10 mL) was degassed and heated with N 2 Purge 3 times. 2 The reaction mixture was stirred at 80°C for 12 hours under a molten-gas atmosphere. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phases were purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to give a residue which was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate=1 / 1 to ethyl acetate:THF=10:1) to give the title compound as a yellow solid (540 mg, 967.46 μmol, 38% yield, 90% purity). 1 H NMR (400 MHz, DMSO-d 6)δ=10.88(br s,1H),8.64(br s,1H),8.04(s,1H),7.12(br s,1H),7.00(br s,1H),4.65-4.43(m,2H),4.35-4.31(m,1H),4.08-3.98(m,2H),3.55-3.42(m,3 H),2.97-2.83(m,1H),2.63(dt,J=7.0,12.1Hz,2H),2.35-1.86(m,4H),0.98(br d,J=6.5Hz,3H).

[0515] (1 3 R,1 5 S)-2 5 -Chloro-1 4 ,1 4 -Difluoro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-Oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidin-1(1,3)-piperidinylcyclooctane-42-one (32)

[0516] To a solution of 5-((2-((3R,5S)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-7-(2-chloroethoxy)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (180 mg, 358.32 μmol, 1 eq) in anhydrous DMF (30 mL) was added K 2 CO 3 (99.04 mg, 716.64 μmol, 2 eq) and NaI (537.10 mg, 3.58 mmol, 10 eq). In a glove box, the reaction mixture was stirred at 100 ° C for 36 hours. The reaction mixture was concentrated in vacuo and water (50 mL) was added. The mixture was extracted with ethyl acetate (35 mL×3). The combined organic phase was purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to give a residue which was purified by column chromatography (SiO 2 The residue was purified by HPLC-MS / MS (compound No. 5,4-dihydro-2-nitropropene / 1 ... 1 H NMR (400 MHz, DMSO-d 6)δ=10.80(s,1H),8.78(s,1H),8.07(s,1H),7.55(s,1H),6.63(d,J=1.3Hz,1H),4.79-4.66(m,1H),4.58-4. 47(m,1H),4.45-4.36(m,1H),4.13-4.01(m,1H),3.41(s,3H),3.05-2.85(m,2H),2.80-2.64(m,1H),2.54(br s,1H),2.23-2.15(m,1H),2.07-1.89(m,1H),0.96(d,J=6.8Hz,3H).LCMS:[M+1] + =466.2.

[0517] (1 3 R,1 5 S)-2 5 -Chloro-1 4 ,1 4 -Difluoro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -Keto (15)

[0518] To(1 3 R,1 5 S)-25-chloro-1 4 ,1 4 -Difluoro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazo-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4-nitropropane 2 To a solution of 2-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (77.63 mg, 300.50 μmol, 2 eq) in DMSO (1 mL) was added KI (12.47 mg, 75.13 μmol, 0.5 eq) and Cs 2 CO 3(97.91 mg, 300.50 μmol, 2 eq). The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was filtered and analyzed by preparative HPLC (column: Waters Xbridge TM BEH C18 100*30mm*10μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 35%-55%, 8 min) to purify the filtrate to give the title compound as a white solid (19 mg, 33.73 μmol, 22% yield, 98% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=8.88(s,1H),8.08(s,1H),7.60(s,1H),6.76(d,J=1.0Hz,1H),4.77-4.65(m,1H),4.56-4.38(m,3H),4.10-3.99(m,1H),3.82(br dd,J=5.9,10.3Hz,2H),3.46(s,3H),3.28(br s,1H),3.04-2.86(m,2H),2.79-2.64(m,1H),2.54(br s,1H),2.24-2.17(m,1H),2.05-1.87(m,1H),1.69(br dd,J=4.7,9.2Hz,2H),1.18(s,6H),0.97(d,J=6.8Hz,3H).LCMS:[M+H] + =552.4.

[0519] Example 11: (1 3 R,1 5 S)-2 5 -Chloro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro- 41H-5,8-Dioxa-3-aza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -ketone Synthesis of (12)

[0520]

[0521] tert-Butyl (3R,5S)-3-(2-((6-benzylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)ethoxy)-5-methylpiperidine-1-carboxylate

[0522] To a mixture of 5-(benzylamino)-7-hydroxy-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (1 g, 3.71 mmol, 1 eq) and (3S,5R)-3-methyl-5-(2-(tosyloxy)ethoxy)piperidine-1-carboxylic acid tert-butyl ester (1.54 g, 3.71 mmol, 1 eq) in DMSO (15 mL) was added K 2 CO 3(1.03 g, 7.43 mmol, 2 eq). 2 The reaction mixture was stirred at 70°C for 1.5 hours under a 2% CO atmosphere. The reaction mixture was treated with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (80 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to give a residue which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 3 / 1 to 0 / 1) to give the title compound as a yellow solid (1 g, 1.43 mmol, 37% yield, 73% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=10.40-10.33(m,1H),7.36-7.18(m,5H),6.01(s,1H),5.97-5.90(m,1H),5.84(d ,J=1.8Hz,1H),4.21(d,J=5.5Hz,2H),4.04-4.00(m,2H),3.85-3.72(m,3H),3.34(br s,5H),2.05(br d,J=6.1Hz,1H),1.37(s,11H),0.94-0.87(m,2H),0.86(d,J=6.6Hz,3H).

[0523] tert-Butyl (3R,5S)-3-(2-((6-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)ethoxy)-5-methylpiperidine-1-carboxylate

[0524] To a solution of tert-butyl (3R,5S)-3-(2-((6-(benzylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)ethoxy)-5-methylpiperidine-1-carboxylate (1 g, 1.96 mmol, 1 eq) in THF (20 mL) under Ar was added Pd / C (400 mg, 10% purity). The suspension was degassed in vacuo and heated with H 2 Purge several times. 2 The reaction mixture was stirred at 60 °C for 2 hours under (15 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a black oil (0.9 g, crude). LCMS: [M-100+H] + =321.3.

[0525] tert-Butyl (3R,5S)-3-(2-((6-((2,5-dichloropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)ethoxy)-5-methylpiperidine-1-carboxylate

[0526] To a solution of (3R,5S)-tert-butyl 3-(2-((6-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)ethoxy)-5-methylpiperidine-1-carboxylate (900.00 mg, 2.14 mmol, 1 eq) in DMF (10 mL) was added 2,4,5-trichloropyrimidine (785.16 mg, 4.28 mmol, 2 eq) and DIPEA (691.55 mg, 5.35 mmol, 932.01 μL, 2.5 eq). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was treated with water (25 mL) and the precipitate was filtered. The solid was filtered and dried to give the title compound as a white solid (0.7 g, 1.15 mmol, 54% yield, 93% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=10.90(s,1H),9.38(s,1H),8.33(s,1H),6.96(d,J=3.2Hz,2H),4.22-4.02(m,3H),3.90-3.72(m,3H),3.47(s,3H),3.29( s,1H),2.47-2.16(m,2H),2.06(d,J=11.6Hz,1H),1.55-1.44(m,1H),1.37(s,9H),0.99-0.88(m,1H),0.85(d,J=6.8Hz,3H).

[0527] 5-((2,5-dichloropyrimidin-4-yl)amino)-1-methyl-7-(2-(((3R,5S)-5-methylpiperidin-3-yl)oxy)ethoxy)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0528] To a solution of tert-butyl (3R,5S)-3-(2-((6-((2,5-dichloropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)ethoxy)-5-methylpiperidine-1-carboxylate (700.00 mg, 1.23 mmol, 1 eq) in DCM (12 mL) was added TFA (3.23 g, 28.36 mmol, 2.10 mL, 22.99 eq). The reaction mixture was stirred at 25 °C for 30 min. The reaction mixture was concentrated in vacuo to give the title compound as a yellow oil (0.8 g, crude, TFA). LCMS: [M+H] + =467.1

[0529] (1 3 R,1 5 S)-2 5 -Chloro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5,8-Dioxa-3-aza-4(6,4)-benzo[d]imidazo-2(2,4)-pyrimidine-1(1,3)-piperidin-4-cyclooctane 2 -ketone

[0530] To a solution of 5-((2,5-dichloropyrimidin-4-yl)amino)-1-methyl-7-(2-(((3R,5S)-5-methylpiperidin-3-yl)oxy)ethoxy)-1,3-dihydro-2H-benzo[d]imidazol-2-one (800 mg, 1.38 mmol, 1 eq, TFA) in DMSO (75 mL) was added DIPEA (1.78 g, 13.76 mmol, 2.40 mL, 10 eq). The reaction mixture was stirred at 80 °C for 12 hours. The reaction was quenched with water (100 mL), filtered, and purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to purify the solid to give the title compound as a white solid (190 mg, 176.38 μmol, 13% yield). LCMS: [M+H] + =431.2.

[0531] (1 3 R,1 5 S)-2 5 -Chloro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl-4 2 ,4 3-Dihydro-41H-5,8-dioxa-3-aza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -Keto (12)

[0532] To(1 3 R,1 5 S)-2 5 -Chloro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5,8-Dioxa-3-aza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 To a mixture of 4-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (190 mg, 440.95 μmol, 1 eq) and 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (227.82 mg, 881.90 μmol, 2 eq) in DMSO (3 mL) was added Cs 2 CO 3 (287.34 mg, 881.90 μmol, 2 eq) and KI (36.60 mg, 220.48 μmol, 0.5 eq). The reaction mixture was stirred at 80 ° C for 12 hours. The reaction mixture was filtered and purified by preparative HPLC (column: Phenomenex C18 80*40mm*3μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 25%-55%, 8 min) to purify the residue to give the title compound as a white solid (50 mg, 95.74 μmol, 22% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=8.85(s,1H),8.05(s,1H),7.70(s,1H),6.79(s,1H),4.69-4.58(m, 2H),4.45(s,1H),4.43-4.35(m,1H),4.20-4.08(m,1H),3.86-3.68(m, 5H),3.45(s,3H),2.48-2.38(m,2H),2.01-1.89(m,1H),1.76-1.55(m, 3H),1.18(s,6H),1.15-1.07(m,1H),0.88(d,J=6.4Hz,3H).LCMS:[M+H] + =517.4.

[0533] Example 12: (1 3 S,1 5 R)-2 5 -Chloro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5,8-Dioxa-3-aza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -ketone Synthesis of (13)

[0534]

[0535] tert-Butyl (3S,5R)-3-(2-((6-benzylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)ethoxy)-5-methylpiperidine-1-carboxylate

[0536] To a solution of 5-(benzylamino)-7-hydroxy-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (940 mg, 3.49 mmol, 1 eq) and (3R,5S)-3-methyl-5-(2-(tosyloxy)ethoxy)piperidine-1-carboxylic acid tert-butyl ester (1.44 g, 3.49 mmol, 1 eq) in DMSO (10 mL) was added K 2 CO 3 (964.86 mg, 6.98 mmol, 2 eq). The reaction mixture was stirred at 70 °C for 1.5 hours. The reaction was quenched with water (30 mL) and then extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (20 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to give a residue which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to purify the residue to give the title compound as a yellow solid (900 mg, 1.73 mmol, 49% yield). LCMS: [M+H] + =511.3.

[0537] tert-Butyl (3S,5R)-3-(2-((6-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)ethoxy)-5-methylpiperidine-1-carboxylate

[0538] To a solution of tert-butyl (3S,5R)-3-(2-((6-(benzylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)ethoxy)-5-methylpiperidine-1-carboxylate (900 mg, 1.76 mmol, 1 eq) in THF (8 mL) under Ar was added Pd / C (400 mg, 10% purity). The suspension was degassed in vacuo and purged several times. Under H 2 The reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated in vacuo to give the title compound as a black solid (900 mg, crude). LCMS: [M-100+H]+ =321.2.

[0539] tert-Butyl (3S,5R)-3-(2-((6-((2,5-dichloropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)ethoxy)-5-methylpiperidine-1-carboxylate

[0540] To a solution of (3S,5R)-3-(2-((6-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)ethoxy)-5-methylpiperidine-1-carboxylic acid tert-butyl ester (900 mg, 2.14 mmol, 1 eq) and 2,4,5-trichloropyrimidine (785.16 mg, 4.28 mmol, 2 eq) in DMF (9 mL) was added DIEA (553.23 mg, 4.28 mmol, 745.59 μL, 2 eq). The reaction mixture was stirred at 25 °C for 2 hours. The reaction was quenched with water (10 mL) and filtered. The filter cake was dried under reduced pressure to give a residue, which was triturated with (petroleum ether / ethyl acetate=3 / 1, 5 mL) at 25 °C for 10 min to give the title compound as a yellow solid (800 mg, 1.38 mmol, 65% yield, 98% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=10.90(s,1H),9.39(s,1H),8.33(s,1H),6.97(d,J=2.9Hz,2H),4.14(br t,J=4.4Hz,2H),3.88-3.82(m,2H),3.47(s,3H),2.45-2.16(m,3H),2.06(br d,J=11.9Hz,1H),1.55-1.44(m,2H),1.37(s,11H),0.85(d,J=6.5Hz,3H).

[0541] 5-((2,5-dichloropyrimidin-4-yl)amino)-1-methyl-7-(2-(((3S,5R)-5-methylpiperidin-3-yl)oxy)ethoxy)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0542] To a solution of (3S,5R)-3-[2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-3-methyl-2-oxo-1H-benzimidazol-4-yl]oxy]ethoxy]-5-methyl-piperidine-1-carboxylic acid tert-butyl ester (800 mg, 1.41 mmol, 1 eq) in DCM (8 mL) was added TFA (2 mL). The reaction mixture was stirred at 25 °C for 30 min. The reaction mixture was concentrated in vacuo to give the title compound as a yellow oil (800 mg, 1.38 mmol, 98% yield, TFA). LCMS: [M+H] + =467.3.

[0543] (1 3 S,1 5 R)-2 5 -Chloro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5,8-Dioxa-3-aza-4(6,4)-benzo[d]imidazo[2,4]pyrimidine-1(1,3)-piperidin-4-cyclooctane 2 -ketone

[0544] To a solution of (3S,5R)-3-[2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-3-methyl-2-oxo-1H-benzimidazol-4-yl]oxy]ethoxy]-5-methyl-piperidine-1-carboxylic acid tert-butyl ester (800 mg, 1.38 mmol, 1 eq, TFA) in DMSO (36 mL) was added DIEA (1.78 g, 13.76 mmol, 2.40 mL, 10 eq). The reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was concentrated in vacuo to give a residue which was purified by column chromatography (SiO 2 , petroleum ether / THF=5 / 1 to 0 / 1) to give the title compound as a yellow solid (120 mg, 161.53 μmol, 12% yield). 1 HNMR (400 MHz, DMSO-d 6)δ=10.83(s,1H),8.77(s,1H),8.03(s,1H),7.65(d,J=0.9Hz,1H),6.66(d,J=1.3Hz,1H),4.69-4.55(m,2H),4.42-4.35(m ,1H),4.18-4.08(m,1H),3.88-3.66(m,3H),3.40(s,3H),2.47-2.38(m,2H),1.98-1.91(m,1H),1.67-1.54(m,1H),1.12(br d,J=11.2Hz,1H),0.87(d,J=6.8Hz,3H).

[0545] (1 3 S,1 5 R)-2 5 -Chloro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5,8-Dioxa-3-aza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -Keto (13)

[0546] To a solution of (13S,15R)-25-chloro-15,43-dimethyl-42,43-dihydro-41H-5,8-dioxa-3-aza-4(6,4)-benzo[d]imidazol-2(2,4)-pyrimidin-1(1,3)-piperidinylcyclooctan-42-one (90 mg, 208.87 μmol, 1 eq) in DMSO (1 mL) were added KI (17.34 mg, 104.44 μmol, 0.5 eq), Cs 2 CO 3 (136.11 mg, 417.74 μmol, 2 eq) and 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (107.92 mg, 417.74 μmol, 2 eq). The reaction mixture was stirred at 80 ° C for 12 hours, then cooled to 25 ° C and purified by preparative HPLC (column: Waters Xbridge TM BEH C18100*30mm*10μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 40%-70%, 8 min) to afford the title compound as a white solid (20 mg, 38.30 μmol, 18% yield, 96% purity). 1H NMR (400 MHz, DMSO-d 6 )δ=8.85(s,1H),8.05(s,1H),7.70(s,1H),6.79(d,J=1.1Hz,1H),4.69-4.58(m,2H),4.39(br dd,J=3.6,12.8Hz,1H),4.20-4.09(m,1H),3.82(br dd,J=5.3,9.8Hz,3H),3.78-3.67(m,2H),3.45(s,3H),2.47-2.36(m,2H),2.01-1.91(m,1H),1.70(br dd,J=6.3,10.4Hz,2H),1.65-1.56(m,1H),1.18(s,6H),1.12(br d,J=11.3Hz,1H),0.88(d,J=6.5Hz,3H).LCMS:[M+H] + =517.4.

[0547] Example 13: (1 3 R,1 5 S)-2 5 -Chloro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro- 4 1 H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -ketone Synthesis of (16)

[0548]

[0549] tert-Butyl (5-methylpyridin-3-yl)carbamate

[0550] To a solution of 5-methylpyridin-3-amine (12.5 g, 115.59 mmol, 1 eq) in THF (100 mL) was added NaHMDS (1 M, 254.30 mL, 2.2 eq) at 25°C, and the reaction mixture was stirred for 30 min. Then, Boc 2 O (26.99 g, 123.68 mmol, 28.41 mL, 1.07 eq) in THF (25 mL), and the reaction mixture was stirred at 25 ° C for 12 hours. The reaction mixture was quenched with water (50 mL) (combined with another batch of the same scale) and treated with 0.2M HCl (300 mL). The mixture was extracted with EtOAc (500 mL×3). The combined organic phase was washed with brine (500 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to give a residue, which was purified by silica gel column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give the title compound as a white solid (27 g, 128.35 mmol, 56% yield, 99% purity). 1 HNMR (400 MHz, DMSO-d 6)δppm 9.49(s,1H),8.39(s,1H),8.01(s,1H),7.74(s,1H),2.24(s,3H),1.47(s,9H).

[0551] tert-Butyl (5-methylpiperidin-3-yl)carbamate

[0552] To a solution of tert-butyl (5-methylpyridin-3-yl)carbamate (17 g, 81.63 mmol, 1 eq) in AcOH (340 mL) was added Pd / C (14 g, 10% purity) and PtO under Ar. 2 (1.85 g, 8.16 mmol, 0.1 eq). The suspension was degassed in vacuo and heated to 40 % by volume. 2 Purge several times. 2 The reaction mixture was stirred at 80°C for 12 hours under 3 Mpa. The reaction mixture was filtered and the filter cake was washed with MeOH (500 mL x 3). The filtrate was concentrated in vacuo to give a residue, which was washed with saturated NaHCO 3 The aqueous solution was adjusted to pH 8. The mixture was treated with water (400 mL) and then extracted with EtOAc (200 mL×3). The combined organic phases were washed with brine (400 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to give a residue, which was purified by silica gel column chromatography (silica gel, ethyl acetate / MeOH = 6 / 1 to 0 / 1) to give the title compound as a white solid (7.5 g, 35.00 mmol, 43% yield). 1 H NMR (400 MHz, DMSO-d 6 )δ=6.64(br d,J=7.9Hz,1H),3.30-3.15(m,1H),3.05-2.83(m,2H),2.78-2.52(m,2H),2.14-1.97(m,1H),1.89-1.82(m,1H),1.77(br d,J=12.3Hz,1H),1.69-1.41(m,1H),1.39-1.36(m,9H),0.76(d,J=6.7Hz,3H).

[0553] tert-Butyl (1-benzyl-5-methylpiperidin-3-yl)carbamate

[0554] A mixture of tert-butyl (5-methylpiperidin-3-yl)carbamate (10 g, 46.66 mmol, 1 eq), benzaldehyde (5.94 g, 56.00 mmol, 5.66 mL, 1.2 eq) and AcOH (1.40 g, 23.33 mmol, 1.33 mL, 0.5 eq) in DMF (250 mL) was stirred at 15 ° C for 2 hours. Then, sodium triacetoxyborohydride (19.78 g, 93.33 mmol, 2 eq) was added, and the reaction mixture was stirred at 15 ° C for 10 hours. The reaction was quenched with water (1 L), and then extracted with EtOAc (600 mL×3). The combined organic phase was washed with brine (1 L) and dried over anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate in vacuo to obtain a residue, which was purified by preparative HPLC (column: Agela DuraShell C18 250*70mm*10μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 50%-75%, 20 min) to purify the residue to give the title compound as a white solid (5 g, 16.26 mmol, 35% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=7.34-7.22(m,5H),6.73(br d,J=8.1Hz,1H),3.50-3.39(m,3H),2.81(br d,J=7.4Hz,1H),2.67(br d,J=9.2Hz,1H),1.73(br d,J=12.0Hz,1H),1.65-1.49(m,2H),1.39(br s,1H),1.35(s,9H),1.26(br s,1H),0.79(br d,J=6.7Hz,3H).

[0555] tert-Butyl ((3R,5S)-1-benzyl-5-methylpiperidin-3-yl)carbamate and tert-butyl ((3S,5R)-1-benzyl-5-methylpiperidin-3-yl)carbamate

[0556] Tert-butyl (1-benzyl-5-methylpiperidin-3-yl)carbamate (5 g, 16.42 mmol, 1 eq) was separated by SFC (column: REGIS (s, s) WHELK-O1 (250 mm*50 mm, 10 μm); mobile phase: [hexane-IPA]; B%: 5%-5%, 3.5 min) to give tert-butyl ((3R, 5S)-1-benzyl-5-methylpiperidin-3-yl)carbamate as a white solid (1.8 g, 5.79 mmol, 98% yield, 98% purity), and tert-butyl ((3S, 5R)-1-benzyl-5-methylpiperidin-3-yl)carbamate as a white solid (1.8 g, 5.62 mmol, 95% yield, 95% purity). Tert-butyl ((3R,5S)-1-benzyl-5-methylpiperidin-3-yl)carbamate: 1 H NMR (400 MHz, DMSO-d 6 )δ=7.33-7.22 (m, 5H), 6.74 (br d, J=8.2 Hz, 1H), 3.48-3.40 (m, 3H), 2.80 (br d, J=7.9 Hz, 1H), 2.67 (br d, J=9.3 Hz, 1H), 1.73 (br d, J=12.2 Hz, 1H), 1.63-1.50 (m, 2H), 1.44-1.38 (m, 1H), 1.34 (s, 9H), 1.25 (br s, 1H), 0.78 (brd, J=6.7 Hz, 3H). tert-Butyl ((3S,5R)-1-benzyl-5-methylpiperidin-3-yl)carbamate: 1 H NMR (400 MHz, DMSO-d 6 )δ=7.34-7.22(m,5H),6.74(br d,J=8.2Hz,1H),3.44(br d,J=3.7Hz,3H),2.84-2.76(m,1H),2.67(br d,J=8.9Hz,1H),1.72(br d,J=12.0Hz,1H),1.63-1.51(m,2H),1.43-1.38(m,1H),1.34(s,9H),1.25(br s,1H),0.80-0.76(m,3H).

[0557] tert-Butyl ((3R,5S)-5-methylpiperidin-3-yl)carbamate

[0558] To a solution of tert-butyl ((3S,5R)-1-benzyl-5-methylpiperidin-3-yl)carbamate (1.30 g, 4.27 mmol, 1 eq) in THF (13 mL) was added Pd / C (700 mg, 10% purity) under Ar. The suspension was degassed in vacuo and heated with H2 Purge several times. 2 The reaction mixture was stirred at 25° C. under 4% CO (15 psi) for 12 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound as a white solid (0.8 g, crude). 1 H NMR (400 MHz, MeOD-d 4 )δ=3.41(ddd,J=4.5,7.1,11.3Hz,1H),3.11-3.03(m,1H),2.87(br dd,J=3.5,12.4Hz,1H),2.14(t,J=11.6Hz,1H),2.05-1.97(m,1H),1.97-1.9 0(m,1H),1.68-1.54(m,1H),1.43(s,9H),1.40(s,1H),0.87(d,J=6.6Hz,3H).

[0559] tert-Butyl ((3R,5S)-1-(5-chloro-4-((7-(2-chloroethoxy)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)-5-methylpiperidin-3-yl)carbamate

[0560] To a mixture of 7-(2-chloroethoxy)-5-((2,5-dichloropyrimidin-4-yl)amino)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (1.5 g, 3.86 mmol, 1 eq) and tert-butyl ((3R,5S)-5-methylpiperidin-3-yl)carbamate (992.57 mg, 4.63 mmol, 1.2 eq) in DMSO (15 mL) was added DIPEA (997.67 mg, 7.72 mmol, 1.34 mL, 2 eq). The reaction mixture was stirred at 100 °C for 2 hours. The reaction was quenched with water (20 mL) and the solid was filtered. The filter cake was dried in vacuo to give a residue which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to purify the residue to give the title compound as a yellow solid (1.1 g, 1.84 mmol, 48% yield, 95% purity). LCMS: [M+H] + =510.2.

[0561] 5-((2-((3R,5S)-3-amino-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-7-(2-chloroethoxy)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0562] A solution of tert-butyl ((3R,5S)-1-(5-chloro-4-((7-(2-chloroethoxy)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)-5-methylpiperidin-3-yl)carbamate (600 mg, 1.06 mmol, 1 eq) in DCM (10 mL) and TFA (2 mL) was stirred at 25 °C for 30 min. The reaction mixture was concentrated in vacuo to give the title compound as a brown oil (600 mg, crude, TFA). LCMS: [M+H] + =464.4.

[0563] (1 3 R,1 5 S)-2 5 -Chloro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -ketone

[0564] In a glove box, 5-((2-((3R,5S)-3-amino-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-7-(2-chloroethoxy)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (200 mg, 428.85 μmol, 1 eq), K 2 CO 3 A mixture of 4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4- 2 SO 4 Dry, filter and concentrate in vacuo to give a residue which was purified by column chromatography (SiO 2 The residue was purified by filtration (4% by weight, petroleum ether / THF = 4 / 1 to 1 / 1) to give the title compound as a yellow solid (320 mg). 1 H NMR (400 MHz, DMSO-d 6)δ=10.81(br s,1H),8.65(s,1H),8.00(s,1H),7.66(br s,1H),6.87(s,2H),4.80(brd,J=11.1Hz,1H),4.49(br d,J=10.8Hz,1H),4.36(br t,J=10.9Hz,1H),4.07-3.96(m,1H),3.40(br s,3H),3.01(br t,J=11.1Hz,1H),2.94-2.75(m,2H),2.39(br t,J=12.1Hz,1H),2.16-2.10(m,1H),1.90(s,1H),1.82(br d,J=11.9Hz,1H),1.57(br d,J=3.1Hz,1H),0.85(br d,J=6.4Hz,3H).LCMS:[M+1] + =430.2.

[0565] (1 3 R,1 5 S)-2 5 -Chloro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -Keto (16)

[0566] (1 3 R,1 5 S)-2 5 -Chloro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -ketone (290 mg, 674.57 μmol, 1 eq), 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (348.53 mg, 1.35 mmol, 2 eq), KI (55.99 mg, 337.29 μmol, 0.5 eq) and Cs 2 CO 3A mixture of (439.58 mg, 1.35 mmol, 2 eq) in DMSO (3 mL) was degassed and heated with N 2 Purge 3 times. 2 The reaction mixture was stirred at 80°C for 12 hours under a 4% CO atmosphere. The reaction mixture was filtered and analyzed by preparative HPLC (column: Waters Xbridge TM BEH C18 100*30mm*10μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 35%-55%, 8 min) to purify the filtrate to give the title compound as a white solid (23 mg, 44.12 μmol, 7% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=8.74(s,1H),8.02(s,1H),7.70(s,1H),6.79(d,J=1.1Hz,1H),4.79(br d,J=11.6Hz,1H),4.52-4.45(m,2H),4.42-4.34(m,1H),4.02(dt,J=8.1,11.1Hz,1H),3.82(br dd,J=5.2,9.7Hz,2H),3.45(s,3H),3.05-2.97(m,1H),2.91-2.78(m,2H),2.40(t,J=12.3Hz,1H),2.15(br t,J=11.4Hz,1H),1.82(br d,J=12.5Hz,1H),1.69(brdd,J=5.1,9.4Hz,2H),1.63-1.54(m,1H),1.18(s,6H),1 .13(dd,J=2.8,18.5Hz,1H),1.02-0.92(m,1H),0.86(d,J=6.6Hz,3H).LCMS:[M+H] + =516.4.

[0567] Example 14: (1 3 S,1 5 R)-2 5 -Chloro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro- 4 1 H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -ketone Synthesis of (17)

[0568]

[0569] tert-Butyl ((3S,5R)-5-methylpiperidin-3-yl)carbamate

[0570] To a solution of tert-butyl N-[(3S,5R)-1-benzyl-5-methyl-3-piperidinyl]carbamate (1.30 g, 4.27 mmol, 1 eq) in THF (13 mL) was added Pd / C (700 mg, 10% purity) under Ar. The suspension was degassed in vacuo and heated with H 2 Purge several times. 2 The reaction mixture was stirred at 25° C. under 4% CO (15 psi) for 12 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a white solid (0.8 g, crude). 1 H NMR (400 MHz, MeOD-d 4 )δ=3.41(tt,J=4.3,11.3Hz,1H),3.11-3.03(m,1H),2.87(br dd,J=3.5,12.5Hz,1H),2.14(t,J=11.6Hz,1H),2.05-1.90(m,2H),1.61(dt d,J=3.8,7.3,14.7Hz,1H),1.43(s,9H),1.40(s,1H),0.87(d,J=6.6Hz,3H).

[0571] tert-Butyl ((3S,5R)-1-(5-chloro-4-((7-(2-chloroethoxy)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)-5-methylpiperidin-3-yl)carbamate

[0572] To a mixture of 4-(2-chloroethoxy)-6-[(2,5-dichloropyrimidin-4-yl)amino]-3-methyl-1H-benzimidazol-2-one (1.5 g, 3.86 mmol, 1 eq) and tert-butyl N-[(3S,5R)-5-methyl-3-piperidinyl]carbamate (992.57 mg, 4.63 mmol, 1.2 eq) in DMSO (20 mL) was added DIPEA (997.64 mg, 7.72 mmol, 1.34 mL, 2 eq). The reaction mixture was stirred at 100 ° C for 2 hours. The reaction was quenched with water (20 mL), filtered and the solid was dried. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to purify the product to give the title compound as a yellow solid (0.95 g, 1.29 mmol, 33% yield). LCMS: [M-56+H] + =510.2,[M+1] + =566.2.

[0573] 5-((2-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-7-(2-chloroethoxy)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0574] To a solution of tert-butyl N-[(3S,5R)-1-[5-chloro-4-[[7-(2-chloroethoxy)-1-methyl-2-oxo-3H-benzoimidazol-5-yl]amino]pyrimidin-2-yl]-5-methyl-3-piperidinyl]carbamate (600 mg, 1.06 mmol, 1 eq) in DCM (6 mL) was added TFA (1.5 mL). The reaction mixture was stirred at 25 °C for 30 min. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a brown oil (600 mg, crude, TFA). LCMS: [M+H] + =466.2.

[0575] (1 3 S,1 5 R)-2 5 -Chloro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -ketone

[0576] In a glove box, to a solution of 6-[[2-[(3S,5R)-3-amino-5-methyl-1-piperidinyl]-5-chloro-pyrimidin-4-yl]amino]-4-(2-chloroethoxy)-3-methyl-1H-benzimidazol-2-one (200 mg, 344.60 μmol, 1 eq, TFA) in DMF (30 mL) was added K 2 CO 3 (238.13 mg, 1.72 mmol, 5 eq) and NaI (516.53 mg, 3.45 mmol, 10 eq). 2 The reaction mixture was stirred at 100°C for 36 hours under a 2% atmosphere. The reaction mixture was concentrated in vacuo and water (50 mL) was added. The solution was extracted with ethyl acetate (35 mL x 3). The combined organic phases were purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to give a residue which was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate = 0 / 1 to THF / ethyl acetate = 2 / 1) to give the title compound as a yellow solid (250 mg, 430.33 μmol, 42% yield). 1 H NMR (400 MHz, DMSO-d 6 )δ=10.80(s,1H),8.65(s,1H),8.00(s,1H),7.66(s,1H),6.69-6.62(m,2H),4.80(br d,J=11.3Hz,1H),4.51-4.45(m,1H),4.40-4.31(m,1H),4.01(br d,J=7.6Hz,1H),3.42-3.39(m,3H),3.08-2.94(m,1H),2.92-2.78(m,2H),2.40(br t,J=12.2Hz,1H),2.15(br s,1H),1.82(br d,J=12.2Hz,1H),1.63-1.52(m,1H),1.02-0.94(m,1H),0.86(br d,J=6.4Hz,3H).LCMS:[M+H] + =430.2.

[0577] (1 3 S,1 5 R)-2 5 -Chloro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -Keto (17)

[0578] (1 3 S,1 5 R)-2 5 -Chloro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2-ketone (200 mg, 465.22 μmol, 1 eq), (3-hydroxy-3-methyl-butyl) 4-methylbenzenesulfonate (240.36 mg, 930.44 μmol, 2 eq), KI (38.61 mg, 232.61 μmol, 0.5 eq) and Cs 2 CO 3 A mixture of (303.16 mg, 930.44 μmol, 2 eq) in DMSO (2 mL) was degassed and heated with N 2 Purge 3 times. 2 The reaction mixture was stirred at 80°C for 12 hours under a 4% CO atmosphere. The reaction mixture was filtered and purified by preparative HPLC (column: Waters Xbridge TM Prep OBD C18 150*40mm*10μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 30%-60%, 8 min) to purify the filtrate to give the title compound as a white solid (35 mg, 67.15 μmol, 14% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=8.73(s,1H),8.02(s,1H),7.70(s,1H),6.79(d,J=1.3Hz,1H),4.80(br d,J=12.4Hz,1H),4.49(br dd,J=4.0,12.6Hz,1H),4.45(s,1H),4.42-4.33(m,1H),4.02(dt,J=8.0,11.2Hz,1 H),3.86-3.76(m,2H),3.45(s,3H),3.07-2.95(m,1H),2.93-2.76(m,2H),2.40(br t,J=12.2Hz,1H),2.15(br t,J=11.4Hz,1H),1.86-1.78(m,1H),1.74-1.65(m,2H),1.63-1.50(m,1H),1.18(s ,6H),1.16-1.09(m,1H),0.97(q,J=11.8Hz,1H),0.86(d,J=6.6Hz,3H).LCMS:[M+H] + =516.1.

[0579] Example 15: (1 3 S,1 5 R)-25-chloro-1 4 ,1 4 -Difluoro-4 1 -(((1R,3S)-3-Hydroxycyclobutyl)methyl)-1 5 , 4 4 -Dimethyl-4 1 ,4 2 ,4 3 ,4 4 -Tetrahydro-5-oxa-3-aza-4(7,5)-quinoxaline-2(2,4)-pyrimidine-1(1,3)-piperidine Cyclooctane-4 2 ,4 3 -dione (18-1) and (1 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -Difluoro-4 1 -(((1S,3R)-3-Hydroxycyclobutyl)methoxy Base)-1 5 ,4 4 -Dimethyl-4 1 ,4 2 ,4 3 ,4 4 -Tetrahydro-5-oxa-3-aza-4(7,5)-quinoxaline-2(2,4)-pyrimidine-1(1, 3)-Piperidine Cyclooctane-4 2 ,4 3 Synthesis of -dione (18-2)

[0580]

[0581] 6-Bromo-8-methoxy-1-methyl-1,4-dihydroquinoxaline-2,3-dione

[0582] At 25 °C, 4-bromo-6-methoxy-N 1 To a solution of -methylbenzene-1,2-diamine (30 g, 129.82 mmol, 1 eq) in THF (350 mL) was added oxalyl chloride (32.96 g, 259.64 mmol, 22.73 mL, 2 eq) dropwise. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered (combined with another batch of the same scale), and the filter cake was washed with ethyl acetate (300 mL) and dried in vacuo. The residue was triturated with EtOAc (200 mL) at 25 °C for 30 min to give the title compound as a white solid (40 g, 97% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=11.95(s,1H),7.02(d,J=2.0Hz,1H),6.94(d,J=2.0Hz,1H),3.87(s,3H),3.63(s,3H).

[0583] 6-(Benzylamino)-8-methoxy-1-methyl-1,4-dihydroquinoxaline-2,3-dione

[0584] At 25 °C, 6-bromo-8-methoxy-1-methyl-1,4-dihydroquinoxaline-2,3-dione (18 g, 63.14 mmol, 1 eq) and BnNH 2 To a solution of (8.12 g, 75.76 mmol, 8.26 mL, 1.2 eq) in THF (180 mL) was added dropwise LiHMDS (1 M, 151.53 mL, 2.4 eq) and N 2 The mixture was purged for 5 min. Then, BrettPhos (1.69 g, 3.16 mmol, 0.04 eq) and BrettPhos Pd G were added at 25 °C. 3 (1.43 g, 1.58 mmol, 0.02 eq), and in N 2 The resulting mixture was stirred at 80°C for 12 hours under a saturated atmosphere. At 0°C, the mixture was slowly heated with saturated NH 4 The reaction mixture was quenched with aqueous Cl solution (200 mL) (combined with two other batches of the same scale). 2 SO 4Dry, filter, and concentrate the filtrate in vacuo to give a residue which was purified by flash silica gel chromatography (silica gel flash column, 20-100% THF / petroleum ether gradient elution) to give the title compound as a yellow solid (20 g, 94% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=11.62(br s,1H),7.39-7.29(m,4H),7.27-7.19(m,1H),6.45(t,J=6.0Hz,1H),6.19(d,J=2.4H z,1H),5.99(d,J=2.4Hz,1H),4.23(d,J=6.0Hz,2H),3.73(s,3H),3.63-3.57(m,3H).

[0585] 6-(Benzylamino)-8-hydroxy-1-methyl-1,4-dihydroquinoxaline-2,3-dione

[0586] 6-(Benzylamino)-8-methoxy-1-methyl-1,4-dihydroquinoxaline-2,3-dione (20 g, 64.24 mmol, 1 eq) was dissolved in DCM (400 mL) and cooled to -70 °C. 2 BBr in DCM (50 mL) was added 3 (80.47 g, 321.20 mmol, 30.95 mL, 5 eq) was added dropwise to the reaction mixture. The reaction mixture was warmed to 40 °C and stirred for 12 hours. At 0 °C, CHCl 3 The reaction was quenched with 4N HCl / MeOH solution (10:1, 600 mL) and then concentrated in vacuo. The residue was stirred in 4N HCl aqueous solution at 40 °C for 30 min and then filtered. The filter cake was ground with (EtOAc, 100 mL) for 30 min at 25 °C to give the title compound as a yellow solid (11 g, 34.04 mmol, 53% yield, 92% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=11.59(br s,1H),9.80(br s,1H),7.36-7.16(m,5H),6.15-5.88(m,2H),4.18(s,2H),3.66(s,3H).

[0587] (3S,5R)-tert-butyl 3-(3-((7-benzylamino)-4-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)oxy)propyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0588] To a solution of 6-(benzylamino)-8-hydroxy-1-methyl-1,4-dihydroquinoxaline-2,3-dione (1 g, 3.03 mmol, 90% purity, 1 eq) in ACN (10 mL) and DMF (10 mL) was added K 2 CO 3 (836.77 mg, 6.05 mmol, 2 eq) and (3R, 5S)-4,4-difluoro-3-methyl-5-(3-(tosyloxy)propyl)piperidine-1-carboxylic acid tert-butyl ester (1.35 g, 3.03 mmol, 1 eq). The reaction mixture was stirred at 60 °C for 6 hours. Water (50 mL) was added, and the solution was extracted with EtOAc (50 mL×3) (combined with another batch of 1.5 g scale). The combined organic phase was washed with brine (100 mL) and dried over anhydrous Na 2 SO 4 Drying, filtration and concentration in vacuo gave a residue which was purified by flash silica chromatography (silica flash column, 33 to 100% ethyl acetate in petroleum ether gradient elution) to give the title compound as a yellow solid (1 g). 1 H NMR (400 MHz, DMSO-d 6 )δ=11.73-11.60(m,1H),7.27-7.18(m,1H),7.39-7.16(m,4H),6.64(s,2H),6.42(br t,J=6.0Hz,1H),6.17(d,J=2.4Hz,1H),5.99(d,J=2.4Hz,1H),4.23(br d,J=6.0Hz,1H),4.14-3.99(m,1H),3.98-3.87(m,3H),3.82-3.77(m,1H),3.69- 3.56(m,3H),3.31-3.27(m,2H),2.69(s,3H),1.40(s,9H),0.94(d,J=6.8Hz,4H).

[0589] (3S,5R)-tert-butyl 3-[3-[(7-amino-4-methyl-2,3-dioxo-1H-quinoxalin-5-yl)oxy]propyl]-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0590] To a solution of tert-butyl (3S,5R)-3-(3-((7-(benzylamino)-4-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)oxy)propyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate (400 mg, 698.52 μmol, 1 eq) in THF (4 mL) under Ar was added Pd / C (150 mg, 10% purity). The suspension was degassed in vacuo and heated to 40 % purity.2 Purge 3 times. 2 The reaction mixture was stirred at 25°C for 12 hours under 15 psi. The reaction mixture was filtered through a pad of Celite (combined with another batch of the same scale) and the filtrate was concentrated in vacuo to give the red title compound as a yellow solid (800 mg, crude). 1 H NMR (400 MHz, DMSO-d 6 )δ=11.67(br d,J=13.6Hz,1H),7.95(s,1H),6.13(d,J=2.0Hz,1H),5.99(d,J=2.0Hz,1H),5.21(s,1H),4.20-3.88(m,4H),3.65-3. 61(m,2H),2.64-2.53(m,1H),2.22-2.14(m,1H),1.95-1.83(m,3H),1.40(s,9H),1.35(s,4H),0.94(d,J=6.8Hz,3H).

[0591] (3S,5R)-tert-butyl 3-(3-((7-((2,5-dichloropyrimidin-4-yl)amino)-4-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)oxy)propyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0592] To a solution of (3S,5R)-3-(3-((7-amino-4-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)oxy)propyl)-4,4-difluoro-5-methylpiperidine-1-carboxylic acid tert-butyl ester (800 mg, 1.66 mmol, 1 eq) in DMF (8 mL) was added DIPEA (428.55 mg, 3.32 mmol, 577.56 μL, 2 eq) and 2,4,5-trichloropyrimidine (608.22 mg, 3.32 mmol, 2 eq). The reaction mixture was stirred at 25 °C for 2 hours. Water (50 mL) was added, and the solution was extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL) and purified by anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate in vacuo to give a residue which was purified by flash silica gel chromatography (silica gel flash column, 20-100% THF / petroleum ether gradient elution) to give the title compound as a grey solid (750 mg, 83% purity). 1 H NMR (400 MHz, DMSO-d 6)δ=12.17-11.94(m,1H),9.73-9.44(m,1H),8.44-8.34(m,1H),7.26-7.10(m,2H),4.18-4.00(m,3H),3.98-3.85(m,1H) ,3.74-3.63(m,3H),3.32-3.27(m,2H),2.21-2.14(m,2H),1.93-1.84(m,4H),1.43-1.36(m,9H),0.94(d,J=6.8Hz,3H).

[0593] 6-((2,5-dichloropyrimidin-4-yl)amino)-8-(3-((3S,5R)-4,4-difluoro-5-methylpiperidin-3-yl)propoxy)-1-methyl-1,4-dihydroquinoxaline-2,3-dione

[0594] A solution of (3S,5R)-tert-butyl 3-(3-((7-((2,5-dichloropyrimidin-4-yl)amino)-4-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)oxy)propyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate (700 mg, 1.11 mmol, 1 eq) in DCM (10 mL) and TFA (2.5 mL) was stirred at 25 °C for 30 min. The solution was concentrated in vacuo to give the title compound as a yellow solid (700 mg, crude, TFA). LCMS: [M+H] + =529.3.

[0595] (1 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -Difluoro-1 5 ,4 4 -Dimethyl-4 1 ,4 2 ,4 3 ,4 4 -Tetrahydro-5-oxa-3-aza-4(7,5)-quinoxaline-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 ,4 3 -Diketone (28)

[0596] To a solution of 6-((2,5-dichloropyrimidin-4-yl)amino)-8-(3-((3S,5R)-4,4-difluoro-5-methylpiperidin-3-yl)propoxy)-1-methyl-1,4-dihydroquinoxaline-2,3-dione (700 mg, 1.09 mmol, 1 eq, TFA) in DMSO (28 mL) was added DIPEA (1.41 g, 10.88 mmol, 1.90 mL, 10 eq). The reaction mixture was stirred at 80 °C for 12 hours. Water (50 mL) was added, and the solution was extracted with EtOAc (50 mL x 3) (combined with another solution of 50 mg scale). The combined organic phases were washed with brine (50 mL) and purified by anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate in vacuo to give a residue which was purified by flash silica gel chromatography (silica gel flash column, 50-100% THF / petroleum ether gradient elution) to give the title compound as a yellow solid (250 mg, 77% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=12.15-11.80(m,1H),9.10(s,1H),8.11(s,1H),7.61(br s,1H),6.77(s,1H),4.75-4.54(m,2H),4.47(br t,J=11.6Hz,1H),4.21-4.10(m,1H),3.67(s,3H),2.74(br t,J=12.7Hz,1H),2.41-2.28(m,1H),1.99-1.82(m,2H),1.78-1.55(m,2H),1.42-1.30(m,2H),0.97(br d,J=6.5Hz,3H).LCMS:[M+H] + =493.2.

[0597] 3-(Hydroxymethyl)cyclobutan-1-ol

[0598] In N 2 To a mixture of 3-oxocyclobutane-1-carboxylic acid (10 g, 87.64 mmol, 1 eq) in THF (500 mL) was added BH 3 -Me 2 S (10M, 26.29mL, 3eq). The reaction mixture was stirred at 15°C for 3 hours. The reactants (combined with two other batches of the same scale) were cooled to 0°C in an ice bath. MeOH (100mL) was added dropwise to quench the reaction. The solvent was removed under reduced pressure to give the title compound as a yellow oil (26 g, 217.17mmol, 83% yield, 85% purity). 1H NMR (400 MHz, CDCl 3 )δ=5.51-5.15(m,1H),4.45-3.96(m,1H),3.84-3.38(m,2H),2.55-1.81(m,4H),1.76-1.49(m,1H).

[0599] (3-Hydroxycyclobutyl)methyl 4-methylbenzenesulfonate

[0600] To a solution of 3-(hydroxymethyl)cyclobutan-1-ol (26 g, 254.57 mmol, 1 eq) in DCM (300 mL) at 15°C were added TEA (51.52 g, 509.15 mmol, 70.87 mL, 2 eq) and DMAP (3.11 g, 25.46 mmol, 0.1 eq). 2 TosCl (48.53 g, 254.57 mmol, 1 eq) was slowly added at 0°C, and the reaction mixture was stirred at 15°C for 12 hours. The reaction mixture was poured into water (400 mL) and the aqueous phase was extracted with DCM (300 mL×2). The combined organic phases were washed with brine (800 mL) and washed with anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate in vacuo to give a residue, which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 0 to 3 / 1) to give the title compound as a white solid (33 g, 122.80 mmol, yield 48%, purity 95%). 1 H NMR (400 MHz, DMSO-d 6 )δ=7.83-7.72(m,2H),7.52-7.41(m,2H),5.18-4.54(m,1H),4.14-3.83(m, 3H),2.42(s,3H),2.21-2.11(m,1H),2.01-1.78(m,3H),1.53-1.38(m,1H).

[0601] (1 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -Difluoro-4 1 -((3-Hydroxycyclobutyl)methyl)-1 5 ,4 4 -Dimethyl-4 1 ,4 2 ,4 3 ,4 4-Tetrahydro-5-oxa-3-aza-4(7,5)-quinoxaline-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 ,4 3 -Diketone

[0602] To(1 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -Difluoro-1 5 ,4 4 -Dimethyl-4 1 ,4 2 ,4 3 ,4 4 -Tetrahydro-5-oxa-3-aza-4(7,5)-quinoxaline-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 ,4 3 To a solution of -dione (150 mg, 304.32 μmol, 1 eq) in DMSO (2 mL) were added (3-hydroxycyclobutyl)methyl 4-methylbenzenesulfonate (156.00 mg, 608.64 μmol, 2 eq), Cs 2 CO 3 (198.31 mg, 608.64 μmol, 2 eq) and KI (25.26 mg, 152.16 μmol, 0.5 eq). 2 The reaction mixture was stirred at 80° C. for 12 hours. The reaction mixture was filtered (combined with another batch of 100 mg scale), and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC (column: Phenomenex C18 80*40mm*3μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 35%-65%, 8 min) to purify the residue to give the title compound as a white solid (60 mg, 97% purity). LCMS: [M+H] + =577.3.

[0603] (1 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -Difluoro-4 1 -(((1r,3S)-3-Hydroxycyclobutyl)methyl)-1 5 ,4 4 -Dimethyl-4 1 ,4 2 ,4 3 ,44 -Tetrahydro-5-oxa-3-aza-4(7,5)-quinoxaline-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 ,4 3 -dione (18-1) and (1 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -difluoro-4-(((1s,3R)-3-hydroxycyclobutyl)methyl)-1 5 ,4 4 -Dimethyl-4 1 ,4 2 ,4 3 ,4 4 -Tetrahydro-5-oxa-3-aza-4(7,5)-quinoxaline-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 ,4 3 -Diketone (18-2)

[0604] The chromatograms were analyzed by SFC (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 μm); mobile phase: [ACN / EtOH (0.1% NH 3 H 2 O)]; B%: 70%-70%, 13 minutes) purification (1 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -Difluoro-4 1 -((3-Hydroxycyclobutyl)methyl)-1 5 ,4 4 -Dimethyl-4 1 ,4 2 ,4 3 ,4 4 -Tetrahydro-5-oxa-3-aza-4(7,5)-quinoxaline-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 ,4 3 -dione (combined with another 20 mg scale) to afford 18-1 as a white solid (7 mg, 98% purity), and 18-2 as a white solid (20 mg, 97.8% purity).

[0605] 18-1: 1 H NMR (400 MHz, DMSO-d 6)δ=9.01(s,1H),8.15(s,1H),7.77(d,J=1.4Hz,1H),7.05(d,J=1.4Hz,1H),5.04(d,J=6.0Hz,1H),4.70(br d,J=14.0Hz,1H),4.65-4.56(m,1H),4.51-4.41(m,1H),4.40-4.33(m,1H),4.30-4.14(m,2H),4.09(br dd,J=8.4,14.1Hz,1H),3.63(s,3H),2.80-2.72(m,1H),2.65-2.55(m,1H),2.44-2.31(m,1H),2.05-1.98(m,2H),1.95-1.86(m,3H),1.83-1.70(m,1H),1.64(br t,J=13.2Hz,1H),1.39-1.31(m,3H),0.98(d,J=6.6Hz,3H).LCMS:[M+H] + =577.4.

[0606] 18-2: 1 H NMR(400MHz,DMSO-d 6 )δ=9.00(s,1H),8.15(s,1H),7.77(d,J=1.4Hz,1H),7.05(d,J=1.4Hz,1H),5.01(d,J=6.8Hz,1H),4.75-4.55(m,2H),4.53-4.37(m,1H),4.28-4.11(m,2H),4.03(br dd,J=6.6,13.9Hz,1H),3.90-3.77(m,1H),3.63(s,3H),2.76(br t,J=12.8Hz,1H),2.64-2.55(m,1H),2.45-2.31(m,1H),2.30-2.22(m,2H),2.20-2.12(m,1H),2.05-1.85(m,2H),1.83-1.58(m,4H),1.37(dt,J=5.4,12.5Hz,1H),0.98(d,J=6.8Hz,3H).LCMS:[M+H] + =577.4.

[0607] Example 16: (1 3 R,1 5 S)-2 5 -Chloro-1 4 ,1 4 -Difluoro-4 1 -(((1R,3R)-3-Hydroxycyclobutyl)methyl)-1 5 , 4 4 -Dimethyl-4 1 ,4 2 ,4 3 ,4 4 -Tetrahydro-5-oxa-3-aza-4(7,5)-quinoxaline-2(2,4)-pyrimidine-1(1,3)-piperidine Cyclooctane-4 2 ,4 3 -dione (19-1) and (1 3 R,1 5 S)-25-chloro-1 4 ,1 4 -Difluoro-4 1 -(((1S,3S)-3-Hydroxycyclobutyl) Methyl)-1 5 ,4 4 -Dimethyl-4 1 ,4 2 ,4 3 ,4 4 -Tetrahydro-5-oxa-3-aza-4(7,5)-quinoxaline-2(2,4)-pyrimidine-1 (1,3)-Piperidinylcyclooctane-4 2 ,4 3 Synthesis of -dione (19-2)

[0608]

[0609] (3R,5S)-tert-butyl 3-(3-((7-benzylamino)-4-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)oxy)propyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0610] To a solution of 6-(benzylamino)-8-hydroxy-1-methyl-1,4-dihydroquinoxaline-2,3-dione (2.5 g, 8.41 mmol, 1 eq) and (3S,5R)-4,4-difluoro-3-methyl-5-[3-(p-tolylsulfonyloxy)propyl]piperidine-1-carboxylic acid tert-butyl ester (3.76 g, 8.41 mmol, 1 eq) in ACN (25 mL) and DMF (25 mL) was added K 2 CO 3 (2.91 g, 21.02 mmol, 2.5 eq). The reaction mixture was stirred at 60°C for 6 hours. The reaction was quenched with water (40 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (40 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to give a residue which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate / MeOH=3 / 1 / 0 to 0 / 3 / 1) to give the title compound as a yellow solid (1.5 g, 2.28 mmol, 27% yield, 87% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=11.71-11.52(m,1H),7.42-7.18(m,5H),6.42(br t,J=5.9Hz,1H),6.17(d,J=1.4Hz,1H),5.99(s,1H),4.22(br d,J=5.9Hz,1H),4.13-4.01(m,1H),3.98-3.88(m,3H),3.61(s,2H),2.68 -2.55(m,2H),2.03-1.74(m,6H),1.40(s,9H),1.33-1.19(m,2H),0.94(br d,J=6.6Hz,3H).

[0611] (3R,5S)-tert-butyl 3-(3-((7-amino-4-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)oxy)propyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0612] To a solution of tert-butyl (3R,5S)-3-(3-((7-(benzylamino)-4-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)oxy)propyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate (1.3 g, 2.27 mmol, 1 eq) in DMF (15 mL) under Ar was added Pd / C (600 mg, 10% purity). The suspension was degassed in vacuo and heated with H 2 Purge 3 times. 2 The reaction mixture was stirred at 60 °C for 12 hours under (15 psi). The reaction mixture was filtered (combined with another batch of 200 mg scale) and the filtrate was concentrated in vacuo to give the title compound as a black oil (1.5 g). LCMS: [M-56+H] + =427.2.

[0613] (3R,5S)-tert-butyl 3-(3-((7-((2,5-dichloropyrimidin-4-yl)amino)-4-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)oxy)propyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0614] To a solution of (3R,5S)-3-(3-((7-amino-4-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)oxy)propyl)-4,4-difluoro-5-methylpiperidine-1-carboxylic acid tert-butyl ester (1.5 g, 3.11 mmol, 1 eq) and 2,4,5-trichloropyrimidine (1.14 g, 6.22 mmol, 2 eq) in DMF (16 mL) was added DIPEA (803.55 mg, 6.22 mmol, 1.08 mL, 2 eq). The reaction mixture was stirred at 25 °C for 12 hours. The reaction was quenched with water (30 mL) and then extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine (30 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to give a residue which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate / MeOH=4 / 1 / 0 to 0 / 0 / 1) to purify the residue to give the title compound as a yellow solid (1.1 g, 1.26 mmol, 40% yield, 72% purity). LCMS: [M-56+H] + =573.1.

[0615] 6-((2,5-dichloropyrimidin-4-yl)amino)-8-(3-((3R,5S)-4,4-difluoro-5-methylpiperidin-3-yl)propoxy)-1-methyl-1,4-dihydroquinoxaline-2,3-dione

[0616] A solution of (3R,5S)-3-[3-[[7-[(2,5-dichloropyrimidin-4-yl)amino]-4-methyl-2,3-dioxo-1H-quinoxalin-5-yl]oxy]propyl]-4,4-difluoro-5-methyl-piperidine-1-carboxylic acid tert-butyl ester (1 g, 1.59 mmol, 1 eq) in DCM (10 mL) and TFA (2.5 mL) was stirred at 25 °C for 30 min. The reaction mixture was concentrated in vacuo to give the title compound as a yellow oil (1 g, crude, TFA). LCMS: [M+H] + =529.2.

[0617] (1 3 R,1 5 S)-2 5 -Chloro-14,14-difluoro-15,44-dimethyl-4 1 ,4 2 ,4 3 ,4 4 -Tetrahydro-5-oxa-3-aza-4(7,5)-quinoxaline-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 ,4 3 -Diketone

[0618] To a solution of 6-((2,5-dichloropyrimidin-4-yl)amino)-8-(3-((3R,5S)-4,4-difluoro-5-methylpiperidin-3-yl)propoxy)-1-methyl-1,4-dihydroquinoxaline-2,3-dione (1 g, 1.55 mmol, 1 eq, TFA) in DMSO (40 mL) was added DIEA (2.01 g, 15.54 mmol, 2.71 mL, 10 eq). The reaction mixture was stirred at 80 °C for 12 hours. The reaction was quenched with water (60 mL) (combined with another batch of 100 mg scale) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (60 mL) and purified by anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate in vacuo to give a residue, which was purified by column chromatography (SiO 2 The residue was purified by HPLC (ethyl acetate / MeOH=1 / 0 to 0 / 1) to give the title compound as a yellow solid (380 mg). 1 HNMR (400 MHz, DMSO-d 6)δ=12.25-11.79(m,1H),9.08(s,1H),8.10(s,1H),7.60(s,1H),6.76(d,J=1.9Hz,1H),4.73-4.64(m,1H),4.59(br d,J=14.1Hz,1H),4.46(br t,J=11.8Hz,1H),4.20-4.08(m,1H),3.67(s,3H),2.79-2.69(m,1H),2.61-2.52(m,2H),2.43-2.29(m, 1H),2.03-1.81(m,2H),1.80-1.68(m,1H),1.67-1.57(m,1H),1.43-1.30(m,1H),0.97(d,J=6.6Hz,3H).

[0619] (1 3 R,1 5 S)-2 5 -Chloro-1 4 ,1 4 -Difluoro-4 1 -((3-Hydroxycyclobutyl)methyl)-1 5 ,4 4 -Dimethyl-4 1 ,4 2 ,4 3 ,4 4 -Tetrahydro-5-oxa-3-aza-4(7,5)-quinoxaline-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 ,4 3 -Diketone

[0620] To(1 3 R,1 5 S)-25-chloro-1 4 ,1 4 -Difluoro-1 5 ,4 4 -Dimethyl-4 1 ,4 2 ,4 3 ,4 4 -Tetrahydro-5-oxa-3-aza-4(7,5)-quinoxaline-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 ,4 3 To a solution of 2-(3-hydroxycyclobutyl)methyl 4-methylbenzenesulfonate (270.41 mg, 1.05 mmol, 2 eq) in DMSO (2.6 mL) was added Cs 2 CO 3(343.73 mg, 1.05 mmol, 2 eq) and KI (43.78 mg, 263.74 μmol, 0.5 eq). The reaction mixture was stirred at 80 °C for 12 hours. The reaction was quenched with water (20 mL) and extracted with EtOAc (10 mL×3). The combined organic phase was washed with brine (20 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to give a residue which was purified by preparative HPLC (column: Waters Xbridge TM BEH C18100*30mm*10μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 45%-65%, 8 min) to purify the residue to give the title compound as a white solid (60 mg, 102.94 μmol, 20% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=9.05-8.95(m,1H),8.15(s,1H),7.77(d,J=1.3Hz,1H),7.05(s,1H),5.05-4.97(m,1H),4.70(br d,J=12.5Hz,1H),4.64-4.56(m,1H),4.46(br t,J=11.4Hz,1H),4.27-4.15(m,2H),4.03(br dd,J=6.6,13.9Hz,1H),3.88-3.79(m,1H),3.63(s,3H),2.76(br t,J=12.8Hz,1H),2.64-2.54(m,1H),2.44-2.34(m,1H),2.30-2.11(m,3H),1.90(br dd,J=5.6,7.4Hz,2H),1.82-1.59(m,4H),1.44-1.31(m,1H),0.98(d,J=6.6Hz,3H).

[0621] (1 3 R,1 5 S)-2 5 -Chloro-1 4 ,1 4 -Difluoro-4 1 -(((1r,3R)-3-Hydroxycyclobutyl)methyl)-1 5 ,4 4 -Dimethyl-4 1 ,4 2 ,4 3 ,4 4-Tetrahydro-5-oxa-3-aza-4(7,5)-quinoxaline-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 ,4 3 -dione (19-1) and (1 3 R,1 5 S)-2 5 -Chloro-1 4 ,1 4 -Difluoro-4 1 -(((1s,3S)-3-Hydroxycyclobutyl)methyl)-1 5 ,4 4 -Dimethyl-4 1 ,4 2 ,4 3 ,4 4 -Tetrahydro-5-oxa-3-aza-4(7,5)-quinoxaline-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 ,4 3 -Diketone (19-2)

[0622] The separation (1 3 R,1 5 S)-2 5 -Chloro-1 4 ,1 4 -Difluoro-4 1 -((3-Hydroxycyclobutyl)methyl)-1 5 ,4 4 -Dimethyl-4 1 ,4 2 ,4 3 ,4 4 -Tetrahydro-5-oxa-3-aza-4(7,5)-quinoxaline-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 ,4 3 -dione (90 mg) to give 19-1 as a white solid (7 mg, 12% yield, 99% purity), and 19-2 as a white solid (15 mg, 25% yield, 99% purity).

[0623] 19-1: 1 H NMR (400 MHz, DMSO-d 6)δ=9.01(s,1H),8.15(s,1H),7.77(s,1H),7.05(s,1H),5.04(br d,J=5.8Hz,1H),4.70(br d,J=12.6Hz,1H),4.60(br d,J=12.5Hz,1H),4.46(br t,J=12.1Hz,1H),4.40-4.31(m,1H),4.30-4.14(m,2H),4.13-4.01(m,1H),3.63(s,3H),2.83-2.65(m,2H),2.63-2.55(m,1H),2.44-2.30(m,1H),2.09-1.96(m,3H),1.89(br d,J=5.6Hz,3H),1.81-1.57(m,2H),1.44-1.31(m,1H),0.98(br d,J=6.6Hz,3H).LCMS:[M+H] + =577.4.

[0624] 19-2: 1 H NMR(400MHz,DMSO-d 6 )δ=9.00(s,1H),8.15(s,1H),7.77(br s,1H),7.05(br s,1H),5.01(br d,J=6.8Hz,1H),4.70(br d,J=12.3Hz,1H),4.60(br d,J=12.6Hz,1H),4.45(br t,J=11.6Hz,1H),4.26-4.13(m,2H),4.08-3.98(m,1H),4.03(br dd,J=6.4,13.6Hz,1H),3.83(br dd,J=7.3,14.3Hz,1H),3.63(s,3H),2.76(br t,J=12.5Hz,1H),2.63-2.55(m,1H),2.43-2.31(m,1H),2.30-2.21(m,2H),2.20-2.11(m,1H),2.04-1.86(m,2H),1.83-1.59(m,4H),1.44-1.31(m,1H),0.98(br d,J=6.4Hz,3H).LCMS:[M+H] + =577.4.

[0625] Example 17: (1 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -Difluoro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl- 4 2 ,4 3 -Dihydro-4 1 H-5,8-Dioxa-3-aza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinyl ring Octane-4 2 Synthesis of -ketone (33):

[0626]

[0627] tert-Butyl (3S,5R)-3-(2-benzyloxy)ethoxy)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0628] To a solution of tert-butyl 4,4-difluoro-3-hydroxy-5-methyl-piperidine-1-carboxylate (13.00 g, 51.74 mmol, 1 eq) in DMF (100 mL) was added NaH (4.14 g, 103.47 mmol, 60% purity, 2 eq) at 0°C. The reaction mixture was stirred at 0°C for 30 min, then 2-bromoethoxymethylbenzene (13.35 g, 62.08 mmol, 9.82 mL, 1.2 eq) was added. The reaction mixture was heated to 90°C and heated under N 2 Stir for 12 hours. 4 The reaction mixture was slowly quenched with Cl (100 mL) and then extracted with ethyl acetate (150 mL×2). The combined organic phases were washed with brine (200 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The residue was purified by silica gel flash column, 5-50% ethyl acetate / petroleum ether gradient elution) to afford the title compound as a colorless oil (5.7 g, 11.53 mmol, 22% yield, 78% purity). 1 H NMR (400 MHz, CDCl 3 )δ=7.38-7.28(m,5H),4.63-4.55(m,2H),4.35-4.12(m,1H),4.03-3.80(m,3H),3.71-3.62(m,2H),3.60- 3.49(m,1H),2.93(t,J=10.4Hz,1H),2.70(s,1H),2.07-1.88(m,1H),1.46(s,9H),1.07(d,J=6.8Hz,3H).

[0629] To a solution of tert-butyl 3-(2-benzyloxyethoxy)-4,4-difluoro-5-methyl-piperidine-1-carboxylate (5.70 g, 14.79 mmol, 1 eq) in MeOH (60 mL) was added Pd / C (2 g, 10% purity) under Ar. The suspension was degassed in vacuo and heated to 40 ℃ for 2 h. 2 Purge several times. 2 The reaction mixture was stirred at 60° C. under pressure (50 psi) for 12 h. The reaction mixture was filtered and concentrated in vacuo to afford the title compound as a colorless oil (4.3 g, crude). 1H NMR (400 MHz, CDCl 3 )δ=4.20-3.63(m,6H),3.58-3.42(m,1H),3.23-2.63(m,2H),2.55-2.10(m,1H),2.07-1.88(m,1H),1.47(s,9H),1.08(d,J=6.8Hz,3H).

[0630] tert-Butyl (3R,5S)-4,4-difluoro-3-methyl-5-(2-(tosyloxy)ethoxy)piperidine-1-carboxylate

[0631] To a solution of tert-butyl 4,4-difluoro-3-(2-hydroxyethoxy)-5-methyl-piperidine-1-carboxylate (4.3 g, 14.56 mmol, 1 eq) in DCM (40 mL) was added DMAP (177.88 mg, 1.46 mmol, 0.1 eq) and TEA (2.95 g, 29.12 mmol, 4.05 mL, 2 eq). Then, 4-methylbenzenesulfonyl chloride (4.16 g, 21.84 mmol, 1.5 eq) was added at 15 °C. The reaction mixture was stirred at 15 °C for 12 hours. The reaction mixture was treated with water (50 mL) and then extracted with EtOAc (50 mL×3). The combined organic phase was washed with brine (80 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. 2 , petroleum ether / ethyl acetate = 8 / 1 to 1 / 1) to give the title compound as a colorless oil (5 g, 11.01 mmol, 76% yield, 99% purity). 1 H NMR (400 MHz, CDCl 3 )δ=7.81(d,J=8.4Hz,2H),7.35(d,J=8.0Hz,2H),4.19-4.05(m,3H),4.00-3.78(m,3H),3.50-3.36(m ,1H),2.85(s,1H),2.67(s,1H),2.45(s,3H),2.02-1.84(m,1H),1.47(s,9H),1.03(d,J=6.8Hz,3H).

[0632] (3R,5S)-4,4-difluoro-3-methyl-5-(2-(tosyloxy)ethoxy)piperidine-1-carboxylic acid tert-butyl ester and (3S,5R)-4,4-difluoro-3-methyl-5-(2-(tosyloxy)ethoxy)piperidine-1-carboxylic acid tert-butyl ester

[0633] The chromatograms were analyzed by SFC (column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 μm); mobile phase: [CO 2 -EtOH (0.1% NH 3 HO)]; B%: 15%, isocratic elution mode) to separate the cis mixture of (3R,5S)-4,4-difluoro-3-methyl-5-(2-(toluenesulfonyloxy)ethoxy)piperidine-1-carboxylic acid tert-butyl ester to obtain (3R,5S)-4,4-difluoro-3-methyl-5-[2-(toluenesulfonyloxy)ethoxy]piperidine-1-carboxylic acid tert-butyl ester as a white solid (2.2 g, 4.85 mmol, 44% yield, 99% purity); 1 HNMR (400MHz, CDCl 3 )δ=7.81(d,J=8.2Hz,2H),7.35(d,J=8.2Hz,2H),4.19-4.06(m,3H),3.99-3.79(m,3H),3.49-3.35(m,1H),2. 85(s,1H),2.68(s,1H),2.45(s,3H),2.03-1.84(m,1H),1.47(s,9H),1.03(d,J=6.8Hz,3H); LCMS:[M-Boc+H] + =350.2; and (3S,5R)-4,4-difluoro-3-methyl-5-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylic acid tert-butyl ester as a white solid (2.2 g, 4.85 mmol, 44% yield, 99% purity); 1 H NMR (400 MHz, CDCl 3 )δ=7.73(d,J=8.4Hz,2H),7.28(d,J=8.0Hz,2H),4.11-3.99(m,3H),3.92-3.72(m,3H),3.40-3.28(m,1H),2.77(t,J =9.9Hz,1H),2.69-2.52(m,1H),2.38(s,3H),1.95-1.79(m,1H),1.40(s,9H),0.96(d,J=6.8Hz,3H); LCMS:[M-Boc+H] + =350.2.

[0634] tert-Butyl (3S,5R)-3-(2-((6-benzylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)ethoxy)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0635] 6-(Benzylamino)-4-hydroxy-3-methyl-1H-benzimidazol-2-one (800 mg, 2.97 mmol, 1 eq), (3R,5S)-4,4-difluoro-3-methyl-5-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylic acid tert-butyl ester (1.34 g, 2.97 mmol, 1 eq) and K 2 CO 3 A mixture of (821.13 mg, 5.94 mmol, 2 eq) in DMSO (10 mL) was degassed and heated with N 2 Purge three times. 2 The reaction mixture was stirred at 70°C for 2 hours. The reaction mixture was poured into water and filtered. The filter cake was washed with water and dried in vacuo to give the title compound as a yellow solid (800 mg, 1.46 mmol, 49% yield). 1 H NMR (400 MHz, DMSO-d 6 )δ=10.36(s,1H),7.40–7.15(m,5H),6.03(s,1H),5.93(t,J=6.0Hz,1H),5.84(s,1H),4.21(d,J=5.6Hz,2H),4.10–3. 85(m,5H),3.85–3.70(m,2H),3.32(s,3H),2.93–2.64(m,2H),2.10–1.95(m,1H),1.37(s,9H),0.96(d,J=6.8Hz,3H).

[0636] tert-Butyl (3S,5R)-3-(2-((6-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)ethoxy)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0637] To a solution of tert-butyl (3S,5R)-3-(2-((6-(benzylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)ethoxy)-4,4-difluoro-5-methylpiperidine-1-carboxylate (800 mg, 1.46 mmol, 1 eq) in DMF (10 mL) under Ar was added Pd / C (400.00 mg, 375.87 μmol, 10% purity). The suspension was degassed in vacuo and heated with H 2 Purge several times. 2 The reaction mixture was stirred at 20° C. for 24 h under 4% CO (15 psi). The reaction mixture was filtered and then concentrated under reduced pressure to afford the title compound as a yellow solid (600 mg, crude). 1 H NMR (400 MHz, DMSO-d 6)δ=10.36(s,1H),5.96(d,J=1.2Hz,1H),5.91(d,J=1.6Hz,1H),4.76(s,2H),4.13–3.90(m,5H),3.85 –3.67(m,2H),3.35(s,3H),2.97-2.61(m,2H),2.15–1.96(m,1H),1.37(s,9H),0.96(d,J=6.8Hz,3H).

[0638] tert-Butyl (3S,5R)-3-(2-((6-((2,5-dichloropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)ethoxy)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0639] A mixture of tert-butyl (3S,5R)-3-(2-((6-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)ethoxy)-4,4-difluoro-5-methylpiperidine-1-carboxylate (600 mg, 1.31 mmol, 1 eq), 2,4,5-trichloropyrimidine (337.53 mg, 1.84 mmol, 1.4 eq) and DIPEA (339.75 mg, 2.63 mmol, 457.89 μL, 2 eq) in DMF (8 mL) was degassed and heated to 40 ℃ for 10 min. 2 Purge three times. 2 The reaction mixture was stirred at 20°C for 2 hours under atmosphere. The reaction mixture was poured into water and filtered. The filter cake was washed with water and dried in vacuo to give the title compound as a yellow solid (600 mg, 994.29 μmol, 76% yield). 1 H NMR (400 MHz, DMSO-d 6 )δ=10.89(s,1H),9.38(s,1H),8.34(s,1H),7.00-6.94(m,2H),4.23-4.13(m,2H),4.07–3.95(m,3H),3.83–3.70( m,2H),3.47(s,3H),2.97–2.83(m,1H),2.79-2.64(m,1H),2.15–1.96(m,1H),1.37(s,9H),0.96(d,J=6.8Hz,3H).

[0640] 5-((2,5-dichloropyrimidin-4-yl)amino)-7-(2-(((3S,5R)-4,4-difluoro-5-methylpiperidin-3-yl)oxy)ethoxy)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0641] In N 2 A solution of (3S,5R)-tert-butyl 3-(2-((6-((2,5-dichloropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)ethoxy)-4,4-difluoro-5-methylpiperidine-1-carboxylate (800 mg, 1.33 mmol, 1 eq) in HCl / EtOAc (10 mL) was stirred at 20 °C for 1 hour under a 4% carbonyl atmosphere. The reaction mixture was concentrated in vacuo and the residue was dissolved in MeOH (50 mL) and basic resin was added until pH>7. The solution was filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow solid (600 mg, crude). LCMS: [M+H] + =503.2.

[0642] (1 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -Difluoro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5,8-Dioxa-3-aza-4(6,4)-benzo[d]imidazo-2(2,4)-pyrimidine-1(1,3)-piperidin-4-cyclooctane 2 -ketone

[0643] A mixture of 5-((2,5-dichloropyrimidin-4-yl)amino)-7-(2-(((3S,5R)-4,4-difluoro-5-methylpiperidin-3-yl)oxy)ethoxy)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (400 mg, 794.71 μmol, 1 eq) and DIPEA (1.03 g, 7.95 mmol, 1.38 mL, 10 eq) in DMSO (40 mL) was degassed and heated to 40 ℃ with N 2 Purge three times. 2 The reaction mixture was stirred at 80°C for 24 hours under a 4% CO atmosphere. The reaction mixture was concentrated in vacuo and purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give the title compound as a yellow solid (120 mg, 257.03 μmol, 32% yield, 70% purity). 1 H NMR (400 MHz, DMSO-d 6)δ=10.83(s,1H),8.91(s,1H),8.08(s,1H),7.65(s,1H),6.64(s,1H),4.75–4.64(m,1H),4.55–4.30(m,2H),4.2 4-4.10(m,2H),3.88(t,J=6.4Hz,2H),3.41(s,3H),3.00–2.75(m,2H),2.10–1.94(m,1H),0.97(d,J=6.8Hz,3H).

[0644] (1 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -Difluoro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5,8-Dioxa-3-aza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -Ketone (33):

[0645] (1 3 S,1 5 R)-2 5 -Chloro-1 4 ,1 4 -Difluoro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5,8-Dioxa-3-aza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -ketone (120 mg, 257.03 μmol, 1 eq), (3-hydroxy-3-methyl-butyl) 4-methylbenzenesulfonate (99.60 mg, 385.55 μmol, 1.5 eq), KI (21.33 mg, 128.52 μmol, 0.5 eq) and Cs 2 CO 3 A mixture of (167.49 mg, 514.07 μmol, 2 eq) in DMSO (3 mL) was degassed and heated with N 2 Purge three times. 2The reaction mixture was stirred at 80°C for 12 hours under a 4% CO atmosphere. The reaction mixture was concentrated in vacuo and analyzed by p-HPLC (column: Waters TM Xbridge BEH C18 100*30mm*10μm; mobile phase: [H 2 O (10 mM NH 4 HCO 3 )-ACN]; gradient: 35%-65% B in 8.0 min) to give the title compound as a white solid (50 mg, 98.9% purity). 1 HNMR (400 MHz, DMSO-d 6 )δ=9.01(s,1H),8.09(s,1H),7.70(s,1H),6.76(s,1H),4.76–4.64(m,1H),4.55–4.30(m,3H),4.25-4.10(m,2H),3.93-3. 76(m,4H),3.46(s,3H),2.88(s,2H),2.07–1.93(m,1H),1.75–1.63(m,2H),1.18(s,6H),0.97(d,J=6.8Hz,3H).LCMS:[M+H] + =553.1.

[0646] Example 18: (1 3 R,1 5 S)-2 5 -Chloro-1 4 ,1 4 -Difluoro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl- 4 2 ,4 3 -Dihydro-4 1 H-5,8-Dioxa-3-aza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinyl ring Octane-4 2 Synthesis of -ketone (34):

[0647]

[0648] tert-Butyl (3R,5S)-3-(2-((6-benzylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)ethoxy)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0649] To a solution of 5-(benzylamino)-7-hydroxy-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (800 mg, 2.97 mmol, 1 eq) and (3S,5R)-4,4-difluoro-3-methyl-5-(2-(tosyloxy)ethoxy)piperidine-1-carboxylic acid tert-butyl ester (1.27 g, 2.82 mmol, 0.95 eq) in DMSO (10 mL) was added K 2 CO 3 (821.13 mg, 5.94 mmol, 2 eq). 2The reaction mixture was stirred at 70 ° C for 2 hours. The reaction mixture was poured into water (20 mL) and filtered. The filter cake was washed with PE / EtOAc (15 mL, 2: 1). The solid was dried in vacuo to give the title compound as a white solid (600 mg, 933.03 μmol, 31% yield, 85% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=10.36(s,1H),7.38-7.27(m,4H),7.24-7.18(m,1H),6.03(d,J=1.5Hz,1H),5.93(t,J=6.0Hz,1H),5.83(d,J=1.5Hz,1H ),4.22(d,J=6.0Hz,2H),4.09-3.89(m,5H),3.83-3.64(m,2H),3.34(s,3H),2.94-2.61(m,2H),2.12-1.98(m,1H),1.37(br s,9H),0.96(d,J=6.7Hz,3H).

[0650] tert-Butyl (3R,5S)-3-(2-((6-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)ethoxy)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0651] To a solution of tert-butyl (3R,5S)-3-(2-((6-(benzylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)ethoxy)-4,4-difluoro-5-methylpiperidine-1-carboxylate (600 mg, 1.10 mmol, 1 eq) in DMF (12 mL) under Ar was added Pd / C (0.1 g, 10% purity). The suspension was degassed under vacuum and heated to 40 % with H 2 Purge several times. 2 The reaction mixture was stirred at 15 °C for 12 hours under (15 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a brown solid (500 mg, 985.80 μmol, 90% yield, 90% purity). LCMS: [M+H] + =457.4.

[0652] tert-Butyl (3R,5S)-3-(2-((6-((2,5-dichloropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)ethoxy)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0653] To a solution of (3R,5S)-3-(2-((6-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)ethoxy)-4,4-difluoro-5-methylpiperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.10 mmol, 1 eq) in DMF (5 mL) was added DIEA (283.13 mg, 2.19 mmol, 381.57 μL, 2 eq) and 2,4,5-trichloropyrimidine (401.82 mg, 2.19 mmol, 2 eq). The reaction mixture was stirred at 15 °C for 2 hours. Then, water (10 mL) was added and the reaction mixture was filtered. The filter cake was washed with EtOAc (10 mL). The solid was concentrated in vacuo to give the title compound as a grey solid (550 mg, 902.32 μmol, 82% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d 6 )δ=10.90(s,1H),9.39(s,1H),8.34(s,1H),7.02-6.91(m,2H),4.21-4.12(m,2H),4.07-3.93(m,3H),3.82-3.69(m, 2H),3.47(s,3H),2.97-2.88(m,1H),2.72-2.64(m,1H),2.13-2.00(m,1H),1.43-1.32(m,9H),0.96(d,J=6.8Hz,3H).

[0654] 5-((2,5-dichloropyrimidin-4-yl)amino)-7-(2-(((3R,5S)-4,4-difluoro-5-methylpiperidin-3-yl)oxy)ethoxy)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0655] In N 2 A mixture of (3R,5S)-tert-butyl 3-(2-((6-((2,5-dichloropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)ethoxy)-4,4-difluoro-5-methylpiperidine-1-carboxylate (550 mg, 911.43 μmol, 1 eq) in DCM (11 mL) and TFA (2.75 mL) was stirred at 15 °C for 30 minutes under a 4% atmosphere. The reaction mixture was concentrated in vacuo and the residue was dissolved in MeOH (10 mL). Then, a basic resin was added until pH = 8. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow solid (400 mg, 667.56 μmol, 73% yield, 84% purity). LCMS: [M+H] + =503.2.

[0656] (1 3 R,1 5 S)-2 5 -Chloro-1 4 ,1 4 -Difluoro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5,8-Dioxa-3-aza-4(6,4)-benzo[d]imidazo-2(2,4)-pyrimidine-1(1,3)-piperidin-4-cyclooctane 2 -ketone

[0657] To a solution of 5-((2,5-dichloropyrimidin-4-yl)amino)-7-(2-(((3R,5S)-4,4-difluoro-5-methylpiperidin-3-yl)oxy)ethoxy)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (400 mg, 794.71 μmol, 1 eq) in DMSO (16 mL) was added DIPEA (2.05 g, 15.89 mmol, 2.77 mL, 20 eq). The reaction mixture was stirred at 80 °C for 24 hours. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with brine (100 mL) and purified by anhydrous Na 2 SO 4 The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (silica gel, petroleum ether / EtOAc=4 / 1, 0 / 1) to give the title compound as a yellow solid (120 mg, 241.61 μmol, 30% yield). 1 H NMR (400 MHz, DMSO-d 6 )δ=10.81(s,1H),8.90(s,1H),8.08(s,1H),7.65(d,J=1.3Hz,1H),6.64(d,J=1.4Hz,1H) ,4.68(td,J=6.4,12.4Hz,1H),4.51-4.29(m,2H),4.14(td,J=6.7,12.9Hz,2H),3.88(br t,J=6.8Hz,2H),3.41(s,3H),2.98-2.81(m,2H),2.12-1.93(m,1H),0.97(d,J=6.8Hz,3H).

[0658] (1 3 R,1 5 S)-2 5 -Chloro-1 4 ,1 4-Difluoro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5,8-Dioxa-3-aza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -Keto (34)

[0659] To(1 3 R,1 5 S)-2 5 -Chloro-1 4 ,1 4 -Difluoro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5,8-Dioxa-3-aza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 To a solution of 1-hydroxy-3-methyl-butyl)-4-methylbenzenesulfonate (90 mg, 192.77 μmol, 1 eq) and (3-hydroxy-3-methyl-butyl)-4-methylbenzenesulfonate (74.70 mg, 289.16 μmol, 1.5 eq) in DMSO (4 mL) was added Cs 2 CO 3 (125.62 mg, 385.55 μmol, 2 eq) and KI (16.00 mg, 96.39 μmol, 0.5 eq). The reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was concentrated in vacuo (combined with another batch of 30 mg scale) and purified by preparative HPLC (column: Waters TM Xbridge BEH C18 100*30mm5μm; mobile phase: [H 2 O (10 mM NH 4 HCO 3 )-ACN]; gradient: 33%-59% B in 8.0 min) to give the title compound as a white solid (25 mg, 99% purity). 1 HNMR (400 MHz, DMSO-d 6)δ=9.00(s,1H),8.09(s,1H),7.69(s,1H),6.76(s,1H),4.76-4.67(m,1H),4 .52-4.28(m,3H),4.22-4.11(m,2H),3.95-3.78(m,4H),3.46(s,3H),2.89(br s,2H),2.09-1.95(m,1H),1.70(br dd,J=6.1,10.0Hz,2H),1.18(s,6H),0.97(brd,J=6.8Hz,3H).LCMS:[M+H] + =552.21.

[0660] Example 19: (1 3 R,1 5 S)-1 4 ,1 4 ,2 5 -Trifluoro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl-4 2 , 4 3 -Dihydro-4 1 H-5-Oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclohexine 4-Hydroxy-4-nitropropane 2 -ketone (35) and (1 3 S,1 5 R)-1 4 ,1 4 ,2 5 -Trifluoro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl-4 2 ,4 3 - Dihydro-4 1 H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane- 4 2 Synthesis of -ketone (36)

[0661]

[0662] tert-Butyl 3-(1,3-dioxoisoindolin-2-yl)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0663] To a solution of 2-(4,4-difluoro-5-methylpiperidin-3-yl)isoindoline-1,3-dione (10 g, 35.68 mmol, 1 eq) in DCM (20 mL) was added Boc 2 O (7.79 g, 35.68 mmol, 8.20 mL, 1 eq) and TEA (7.22 g, 71.36 mmol, 9.93 mL, 2 eq). The reaction mixture was stirred at 15 °C for 12 hours. Water (100 mL) was added, and the solution was extracted with DCM (100 mL×3). The combined organic phase was washed with brine (100 mL) and washed with anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate in vacuo. Purify the residue by flash silica gel chromatography (silica gel flash column, 0-50% ethyl acetate / petroleum ether gradient eluent) to give the title compound as a yellow oil (9 g, 23.19 mmol, 88% yield, 98% purity). 1 H NMR (400 MHz, CDCl 3 )δ=7.93-7.86(m,2H),7.79-7.73(m,2H),4.57-4.37(m,1H),4.36-4.00(m,3 H),2.97-2.66(m,1H),2.32-2.08(m,1H),1.48(s,9H),1.08(d,J=6.7Hz,3H).

[0664] tert-Butyl 3-amino-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0665] To a solution of tert-butyl 3-(1,3-dioxoisoindolin-2-yl)-4,4-difluoro-5-methylpiperidine-1-carboxylate (9.00 g, 23.66 mmol, 1 eq) in EtOH (90 mL) was added MeNH 2 (90 mL, 40% purity). The reaction mixture was stirred at 70 °C for 1 hour. The reaction mixture was concentrated in vacuo to afford the title compound as a yellow oil (5.6 g, 22.37 mmol, 95% yield). 1 H NMR (400 MHz, CDCl 3 )δ=4.40-3.82(m,2H),3.00-2.83(m,1H),2.59(br d,J=9.3Hz,2H),2.09-1.85(m,1H),1.46(s,9H),1.41-1.27(m,2H),1.05(d,J=6.8Hz,3H).

[0666] 4,4-Difluoro-5-methylpiperidin-3-amine

[0667] To a solution of tert-butyl 3-amino-4,4-difluoro-5-methylpiperidine-1-carboxylate (5.6 g, 22.37 mmol, 1 eq) in DCM (30 mL) was added TFA (15 mL). The reaction mixture was stirred at 15 °C for 1 hour. The reaction mixture was concentrated in vacuo to give the title compound as a yellow solid (8 g, 21.15 mmol, 95% yield, 2TFA). 1 H NMR (400 MHz, DMSO-d 6 )δ=9.38(br s,4H),4.14-3.93(m,1H),3.66(br d,J=12.5Hz,1H),3.46(br d,J=12.9Hz,1H),3.13(t,J=12.5Hz,1H),2.86(t,J=12.9Hz,1H),2.58-2.50(m,1H),1.04(d,J=6.8Hz,3H).

[0668] Ethyl 2-((6-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetate

[0669] To a solution of ethyl 2-((6-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetate (9 g, 33.93 mmol, 1 eq) and 2,4-dichloro-5-fluoro-pyrimidine (11.33 g, 67.86 mmol, 2 eq) in DMF (72 mL) was added DIPEA (8.77 g, 67.86 mmol, 11.82 mL, 2 eq). 2 The reaction mixture was stirred at 15° C. for 2 h. Water (100 mL) was added and the mixture was filtered, and the filter cake was washed with EtOAc (100 mL) and dried in vacuo to give the title compound as a white solid (10 g, 23.25 mmol, 69% yield). 1 H NMR (400 MHz, DMSO-d 6 )δ=10.94(s,1H),9.84(s,1H),8.27(d,J=3.3Hz,1H),7.18(s,1H),7.01(d,J=1. 0Hz, 1H), 4.82 (s, 2H), 4.19 (q, J = 7.2Hz, 2H), 3.49 (s, 3H), 1.21 (t, J = 7.2Hz, 3H).

[0670] Ethyl 2-((6-((2-(3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-fluoropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetate

[0671] In N 2 A solution of ethyl 2-((6-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetate (4 g, 10.11 mmol, 1 eq) and 4,4-difluoro-5-methyl-piperidin-3-amine (6.12 g, 16.17 mmol, 1.6 eq, TFA) in DMSO (80 mL) and DIPEA (16 mL) was stirred at 130 °C for 12 hours. The reaction mixture (combined with another batch of 1 g scale) was poured into water (200 mL) and filtered. The filter cake was washed with water (100 mL) and dried under vacuum. The residue was triturated with PE / EtOAc (20 mL, 3: 1) at 15 °C for 30 minutes. The mixture was filtered and the filter cake was dried under vacuum to give the title compound as a yellow solid (4.3 g, 66% yield). 1 H NMR (400 MHz, DMSO-d 6)δ=10.91(s,1H),9.17(s,1H),7.99(d,J=3.5Hz,1H),7.11(d,J=7.6Hz,2H),4.83(s,2H),4.62-4.46(m,2H),4.18(q,J=7.1Hz, 2H),3.53-3.45(m,3H),2.97-2.82(m,1H),2.71-2.61(m,2H),2.08-1.93(m,1H),1.88-1.52(m,2H),1.24-1.17(m,3H),0.99(br d,J=6.6Hz,3H).

[0672] 2-((6-((2-(3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-fluoropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetic acid

[0673] To ethyl 2-((6-((2-(3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-fluoropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetate (3.3 g, 6.48 mmol, 1 eq) in EtOH (30 mL) and H 2 LiOH·H O (6 mL) was added to the solution 2 The reaction mixture was stirred at 15 °C for 2 hours. The reaction mixture was concentrated in vacuo (combined with another batch of 1 g scale) and water (20 mL) was added. The solution was acidified with 1 N HCl until pH = 4. The mixture was filtered and the filter cake was dried in vacuo to give the title compound as a yellow solid (2.8 g, 68% yield). 1 H NMR (400 MHz, DMSO-d 6 )δ=10.78(s,1H),9.08(s,1H),7.96(d,J=3.5Hz,1H),6.77(s,1H),6.53(br s,1H),4.84-4.75(m,1H),4.63(br d,J=10.6Hz,1H),4.44(d,J=15.7Hz,1H),4.24(br d,J=15.7Hz,1H),3.76-3.62(m,1H),3.47(s,3H),2.66-2.53(m,2H),2.30-2.12(m,1H),1.02(d,J=6.7Hz,3H).

[0674] 1 4 ,1 4 ,25 -Trifluoro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 ,7-dione

[0675] To a solution of 2-[[6-[[2-(3-amino-4,4-difluoro-5-methyl-1-piperidinyl)-5-fluoro-pyrimidin-4-yl]amino]-3-methyl-2-oxo-1H-benzimidazol-4-yl]oxy]acetic acid (2 g, 4.15 mmol, 1 eq) in DMF (28 mL) was added HATU (1.58 g, 4.15 mmol, 1 eq) and DIPEA (1.07 g, 8.31 mmol, 1.45 mL, 2 eq). 2 The reaction mixture was stirred at 15 ° C for 2 hours. The reaction mixture (combined with another batch of 0.8g scale) was poured into water (100mL), filtered, and washed with water (50mL). The filter cake was dried in vacuo, and the residue was ground with MeOH (10mL) at 15 ° C for 10 minutes. The mixture was filtered and the filter cake was dried in vacuo to give the title compound as a yellow solid (2g, 74% yield). 1 H NMR (400 MHz, DMSO-d 6 )δ=10.78(s,1H),9.18(s,1H),8.51(br d,J=8.1Hz,1H),7.95(br d,J=3.5Hz,1H),7.19(s,1H),6.49(s,1H),4.92(br d,J=14.8Hz,1H),4.63(br d,J=14.7Hz,2H),4.45(br d,J=14.3Hz,1H),4.32-4.22(m,1H),3.99-3.87(m,1H),3.46(s,3H),3.31-3.23(m,1H),3.17(d,J=4.8Hz,1H),1.09(br d,J=6.8Hz,3H).

[0676] 1 4 ,1 4 ,2 5 -Trifluoro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -ketone

[0677] In N 2 At 0℃ to 1 4 ,1 4 ,2 5 -Trifluoro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 ,7-dione (1.4 g, 3.02 mmol, 1 eq) was added to a THF (27 mL) solution of BH 3 ·THF (1M, 12.08 mL, 4 eq). The reaction mixture was stirred at 50°C for 5 hours. 2 Next, saturated NH 4 The reaction mixture was slowly quenched with Cl (50 mL). After stirring at 15 °C for 30 min, the mixture was extracted with ethyl acetate (40 mL x 3). The organic layer was purified by Na 2 SO 4 Dry, filter, and concentrate the filtrate in vacuo and triturate the residue with EtOAc (5 mL) (combined with another batch on a 600 mg scale) and filter. Dry the filtrate in vacuo to give the title compound as a yellow solid (870 mg, 44% yield). 1 H NMR (400 MHz, DMSO-d 6 )δ=10.77(br d,J=3.5Hz,1H),9.30(br s,1H),8.03(br t,J=3.8Hz,1H),7.69(br s,1H),6.61-6.52(m,1H),4.76-4.23(m,3H),4.08(br d,J=8.7Hz,1H),3.41(br d,J=3.9Hz,3H),3.25(br dd,J=4.9,8.5Hz,1H),2.98(br d,J=1.5Hz,2H),2.74(br t,J=11.1Hz,1H),2.62-2.53(m,1H),2.32-2.08(m,1H),2.03-1.86(m,1H),0.96(br d,J=6.0Hz,3H).

[0678] 1 4 ,14 ,2 5 -Trifluoro-41-(3-hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -ketone

[0679] To 1 4 ,1 4 ,2 5 -Trifluoro-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 To a solution of 1-hydroxy-3-methyl-butyl)-4-methylbenzenesulfonate (290 mg, 645.26 μmol, 1 eq) in DMSO (5 mL) was added Cs 2 CO 3 (420.48 mg, 1.29 mmol, 2 eq) and KI (53.56 mg, 322.63 μmol, 0.5 eq). 2 The reaction mixture was stirred at 80°C for 10 hours. The reaction mixture was concentrated in vacuo and analyzed by preparative HPLC (column: Waters TM XbridgeBEH C18 250*50mm*10μm; mobile phase: [H 2 O (10 mM NH 4 HCO 3 )-ACN]; gradient: 30%-60% B in 10 min) to give the title compound as a white solid (350 mg, 640.45 μmol, 33% yield). 1 H NMR (400 MHz, DMSO-d 6)δ=9.40(s,1H),8.04(d,J=3.7Hz,1H),7.74(s,1H),6.67(d,J=1.2Hz,1H),4.75-4.66(m,1H),4.55-4.46(m,2H),4.40-4. 25(m,1H),4.15-4.02(m,1H),3.81(brdd,J=6.1,10.1Hz,2H),3.46(s,3H),3.31-3.19(m,1H),3.03-2.93(m,2H),2.74(br t,J=12.6Hz,1H),2.61-2.51(m,1H),2.28-2.19(m,1H),2.04-1.85(m,1H),1.68(br dd,J=5.1,9.7Hz,2H),1.18(s,6H),0.96(d,J=6.7Hz,3H).

[0680] (1 3 R,1 5 S)-1 4 ,1 4 ,2 5 -Trifluoro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -ketone (35) and (1 3 S,1 5 R)-1 4 ,1 4 ,2 5 -Trifluoro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -Keto (36)

[0681] The chromatograms were analyzed by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [CO 2 -MeOH (0.1% NH 3 H2 O)]; B%: 40%, isocratic elution mode) separation 1 4 ,1 4 ,2 5 -Trifluoro-4 1 -(3-Hydroxy-3-methylbutyl)-1 5 ,4 3 -Dimethyl-4 2 ,4 3 -Dihydro-4 1 H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazole-2(2,4)-pyrimidine-1(1,3)-piperidinylcyclooctane-4 2 -ketone (350 mg, 653.52 μmol, 1 eq) was added to give compound 35 as a white solid (120 mg, 224.06 μmol, 34% yield), and compound 36 as a white solid (125 mg, 233.40 μmol, 36% yield). Compound 35: 1 H NMR (400 MHz, DMSO-d 6 )δ=9.39(s,1H),8.04(d,J=3.8Hz,1H),7.74(s,1H),6.67(s,1H),4.69(br d,J=12.9Hz,1H),4.54-4.44(m,2H),4.38-4.29(m,1H),4.13-4.03(m,1H),3.81(br dd,J=6.6,9.7Hz,2H),3.46(s,3H),3.30-3.19(m,1H),3.04-2.92(m,2H),2.74(br t,J=12.6Hz,1H),2.59-2.53(m,1H),2.26-2.18(m,1H),2.05-1.86(m,1H),1.68(br dd,J=5.2,9.7Hz,2H),1.18(s,6H),0.96(d,J=6.6Hz,3H).LCMS:[M+H] + =536.2. Compound 36: 1 H NMR (400 MHz, DMSO-d 6)δ=9.40(s,1H),8.04(d,J=3.6Hz,1H),7.74(s,1H),6.67(d,J=1.0Hz,1H),4.69(br d,J=13.0Hz,1H),4.54-4.44(m,2H),4.39-4.29(m,1H),4.14-4.03(m,1H),3.81(br dd,J=6.4,9.9Hz,2H),3.46(s,3H),3.29-3.19(m,1H),3.04-2.89(m,2H),2.80 -2.69(m,1H),2.59-2.53(m,1H),2.25-2.19(m,1H),2.03-1.87(m,1H),1.68(br dd,J=4.9,9.6Hz,2H),1.18(s,6H),0.96(d,J=6.8Hz,3H).LCMS:[M+H] + =536.2.

[0682] Example 20: Degradation Activity

[0683] HiBiT Solution

[0684] Cellular degradation assay in Su-DHL-4 cells (HiBiT, Promega TM )Determine DC 50 (Concentration to achieve 50% degradation) values ​​(Table 1). Endogenous BCL6 was labeled with 11 amino acids SmBiT by CRISPR / Cas9 gene editing and single cell clone selection. After 24 hours of compound treatment, cells were lysed and incubated with LgBiT protein to reconstitute complete nanoluciferase. Then, substrate was added and relative luciferase units were measured. The degradation level of each treatment is expressed as a percentage compared to the control 100% DMSO (Prism).

[0685] Table 1. Degradation activity of compounds

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693]

[0694]

[0695]

[0696]

[0697] All patent publications and non-patent publications are indicative of the level of skill of those skilled in the art to which the invention pertains. All of these publications are incorporated herein by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

[0698] Although the present invention has been described herein with reference to specific embodiments, it should be understood that these embodiments are only for illustrating the principles and applications of the present invention. Therefore, it should be understood that various modifications can be made to the illustrative embodiments and other arrangements can be designed without departing from the spirit and scope of the present invention as defined in the appended claims.

Claims

1. A compound having a structure shown in Formula I: or a pharmaceutically acceptable salt or stereoisomer thereof, in: X1 is N, CH, CCl, CF or CCN; X2 is N or CR4; R4 is H, (C1-C4)alkyl, halogen, OH, NH2, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C2-C4)alkenyl, (C2-C4)alkynyl, NO2, CN, NH(C1-C4)alkyl or N(C1-C4alkyl)2; R1 is H, OH or halogen; R2 is H, OH or halogen; R3 is H, halogen or CN; Y is CH2, NH or O; Z is CH2, NH, S or O; n is 0, 1, or 2; A is X3 is CH or N; R5 is H, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C1-C6) aminoalkyl, (C3-C6) carbocyclyl, 4 to 7 membered heterocyclyl, (C1-C6) alkyl-(C3-C7) carbocyclyl or (C3-C7) carbocyclyl-4 to 7 membered heterocyclyl; wherein the alkyl, carbocyclyl or heterocyclyl is further optionally replaced by one or more identical or different R 13 Group substitution, where R 13 is (C1-C6)alkyl, (C1-C6)alkoxy, halogen, NH2, OH, (C1-C6)haloalkyl, NH(C1-C6)alkyl or N((C1-C6)alkyl)2, (C3-C6)carbocyclyl, 4- to 7-membered heterocyclyl, or R5 is –L-Y1-Z1, where L is absent or is (C1-C5)alkylene, optionally substituted with one or more substituents selected from (C1-C2)alkyl and oxo; Y1 is absent or is O, S, S(O), S(O)2, NR', C(O), C(O)O, OC(O), C(O)N(R'), N(R')C(O), N(R')C(O)N(R'), N(R')C(O)O, OC(O)N(R'), S(O)2N(R') or N(R')S(O)2; Each R' is independently H or (C1-C4) alkyl; Z1 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C 10 ) carbocyclyl or 3 to 10 membered heterocyclyl, wherein Z1 is optionally substituted by one or more substituents independently selected from the group consisting of (C1-C4) alkyl, halogen, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, NH2, (C1-C4) aminoalkyl, CN, OH, carboxyl, carbamoyl, aminosulfonyl, mercapto, urea, NR r R s , OR r 、C(O)R r 、C(O)OR r 、OC(O)R r 、C(O)NR r R s 、N(R r )C(O)R r 、S(O) 0-2 R r 、S(O)2NR r R s 、N(R r )SO2R r 、Si(R r )(R s )R t and (CH2) 1-3 NR r R s ; where R r , R s and R t are each independently H, (C1-C6)alkyl or (C3-C6)cycloalkyl; or R r and R s together with the nitrogen atom to which they are attached, form a 4- to 9-membered heterocyclyl group, which is optionally substituted with one or more substituents selected from (C1-C4)alkyl, halogen, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C1-C4)alkoxy, (C1-C4)alkylamino, NH2, CN and OH; R6 is – L1CR 14 R 15 R 16 or –CH=CH–R 16 ,in L1 is absent or is O, S, (C1-C4)alkylene, -O-(C1-C4)alkylene or -S-(C1-C4)alkylene; R 14 is H or (C1-C4)alkyl; R 15 is H or (C1-C4) alkyl, or R 14 and R 15 Together with the carbon atom to which they are attached, they form a (C3-C5) carbocyclyl, a 4- to 7-membered heterocyclyl, or C=O; R 16 (C1-C6) alkyl, –NR 17 R 18 ,–OR 17 , –C(O)R 17 , –C(O)OR 17 , –N(R 18 )C(O)R 17 , –C(O)NR 17 R 18 、–S(O)-(C1-C6)alkyl、–S(O)2-(C1-C6)alkyl、–P(O)-(C1-C6alkyl)2、–C(NH)NH2、–(C1-C4)alkyl-NR 18 C(O)R 17 or a 4- to 7-membered heterocyclic group, wherein R 17 is H, 3- to 6-membered heterocyclyl or (C1-C4)alkyl, which is optionally substituted by one or more identical or different groups selected from the group consisting of OH, Cl, F, CF3, N(C1-C4alkyl)2, (C3-C6)carbocyclyl, 3- to 6-membered heterocyclyl, (C2-C4)alkenyl and (C2-C4)alkynyl; R 18 is H or (C1-C4)alkyl; R7 is H, methyl, –(CH2) 1-3 W1W2 or in W1 is CR 19 R 19’ or C(O); R 19 and R 19’ is independently H, (C1-C2)alkyl, F, OH, CN, NO2, (C1-C2)alkoxy, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, NH2, NH(C1-C2)alkyl or N(C1-C2alkyl)2, or R 19 and R 19’ Together with the carbon atom to which they are attached, they form C(O), (C3-C6)carbocyclyl, or 3- to 6-membered heterocyclyl, which is optionally substituted with one or more substituents independently selected from the group consisting of (C1-C2)alkyl, halogen, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, (C1-C2)alkoxy, (C1-C2)alkylamino, NH2, CN, and OH; W2 is CN, OH, 5- or 6-membered heteroaryl, phenyl, C(O)-(C1-C2)alkyl, S(O)2-(C1-C2)alkyl, S(O)(NH)-(C1-C2)alkyl, C(O)OCH3, C(O)NHCH3, CR 20 R 21 R 22 , NH2, NH(C1-C2)alkyl or N(C1-C2alkyl)2, wherein R 20 is H, (C1-C2)alkyl, F, Cl, Br, OH, NH2, CN, NO2, (C1-C2)alkoxy, (C1-C2)haloalkyl or (C1-C2)haloalkoxy; R 21 is H, (C1-C2)alkyl, F, Cl, Br, OH, CN, NO2, (C1-C2)alkoxy, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, or –Y2-L2-Z2, where Y2 is absent or is O, S, S(O), S(O)2, NR', C(O), C(O)O, OC(O), C(O)N(R'), N(R')C(O), S(O)2N(R'), or N(R')SO2; L2 is absent or is (C1-C2) alkylene; Z2 is H, (C1-C6)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, phenyl, (C3-C6)carbocyclyl, or 4- to 6-membered heterocyclyl, wherein Z2 is optionally substituted with one or more substituents independently selected from the group consisting of (C1-C4)alkyl, halogen, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C1-C4)alkoxy, (C1-C4)alkylamino, NH2, CN, OH, C(O)R', C(O)OR', OC(O)R', C(O)NR'R', and N(R')C(O)R', wherein each R' is independently H or (C1-C4)alkyl; or R 20 and R 21 Together with the carbon atom to which they are attached, they form a (C3-C6)carbocyclyl or a 3- to 6-membered heterocyclyl, which is optionally substituted with one or more substituents selected from the group consisting of (C1-C2)alkyl, halogen, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, (C1-C2)alkoxy, (C1-C2)alkylamino, NH2, CN and OH; R 22 is (C1-C2)alkyl, -C(O)OR", OR", -C(O)NR", NR"R", phenyl or 5-membered heteroaryl, wherein each R" is independently H or (C1-C2)alkyl; A" is a (C4-C6)carbocyclyl or a 4- to 6-membered heterocyclyl, which is optionally substituted with one or more substituents independently selected from the group consisting of (C1-C2)alkyl, halogen, OH, oxo, CN, and (C1-C2)alkoxy; W3 is NR 23 or CR 24 R24', where R 23 is H, (C1-C2)alkyl, (C1-C4)haloalkyl, (C1-C4)hydroxyalkyl, -C(O)CH3 or -C(O)O-(C1-C4)alkyl; R 24 and R 24’ are independently H, (C1-C2)alkyl, cyclopropyl, F, Cl, Br, OH, NH2, CN, NO2, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, (C1-C2)alkoxy, -C(O)OR", NR"R", phenyl or 5-membered heteroaryl; R8 is H, (C1-C4)alkyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl or CN, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of (C1-C4)alkyl, (C3-C6)cycloalkyl, OH, (C1-C2)alkoxy, NH2, NH(C1-C2)alkyl, N((C1-C2)alkyl)2, (C1-C2)aminoalkyl and halogen; R8' is H, (C1-C4)alkyl, CN, (C1-C4)haloalkyl, or -Y3-L3-Z3, wherein Y3 is absent or is C(O)O or C(O)N(R"); L3 is absent or is (C1-C2) alkylene; Z3 is H, (C1-C6) alkyl, phenyl, (C3-C6) cycloalkyl or 4 to 6 membered heterocyclyl, wherein Z3 is optionally substituted by one or more substituents independently selected from the group consisting of (C1-C2) alkyl, halogen, (C1-C2) haloalkyl, (C1-C2) haloalkoxy, (C1-C2) alkoxy, NH2, NO2, CN and OH, or R8 and R8' together with the carbon atoms to which they are attached form a (C4-C6) carbocyclyl or a 4- to 6-membered heterocyclyl; A' is a 6- or 7-membered heterocyclyl, which, in addition to R8 and R8', is optionally further substituted by one or more substituents independently selected from the group consisting of oxo, (C1-C2)alkyl, cyclopropyl, spirocyclopropyl, halogen, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, (C1-C2)alkoxy, NH2, CN and OH; X4 is CR 25 or N, where R 25 is H, F, Cl or methyl; R9 is H, (C1-C2)alkyl, (C3-C4)cycloalkyl, (C1-C2)haloalkyl, CN, (C2-C4)alkenyl or (C2-C4)alkynyl; R9' is (C1-C4)alkyl, CN, (C1-C4)haloalkyl or -Y4-L4-Z4, wherein Y4 is absent or is C(O), C(O)O, OC(O), C(O)N(R”) or S(O)2N(R”); L4 is absent or is (C1-C2)alkylene, which is optionally substituted with one or more substituents selected from (C1-C2)alkyl and oxo; Z4 is H, (C1-C6) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, phenyl, (C3-C6) carbocyclyl, (C3-C6) cycloalkenyl or 4 to 6 membered heterocyclyl, wherein Z4 is optionally substituted by one or more substituents independently selected from the group consisting of oxo, (C1-C4) alkyl, (C3-C6) cycloalkyl, halogen, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, (C1-C4) alkoxy, (C1-C4) alkylamino, NH2, NO2, CN, OH, C(O)R u 、C(O)OR u 、OC(O)R u 、C(O)NR u R u and N(R u )C(O)R u , where each R u are independently H, (C1-C4)alkyl, (C3-C6)cycloalkyl, or Z4 is –Q-L5-W4, where Q is absent or is O, NH, or N(C1-C2)alkyl; L5 is absent or is (C1-C2)alkylene, which is optionally substituted with one or more substituents selected from oxo and (C1-C2)alkyl; W4 is (C1-C4)alkyl, phenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5- or 6-membered heterocyclyl, wherein W4 is optionally substituted by one or more substituents independently selected from the group consisting of (C1-C4)alkyl, halogen, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C1-C4)alkoxy, (C1-C4)alkylamino, NH2, NO2, CN or OH; or R9 and R9' together with the carbon atom to which they are attached form (C3-C 10 ) carbocyclic or 4 to 10 membered heterocyclic, which is optionally substituted by one or more substituents independently selected from the group consisting of oxo, (C1-C2) alkyl, halogen, (C1-C2) haloalkyl, (C1-C2) haloalkoxy, (C1-C2) alkoxy, (C1-C2) alkylamino, NH2, NO2, CN or OH; or the (C3-C 10 ) carbocyclyl or 4 to 10 membered heterocyclyl is optionally fused to a 5 or 6 membered heteroaryl or benzene ring, and the 5 or 6 membered heteroaryl or benzene ring is optionally substituted with (C1-C2)alkyl, halogen, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, (C1-C2)alkoxy, (C1-C2)alkylamino, NH2, NO2, CN or OH; R9" is H, (C1-C4) alkyl, (C1-C2) haloalkyl, (C1-C2) alkoxy, (C1-C2) haloalkoxy, CN, NO2, ethynyl, phenyl, or 5- or 6-membered heteroaryl, wherein the alkyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, and NH2; X5 is absent or is (C3-C6)carbocyclyl, (C3-C6)carbocyclyl(C=O) or SO2; R 10 and R 10 ' are each independently H, (C1-C3) alkyl, (C1-C3) hydroxyalkyl, (C1-C3) aminoalkyl, or R 10 and R 10 ' together with the same carbon atom to which they are attached form a (C3-C6) carbocyclyl or a 4- to 6-membered heterocyclyl, wherein the alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl or heterocyclyl is optionally substituted by one or more identical or different R 10a Group substitution, where R 10a is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-(C1-C3)alkoxy, halogen, NH2, OH, (C1-C6)haloalkyl, NH-(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl, 4- to 6-membered heterocyclyl, or R 10 ' and R 11 'Together with the carbon atom to which they are attached, they form a (C3-C6) carbocyclyl or a 4- to 6-membered heterocyclyl; R 11 and R 11 ' are each independently H, (C1-C3) alkyl, (C1-C3) hydroxyalkyl, (C1-C3) aminoalkyl, or R 11 and R 11 'Together with the same carbon atom to which they are attached, they form C=O, (C3-C6) carbocyclyl or 4- to 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by one or more identical or different R 11a group substituted, where each R 11a are independently (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-(C1-C3)alkoxy, halogen, NH2, OH, (C1-C6)haloalkyl, NH-(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl or 4- to 6-membered heterocyclyl, or two of R 11a The groups, together with the same carbon atom to which they are attached, form C=O; R 12 is H, OH, NH-(C1-C6) alkyl, NH-(C1-C6) hydroxyalkyl, NH-(C1-C6) aminoalkyl, NH-(C3-C6) carbocyclyl, NH-4 to 6-membered heterocyclyl, NH-(C1-C6) alkyl-(C3-C6) carbocyclyl or NH-(C1-C6) alkyl-4 to 6-membered heterocyclyl, wherein the alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl or heterocyclyl is further optionally replaced by one or more identical or different R 12a group substituted, where each R 12a is independently (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-(C1-C3)alkoxy, halogen, NH2, OH, (C1-C6)haloalkyl, NH-(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl or 4- to 6-membered heterocyclyl; m is 0, 1, or 2; and o is either 0 or 1.

2. The compound according to claim 1, wherein Z is O.

3. The compound according to claim 1, wherein Z is CH2.

4. The compound according to claim 1, wherein Y is CH2. The compound according to claim 1 , wherein Y is O. The compound according to claim 1 , wherein Y is NH.

7. The compound according to claim 1, wherein n is 0.

8. The compound according to claim 1, wherein n is 1.

9. The compound according to claim 1, wherein n is 2.

10. The compound of claim 1, wherein R1 and R2 are each H.

11. The compound of claim 1, wherein R1 and R2 are each halogen.

12. The compound according to claim 11, wherein R1 and R2 are each F.

13. The compound according to claim 1, wherein X1 is N.

14. The compound of claim 1, wherein R3 is halogen.

15. The compound according to claim 14, wherein R3 is Cl or F.

16. The compound of claim 1, wherein X2 is CH.

17. The compound according to claim 1, wherein A is And the compound of formula (I) has the structure of formula I-1, or a pharmaceutically acceptable salt or stereoisomer thereof.

18. The compound of claim 17, wherein R5 is methyl.

19. The compound of claim 17, wherein X3 is CH.

20. The compound according to claim 17, wherein R6 is -L1CR 14 R 15 R 16 .

21. The compound of claim 20, wherein L1 is -O-(C1)alkylene.

22. The compound according to claim 20, wherein R 14 and R 15 Together with the same carbon atom to which they are attached they form C=O.

23. The compound according to claim 20, wherein R 16 It is methyl, OH, NH2 or NHMe.

24. The compound according to claim 17, which has the structure of Formula I-1a, or a pharmaceutically acceptable salt or stereoisomer thereof.

25. The compound according to claim 1, wherein A is And the compound of formula (I) has the structure of formula I-2, or a pharmaceutically acceptable salt or stereoisomer thereof.

26. The compound of claim 25, wherein R5 is methyl.

27. The compound of claim 25, wherein R7 is -(CH2)2W1W2.

28. The compound according to claim 27, wherein W1 is CR 19 R 19’ .

29. The compound according to claim 28, wherein R 19 and R 19’ All are methyl.

30. The compound of claim 27, wherein W2 is CN, OH or NH2.

31. The compound of claim 25, wherein R7 is H or methyl.

32. The compound according to claim 25, which has the structure of Formula I-2a, I-2b or I-2c: or a pharmaceutically acceptable salt or stereoisomer thereof.

33. The compound according to claim 1, wherein A is And the compound of formula (I) has the structure of formula I-3, or a pharmaceutically acceptable salt or stereoisomer thereof.

34. The compound of claim 33, wherein R5 is methyl.

35. The compound of claim 33, wherein R8 is (C3-C6)cycloalkyl and R8' is H.

36. compounds according to claim 33, wherein A 'is a 7-membered heterocyclic radical, wherein the heterocyclic radical contains 2 heteroatoms selected from N and O, and except R8 and R8', it is optionally further substituted by one or more substituents independently selected from the group consisting of oxo, (C1-C2) alkyl, cyclopropyl, spirocyclopropyl, halogen, (C1-C2) haloalkyl, (C1-C2) alkoxy, NH2, CN and OH.

37. The compound according to claim 33, having the structure of formula I-3a, or a pharmaceutically acceptable salt or stereoisomer thereof.

38. The compound according to claim 1, wherein A is And the compound of formula (I) has the structure of formula I-4, or a pharmaceutically acceptable salt or stereoisomer thereof.

39. The compound according to claim 1, wherein A is And the compound of formula (I) has the structure of formula I-5, or a pharmaceutically acceptable salt or stereoisomer thereof.

40. The compound according to claim 1, wherein A is And the compound of formula (I) has the structure of formula I-6, , or a pharmaceutically acceptable salt or stereoisomer thereof.

41. The compound of claim 40, wherein R5 is methyl.

42. The compound of claim 40, wherein m is 1.

43. The compound of claim 40, wherein m is 0.

44. The compound of claim 40, wherein X5 is absent.

45. The compound of claim 40, wherein o is 1.

46. ​​The compound according to claim 45, wherein R 10 and R 11 Each is H, and R 10 ' and R 11 'Together with the carbon atom to which they are attached, they form a cyclobutyl group.

47. The compound according to claim 40, wherein R 12 It's OH.

48. The compound of claim 40, wherein o is 0.

49. The compound according to claim 48, wherein R 12 It's H.

50. The compound according to claim 40, having a structure of Formula I-6a or I-6b, or a pharmaceutically acceptable salt or stereoisomer thereof.

51. The compound according to claim 1, which is: or a pharmaceutically acceptable salt or stereoisomer thereof.

52. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 51 or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

53. A method of treating a disease or condition involving aberrant B-cell lymphoma 6 (BCL6) activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-51 or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of claim 52.

54. The method of claim 53, wherein the disease or condition is cancer.

55. The method of claim 54, wherein the cancer is a lymphoid malignancy.

56. The method of claim 55, wherein the lymphoid malignancy is peripheral T-cell lymphoma (PTCL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia / lymphoma (ALL), or cutaneous T-cell lymphoma.

57. The method of claim 55 or 56, further comprising administering an additional anti-cancer agent.

58. The method of claim 56, wherein the additional anti-cancer agent is an enhancer of zeste homolog 2 (EZH2) inhibitor.

59. The method of claim 53, wherein the disease or condition is an inflammatory disease.

60. The method of claim 59, wherein the inflammatory disease is inflammatory bowel disease, myocarditis, endometriosis, atherosclerosis, an allergic disease, or an autoimmune disease.

61. The method of claim 60, wherein the allergic disease is asthma or hay fever.

62. The method of claim 60, wherein the autoimmune disease is noninfectious meningitis, autoimmune encephalitis, transverse myelitis, or acute disseminated encephalomyelitis.

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