Macrocyclic BCL6 degraders

Abstract

Compounds, compositions and methods for treating diseases and disorders associated with aberrant B-cell lymphoma 6 (BCL6) activity are described.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 396,381, filed August 9, 2022, U.S. Provisional Application No. 63 / 432,580, filed December 14, 2022, and U.S. Provisional Application No. 63 / 465,584, filed May 11, 2023, each of which is incorporated by reference in its entirety. [Background technology]

[0002] Small molecule-induced protein degradation has emerged as a powerful therapeutic strategy, as demonstrated by the clinical efficacy of thalidomide analogs for the treatment of hematological malignancies. Thalidomide analogs, including lenalidomide and pomalidomide, inhibit Cullin Really Interesting New Gene (RING) ligase 4-cereblon (CRBN) (CRL4). CRBN ) regulates the activity of E3 ubiquitin ligases to recruit and ubiquitinate neosubstrates, including Ikaros family zinc finger 1 (IKZF1), IKZF3, and casein kinase 1-alpha (CK1α), leading to their proteasomal degradation (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 arylsulfonamides, which are involved in the degradation of CRL4-DNA damage-binding protein 1 (DDB1) and CUL4-associated factor 15 (DCAF15) (CRL4). DCAF15 )-dependently promotes the destruction of RNA-binding motif protein 39 (RBM39) (Han et al., Science 356:eaal3755 (2017)).

[0003] Other types of small molecules, including heterobifunctional degraders (also known as PROTACs) (Toure et al., Angew. Chem. Int. Ed. Engl. 55:1966-1973 (2016)), 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 engage both the E3 ligase and the target protein substrate, 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)).

[0004] While degraders have shown remarkable efficacy and sustained depletion for some target proteins, other proteins have proven refractory to this approach. One such example is the B-cell lymphoma 6 (BCL6) protein, for which heterobifunctional degraders have shown insufficient target modulation to induce growth inhibition (McCoull et al., ACS Chem. Biol. 13:3131-3141 (2018)).

[0005] BCL6 was first identified as a genetic locus affected by chromosomal translocations in diffuse large B-cell lymphoma (DLBCL). It is now known to be broadly expressed in many lymphomas. Its role in lymphomagenesis stems from its function in the humoral immune system, where upregulation of BCL6 is required for the formation of germinal centers (GCs) during humoral immune responses (Ye et al., Nat. Genet. 16:161-170 (1997); Dent et al., Science 276:89-92 (1997)). GCs are transient structures that form in response to antigenic stimulation. Within GCs, B cells undergo immunoglobulin affinity maturation, allowing for massive proliferation and the mutagenic effects of the DNA-editing enzyme AICDA (Klein et al., Nat. Rev. Immunol. 8:22-33 (2008)). These activities are orchestrated by and dependent on BCL6, a powerful transcriptional repressor that silences hundreds of genes. Some of these target genes control DNA damage sensing (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 represses genes required for withdrawal from the GC reaction and plasma cell differentiation (e.g., IRF4, PRDM1). This ensures that GC B cells have sufficient time to acquire somatic hypermutation of their immunoglobulin genes. Therefore, deregulated repression of these target genes can result in malignant transformation of B cells.

[0006] BCL6 also regulates numerous oncogenes in GC B cells, including MYC, BCL2, BMI1, and CCND1 (Ci et al., Blood 113:5536-5548 (2009)). Through this function, BCL6 may mitigate its own pro-oncogenic checkpoint suppression effect, thus reducing the potential for malignant transformation of GC B cells. This effect is abrogated in the presence of BCL2 or MYC translocations, which drive the expression of these oncogenes through aberrant regulatory elements. The presence of both MYC and / or BCL2 together with BCL6 (regardless of translocation) is clearly detrimental, as it results in simultaneous BCL6-mediated checkpoint suppression in B cells, along with 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 disruption of the BCL6 transcription complex via CD40-induced ERK signaling and downregulation of BCL6 mRNA by IRF4 and PRDM1 (Polo et al., Blood 112:644-651 (2008)). Termination of BCL6 function is required for B cells to terminate GC responses.

[0007] BCL6 is a promising drug target for non-Hodgkin's 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)). Pathologically elevated BCL6 expression, resulting from somatic BCL6 translocations, exon mutations, promoter mutations, or mutations in regulatory pathways, 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, enabling the rapid development of germinal center (GC) B cells and resistance to genomic instability caused by immunoglobulin gene hypermutation and class switch recombination (Hatzi et al., Trends Mol. Med. 20:343-352 (2014)). BCL6 represses 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 lymphoid cells results in 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 has limited their translation into clinical therapeutics (Cerchietti et al., Cancer Cell 17:400-411 (2010); Cardenas et al., J. Clin. Invest. 126:3351-3362 (2016)).

[0008] The Broad complex / Tramtrack / Bric-a-brac (BTB) proteins are a diverse protein family characterized by the presence of a common protein-protein interaction domain known as the BTB domain. BTB proteins have diverse functions ranging from transcriptional regulation and chromatin remodeling to protein degradation and cytoskeletal regulation. Functional specificity is determined, in part, by additional domains present in a given BTB protein as well as by its interacting partners. Studies of BTB proteins in Drosophila and mammalian systems have revealed the importance of these proteins in multiple developmental contexts, as well as in cancer and neurological and musculoskeletal diseases. BTB proteins play important roles in transcriptional regulation and chromatin remodeling (Chaharbakhshi et al., Genesis 54:505-518 (2016)).

[0009] The BTB domain mediates various functions of BCL6, such as homodimerization and interaction with corepressor proteins (Ghetu et al., Mol. Cell 29:384-391 (2008); Ahmad et al., Mol. Cell 12:1551-1564 (2003)). Techniques that disrupt the protein-protein interaction between the BTB domain of BCL6 and its corepressors may be useful for combating BCL6-related diseases. Summary of the Invention [Means for solving the problem]

[0010] A first aspect of the present disclosure is a compound of formula (I): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, (In the formula, X1 is N, CH, CCl, CF, or CCN; X2 is N or CR4; R4 is H, (C1-C4)alkyl, halo, 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 halo; R2 is H, OH, or halo; R3 is H, halo, or CN; Y is CH, NH, or O; Z is CH, NH, S, or O; n is 0, 1, or 2; A is, [ka] and; 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; said alkyl, carbocyclyl, or heterocyclyl may be optionally substituted with one or more of the same or different R 13 may be further substituted by groups, R 13 is (C1-C6)alkyl, (C1-C6)alkoxy, halo, 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, 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, where Z1 is (C1-C4) alkyl, halo, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, NH2, (C1-C4) aminoalkyl, CN, OH, carboxy, carbamoyl, sulfamoyl, mercapto, ureido, 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)NR r R s , N(R r )SO2R r , Si(R r )(R s )R t and (CH2) 1-3 NR r R s and optionally substituted with one or more substituents independently selected from: r , R s and R tare each independently H, (C-C) alkyl, or (C-C) cycloalkyl; or R r and R s together with the nitrogen atom to which they are attached form a 4- to 9-membered heterocyclyl optionally substituted by one or more substituents selected from (C1-C4)alkyl, halo, (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 where L1 is absent, 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 atoms to which they are attached form a (C3-C5) carbocyclyl, a 4- to 7-membered heterocyclyl, or C=O; R 16 is (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)alkylNR 18 C(O)R 17 or 4- to 7-membered heterocyclyl, R 17is H, a 3- to 6-membered heterocyclyl, or a (C1-C4)alkyl optionally substituted with one or more identical or different groups selected from OH, Cl, F, CF3, N(C1-C4 alkyl)2, (C3-C6)carbocyclyl, a 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 [ka] where W1 is CR 19 R 19 or C(O); R 19 and R 19’ are independently H, (C-C)alkyl, F, OH, CN, NO, (C-C)alkoxy, (C-C)haloalkyl, (C-C)haloalkoxy, NH, NH(C-C)alkyl, or N(C-Calkyl), or R 19 and R 19’ together with the carbon atoms to which they are attached form C(O), (C3-C6)carbocyclyl or 3- to 6-membered heterocyclyl, which is optionally substituted by one or more substituents independently selected from (C1-C2)alkyl, halo, (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, where R 20is 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, 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 (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, where Z2 is optionally substituted with one or more substituents independently selected from (C1-C4)alkyl, halo, (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', where each R' is independently H or (C1-C4)alkyl; or R 20 and R 21 together with the carbon atoms to which they are attached form a (C-C)carbocyclyl or a 3- to 6-membered heterocyclyl optionally substituted by one or more substituents selected from (C-C)alkyl, halo, (C-C)haloalkyl, (C-C)haloalkoxy, (C-C)alkoxy, (C-C)alkylamino, NH, CN and OH; R 22is (C1-C2)alkyl, —C(O)OR″, OR″, —C(O)NR″, NR″R″, phenyl, or 5-membered heteroaryl, where each R″ is independently H or (C1-C2)alkyl; A'' is (C4-C6)carbocyclyl or 4- to 6-membered heterocyclyl optionally substituted with one or more substituents independently selected from (C1-C2)alkyl, halo, OH, oxo, CN, and (C1-C2)alkoxy; W3 is NR 23 or CR 24 R 24 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 said alkyl or cycloalkyl is optionally substituted by one or more substituents selected from (C1-C4)alkyl, (C3-C6)cycloalkyl, OH, (C1-C2)alkoxy, NH2, NH(C1-C2)alkyl, N((C1-C2)alkyl)2, (C1-C2)aminoalkyl, and halo; R8' is H, (C1-C4)alkyl, CN, (C1-C4)haloalkyl, or -Y3-L3-Z3, wherein Y3 is absent, C(O)O or C(O)N(R''); L3 is absent or (C1-C2) alkylene; Z3 is H, (C1-C6)alkyl, phenyl, (C3-C6)cycloalkyl, or 4- to 6-membered heterocyclyl, where Z3 is optionally substituted with one or more substituents independently selected from (C1-C2)alkyl, halo, (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', may be further substituted by one or more substituents independently selected from oxo, (C1-C2) alkyl, cyclopropyl, spiro-cyclopropyl, halo, (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, Y4 is absent, C(O), C(O)O, OC(O), C(O)N(R''), or S(O)2N(R''); L4 is absent or is a (C1-C2)alkylene 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, where Z4 is oxo, (C1-C4)alkyl, (C3-C6)cycloalkyl, halo, (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 and optionally substituted with one or more substituents independently selected from u are independently H, (C1-C4) alkyl, (C3-C6) cycloalkyl, or Z4 is -Q-L5-W4, where Q is absent, O, NH, or N(C1-C2)alkyl; L5 is absent or (C1-C2)alkylene 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, where W4 is optionally substituted with one or more substituents independently selected from (C1-C4)alkyl, halo, (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 atoms to which they are attached, form a (C3-C 10) carbocyclyl or 4- to 10-membered heterocyclyl, which may be substituted by one or more substituents independently selected from oxo, (C1-C2) alkyl, halo, (C1-C2) haloalkyl, (C1-C2) haloalkoxy, (C1-C2) alkoxy, (C1-C2) alkylamino, NH2, NO2, CN, or OH; or said (C3-C 10 ) carbocyclyl or 4-10 membered heterocyclyl may be fused to a 5- or 6-membered heteroaryl or phenyl ring, and said 5- or 6-membered heteroaryl or phenyl ring may be substituted by (C1-C2) alkyl, halo, (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, acetylenyl, phenyl, or 5- or 6-membered heteroaryl, wherein said alkyl, phenyl, or heteroaryl is optionally substituted by one or more substituents independently selected from halo, OH, and NH2; X5 is absent, (C3-C6)carbocyclyl, (C3-C6)carbocyclyl(C=O), or SO2; R 10 and R 10 each ' is 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, and said alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl or heterocyclyl may be optionally joined by one or more of the same or different R 10a may be substituted by a group, R 10ais (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-(C1-C3)alkoxy, halo, 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 atoms to which they are attached form a (C3-C6) carbocyclyl or a 4- to 6-membered heterocyclyl; R 11 and R 11 each ' is 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 form C=O, (C3-C6)carbocyclyl, or 4- to 6-membered heterocyclyl, said carbocyclyl or heterocyclyl being optionally joined by one or more of the same or different R 11a groups, and each R 11a are independently (C-C) alkyl, (C-C) alkoxy, (C-C) alkyl-(C-C) alkoxy, halo, NH, OH, (C-C) haloalkyl, NH-(C-C) alkyl, N((C-C) alkyl), (C-C) carbocyclyl, or 4- to 6-membered heterocyclyl, or two R 11a groups together with the same carbon atom to which they are attached to 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, and said alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl, or heterocyclyl may be selected from one or more of the same or different R 12agroups, where each R 12a are independently (C-C)alkyl, (C-C)alkoxy, (C-C)alkyl-(C-C)alkoxy, halo, NH, OH, (C-C)haloalkyl, NH-(C-C)alkyl, N((C-C)alkyl), (C-C)carbocyclyl, or 4- to 6-membered heterocyclyl; m is 0, 1, or 2; and o is 0 or 1.)

[0011] Another aspect of the present disclosure is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer and a pharmaceutically acceptable carrier.

[0012] A further aspect of the present disclosure is directed to a method for treating a disease or disorder associated with abnormal BCL6 activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is an inflammatory disease.

[0013] 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 lymphoblastic leukemia / lymphoma (ALL), cutaneous T-cell lymphoma, chronic myeloid leukemia, or B-cell non-Hodgkin's lymphoma. DETAILED DESCRIPTION OF THE INVENTION

[0014] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of this specification belongs. As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings indicated to facilitate understanding of this disclosure.

[0015] As used in this 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, etc.

[0016] Unless otherwise specified, the term "about" means within 10% (eg, within 5%, 2%, or 1%) of the particular value modified by the term "about."

[0017] The transitional phrase "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 refers to the heterocyclic group having that minimum number of heteroatoms. In contrast, the transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional phrase "consisting essentially of" limits the claim to the specific materials or steps of the disclosure and "those that do not materially affect the basic and novel characteristics."

[0018] With respect to the compounds of the present disclosure, to the extent the following terms are used herein to further describe them, the following definitions apply.

[0019] As used herein, the term "alkyl" refers to a saturated, straight- or branched-chain monovalent hydrocarbon group. In some embodiments, the alkyl radical is a C1-C6 group. In some embodiments, unless otherwise disclosed for any one or more groups of a compound of Formula (I), the alkyl radical is a C0-C6, C0-C5, C0-C3, C1-C6, C1-C5, C1-C4, or C1-C3 group (C0 alkyl refers to a bond). Examples of alkyl groups include methyl, ethyl, 1-propyl, 2-propyl, i-propyl, 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 a C1-C3 alkyl group. In some embodiments, the alkyl group is a C1-C2 alkyl group. In some embodiments, the alkyl group is a methyl group.

[0020] As used herein, the term "alkylene" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing no unsaturation, having 1 to 6 carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, etc., linking the remainder of the molecule to a radical group. The alkylene chain may be attached to the remainder of the molecule through a single bond and to the radical group through a single bond. In some embodiments, unless otherwise disclosed for any one or more groups of the compounds of Formula (I), an alkylene group contains 1 to 4 carbon atoms (C1-C4 alkylene). In other embodiments, an alkylene group contains 1 to 3 carbon atoms (C1-C3 alkylene). In other embodiments, an alkylene group contains 1 to 2 carbon atoms (including C1-C2 alkylene). In other embodiments, an alkylene group contains 1 carbon atom (C1 alkylene).

[0021] As used herein, the term "alkenyl" refers to a straight- or branched-chain monovalent hydrocarbon radical having at least one carbon-carbon double bond. Alkenyl includes radicals having "cis" and "trans" orientations, alternatively "E" and "Z" orientations. In some embodiments, an alkenyl radical is a C2-C6 alkyl group. 15 In some embodiments, unless otherwise disclosed for any one or more groups of compounds of Formula (I), the alkenyl radical is a C-C 12 , C2-C 10 , C2-C8, C2-C6 or C2-C3 groups. Examples include ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl.

[0022] As used herein, the term "alkynyl" refers to a straight- or branched-chain monovalent hydrocarbon group having at least one carbon-carbon triple bond. In some embodiments, an alkynyl radical is a C-C 15 In some embodiments, unless otherwise disclosed for any one or more groups of compounds of formula (I), the alkynyl radical is a C-C 12 , C2-C 10 , C2-C8, C2-C6 or C2-C3. Examples include ethynylprop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl and but-3-ynyl.

[0023] The term "alkoxyl" or "alkoxy" as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto as the point of attachment. In some embodiments, the alkoxyl group is methoxy, ethoxy, propyloxy, or tert-butoxy. An "ether" is two hydrocarbyl groups covalently linked by an oxygen. Thus, the alkyl substituent that makes the alkyl an ether is or resembles an alkoxyl, as can be represented by one of -O-alkyl, -O-alkenyl, and -O-alkynyl.

[0024] As used herein, the term "halogen" (or "halo" or "halide") refers to fluorine, chlorine, bromine, or iodine.

[0025] As used herein, the term "cyclic group," used alone or as part of a larger moiety, broadly refers to any group containing saturated, partially saturated, or aromatic ring systems, e.g., carbocyclic (cycloalkyl, cycloalkenyl), heterocyclic (heterocycloalkyl, heterocycloalkenyl), aryl, and heteroaryl groups. A cyclic group can have one or more (e.g., fused) ring systems. Thus, for example, a cyclic group can contain one or more carbocyclic, heterocyclic, aryl, or heteroaryl groups.

[0026] As used herein, the term "carbocycle" (also "carbocyclyl"), used alone or as part of a larger moiety, refers to a group containing a saturated, partially unsaturated, or aromatic ring system having from 3 to 12 carbon atoms, i.e., a group 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 ring systems, and combinations thereof. In one embodiment, a carbocyclyl contains from 3 to 10 carbon atoms (C3-C 10 In one embodiment, the carbocyclyl contains 3 to 6 carbon atoms (C3-C6). In one embodiment, the carbocyclyl contains 5 to 6 carbon atoms (C5-C6). In some embodiments, the carbocyclyl, as a bicycle, contains C6-C 10 In another embodiment, the carbocyclyl, as a spiro system, includes C5-C 11Representative 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 spirocarbocyclyls 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 aryl ring systems as defined herein. The term carbocyclyl also includes cycloalkyl rings (e.g., saturated or partially unsaturated monocyclic carbocycles, bicyclic carbocycles, 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 heterocycles), where a radical or point of attachment is on the carbocycle.

[0027] Thus, the term carbocycle as used herein means R c is an alkylene chain of formula --R c The term carbocyclyl, as used herein, also encompasses carbocyclylalkyl groups, which refer to the group R c is an alkylene chain of the formula --O--R c Also included are carbocyclylalkoxy groups, which refer to groups attached through the oxygen atom of a -carbocyclyl.

[0028] As used herein, the term "aryl" (e.g., "aralkyl" where the terminal carbon atom on an alkyl group is the point of attachment, e.g., a benzyl group), "aralkoxy" where an oxygen atom is the point of attachment, or "aroxyalkyl" where the point of attachment is on an aryl group) used alone or as part of a larger moiety refers to a group containing a monocyclic, bicyclic, or tricyclic carbocyclic ring system, including fused rings, in which at least one ring in the system is aromatic. In some embodiments, an aralkoxy group is a benzoxy group. The term "aryl" may be used interchangeably with the term "aryl ring." In one embodiment, aryl includes groups having 6 to 12 carbon atoms. In another embodiment, aryl includes groups having 6 to 10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, biphenyl, 1,2,3,4-tetrahydronaphthalenyl, and the like, which may be substituted or independently substituted with one or more substituents described herein. A particular aryl is phenyl. In some embodiments, an aryl group comprises an aryl ring fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., carbocycles or heterocycles), where the radical or point of attachment is on the aryl ring.

[0029] Thus, the term aryl refers to R c is an alkylene chain such as methylene or ethylene; c -aryl groups, including aralkyl groups (e.g., benzyl). In some embodiments, the aralkyl group is an optionally substituted benzyl group. The term aryl, as used herein, refers to an R c is an alkylene chain such as methylene or ethylene; c Also included is an aralkoxy group, which refers to a group bonded through the oxygen atom of an --aryl.

[0030] As used herein, the term "heterocyclyl," used alone or as part of a larger moiety, refers to "carbocyclyl" and includes saturated, partially unsaturated, or aromatic ring systems in which one or more (e.g., 1, 2, 3, 4, or 5) carbon atoms are replaced by a heteroatom or heteroatom-containing group (e.g., O, N, N(O), S, S(O), or S(O)). The term heterocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged, and spirocyclic ring systems, as well as 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 heteroaryl ring system, such as a 5- to 12-membered heteroaryl ring system. The term heterocyclyl also includes C2-C8 heterocycloalkyl, which are saturated or partially unsaturated monocyclic, bicyclic, or spirocyclic ring systems containing 2 to 8 carbons and one or more (e.g., 1, 2, or 3) heteroatoms.

[0031] In some embodiments, heterocyclyl groups contain 3 to 12 ring atoms, including monocyclic, bicyclic, tricyclic, and spirocyclic systems, where the ring atoms are carbon and 1 to 5 ring atoms are heteroatoms such as nitrogen, sulfur, or oxygen. In some embodiments, heterocyclyls contain 3 to 7-membered monocyclic rings having one or more heteroatoms selected from O, N, and S. In some embodiments, heterocyclyls contain 4 to 6-membered monocyclic rings having one or more heteroatoms selected from O, N, and S. In some embodiments, heterocyclyls contain 3-membered monocyclic rings. In some embodiments, heterocyclyls contain 4-membered monocyclic rings. In some embodiments, heterocyclyls contain 5 to 6-membered monocyclic rings. In some embodiments, heterocyclyl groups contain 0 to 3 double bonds. In any of the foregoing embodiments, heterocyclyls contain 1, 2, 3, or 4 heteroatoms. Any nitrogen or sulfur heteroatom may be optionally oxidized (e.g., NO, SO, SO), and any nitrogen heteroatom may be optionally substituted (e.g., methyl, isopropyl), and / or quaternized (e.g., [NR]). + Cl - , [NR4] + OH -Representative examples of heterocyclyl include oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydropyranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, and oxazinanyl. , thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzo[d ]imidazolyl, 1,6-dihydroimidazole[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, thiophenyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolinyl Zolidinyl, dithianyl, dithiolanyl, pyrimidinanyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl, piperazinedionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azaspiro[4.5]decan-2-onyl (only), azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, and 1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclyls containing sulfur or oxygen atoms and 1 to 3 nitrogen atoms include 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 heterocyclyls 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-tetrazol-5-yl). Representative examples of benzofused 5-membered heterocyclyls include benzoxazol-2-yl, benzothiazol-2-yl, and benzimidazol-2-yl. Examples of 6-membered heterocyclyls containing 1 to 3 nitrogen atoms and optionally sulfur or oxygen atoms include pyridyl (e.g., pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl), pyrimidyl (e.g., pyrimid-2-yl and pyrimid-4-yl), triazinyl (e.g., 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl), pyridazinyl (e.g., pyridazin-3-yl), and pyrazinyl. In some embodiments, a heterocyclic group comprises a heterocycle fused to one or more (e.g., one or two) different cyclic groups (e.g., carbocycles or heterocycles), where the radical or point of attachment is on the heterocycle, and in some embodiments, the point of attachment is a heteroatom contained in the heterocycle.

[0032] Thus, the term heterocycle, as used herein, includes N-heterocyclyl groups, which refer to heterocyclyl groups containing at least one nitrogen atom, where the heterocyclyl group is attached to the rest of the molecule through a 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, as used herein, also includes C-heterocyclyl groups, which refer to heterocyclyl groups containing at least one heteroatom, where the heterocyclyl group is attached to the rest of the molecule through a carbon atom in the heterocyclyl group. Representative examples of C-heterocyclyl radicals include 2- or 3-morpholinyl, 2-, 3-, or 4-piperidinyl, 2-piperazinyl, and 2- or 3-pyrrolidinyl. The term heterocycle also refers to the heterocyclic ring, as disclosed above, R c is an alkylene chain of formula --R c The term heterocycle, as used herein, also refers to the group R c is an alkylene chain of the formula --O--R c - includes heterocyclylalkoxy groups, which refer to radicals attached through the oxygen atom of a heterocyclyl.

[0033] As used herein, the term "heteroaryl" (e.g., "heteroarylalkyl" (also "heteroaralkyl"), or "heteroarylalkoxy" (also "heteroaralkoxy")), used alone or as part of a larger moiety, refers to a monocyclic, bicyclic, or tricyclic ring system having 5 to 12 ring atoms, in which at least one ring is aromatic and contains at least one heteroatom. In one embodiment, heteroaryl includes 5- to 6-membered monocyclic aromatic groups in which one or more ring atoms is O, N, or S. Representative examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, imidazopyridyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, purinyl, deazapurinyl, and benzoxazolyl.

[0023] The term "heteroaryl" also includes groups in which a heteroaryl is fused to one or more cyclic (e.g., carbocyclyl, or heterocyclyl) rings, and the radical or point of attachment is on the heteroaryl ring.Non-limiting examples include indolyl, indolizinyl, isoindolyl, benzothienyl, benzothiophenyl, methylenedioxyphenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzodioxazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic, bicyclic, or tricyclic. In some embodiments, a heteroaryl group comprises a heteroaryl ring fused to one or more (e.g., one or two) different cyclic groups (e.g., carbocyclic or heterocyclic rings), where the radical or point of attachment is on the heteroaryl ring, and in some embodiments, the point of attachment is a heteroatom contained in the heterocyclic ring.

[0034] Thus, the term heteroaryl, as used herein, encompasses N-heteroaryl groups, which refer to heteroaryl groups, as defined above, containing at least one nitrogen, where the point of attachment of the heteroaryl group to the remainder of the molecule is through a nitrogen atom in the heteroaryl group. The term heteroaryl, as used herein, also encompasses C-heteroaryl groups, which refer to heteroaryl groups, as defined above, where the point of attachment of the heteroaryl group to the remainder of the molecule is through a carbon atom in the heteroaryl group. The term heteroaryl also encompasses R, as disclosed above. c is an alkylene chain as defined above c The term heteroaryl, as used herein, also refers to the group R c is an alkylene group as defined above c -includes heteroaralkoxy (or heteroarylalkoxy) groups, which refers to groups attached through an oxygen atom of a heteroaryl.

[0035] Unless otherwise stated, and unless further defined for any particular group in the compounds of Formula (I), any of the groups described herein can be substituted or unsubstituted. Unless otherwise disclosed for any particular group, representative examples of substituents include alkyl (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), substituted alkyl (e.g., substituted C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), alkoxy (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), substituted alkoxy (e.g., substituted C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), and the like. -C3, C1-C2, C1), haloalkyl (e.g., CF3), alkenyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), substituted alkenyl (e.g., substituted C2-C6, C2-C5, C2-C4, C2-C3, C2), alkynyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), substituted alkynyl (e.g., substituted C2-C6, C2-C5, C2-C4, C2-C3, C2), cyclic (e.g., C3-C 12 , C5-C6), substituted cyclic (e.g., substituted C3-C 12 , C5-C6), carbocyclic (e.g., C3-C 12 , C5-C6), substituted carbocyclic (e.g., C3-C 12 , C5-C6), heterocyclic (e.g., 3- to 12-membered, 5- to 6-membered), substituted heterocyclic (e.g., substituted 3- to 12-membered, 5- to 6-membered), aryl (e.g., benzyl and phenyl), substituted aryl (e.g., substituted benzyl or substituted phenyl), heteroaryl (e.g., pyridyl or pyrimidyl), substituted heteroaryl (e.g., substituted pyridyl or substituted pyrimidyl), aralkyl (e.g., benzyl), substituted aralkyl (e.g., substituted benzyl), halo, hydroxyl, aryloxy (e.g., C6-C 12 , C6), substituted aryloxy (e.g., substituted C6-C 12 , C6), alkylthio (e.g., C1-C6), substituted alkylthio (e.g., substituted C1-C6), arylthio (e.g., C6-C 12 , C6), substituted arylthio (e.g., substituted C6-C 12, C6), cyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, thio, substituted thio, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfinamide, substituted sulfinamide, sulfonamide, substituted sulfonamide, urea, substituted urea, carbamic acid, substituted carbamic acid, amino acid, and peptide groups.

[0036] Generally, compounds of the present disclosure have the formula (I): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, (In the formula, X1 is N, CH, CCl, CF, or CCN; X2 is N or CR4; R4 is H, (C1-C4)alkyl, halo, 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 halo; R2 is H, OH, or halo; R3 is H, halo, or CN; Y is CH, NH, or O; Z is CH, NH, S, or O; n is 0, 1, or 2; A is, [ka] and; 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; said alkyl, carbocyclyl, or heterocyclyl may be optionally substituted with one or more of the same or different R 13 may be further substituted by groups, R 13 is (C1-C6)alkyl, (C1-C6)alkoxy, halo, 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 (C1-C5)alkylene optionally substituted with one or more substituents selected from (C1-C2)alkyl and oxo; Y1 is absent, 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, where Z1 is (C1-C4) alkyl, halo, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, NH2, (C1-C4) aminoalkyl, CN, OH, carboxy, carbamoyl, sulfamoyl, mercapto, ureido, NR r R s , OR r , C(O)R r , C(O)OR r ,OC(O)R r , C(O)NR r Rs , N(R r )C(O)R r , S(O) 0-2 R r , S(O)NR r R s , N(R r )SO2R r , Si(R r )(R s )R t and (CH2) 1-3 NR r R s and optionally substituted with one or more substituents independently selected from: r , R s and R t are each independently H, (C-C) alkyl, or (C-C) cycloalkyl; or R r and R s together with the nitrogen atom to which they are attached form a 4- to 9-membered heterocyclyl optionally substituted by one or more substituents selected from (C1-C4)alkyl, halo, (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 where L1 is absent, 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 atoms to which they are attached form a (C3-C5) carbocyclyl, a 4- to 7-membered heterocyclyl, or C=O; R 16 is (C1-C6) alkyl, -NR17 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 4- to 7-membered heterocyclyl, R 17 is H, a 3- to 6-membered heterocyclyl, or a (C1-C4)alkyl optionally substituted with one or more identical or different groups selected from OH, Cl, F, CF3, N(C1-C4 alkyl)2, (C3-C6)carbocyclyl, a 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 [ka] where W1 is CR 19 R 19 or C(O); R 19 and R 19’ are independently H, (C-C)alkyl, F, OH, CN, NO, (C-C)alkoxy, (C-C)haloalkyl, (C-C)haloalkoxy, NH, NH(C-C)alkyl, or N(C-Calkyl), or R 19 and R 19’together with the carbon atoms to which they are attached form a C(O), (C3-C6)carbocyclyl or 3- to 6-membered heterocyclyl optionally substituted by one or more substituents independently selected from (C1-C2)alkyl, halo, (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, where 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, 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 (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, where Z2 is optionally substituted with one or more substituents independently selected from (C1-C4)alkyl, halo, (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', where each R' is independently H or (C1-C4)alkyl; or R 20 and R 21 together with the carbon atoms to which they are attached form a (C-C)carbocyclyl or a 3- to 6-membered heterocyclyl optionally substituted by one or more substituents selected from (C-C)alkyl, halo, (C-C)haloalkyl, (C-C)haloalkoxy, (C-C)alkoxy, (C-C)alkylamino, NH, CN and OH; R 22 is (C1-C2)alkyl, —C(O)OR″, OR″, —C(O)NR″, NR″R″, phenyl, or 5-membered heteroaryl, where each R″ is independently H or (C1-C2)alkyl; A'' is (C4-C6)carbocyclyl or 4- to 6-membered heterocyclyl optionally substituted with one or more substituents independently selected from (C1-C2)alkyl, halo, OH, oxo, CN, and (C1-C2)alkoxy; W3 is NR 23 or CR 24 R 24 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 24are 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 said alkyl or cycloalkyl is optionally substituted by one or more substituents selected from (C1-C4)alkyl, (C3-C6)cycloalkyl, OH, (C1-C2)alkoxy, NH2, NH(C1-C2)alkyl, N((C1-C2)alkyl)2, (C1-C2)aminoalkyl, and halo; R8' is H, (C1-C4)alkyl, CN, (C1-C4)haloalkyl, or -Y3-L3-Z3, wherein Y3 is absent, C(O)O or C(O)N(R''); L3 is absent or (C1-C2) alkylene; Z3 is H, (C1-C6)alkyl, phenyl, (C3-C6)cycloalkyl, or 4- to 6-membered heterocyclyl, where Z3 is optionally substituted with one or more substituents independently selected from (C1-C2)alkyl, halo, (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', may be further substituted by one or more substituents independently selected from oxo, (C1-C2) alkyl, cyclopropyl, spiro-cyclopropyl, halo, (C1-C2) haloalkyl, (C1-C2) haloalkoxy, (C1-C2) alkoxy, NH2, CN, and OH; X4 is CR 25or 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, Y4 is absent, C(O), C(O)O, OC(O), C(O)N(R''), or S(O)2N(R''); L4 is absent or (C1-C2) alkylene 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, where Z4 is oxo, (C1-C4)alkyl, (C3-C6)cycloalkyl, halo, (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 and optionally substituted with one or more substituents independently selected from u are independently H, (C1-C4) alkyl, (C3-C6) cycloalkyl, or Z4 is -Q-L5-W4, where Q is absent, O, NH, or N(C1-C2)alkyl; L5 is absent or (C1-C2)alkylene 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, where W4 is optionally substituted by one or more substituents independently selected from (C1-C4)alkyl, halo, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C1-C4)alkoxy, (C1-C4)alkylamino, NH2, NO2, CN, or OH; or R and R′, together with the carbon atom to which they are attached, are optionally substituted by one or more substituents independently selected from oxo, (C-C) alkyl, halo, (C-C) haloalkyl, (C-C) haloalkoxy, (C-C) alkoxy, (C-C) alkylamino, NH, NO, CN, or OH (C-C 10 ) carbocyclyl or 4- to 10-membered heterocyclyl, or 10 ) carbocyclyl or 4-10 membered heterocyclyl may be fused to a 5- or 6-membered heteroaryl or phenyl ring, and said 5- or 6-membered heteroaryl or phenyl ring may be substituted by (C1-C2) alkyl, halo, (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, acetylenyl, phenyl, or 5- or 6-membered heteroaryl, wherein said alkyl, phenyl, or heteroaryl is optionally substituted by one or more substituents independently selected from halo, OH, and NH2; X5 is absent, (C3-C6)carbocyclyl, (C3-C6)carbocyclyl(C=O), or SO2; R 10 and R 10 each ' is 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, and said alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl, or heterocyclyl may be optionally substituted with one or more of the same or different R 10a groups, where R 10a is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-(C1-C3)alkoxy, halo, 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 atoms to which they are attached form a (C3-C6) carbocyclyl or a 4- to 6-membered heterocyclyl; R 11 and R 11 each ' is 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 form C=O, (C3-C6)carbocyclyl, or 4- to 6-membered heterocyclyl, said carbocyclyl or heterocyclyl being optionally joined by one or more of the same or different R 11a groups, where each R 11aare independently (C-C) alkyl, (C-C) alkoxy, (C-C) alkyl-(C-C) alkoxy, halo, NH, OH, (C-C) haloalkyl, NH-(C-C) alkyl, N((C-C) alkyl), (C-C) carbocyclyl, or 4- to 6-membered heterocyclyl, or two R 11a groups together with the same carbon atom to which they are attached to 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, and said alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl, or heterocyclyl may be selected from one or more of the same or different R 12a groups, where each R 12a are independently (C-C)alkyl, (C-C)alkoxy, (C-C)alkyl-(C-C)alkoxy, halo, NH, OH, (C-C)haloalkyl, NH-(C-C)alkyl, N((C-C)alkyl), (C-C)carbocyclyl, or 4- to 6-membered heterocyclyl; m is 0, 1, or 2; and o is 0 or 1.)

[0037] In some embodiments, Z is O. In some embodiments, Z is CH.

[0038] In some embodiments, Y is CH. In some embodiments, Y is O. In some embodiments, Y is NH.

[0039] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0040] In some embodiments, R1 and R2 are each H. In some embodiments, R1 and R2 are each halo. In some embodiments, R1 and R2 are each F.

[0041] In some embodiments, R3 is halo. In some embodiments, R3 is Cl.

[0042] In some embodiments, X 1 is N.

[0043] In some embodiments, X2 is CH.

[0044] In some embodiments, Z is O and Y is CH2. 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 CH2 and Y is CH2. In some embodiments, Z is CH2 and Y is O. In some embodiments, Z is CH2 and Y is NH.

[0045] In some embodiments, Z is O, Y is CH2, 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 CH2, Y is CH2, and n is 1. In some embodiments, Z is CH2, Y is O, and n is 1. In some embodiments, Z is CH2, Y is NH, and n is 1.

[0046] In some embodiments, Z is O, Y is CH2, n is 1, and R1 and R2 are each H or F. In some embodiments, Z is O, Y is O, n is 1, and R1 and R2 are each H or F. In some embodiments, Z is O, Y is NH, n is 1, and R1 and R2 are each H or F. In some embodiments, Z is CH2, Y is CH2, n is 1, and R1 and R2 are each H or F. In some embodiments, Z is CH2, Y is O, n is 1, and R1 and R2 are each H or F. In some embodiments, Z is CH2, Y is O, n is 1, and R1 and R2 are each H or F. In some embodiments, Z is CH2, Y is NH, n is 1, and R1 and R2 are each H or F.

[0047] In some embodiments, Z is O, Y is CH2, n is 1, R1 and R2 are each H or F, and R3 is Cl. In some embodiments, Z is O, Y is O, n is 1, R1 and R2 are each H or F, and R3 is Cl. In some embodiments, Z is O, Y is NH, n is 1, R1 and R2 are each H or F, and R3 is Cl. In some embodiments, Z is CH2, Y is CH2, n is 1, R1 and R2 are each H or F, and R3 is Cl. In some embodiments, Z is CH2, Y is O, n is 1, R1 and R2 are each H or F, and R3 is Cl. In some embodiments, Z is CH2, Y is O, n is 1, R1 and R2 are each H or F, and R3 is Cl. In some embodiments, Z is CH2, Y is O, n is 1, R1 and R2 are each H or F, and R3 is Cl.

[0048] In some embodiments, Z is O, Y is CH2, n is 1, R1 and R2 are each H or F, R3 is Cl, and X1 and X2 are independently N or CH. In some embodiments, Z is O, Y is O, n is 1, R1 and R2 are each H or F, R3 is Cl, and X1 and X2 are independently N or CH. In some embodiments, Z is O, Y is NH, n is 1, R1 and R2 are each H or F, R3 is Cl, and X1 and X2 are independently N or CH. In some embodiments, Z is CH2, Y is CH2, n is 1, R1 and R2 are each H or F, R3 is Cl, and X1 and X2 are independently N or CH. In some embodiments, Z is CH2, Y is O, n is 1, R1 and R2 are each H or F, R3 is Cl, and X1 and X2 are independently N or CH. In some embodiments, Z is CH2, Y is NH, n is 1, R1 and R2 are each H or F, R3 is Cl, and X1 and X2 are independently N or CH.

[0049] In some embodiments, compounds of the present disclosure have formula (Ia-If): [ka] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0050] In some embodiments, compounds of the present disclosure have the following formula: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0051] In some embodiments, A is [ka] and the compound of formula (I) is represented by formula I-1, [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0052] In some aspects of Formula I-1, R5 is optionally substituted (C1-C6) alkyl. In some embodiments of Formula I-1, R5 is methyl.

[0053] In some embodiments of Formula I-1, X3 is CH.

[0054] In some embodiments of Formula I-1, R6 is -L1CR 14 R 15 R 16 In some embodiments of Formula I-1, L1 is -O-(C1-C4)alkylene. In some embodiments of Formula I-1, L1 is -O-(C1)alkylene. In some embodiments of Formula I-1, R 14 and R 15 together with the same carbon atom to which they are attached to form C=O. In some embodiments of Formula I-1, R 16 is methyl, OH, NH, or NHMe. In some embodiments of Formula I-1, R 16 is NHMe.

[0055] In some embodiments of Formula I-1, R5 is (C1-C6) alkyl, X3 is CH, and R6 is -L1CR 14 R 15 R 16 L1 is —O—(C1-C4)alkylene, and R 14 and R 15 join with the same carbon atom to which they are attached to form C=O, and R 16 is methyl, OH, NH2, or NHMe.

[0056] In some embodiments, the compound of formula I-1 has the formula I-1a: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0057] In some embodiments, the compound of formula I-1a has the formula I-1a1 or I-1ab: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0058] In some embodiments, A is [ka] and the compound of formula (I) is represented by formula I-2, [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0059] In some embodiments of Formula I-2, R5 is optionally substituted (C1-C6) alkyl. In some embodiments of Formula I-2, R5 is methyl.

[0060] In some embodiments of Formula I-2, R7 is -(CH2) 1-3 In some embodiments of Formula I-2, R7 is -(CH2)2W1W2. In some embodiments of Formula I-2, W1 is CR 19 R 19’ In some embodiments of Formula I-2, R 19 and R 19’are both methyl. In some embodiments of Formula I-2, W2 is CN, OH, or NH2. In some embodiments of Formula I-2, W2 is OH. In some embodiments of Formula I-2, R7 is H. In some embodiments of Formula I-2, R7 is methyl.

[0061] In some embodiments of Formula I-2, R7 is -(CH2) 1-2 In some embodiments of Formula I-2, W is 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, W2 is CR 20 R 21 R 22 In some embodiments of Formula I-2, R 20 and R 21 are both H and R 22 is OH. In some embodiments of Formula I-2, R 20 and R 21 are both methyl, and R 22 is OH. In some embodiments of Formula I-2, R 20 and R 21 are both H and R 22 is S(O)(NH)—(C1-C2)alkyl. In some embodiments of Formula I-2, R 20 and R 21 together with the carbon atoms to which they are attached form a 4- to 6-membered heterocyclyl optionally substituted by one or more substituents selected from (C-C)alkyl, halo, (C-C)haloalkyl, (C-C)haloalkoxy, (C-C)alkoxy, (C-C)alkylamino, NH, CN, and OH; R 22 is OH.

[0062] In some embodiments of Formula I-2, R5 is (C1-C6) alkyl and R7 is -(CH2) 1-3In some embodiments of Formula I-2, R5 is methyl and R7 is —(CH2)2W1W2, where W1 is CR 19 R 19’ and R 19 and R 19’ are both methyl and W2 is CN, OH or NH2.

[0063] In some embodiments of Formula I-2, R5 is (C1-C6) alkyl and R7 is H. In some embodiments of Formula I-2, R5 is methyl and R7 is H.

[0064] In some embodiments of Formula I-2, R5 is (C1-C6) alkyl and R7 is methyl. In some embodiments of Formula I-2, R5 is methyl and R7 is methyl.

[0065] In some embodiments of Formula I-2, R5 is (C1-C6) alkyl and R7 is -(CH2) 1-2 W1W2, where W1 is CR 19 R 19’ and W2 is 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 are both H and R 22 is OH. In some embodiments of Formula I-2, R 20 and R 21 are both methyl, and R 22 is OH. In some embodiments of Formula I-2, R 20 and R 21 are both H and R 22 is S(O)(NH)—(C1-C2)alkyl. In some embodiments of Formula I-2, R 20 and R 21together with the carbon atoms to which they are attached form a 4- to 6-membered heterocyclyl optionally substituted by one or more substituents selected from (C-C)alkyl, halo, (C-C)haloalkyl, (C-C)haloalkoxy, (C-C)alkoxy, (C-C)alkylamino, NH, CN, and OH; R 22 is OH.

[0066] In some embodiments, the compound of formula I-2 has the formula I-2a: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0067] In some embodiments, the compound of formula I-2a has the formula I-2a1 or I-2a2: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0068] In some embodiments, the compound of formula I-2 has formula I-2b: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0069] In some embodiments, the compound of formula I-2b has the formula I-2b1 or I-2b2: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0070] In some embodiments, the compound of formula I-2 has formula I-2c: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0071] In some embodiments, the compound of formula I-2c has the formula I-2c1 or I-2c2: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0072] In some embodiments, A is [ka] and the compound of formula (I) is represented by formula I-3, [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0073] In some embodiments of Formula I-3, R5 is optionally substituted (C1-C6) alkyl. In some embodiments of Formula I-3, R5 is methyl.

[0074] In some embodiments of Formula I-3, R8 is (C3-C6)cycloalkyl and R8' is H. In some embodiments of Formula I-3, R8 is cyclopropyl and R8' is H.

[0075] In some embodiments of Formula I-3, A' is a 7-membered heterocyclyl, wherein the heterocyclyl contains two heteroatoms selected from N and O and may be further substituted by one or more substituents independently selected from, in addition to R8 and R8', oxo, (C1-C2) alkyl, cyclopropyl, spiro-cyclopropyl, halo, (C1-C2) haloalkyl, (C1-C2) alkoxy, NH2, CN, and OH.

[0076] In some embodiments of Formula I-3, R5 is (C1-C6)alkyl, R8 is (C3-C6)cycloalkyl, R8' is H, and A' is a 7-membered heterocyclyl, wherein the heterocyclyl contains two heteroatoms selected from N and O and may be further substituted, in addition to R8 and R8', by one or more substituents independently selected from oxo, (C1-C2)alkyl, cyclopropyl, spiro-cyclopropyl, halo, (C1-C2)haloalkyl, (C1-C2)alkoxy, NH2, CN, and OH.

[0077] In some embodiments, the compound of formula I-3 has formula I-3a: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0078] In some embodiments, the compound of formula I-3a has the formula I-3a1 or I-3a2: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0079] In some embodiments, A is [ka] and the compound of formula (I) is represented by formula I-4, [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0080] In some embodiments of Formula I-4, R5 is optionally substituted (C1-C6) alkyl. In some embodiments of Formula I-4, R5 is methyl.

[0081] In some embodiments of Formula I-4, X4 is CH. In some embodiments of Formula I-4, X4 is NH.

[0082] In some embodiments, A is [ka] and the compound of formula (I) is represented by formula I-5, [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0083] In some embodiments of Formula I-5, R5 is a 4-membered heterocyclyl or a 4-membered heterocyclyl(C2)alkyl; said alkyl, carbocyclyl, or heterocyclyl may be joined by one or more of the same or different R 13 In some embodiments of Formula I-5, R2 is a 4-membered heterocyclyl or a 4-membered heterocyclyl(C2)alkyl, wherein the heterocyclyl contains one heteroatom selected from N and O.

[0084] In some embodiments of Formula I-5, R2 is (C1-C6)alkyl, (C1-C6)alkyl-OH, (C1-C6)alkyl-NH(C1-C6)alkyl, or (C1-C6)alkyl-N((C1-C6)alkyl)2.

[0085] In some embodiments of Formula I-5, R6 is -L1CR 14 R 15 R 16 In some embodiments of Formula I-5, L1 is -O-(C1-C4)alkylene. In some embodiments of Formula I-5, L1 is -O-(C1)alkylene. In some embodiments of Formula I-5, R 14 and R 15 together with the same carbon atom to which they are attached to form C=O. In some embodiments of Formula I-5, R16 is methyl, OH, NH, or NHMe. In some embodiments of Formula I-5, R 16 is NHMe.

[0086] In some embodiments, A is [ka] and the compound of formula (I) is represented by formula I-6, [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0087] In some embodiments of Formula I-6, R5 is optionally substituted (C1-C6) alkyl. In some embodiments of Formula I-6, R5 is methyl.

[0088] In some embodiments of Formula I-6, m is 0.

[0089] In some embodiments of Formula I-6, m is 1.

[0090] In some embodiments of Formula I-6, X5 is absent.

[0091] In some embodiments of Formula I-6, o is 0.

[0092] In some embodiments of Formula I-6, o is 1.

[0093] In some embodiments of Formula I-6, R 10 and R 11 are H and R 10 ' and R 11 ' together with the carbon atom to which they are attached form cyclobutyl.

[0094] In some embodiments of Formula I-6, R 12 is OH.

[0095] In some embodiments of Formula I-6, R5 is (C1-C6) alkyl, m is 1, X5 is absent, o is 1, and R 10 and R 11 are H and R 10 ' and R 11 ' together with the carbon atom to which they are attached form a cyclobutyl, and R 12 is OH.

[0096] In some embodiments of Formula I-6, R5 is (C1-C6) alkyl, m is 0, X5 is absent, o is 0, and R 12 is H.

[0097] In some embodiments, the compound of formula I-6 has the formula I-6a: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0098] In some embodiments, the compound of formula I-6a has the formula I-6a1 or I-6a2 [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0099] In some embodiments, the compound of formula I-6 has the formula I-6b [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0100] In some embodiments, the compound of formula I-6b has formula I-6b1 or I-6b2 [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0101] In some embodiments of Formulas I-1a through I-6b, Z is O. In some embodiments of Formulas I-1a through I-6b, Z is CH2.

[0102] In some embodiments of Formulas I-1a through I-6b, Y is CH. In some embodiments of Formulas I-1a through I-6b, Y is O. In some embodiments, Y is NH.

[0103] In some embodiments of Formulas I-1a through I-6b, n is 0. In some embodiments of Formulas I-1a through I-6b, n is 1. In some embodiments of Formulas I-1a through I-6b, n is 2.

[0104] In some embodiments of Formulas I-1a through I-6b, R1 and R2 are each H. In some embodiments of Formulas I-1a through I-6b, R1 and R2 are each halo. In some embodiments of Formulas I-1a through I-6b, R1 and R2 are each F.

[0105] In some embodiments of Formulas I-1a through I-6b, R3 is halo. In some embodiments of Formulas I-1a through I-6b, R3 is Cl. In some embodiments of Formulas I-1a through I-6b, R3 is F.

[0106] In some embodiments of Formulas I-1a through I-6b, X 1 is N.

[0107] In some embodiments of Formulas I-1a through I-6b, X2 is CH.

[0108] In some embodiments of Formulas I-1a through I-6b, Z is O and Y is CH2. In some embodiments of Formulas I-1a through I-6b, Z is O and Y is O. In some embodiments of Formulas I-1a through I-6b, Z is O and Y is NH. In some embodiments of Formulas I-1a through I-6b, Z is CH2 and Y is CH2. In some embodiments of Formulas I-1a through I-6b, Z is CH2 and Y is O. In some embodiments of Formulas I-1a through I-6b, Z is CH2 and Y is NH.

[0109] In some embodiments of Formulas I-1a through I-6b, Z is O, Y is CH2, and n is 1. In some embodiments of Formulas I-1a through I-6b, Z is O, Y is O, and n is 1. In some embodiments of Formulas I-1a through I-6b, Z is O, Y is NH, and n is 1. In some embodiments of Formulas I-1a through I-6b, Z is CH2, Y is CH2, and n is 1. In some embodiments of Formulas I-1a through I-6b, Z is CH2, Y is O, and n is 1. In some embodiments of Formulas I-1a through I-6b, Z is CH2, Y is O, and n is 1. In some embodiments of Formulas I-1a through I-6b, Z is CH2, Y is NH, and n is 1.

[0110] In some embodiments of Formulas I-1a through I-6b, Z is O, Y is CH2, n is 1, and R1 and R2 are each H or F. In some embodiments of Formulas I-1a through I-6b, Z is O, Y is O, n is 1, and R1 and R2 are each H or F. In some embodiments of Formulas I-1a through I-6b, Z is O, Y is NH, n is 1, and R1 and R2 are each H or F. In some embodiments of Formulas I-1a through I-6b, Z is CH2, Y is CH2, n is 1, and R1 and R2 are each H or F. In some embodiments of Formulas I-1a through I-6b, Z is CH2, Y is O, n is 1, and R1 and R2 are each H or F. In some embodiments of Formulas I-1a through I-6b, Z is CH 2 , Y is NH, n is 1, and R 1 and R 2 are each H or F.

[0111] In some embodiments of Formulas I-1a through I-6b, Z is O, Y is CH2, n is 1, R1 and R2 are each H or F, and R3 is Cl or F. In some embodiments of Formulas I-1a through I-6b, Z is O, Y is O, n is 1, R1 and R2 are each H or F, and R3 is Cl or F. In some embodiments of Formulas I-1a through I-6b, Z is O, Y is NH, n is 1, R1 and R2 are each H or F, and R3 is Cl or F. In some embodiments of Formulas I-1a through I-6b, Z is CH2, Y is CH2, n is 1, R1 and R2 are each H or F, and R3 is Cl or F. In some embodiments of Formulas I-1a through I-6b, Z is CH, Y is O, n is 1, R and R are each H or F, and R is Cl or F. In some embodiments of Formulas I-1a through I-6b, Z is CH, Y is NH, n is 1, R and R are each H or F, and R is Cl or F.

[0112] In some embodiments of Formulas I-1a through I-6b, Z is O, Y is CH2, n is 1, R1 and R2 are each H or F, R3 is Cl or F, and X1 and X2 are independently N or CH. In some embodiments of Formulas I-1a through I-6b, Z is O, Y is O, n is 1, R1 and R2 are each H or F, R3 is Cl or F, and X1 and X2 are independently N or CH. In some embodiments of Formulas I-1a through I-6b, Z is O, Y is NH, n is 1, R1 and R2 are each H or F, R3 is Cl or F, and X1 and X2 are independently N or CH. In some embodiments of Formulas I-1a through I-6b, Z is CH2, Y is CH2, n is 1, R1 and R2 are each H or F, R3 is Cl or F, and X1 and X2 are independently N or CH. In some embodiments of Formulas I-1a through I-6b, Z is CH2, Y is O, n is 1, R1 and R2 are each H or F, R3 is Cl or F, and X1 and X2 are independently N or CH. In some embodiments of Formulas I-1a through I-6b, Z is CH2, Y is NH, n is 1, R1 and R2 are each H or F, R3 is Cl or F, and X1 and X2 are independently N or CH.

[0113] In some embodiments, compounds of the present disclosure have the following structure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0114] The compounds of the present disclosure may be in the form of free acid or free base, or pharmaceutically acceptable salt. Pharmaceutically acceptable salts of the compounds of the present disclosure can be formed, for example, by reacting a suitable free base of the compound of the present invention with a suitable pharmaceutically acceptable acid in a suitable solvent under standard conditions known in the art. For example, see 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).

[0115] The compounds of the present disclosure may have at least one chiral center and therefore may be in the form of stereoisomers, which, as used herein, encompass all isomers of individual compounds that differ only in the orientation of their atoms in space. The term stereoisomer includes enantiomers (enantiomers containing the (R-) or (S-) configuration of a compound), mixtures of enantiomers of a compound (physical mixtures of enantiomers, and racemates or racemic mixtures), geometric (cis / trans or E / Z, R / S) isomers of a compound, and isomers of compounds with two or more chiral centers that are not mirror images of one another (diastereoisomers). The chiral centers of a compound may undergo epimerization in vivo; therefore, for these compounds, administration of a compound in its (R-) form is considered equivalent to administration of the compound in its (S-) form. Thus, the compounds of the present disclosure may be prepared and used in the form of individual isomers, substantially free of other isomers, or in the form of mixtures of various isomers, e.g., racemic mixtures of stereoisomers.

[0116] In some embodiments, the compounds of formula (I) are isotopic derivatives in that they have at least one desired isotopic substitution of an atom at an amount greater than the natural abundance of the isotope, i.e., enriched. In one embodiment, the compound contains deuterium or multiple deuterium atoms. As used herein, the term "hydrogen" or H refers to protium ( 1 H) and deuterium ( 2 "H" refers to all isotopes of hydrogen, including H. As used herein, the term "compound" encompasses isotopic derivatives.

[0117] The compounds of formula (I) may also be in the form of N-oxides of the compounds, crystalline forms (also known as polymorphs), co-crystals, active metabolites of the compounds having the same type of activity, prodrugs, tautomers, and unsolvated and solvated (e.g., hydrated) forms with pharmaceutically acceptable solvents such as water, ethanol, etc. As used herein, the term "compound" encompasses all of these forms.

[0118] The compound of formula (I) can be prepared by crystallization under different conditions and can exist as one or a combination of polymorphic forms of the compound. For example, different polymorphs can be identified and / or prepared by using different solvents or different solvent mixtures for recrystallization, by performing crystallization at different temperatures, or by using various cooling modes ranging from very fast to very slow cooling during crystallization. Polymorphs can also be obtained by heating or melting the compound, followed by gradual or rapid cooling. The presence of polymorphs can be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction, and / or other known techniques.

[0119] 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 connected by non-covalent interactions. As used herein, the term "co-crystal former" refers to a compound that forms an intermolecular interaction with the compound of Formula (I) and is capable of co-crystallizing 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-hydroxycaproic acid, lactic acid, sorbic acid, tartaric acid, ferulic acid, suberic acid, picolinic acid, salicylic acid, maleic acid, saccharin, 4,4'-bipyridine p-aminosalicylic acid, nicotinamide, urea, isonicotinamide, methyl-4-hydroxybenzoate, adipic acid, terephthalic acid, resorcinol, pyrogallol, phloroglucinol, hydroxyquinol, isoniazid, theophylline, adenine, theobromine, phenacetin, phenazone, etophylline, and phenobarbital.

[0120] Synthesis method In another aspect, the present disclosure is directed to methods for making a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof. Generally, a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, can be prepared by any process known to be applicable to the preparation of chemically related compounds. A compound of formula (I) will be better understood in connection with the synthetic schemes set forth in the various examples, which illustrate non-limiting methods by which a compound of formula (I) can be prepared.

[0121] Pharmaceutical Composition Another aspect of the present disclosure is directed 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. The term "pharmaceutically acceptable carrier," as known in the art, refers to a pharmaceutically acceptable material, composition, or vehicle suitable for administering a compound of the present disclosure to a mammal. Suitable carriers include, for example, liquids (both aqueous and non-aqueous, and combinations thereof), solids, encapsulating materials, gases, and combinations thereof (e.g., semi-solids), and gases, which function to carry or transport a compound from one organ or part of the body to another organ or part of the body. A carrier is "acceptable" in the sense of being physiologically inert, compatible with the other ingredients of the formulation, and not harmful to the subject or patient. Depending on the type of formulation, the composition may also include one or more pharmaceutically acceptable excipients.

[0122] Generally, the compounds of formula (I) and their pharmaceutically acceptable salts and stereoisomers can be formulated into a given type of composition according to conventional pharmaceutical practices 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 may 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). Generally, the most appropriate administration route will depend on various factors, including, for example, the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract) 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 be advantageous in that the compound may be administered relatively quickly, such as in single-dose treatments and / or acute conditions.

[0123] In some embodiments, the compounds of formula (I) are formulated for oral or intravenous administration (eg, systemic intravenous injection).

[0124] Thus, the compounds of formula (I) can be formulated into solid compositions (e.g., powders, tablets, dispersible granules, capsules, cachets, and suppositories), liquid compositions (e.g., solutions in which the compound is dissolved, suspensions in which solid particles of the compound are dispersed, 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 sustained release.

[0125] Oral solid dosage forms include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with a carrier such as sodium citrate or dicalcium phosphate, and a) a filler or extender such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) a binder such as methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) a humectant such as glycerol, d) a cross-linked polymer (e.g., cross-linked polyvinylpyrrolidone (crospovidone), cross-linked sodium carboxymethylcellulose ( They are mixed with additional carriers or excipients such as disintegrating agents such as croscarmellose sodium, sodium starch glycolate, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft- and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings. They may further contain an opacifying agent.

[0126] In some embodiments, the compound of formula (I) can be formulated in hard or soft gelatin capsules.Representative excipients that can be used include pregelatinized starch, magnesium stearate, mannitol, sodium stearyl fumarate, lactose anhydrous, microcrystalline cellulose, and croscarmellose sodium.The gelatin shell can contain gelatin, titanium dioxide, iron oxide, and coloring agents.

[0127] The liquid dosage form for oral administration includes solution, suspension, emulsion, microemulsion, syrup and elixir.In addition to compound, liquid dosage form can contain water or other solvent, solubilizer and emulsifier, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, 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 ester of sorbitan, and their mixtures, and the like, and the like.Oral composition can also contain excipients such as wetting agent, suspending agent, coloring agent, sweetener, flavoring agent and fragrance.

[0128] Injectable preparations for parenteral administration may include sterile aqueous or oily suspensions. They may be formulated according to standard techniques using appropriate dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such 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. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, fixed oil, including synthetic mono- or diglycerides, may be used. In addition, fatty acids such as oleic acid are used in injectable preparations. Injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable media before use. The effect of a compound can be prolonged by slowing its absorption, which can be accomplished by using a liquid suspension with poor water solubility or crystalline or amorphous material. Prolonged absorption of a compound from a parenterally administered formulation can also be achieved by suspending the compound in an oil vehicle.

[0129] In certain embodiments, compounds of Formula (I) can be administered locally rather than systemically, for example, by directly injecting the conjugate into an organ, often in a depot or sustained-release formulation. In specific embodiments, long-acting formulations are administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers, such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). The release rate of the compound can be controlled by varying the compound-to-polymer ratio and the properties of the particular polymer used. Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. In yet other embodiments, the compound is delivered in a targeted drug delivery system, for example, liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are targeted to and selectively taken up by the organ.

[0130] The compositions may be formulated for buccal or sublingual administration and include examples of tablets, lozenges and gels.

[0131] The compound of formula (I) can be formulated for administration by inhalation.Various forms suitable for administration by inhalation include aerosol, mist or powder.The pharmaceutical composition can be delivered in the form of aerosol spray presentation from a pressurized pack or nebulizer using suitable propellant (for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas).In some embodiments, the dosage unit of pressurized aerosol can be determined by providing a valve to deliver a metered amount.In some embodiments, for example, capsules and cartridges containing gelatin for use in inhaler or insufflator can be formulated to contain a powder mixture of the compound and suitable powder base such as lactose or starch.

[0132] The compound of formula (I) can be formulated for topical administration, and topical administration as used herein refers to intradermal administration of the formulation to the epidermis.These types of compositions are typically in the form of ointments, pastes, creams, lotions, gels, solutions and sprays.

[0133] Representative examples of carriers useful for formulating compounds for topical application include solvents (e.g., alcohols, polyalcohols, water), creams, lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffer solutions (e.g., hypotonic or buffered saline). Creams can be formulated with saturated or unsaturated fatty acids, such as stearic acid, palmitic acid, oleic acid, palmito-oleic acid, cetyl, or oleyl alcohol. Creams may also contain nonionic surfactants, such as polyoxy-40-stearate.

[0134] In some embodiments, topical formulations may also contain excipients, such as penetration enhancers.These agents can transport pharmacologically active compounds through the stratum corneum to the epidermis or dermis, preferably with little or no systemic absorption.A wide variety of compounds have been evaluated for their effectiveness in increasing the penetration rate of drugs through the skin.See, for example, Percutaneous Penetration Enhancers, Maibach HI and Smith HE (eds.), CRC Press, Inc., Boca Raton, Fla. (1995), which reviews the use and testing 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 SI (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), ethyl alcohol, isopropyl alcohol, octylphenyl polyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decylmethyl sulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate), and N-methylpyrrolidone.

[0135] Representative examples of other excipients that may be included in topical and other types of formulations (to the extent compatible) include preservatives, antioxidants, moisturizers, emollients, buffers, solubilizers, skin protectants, and surfactants. Suitable preservatives include alcohols, quaternary amines, organic acids, parabens, and phenols. 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 moisturizers include glycerin, sorbitol, polyethylene glycol, urea, and propylene glycol. Suitable buffers include citric acid, hydrochloric acid, and lactic acid buffers. Suitable solubilizers include quaternary ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates. Suitable skin protectants include vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, and zinc oxide.

[0136] Transdermal formulations typically use transdermal delivery devices and transdermal delivery patches, where compounds are formulated in lipophilic emulsions or buffered aqueous solutions dissolved and / or dispersed in polymers or adhesives. Patches can be constructed for continuous, pulsatile, or on-demand delivery of pharmaceuticals. Transdermal delivery of compounds can be achieved by iontophoretic patches. Transdermal patches can provide controlled delivery of compounds, where the absorption rate is slowed by using rate-controlling membranes or by trapping the compound in a polymer matrix or gel. Absorption enhancers can be used to increase absorption, and examples include absorbable pharmaceutically acceptable solvents that aid passage through the skin.

[0137] Ophthalmic preparations include eye drops.

[0138] Preparations for rectal administration include enemas, rectal gels, rectal foams, rectal aerosols, and retention enemas, which may contain conventional suppository bases such as cocoa butter or other glycerides, and synthetic polymers such as polyvinylpyrrolidone, PEG, etc. Compositions for rectal or vaginal administration can also be formulated as suppositories, which can be prepared by mixing the compound with suitable non-irritating carriers and excipients, such as cocoa butter, a mixture of fatty acid glycerides, polyethylene glycol, suppository wax, and combinations thereof, all of which are solid at ambient temperature but liquid at body temperature, and therefore melt in the rectum or vaginal cavity and release the compound.

[0139] Dosage As used herein, the term "therapeutically effective amount" refers to an amount of a compound of formula (I) or its pharmaceutically acceptable salt or stereoisomer that is effective in bringing about a desired therapeutic response in a specific patient suffering from a disease or disorder mediated by abnormal BCL6 activity. Thus, the term "therapeutically effective amount" includes the amount of a compound or its pharmaceutically acceptable salt or stereoisomer that, when administered, is sufficient to induce positive changes in the disease or disorder being treated, or to prevent the onset or progression of the disease or disorder, or to alleviate to some extent one or more symptoms of the disease or disorder being treated in a subject, or simply kill or inhibit the growth of diseased (e.g., cancer) cells, or reduce the amount of BCL6 in diseased cells.

[0140] The total daily dose of compound and its method of use can be determined according to standard medical practice, for example, by attending physician with sound medical judgment.The specific therapeutically effective dose for any specific subject can depend on various factors, including the disease or disorder being treated and its severity (for example, its current state); the subject's age, weight, general health condition, sex and diet; administration time, administration route and the excretion rate of the specific compound used; treatment period; the drug used in combination with or simultaneously with compound; and similar factors well known in the medical field (for example, see 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)).

[0141] How to use In some embodiments, the present disclosure is directed to treating diseases or disorders involving (e.g., characterized by or mediated by) aberrant BCL6 activity (e.g., elevated levels of BCL6, or otherwise functionally abnormal, e.g., deregulated levels of BCL6) relative to non-pathological conditions. Such diseases and disorders include cancer and inflammatory diseases and disorders. The method involves 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.

[0142] 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, such as a human or a non-human mammal. The methods are also applicable to companion animals such as dogs and cats. A subject "in need" of treatment according to the present disclosure may "have or be suspected of having" a particular cancer, have been positively diagnosed, or otherwise exhibit a sufficient number of risk factors or a sufficient number or combination of signs or symptoms that allow a medical professional to diagnose or suspect the subject of having cancer. Thus, subjects suffering from a particular disease or disorder and subjects suspected of having a particular disease or disorder are not necessarily two distinct groups.

[0143] In some embodiments, the method is intended to treat a subject with cancer. The method includes the treatment of adult tumors / cancers and pediatric tumors / cancers. The cancer may be a tumor that is newly vascularized, or is not yet substantially newly vascularized, or is not newly vascularized.

[0144] In some embodiments, the cancer is a lymphoid malignancy.

[0145] 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.

[0146] In some embodiments, the methods of the present disclosure involve treating a subject with a cell proliferative disease or disorder of the blood system.

[0147] In some embodiments, the methods are directed to treating a subject having an inflammatory disease or disorder.

[0148] In some embodiments, the inflammatory disease or disorder is inflammatory bowel disease, myocarditis, endometriosis, atherosclerosis, an allergic disease or disorder, or an autoimmune disease or disorder. In some embodiments, the allergic disease or disorder is asthma or hay fever. In some embodiments, the autoimmune disease is non-infectious meningitis, autoimmune encephalitis, transverse myelitis, or acute disseminated encephalomyelitis.

[0149] The compounds of Formula (I) can be administered to cancer patients as monotherapy or in combination therapy. The therapy can be "frontline / first-line" as initial treatment for patients who have not previously received an anticancer treatment regimen, alone or in combination with other treatments; or "second-line" as treatment for patients who have previously received an anticancer treatment regimen, alone or in combination with other treatments; or "third-line," "fourth-line," etc., alone or in combination with other treatments. Therapy can also be given to patients who have previously received unsuccessful or partially successful treatments but who have become non-responsive or intolerant to a particular treatment. Therapy can also be given as adjuvant therapy, i.e., to prevent cancer recurrence in patients who currently have no detectable disease, or after surgical removal of a tumor. Thus, in some embodiments, the compounds can be administered to patients who have received another therapy, such as chemotherapy, radioimmunotherapy, surgical therapy, immunotherapy, radiation therapy, targeted therapy, or any combination thereof.

[0150] The disclosed methods may involve administering a compound of Formula (I) or a pharmaceutical composition thereof 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 dosing frequency may range from once daily to about once every 8 weeks. In some embodiments, the dosing frequency ranges from about once daily to 1, 2, 3, 4, 5, or 6 weeks, and in other embodiments, involves at least one 28-day cycle comprising 3 weeks (21 days) of daily administration followed by a 7-day "off" period. In other embodiments, the compound may be administered twice daily (BID) for two and a half days (5 doses total) or once daily (QD) for two days (2 doses total). In other embodiments, the compound may be administered once daily (QD) for five days.

[0151] Combination therapy The compounds of formula (I) and their pharmaceutically acceptable salts and stereoisomers can be used in combination with or simultaneously with at least one other active agent, such as an anticancer agent or regimen, in the treatment of cancer. In this context, the terms "in combination" and "simultaneously" mean that the agents are administered simultaneously, including substantially simultaneous administration in the same or separate dosage forms and by the same or different administration modes, or sequentially, for example, as part of the same treatment regimen or by sequential treatment regimens. Thus, when administered sequentially, the first of the two compounds may still be detectable at effective concentrations at the treatment site at the time the second compound begins to be administered. The order and time intervals can be determined so that they can act together (e.g., synergistically) to provide greater benefits than if they were administered separately. For example, therapeutic agents can be administered sequentially at the same time or at different times in any order; however, if not administered simultaneously, they can be administered sufficiently close in time to provide the desired therapeutic effect, which may be in the form of a synergistic effect. Thus, these terms are not limited to administering active agents exactly at the same time.

[0152] In some embodiments, the treatment regimen may include administering a compound of Formula (I) in combination with one or more additional therapeutic agents known for use in treating cancer. The dosage of the additional therapeutic agent may be the same as or lower than the known or recommended 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. Patent No. 9,101,622 (section 5.2 thereof) and U.S. Patent No. 9,345,705 B2 (columns 12-18 thereof). Representative examples of additional anti-cancer agents and treatment regimens include radiation therapy, chemotherapeutic agents (e.g., antimitotic agents, antiangiogenic agents, antihormonal agents, autophagy inhibitors, alkylating agents, intercalating antibiotics, growth factor inhibitors, antiandrogens, signal transduction pathway inhibitors, microtubule inhibitors, platinum coordination complexes, HDAC inhibitors, proteasome inhibitors, and topoisomerase inhibitors), immunomodulatory agents, therapeutic antibodies (e.g., monospecific and bispecific antibodies), and CAR-T therapy.

[0153] In some embodiments, the compound of Formula (I) and the additional (e.g., anticancer) therapeutic agent may be administered less than 5 minutes apart, less than 30 minutes apart, less than 1 hour apart, about 1 hour apart, about 1 to about 2 hours apart, about 2 to about 3 hours apart, about 3 to about 4 hours apart, about 4 to about 5 hours apart, about 5 to about 6 hours apart, about 6 to about 7 hours apart, about 7 to about 8 hours apart, about 8 to about 9 hours apart, about 9 to about 10 hours apart, about 10 to about 11 hours apart, about 11 to about 12 hours apart, about 12 to 18 hours apart, 18 to 24 hours apart, 24 to 36 hours apart, 36 to 48 hours apart, 48 to 52 hours apart, 52 to 60 hours apart, 60 to 72 hours apart, 72 to 84 hours apart, 84 to 96 hours apart, or 96 to 120 hours apart. Two or more (eg, anti-cancer) therapeutic agents may be administered during a single patient visit.

[0154] It is understood that when the active ingredients of the combination are not administered in the same pharmaceutical composition, they can be administered to the subject in need in any order.For example, the compound of the present disclosure can be administered to the subject in need before (for example, 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 before), at the same time, or after (for example, 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) the administration of additional therapeutic agent. In various embodiments, therapeutic agents are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1-2 hours apart, 2-3 hours apart, 3-4 hours apart, 4-5 hours apart, 5-6 hours apart, 6-7 hours apart, 7-8 hours apart, 8-9 hours apart, 9-10 hours apart, 10-11 hours apart, 11-12 hours apart, 24 hours or less apart, or 48 hours or less apart. In one example, the (e.g., anti-cancer) therapeutic agents are administered within the same outpatient clinic. In another example, anti-cancer drug combination therapies may be administered 1 minute to 24 hours apart.

[0155] In some embodiments, the compound of Formula (I) and the additional anticancer agent or therapeutic agent are administered cyclically. Cycling therapy involves administering one anticancer therapeutic agent for a period of time, followed by administering a second anticancer therapeutic agent for a period of time, and repeating this sequential administration, i.e., cycle, to reduce the development of resistance to one or both of the anticancer therapeutic agents, avoid or reduce side effects of one or both of the anticancer therapeutic agents, and / or improve the efficacy of the treatment. In one example, cycling 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., cycle, to reduce the development of resistance to one of the anticancer therapeutic agents, avoid or reduce side effects of one of the anticancer therapeutic agents, and / or improve the efficacy of the anticancer therapeutic agents.

[0156] In some embodiments, compounds of the present disclosure may be used in combination with other anti-cancer agents, examples of which include etoposide (e.g., lymphomas and non-lymphocytic leukemias), vincristine (e.g., leukemias), 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), Keytruda® (e.g., Hodgkin's lymphoma), and dexamethasone (e.g., acute multiple myeloma).

[0157] 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.

[0158] These and other aspects of the present disclosure will be further understood through consideration of the following examples, which are intended to illustrate particular embodiments of the disclosure but are not intended to limit its scope, which is defined by the claims. [Example]

[0159] 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)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 3 Synthesis of (-yl)oxy)-N-methylacetamide (4) [ka]

[0160] 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)ethyl-4-methylbenzenesulfonate

[0161] To a solution of 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)ethanol (10 g, 37.13 mmol, 1 equiv.) in DCM (210 mL) was added 4-methylbenzenesulfonyl chloride (8.49 g, 44.56 mmol, 1.2 equiv.), DMAP (453.60 mg, 3.71 mmol, 0.1 equiv.), and TEA (7.51 g, 74.26 mmol, 10.34 mL, 2 equiv.). The mixture was stirred at 15 °C for 12 h. After adding water (200 mL), the solution (combined with another batch of the same scale) was extracted with DCM (300 mL × 3). The combined organic phase was washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (silica flash column, eluent of 0-50% ethyl acetate / petroleum ether gradient) to give the title compound as a yellow oil (22 g, 47.27 mmol, 64% yield, 91% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (d, J = 8. 11 Hz, 2H), 7.47 (br d, J = 7.87 Hz, 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, 3H), 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 = 6.68 Hz, 3H).

[0162] 3-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)propanenitrile

[0163] To a mixture of 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)ethyl-4-methylbenzenesulfonate (22 g, 51.95 mmol, 1 equiv.) in DMSO (450 mL) was added NaCN (11.55 g, 235.68 mmol, 4.54 equiv.) under N2. The mixture was stirred at 50 °C for 4 h. The reaction mixture was cooled to 15 °C, diluted with HO (1000 mL), extracted with EtOAc (1000 mL × 2), and the combined organic phase was washed with brine (1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (silica flash column, eluent: 0–50% ethyl acetate / petroleum ether gradient) to give the title compound as a yellow oil (8 g, 25.29 mmol, 49% yield, 88% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 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, 7.37 Hz, 1H), 0.88 (d, J = 6.79 Hz, 3H).

[0164] Methyl 3-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)propanoate

[0165] A mixture of 3-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)propanenitrile (8 g, 28.74 mmol, 1 equiv.) in HCl / MeOH (160 mL) was stirred at 80 °C for 12 h. The mixture was concentrated in vacuo. The residue was adjusted to pH = 8 with saturated aqueous NaHCO (100 mL), and then extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (silica flash column, eluent: 0–50% ethyl acetate / petroleum ether gradient) to give the title compound as a yellow oil (4.9 g, 15.74 mmol, 55% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 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 = 7.70 Hz, 2H), 1.90 - 2.19 (m, 5H), 1.48 - 1.61 (m, 1H), 0.97 (d, J = 6.72 Hz, 3H).

[0166] 3-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)propan-1-ol

[0167] To a mixture of methyl 3-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)propanoate (7.07 g, 22.71 mmol, 1 equiv.) in THF (70 mL) was added LiAlH (1.03 g, 27.25 mmol, 1.2 equiv.) slowly under N at 0 °C. The mixture was stirred at 15 °C for 1 h. Water (approximately 1 mL) was added dropwise to the mixture at 15 °C until no more bubbles were generated. The mixture was dried over anhydrous NaSO (approximately 20 g) 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). 1H NMR (400 MHz, CDCl3) δ ppm 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 = 6.80 Hz, 3H).

[0168] tert-Butyl 4,4-difluoro-3-(3-hydroxypropyl)-5-methyl-piperidine-1-carboxylate

[0169] To a solution of 3-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)propan-1-ol (4.9 g, 17.29 mmol, 1 equiv.) in EtOH (50 mL) was added Pd / C (1 g, 10% purity) and BocO (7.55 g, 34.59 mmol, 7.95 mL, 2 equiv.) under Ar. The suspension was degassed under vacuum and purged with H several times. The mixture was stirred under H (50 psi) at 60 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound as a gray oil (6.6 g, crude). 1 H NMR (400 MHz, CDCl3) δ ppm 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 = 6.40 Hz, 3H).

[0170] tert-Butyl 4,4-difluoro-3-methyl-5-[3-(p-tolylsulfonyloxy)propyl]piperidine-1-carboxylate

[0171] To a solution of tert-butyl 4,4-difluoro-3-(3-hydroxypropyl)-5-methyl-piperidine-1-carboxylate (6.6 g, 22.50 mmol, 1 equiv.) in DCM (70 mL) was added TEA (4.55 g, 45.00 mmol, 6.26 mL, 2 equiv.) and TsCl (4.29 g, 22.50 mmol, 1 equiv.) 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 phase was washed with brine (120 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified 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, yield 55%, purity 98%). 1 H NMR (400 MHz, CDCl3) δ ppm 7.79 (d, J = 8.40 Hz, 2H), 7.36 (d, J = 8.00 Hz, 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 = 6.80 Hz, 3H).

[0172] (3R,5S)-tert-Butyl 4,4-difluoro-3-methyl-5-[3-(p-tolylsulfonyloxy)propyl]piperidine-1-carboxylate (10C) and tert-butyl (3S,5R)-4,4-difluoro-3-methyl-5-[3-(p-tolylsulfonyloxy)propyl]piperidine-1-carboxylate

[0173] tert-Butyl 4,4-difluoro-3-methyl-5-[3-(p-tolylsulfonyloxy)propyl]piperidine-1-carboxylate (3 g, 6.70 mmol, 1 equiv.) was purified by SFC (column: DAICEL CHIRALPAKIC (250 mm*50 mm, 10 μm); mobile phase: [0.1% NH3H2O IPA]; B%: 35%-35%, 4.5 min) to give tert-butyl (3R,5S)-4,4-difluoro-3-methyl-5-[3-(p-tolylsulfonyloxy)propyl]piperidine-1-carboxylate (1.3 g, 2.87 mmol, 43% yield, 99% purity) as a colorless oil and tert-butyl (3S,5R)-4,4-difluoro-3-methyl-5-[3-(p-tolylsulfonyloxy)propyl]piperidine-1-carboxylate (1.3 g, 2.84 mmol, 42% yield, 98% purity) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 7.79 (d, J = 8.11 Hz, 2H), 7.35 (br d, J = 7.99 Hz, 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, CDCl3) δ ppm 7.79 (d, J = 8.34 Hz, 2H), 7.36 (d, J = 7.99 Hz, 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 = 6.68 Hz, 3H).

[0174] (3R,5S)-tert-Butyl 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-carboxylate

[0175] To a mixture of 2-[(8-hydroxy-1-methyl-6-nitro-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide (100 mg, 325.46 μmol, 1 equiv.) and tert-butyl (3R,5S)-4,4-difluoro-3-methyl-5-[3-(p-tolylsulfonyloxy)propyl]piperidine-1-carboxylate (218.48 mg, 488.19 μmol, 1.5 equiv.) in DMF (1 mL) was added KCO (89.96 mg, 650.92 μmol, 2 equiv.). The reaction mixture was then stirred at 60° C. for 12 hours. The reaction mixture (combined with another 60 mg batch) was treated with HO (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo. The residue was triturated 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, purity 83%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (br s, 1H), 7.90 (br d, J = 2.45 Hz, 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 = 6.48 Hz, 3H). LCMS: [M+H] + = 583.4.

[0176] (3S,5R)-tert-butyl 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-carboxylate

[0177] To a solution of tert-butyl (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-carboxylate (150.00 mg, 257.47 μmol, 1 equiv.) in DMF (3 mL) was added Pd / C (0.1 g, 10% purity) under Ar. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 15 °C for 12 hours. The reaction mixture (combined with another 50 mg batch) was filtered, and the filtrate was concentrated under vacuum to give the title compound as a yellow oil (160 mg, crude). 1 H NMR (400 MHz, CDCl3) δ ppm 7.36 - 7.46 (m, 1H), 6.76 (s, 1H), 6.39 (d, J = 2.27 Hz, 1H), 6.34 (d, J = 2.27 Hz, 1H), 4.51 (s, 2H), 4.16 - 4.35 (m, 1H), 4.01 (br t, J = 5.84 Hz, 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 = 6.68 Hz, 3H). LCMS: [M+H] + = 553.2.

[0178] (3S,5R)-tert-butyl 3-[3-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolyl]oxy]propyl]-4,4-difluoro-5-methyl-piperidine-1-carboxylate

[0179] To a mixture of tert-butyl (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-carboxylate (100 mg, 180.96 μmol, 1 equiv.) and 2,4,5-trichloropyrimidine (66.38 mg, 361.92 μmol, 2 equiv.) in DMF (1 mL) was added DIPEA (58.47 mg, 452.40 μmol, 78.80 μL, 2.5 equiv.). The reaction mixture was then stirred at 15° C. for 12 hours. The reaction mixture (combined with another 30 mg batch) was treated with HO (2 mL), and the suspension was then filtered, and the solid was collected and dried under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / THF=1 / 1 to 0 / 1) to give the title compound as a white solid (130 mg, purity 73%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.57 (br s, 1H), 8.39 (br s, 1H), 7.92 (br s, 1H), 7.44 (br d, J = 7.63 Hz, 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 = 5.75 Hz, 3H). LCMS: [M+H] + = 699.4.

[0180] 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-8-[3-[(3S,5R)-4,4-difluoro-5-methyl-3-piperidyl]propoxy]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide

[0181] A solution of tert-butyl (3S,5R)-3-[3-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolyl]oxy]propyl]-4,4-difluoro-5-methyl-piperidine-1-carboxylate (130 mg, 185.83 μmol, 1 equiv) 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.

[0182] 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)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 3 -yl)oxy)-N-methylacetamide (4)

[0183] To a solution of 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-8-[3-[(3S,5R)-4,4-difluoro-5-methyl-3-piperidyl]propoxy]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (150 mg, 210.24 μmol, 1 equiv., TFA) in DMF (1.5 mL) was added DIPEA (271.71 mg, 2.10 mmol, 366.19 μL, 10 equiv.). The reaction mixture was then stirred at 80° C. for 12 hours. The reaction mixture was concentrated under vacuum to give a residue, which was purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water NH4HCO3)-ACN]; B%: 45%~75%, 8 min) to give the title compound as a white solid (15 mg, 25.84 μmol, yield 12%, purity 97%).1 H NMR (400 MHz, DMSO-d6) δ ppm 8.99 (s, 1H), 8.10 (s, 1H), 7.95 (br d, J = 4.29 Hz, 1H), 7.86 (d, J = 1.55 Hz, 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 = 12.64 Hz, 1H), 2.66 (d, J = 4.53 Hz, 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 = 6.68 Hz, 3H). LCMS: [M+H] + =563.3.

[0184] 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)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 3 Synthesis of (-yl)oxy)-N-methylacetamide (5) [ka]

[0185] tert-Butyl (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-carboxylate

[0186] To a solution of 2-[(8-hydroxy-1-methyl-6-nitro-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide (120 mg, 390.55 μmol, 1 equivalent) in DMF (2 mL) was added KCO (107.96 mg, 781.10 μmol, 2 equivalents) and tert-butyl (3S,5R)-4,4-difluoro-3-methyl-5-[3-(p-tolylsulfonyloxy)propyl]piperidine-1-carboxylate (262.18 mg, 585.83 μmol, 1.5 equivalents). The mixture was stirred at 60 °C for 12 hours. The reaction mixture (combined with another 30 mg batch) 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 under vacuum. The crude product was triturated with petroleum ether:ethyl acetate=1 / 1 (approximately 2 mL) for 5 minutes at 20° C. The mixture was filtered and the filter cake was dried in vacuo to give the title compound as a white solid (130 mg). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (d, J = 2.20 Hz, 1H), 7.93 (br d, J = 4.16 Hz, 1H), 7.76 (d, J = 2.20 Hz, 1H), 7.46 (s, 1H), 4.57 (s, 2H), 4.23 (br t, J = 5.20 Hz, 2H), 3.99 - 4.17 (m, 1H), 3.90 (s, 4H), 2.66 (d, J = 4.52 Hz, 5H), 1.79 - 2.11 (m, 5H), 1.40 (s, 10H), 0.94 (d, J = 6.60 Hz, 3H).

[0187] (3R,5S)-tert-butyl 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-carboxylate

[0188] To a solution of tert-butyl (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-carboxylate (100 mg, 171.65 μmol, 1 equiv.) in DMF (2 mL) was added Pd / C (40 mg, 10% purity) under Ar. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 15 °C for 12 h. The reaction mixture (combined with another 30 mg batch) was filtered through a Celite® pad, and the filtrate was concentrated under vacuum to give the title compound as a yellow solid (120 mg, crude). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.85 - 7.98 (m, 2H), 6.94 (s, 1H), 6.45 (d, J = 2.13 Hz, 1H), 6.26 (d, J = 2.25 Hz, 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 = 6.75 Hz, 3H).

[0189] (3R,5S)-tert-butyl 3-[3-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolyl]oxy]propyl]-4,4-difluoro-5-methyl-piperidine-1-carboxylate

[0190] To a mixture of tert-butyl (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-carboxylate (100 mg, 180.96 μmol, 1 equiv.) and 2,4,5-trichloropyrimidine (66.38 mg, 361.92 μmol, 2 equiv.) in DMF (1 mL) was added DIEA (58.47 mg, 452.40 μmol, 78.80 μL, 2.5 equiv.). The reaction mixture was then stirred at 15° C. for 12 hours. The reaction mixture (combined with another 20 mg batch) was treated with HO (2 mL). The suspension was then filtered, and the solid was collected and dried under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / THF=1 / 1 to 0 / 1) to give the title compound as a black solid (110 mg, purity 94%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.58 (s, 1H), 8.40 (s, 1H), 7.93 (br d, J = 4.50 Hz, 1H), 7.44 (br d, J = 7.63 Hz, 2H), 7.13 (s, 1H), 4.57 (s, 2H), 4.09 (br t, J = 5.57 Hz, 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 = 6.75 Hz, 3H).

[0191] 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-8-[3-[(3R,5S)-4,4-difluoro-5-methyl-3-piperidyl]propoxy]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide

[0192] A solution of tert-butyl (3R,5S)-3-[3-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolyl]oxy]propyl]-4,4-difluoro-5-methyl-piperidine-1-carboxylate (80 mg, 114.36 μmol, 1 equiv) in TFA (800.00 μL) and DCM (2.4 mL) was stirred at 15° C. for 1 hour. The solution was concentrated under vacuum to give the title compound as a yellow oil (80 mg, crude, TFA salt). LCMS: [M+H] + = 599.3.

[0193] 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)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 3 -yl)oxy)-N-methylacetamide (5)

[0194] A mixture of 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-8-[3-[(3R,5S)-4,4-difluoro-5-methyl-3-piperidyl]propoxy]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (80 mg, 112.13 μmol, 1 equiv., TFA), DIEA (144.92 mg, 1.12 mmol, 195.30 μL, 10 equiv.) in DMF (1 mL) was stirred for 12 h at 80° C. The solution (combined with another 30 mg batch) was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 30%-60%, 8 min) to give the title compound as a white solid (10mg, purity 96%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.99 (s, 1H), 8.11 (s, 1H), 7.91 - 7.98 (m, 1H), 7.86 (d, J = 1.83 Hz, 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 = 12.53 Hz, 1H), 2.66 (d, J = 4.65 Hz, 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 = 6.72 Hz, 3H). LCMS: [M+H] + =563.3.

[0195] Example 3: 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)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 3 Synthesis of (-yl)oxy)-N-methylacetamide (6) [ka]

[0196] 5-Methylpyridin-3-ol hydrochloride

[0197] To a solution of 5-methylpyridin-3-ol (10 g, 91.64 mmol, 1 equiv) 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 h. The mixture was filtered, and the filter cake was dried in vacuo to give the title compound as a white solid (26.68 g, crude, HCl salt). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.97 (b, 1H), 8.19 - 8.42 (m, 2H), 7.88 (s, 1H), 2.40 (s, 3H).

[0198] 5-Methylpiperidin-3-ol

[0199] To a solution of 5-methylpyridin-3-ol (13 g, 89.29 mmol, 1 equiv., HCl) in AcOH (110 mL) under Ar was added PtO (1.30 g, 8.93 mmol, 0.1 equiv.). The suspension was degassed under vacuum and purged with H several times. The mixture was stirred under H (200 psi) at 50 °C for 16 h. The mixture was filtered through Celite®, and the filtrate was concentrated under vacuum to give the title compound as a yellow oil (33 g, crude, HOAc). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.94 - 9.58 (m, 2H), 3.67 - 3.83 (m, 1H), 2.94 - 3.22 (m, 2H), 2.67 (br t, J = 10.01 Hz, 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, 6.75 Hz, 3H).

[0200] 3-Hydroxy-5-methyl-piperidine-1-carboxylic acid tert-butyl ester

[0201] To a mixture of 5-methylpiperidin-3-ol (11 g, 62.78 mmol, 1 equiv., HOAc) and NaCO (13.31 g, 125.55 mmol, 2 equiv.) in EtOAc (100 mL) and HO (100 mL), BocO (13.70 g, 62.78 mmol, 14.42 mL, 1 equiv.) was added dropwise at 0 °C under N. The mixture was then stirred at 15 °C for 12 h. The mixture (combined with two other batches of the same scale) was extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with brine (500 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (silica flash column, eluent of 0-50% ethyl acetate / petroleum ether gradient) to give the title compound as a white solid (10 g, 46.45 mmol, 25% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 4.23 (br s, 1H) 3.82 - 4.09 (m, 1H) 3.62 (br d, J = 4.05 Hz, 1H) 2.38 (br t, J = 10.67 Hz, 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 = 11.92 Hz, 1H) 0.92 (d, J = 6.68 Hz, 3H).

[0202] tert-Butyl 3-(2-benzyloxyethoxy)-5-methyl-piperidine-1-carboxylate

[0203] To a solution of tert-butyl 3-hydroxy-5-methyl-piperidine-1-carboxylate (10 g, 46.45 mmol, 1 equiv.) in DMF (100 mL) was added NaH (3.72 g, 92.90 mmol, 60% purity, 2 equiv.) portionwise at 0 °C under N. The mixture was stirred at 0 °C for 30 min, then 2-bromoethoxymethylbenzene (11.99 g, 55.74 mmol, 8.82 mL, 1.2 equiv.) was added at 0 °C, and the mixture was heated to 90 °C and stirred for 11.5 h. The mixture was quenched with saturated aqueous NH4Cl (200 mL) at 15 °C, and the mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phase was washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (silica flash column, eluent of 5-40% ethyl acetate / petroleum ether gradient) to give the title compound as a yellow oil (4.2 g, 9.98 mmol, 44% yield, 83% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 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 = 4.63 Hz, 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 = 12.09 Hz, 1H), 0.92 (d, J = 6.63 Hz, 3H).

[0204] tert-Butyl 3-(2-hydroxyethoxy)-5-methylpiperidine-1-carboxylate

[0205] To a solution of tert-butyl 3-(2-benzyloxyethoxy)-5-methyl-piperidine-1-carboxylate (4.2 g, 12.02 mmol, 1 equiv) in MeOH (50 mL) was added Pd / C (2 g, 10% purity) under N. The suspension was degassed under vacuum and purged with H several times. The mixture was stirred under H (50 psi) at 60 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give the title compound as a black oil (3.3 g, 9.29 mmol, 77% yield, 73% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 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 = 11.25 Hz, 1H), 2.04 - 2.30 (m, 3H), 1.54 - 1.67 (m, 1H), 1.46 (s, 9H), 0.99 (q, J = 11.98 Hz, 1H), 0.92 (d, J = 6.60 Hz, 3H).

[0206] tert-Butyl 3-methyl-5-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate

[0207] To a mixture of tert-butyl 3-(2-hydroxyethoxy)-5-methyl-piperidine-1-carboxylate (3.3 g, 12.72 mmol, 1 equiv.) in DCM (30 mL) was added DMAP (155.45 mg, 1.27 mmol, 0.1 equiv.) and TEA (1.42 g, 14.00 mmol, 1.95 mL, 1.1 equiv.). Then, TsCl (2.67 g, 14.00 mmol, 1.1 equiv.) was added to the mixture at 0 °C under N2. The mixture was stirred at 15 °C for 12 h. 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), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give the title compound as a yellow oil (3.5 g, 8.32 mmol, yield 65%, purity 98%). 1 H NMR (400 MHz, CDCl3) δ ppm 7.80 (d, J=8.34 Hz, 2 H) 7.34 (d, J=8.11 Hz, 2 H) 4.07 - 4.34 (m, 3 H) 3.80 - 4.06 (m, 1 H) 3.61 - 3.73 (m, 2 H) 3.12 - 3.30 (m, 1 H) 2.45 (s, 3 H) 2.09 - 2.38 (m, 2 H) 1.95 - 2.04 (m, 1 H) 1.48 - 1.60 (m, 1 H) 1.45 (s, 9 H) 0.80 - 0.95 (m, 4 H).

[0208] tert-Butyl (3S,5R)-3-methyl-5-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate (8C) and tert-butyl (3R,5S)-3-methyl-5-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate

[0209] tert-Butyl 3-methyl-5-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate (900 mg, 2.18 mmol, 1 equiv.) was purified by SFC (column: DAICEL CHIRALPAK Separation by IG (250 mm*30 mm, 10 μm); mobile phase: [Neu-ETOH]; B%: 20%-20%, 6 min) gave tert-butyl (3S,5R)-3-methyl-5-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate (380 mg, 909.74 μmol, 42% yield, 99% purity) as a colorless oil and tert-butyl (3R,5S)-3-methyl-5-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate (380 mg, 900.55 μmol, 41% yield, 98% purity) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 7.81 (d, J = 8.25 Hz, 2H), 7.35 (d, J = 8.13 Hz, 2H), 4.14 (t, J = 4.82 Hz, 2H), 3.66 - 3.72 (m, 2H), 3.18 - 3.26 (m, 1H), 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 H NMR (400 MHz, CDCl3) δ ppm 7.81 (d, J = 8.25 Hz, 2H), 7.35 (d, J = 8.13 Hz, 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).

[0210] 7-Methoxy-1-methyl-indoline-2,3-dione

[0211] To a solution of 7-methoxyindoline-2,3-dione (50 g, 56.45 mmol, 1 equiv.) in DMF (600 mL) was added KCO (58.5 g, 84.67 mmol, 1.5 equiv.) in one portion. The reaction mixture was stirred at 20 °C for 30 min, and then MeI (52.08 g, 73.38 mmol, 22.85 mL, 1.3 equiv.) was added to the reaction mixture. The mixture was stirred at 20 °C for 11.5 h. The reaction mixture was then poured into water (2000 mL), slowly acidified to pH = 3 with 2 N HCl (aq.), and stirred for 45 min. The resulting precipitate was collected by filtration, washed with water (500 mL), and dried under vacuum to afford the title compound as a red solid (50 g, 215.76 mmol, 73% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.41 (dd, J = 8.17, 0.89 Hz, 1H), 7.14 - 7.18 (m, 1H), 7.06 - 7.12 (m, 1H), 3.88 (s, 3H), 3.35 (s, 3H).

[0212] 7-Methoxy-1-methyl-5-nitro-indoline-2,3-dione

[0213] To a solution of NaNO (22.23 g, 261.53 mmol, 2 equiv.) in HSO (150 mL) was added rapidly a solution of 7-methoxy-1-methyl-indoline-2,3-dione (25 g, 130.76 mmol, 1 equiv.) in HSO (150 mL) at 0 °C. The reaction was stirred at 15 °C for 12 h. The reaction mixture (combined with another batch of the same scale) was then 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 dried over NaSO, filtered, and the filtrate was concentrated in vacuo to give the title compound as a red solid (60 g, crude). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.10 (d, J = 1.88 Hz, 1H), 7.90 (d, J = 2.13 Hz, 1H), 4.02 (s, 3H), 3.41 (s, 3H).

[0214] 7-Hydroxy-1-methyl-5-nitro-indoline-2,3-dione

[0215] A solution of 7-methoxy-1-methyl-5-nitro-indoline-2,3-dione (33 g, 139.72 mmol, 1 equiv.) in HBr (500 mL, 48% purity) was stirred at 120 °C for 12 h. The reaction mixture (combined with another batch of the same scale) was then slowly poured into ice / water while maintaining the temperature at 0 °C. The resulting aqueous solution was then washed with EtOAc (2 L × 3). The combined organics were dried over Na SO , filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (silica flash column, eluent: 10–50% ethyl acetate / petroleum ether gradient) to give the title compound as a red solid (20 g). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.16 (br s, 1H), 7.90 (d, J = 2.20 Hz, 1H), 7.75 (d, J = 2.20 Hz, 1H), 3.41 (s, 3H).

[0216] 7-Benzyloxy-1-methyl-5-nitro-indoline-2,3-dione

[0217] A solution of 7-hydroxy-1-methyl-5-nitro-indoline-2,3-dione (9 g, 40.51 mmol, 1 equiv.) in DMF (90 mL) was added, and K2CO3 (6.72 g, 48.61 mmol, 1.2 equiv.) was added and stirred at 15 °C for 30 min. BnBr (7.62 g, 44.56 mmol, 5.29 mL, 1.1 equiv.) was then added dropwise, and the mixture was stirred at 15 °C for 11.5 h. To the mixture (combined with another batch of the same scale), water (200 mL) and brine (200 mL) were added, followed by extraction with ethyl acetate (300 mL × 3). The combined organic phase was washed with brine (1000 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (silica flash column, eluent of 10-50% ethyl acetate / petroleum ether gradient) to give the title compound as a red solid (12 g, 23.63 mmol, 29% yield, 61% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.55 - 7.50 (m, 2H), 7.45 (t, J = 7.3 Hz, 2H), 7.40 - 7.36 (m, 1H), 5.40 (s, 2H), 3.39 (s, 3H).

[0218] 8-Benzyloxy-3-hydroxy-1-methyl-6-nitro-quinolin-2-one

[0219] To a solution of 7-benzyloxy-1-methyl-5-nitro-indoline-2,3-dione (4.2 g, 13.45 mmol, 1 equiv.) in DCM (80 mL) was added TMSCHN (2 M, 13.45 mL, 2 equiv.) dropwise at 0 °C, and the reaction mixture was then stirred at 15 °C for 1.5 h. The reaction mixture (combined with another batch of the same scale) was quenched with HOAc until no more bubbles were generated. H2O (250 mL) was then added to the mixture. The resulting mixture was extracted with DCM (300 mL × 3). The combined organic phase was washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with DCM (20 mL) at 15 °C for 30 min. The suspension was then filtered and the solid was washed 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-d6) δ ppm 10.03 (s, 1H), 8.19 (d, J = 2.26 Hz, 1H), 7.84 (d, J = 2.27 Hz, 1H), 7.55 (br d, J = 7.15 Hz, 2H), 7.35 - 7.47 (m, 3H), 7.29 (s, 1H), 5.33 (s, 2H), 3.88 (s, 3H).

[0220] 2-[(8-benzyloxy-1-methyl-6-nitro-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide

[0221] 2-Bromo-N-methyl-acetamide (1.35 g, 8.90 mmol, 1.2 equiv.) and CsCO (4.83 g, 14.83 mmol, 2 equiv.) were added to a solution of 8-benzyloxy-3-hydroxy-1-methyl-6-nitro-quinolin-2-one (2.42 g, 7.42 mmol, 1 equiv.) in DMF (70 mL). After stirring the reaction mixture at 15 °C for 12 h, the reaction mixture was treated with HO (100 mL) and filtered. The filter cake was collected and dried under vacuum to give the title compound as a light brown solid (2.5 g, crude). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.26 (br s, 1H), 7.92 (br s, 2H), 7.55 (br d, J = 6.20 Hz, 2H), 7.41 - 7.49 (m, 3H), 7.39 (br d, J = 5.60 Hz, 1H), 5.29 - 5.39 (m, 2H), 4.50 - 4.65 (m, 2H), 3.86 (br s, 3H), 2.60 - 2.71 (m, 3H).

[0222] 2-[(8-hydroxy-1-methyl-6-nitro-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide

[0223] 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 equiv.) in DCM (150 mL) was added BCl (1 M, 12.58 mL, 2 equiv.) at 70° C. The reaction mixture was then stirred at 15° C. for 12 hours. The reaction mixture (combined with another batch on a 50 mg scale) was quenched at −70° C. with a mixture of (CHCl:MeOH=10:1, 750 mL). The reaction mixture was then warmed to 15° C. and stirred for 20 minutes. 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 H NMR (400 MHz, DMSO-d6) δ ppm 11.07 (s, 1H), 8.04 (d, J = 2.50 Hz, 1H), 7.90 (br d, J = 4.38 Hz, 1H), 7.69 (d, J = 2.63 Hz, 1H), 7.40 (s, 1H), 4.56 (s, 2H), 3.94 (s, 3H), 2.66 (d, J = 4.75 Hz, 3H).

[0224] tert-Butyl (3S,5R)-3-methyl-5-[2-[[1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-6-nitro-2-oxo-8-quinolyl]oxy]ethoxy]piperidine-1-carboxylate

[0225] 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 equiv.) and tert-butyl (3S,5R)-3-methyl-5-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate (336.47 mg, 813.65 μmol, 1 equiv.) in DMF (3 mL) was added KCO (281.14 mg, 2.03 mmol, 2.5 equiv.). The mixture was stirred at 60°C for 3 hours. The mixture was cooled to 20°C, and water (3 mL) was added, causing the formation of a precipitate. The mixture was filtered, and the filter cake was washed with water (5 mL × 2) and then 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-d6) δ ppm 8.22 (d, J = 2.25 Hz, 1H), 7.91 (br d, J = 2.25 Hz, 1H), 7.80 (d, J = 2.38 Hz, 1H), 7.45 (s, 1H), 4.57 (s, 2H), 4.33 (br t, J = 3.94 Hz, 2H), 4.03 - 4.19 (m, 1H), 3.92 - 3.95 (m, 3H), 3.73 - 3.92 (m, 4H), 2.67 (d, J = 4.50 Hz, 3H), 2.14 - 2.44 (m, 2H), 2.09 (br d, J = 12.26 Hz, 1H), 1.43 - 1.56 (m, 1H), 1.38 (s, 9H), 0.89 - 0.98 (m, 1H), 0.87 (d, J = 6.63 Hz, 3H).

[0226] (3R,5S)-tert-butyl 3-[2-[[6-amino-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolyl]oxy]ethoxy]-5-methyl-piperidine-1-carboxylate

[0227] To a solution of tert-butyl (3S,5R)-3-methyl-5-[2-[[1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-6-nitro-2-oxo-8-quinolyl]oxy]ethoxy]piperidine-1-carboxylate (350 mg, 638.01 μmol, 1 equiv.) in DMF (5 mL) was added Pd / C (0.1 g, 10% purity) under Ar. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 20°C for 12 hours. The mixture was filtered through Celite® and the filter cake was washed with DMF (approximately 15 mL). The filtrate was concentrated in vacuo to give the title compound as a yellow solid (340 mg, crude). LCMS: [M+H] + = 519.4.

[0228] tert-Butyl (3R,5S)-3-[2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolyl]oxy]ethoxy]-5-methyl-piperidine-1-carboxylate

[0229] To a solution of tert-butyl (3R,5S)-3-[2-[[6-amino-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolyl]oxy]ethoxy]-5-methyl-piperidine-1-carboxylate (340 mg, 655.61 μmol, 1 equiv.) and 2,4,5-trichloropyrimidine (240.51 mg, 1.31 mmol, 2 equiv.) in DMF (3.5 mL) was added DIPEA (169.46 mg, 1.31 mmol, 228.39 mL, 2 equiv.). The mixture was stirred at 20 °C for 12 h. The reaction mixture was purified by flash silica gel chromatography (silica flash column, eluent: 10–100% EtOH / ethyl acetate) to give approximately 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 give the title compound as a yellow solid (200 mg, 283.67 mmol, 43% yield, 94% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.58 (s, 1H), 8.39 (s, 1H), 7.94 (br d, J = 4.50 Hz, 1H), 7.42 (s, 2H), 7.14 (s, 1H), 4.57 (s, 2H), 4.18 (br t, J = 4.06 Hz, 3H), 3.85 - 3.95 (m, 5H), 3.79 (dt, J = 7.63, 3.69 Hz, 1H), 2.66 (d, J = 4.63 Hz, 3H), 2.14 - 2.46 (m, 2H), 2.07 (br d, J = 11.51 Hz, 1H), 1.43 - 1.57 (m, 1H), 1.38 m 1.34 (m, 10H), 0.93 (q, J = 11.84 Hz, 1H), 0.86 (d, J = 6.63 Hz, 3H).

[0230] 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-8-[2-[[(3R,5S)-5-methyl-3-piperidyl]oxy]ethoxy]-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide

[0231] A solution of tert-butyl (3R,5S)-3-[2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolyl]oxy]ethoxy]-5-methyl-piperidine-1-carboxylate (200.00 mg, 300.50 μmol, 1 equiv) in DCM (2 mL) and TFA (0.5 mL) was stirred at 20° C. for 1 h. The mixture was concentrated in vacuo to give the title compound as a yellow oil (220 mg, crude, TFA). LCMS: [M+H] + =565.2.

[0232] 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)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 3 -yl)oxy)-N-methylacetamide (6)

[0233] To a solution of 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-8-[2-[[(3R,5S)-5-methyl-3-piperidyl]oxy]ethoxy]-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (220 mg, 323.78 μmol, 1 equiv., TFA) in DMSO (9 mL) was added DIPEA (418.46 mg, 3.24 mmol, 563.96 mL, 10 equiv.). The mixture was stirred at 80° C. for 12 hours. The mixture was filtered, and the filtrate was directly purified without workup. The filtrate was purified by p-HPLC (column: Waters Xbridge™ BEH C18 100*30 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 40%-60%, 8 min) to give the title compound as a yellow solid (21 mg, 37.48 μmol, yield 12%, purity 94%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.99 (s, 1H), 8.02 - 8.11 (m, 2H), 7.94 (br d, J = 4.05 Hz, 1H), 7.08 (d, J = 1.79 Hz, 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 = 4.53 Hz, 3H), 2.52 - 2.59 (m, 2H), 1.98 (br d, J = 11.68 Hz, 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.

[0234] Example 4: 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)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 3 Synthesis of (-yl)oxy)-N-methylacetamide (7) [ka]

[0235] tert-Butyl (3R,5S)-3-methyl-5-[2-[[1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-6-nitro-2-oxo-8-quinolyl]oxy]ethoxy]piperidine-1-carboxylate

[0236] To a solution of 2-[(8-hydroxy-1-methyl-6-nitro-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide (200 mg, 650.92 μmol, 1 equiv.) and tert-butyl (3R,5S)-3-methyl-5-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate (269.17 mg, 650.92 μmol, 1 equiv.) in DMF (3 mL) was added KCO (224.91 mg, 1.63 mmol, 2.5 equiv.). The mixture was stirred at 60 °C for 3 h. The mixture (combined with another 50 mg batch) was cooled to 20 °C, and approximately 3 mL of water was added. A precipitate formed. 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, purity 93.4%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (d, J = 2.50 Hz, 1H), 7.92 (br d, J = 4.25 Hz, 1H), 7.81 (d, J = 2.50 Hz, 1H), 7.46 (s, 1H), 4.57 (s, 2H), 4.33 (t, J = 4.13 Hz, 2H), 4.01 - 4.21 (m, 1H), 3.94 (s, 3H), 3.71 - 3.93 (m, 4H), 2.66 (d, J = 4.50 Hz, 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 = 6.63 Hz, 3H).

[0237] tert-Butyl (3S,5R)-3-[2-[[6-amino-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolyl]oxy]ethoxy]-5-methyl-piperidine-1-carboxylate

[0238] To a solution of tert-butyl (3R,5S)-3-methyl-5-[2-[[1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-6-nitro-2-oxo-8-quinolyl]oxy]ethoxy]piperidine-1-carboxylate (350 mg, 638.01 μmol, 1 equiv.) in DMF (5 mL) was added Pd / C (0.1 g, 10% purity) under Ar. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 20°C for 12 hours. The mixture was filtered through Celite®, the filter cake was washed with DMF (approximately 15 mL), and the filtrate was concentrated under vacuum to give the title compound as a yellow solid (340 mg, crude). LCMS: [M+H] + = 519.4.

[0239] tert-Butyl (3S,5R)-3-[2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolyl]oxy]ethoxy]-5-methyl-piperidine-1-carboxylate

[0240] To a solution of tert-butyl (3S,5R)-3-[2-[[6-amino-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolyl]oxy]ethoxy]-5-methyl-piperidine-1-carboxylate (340 mg, 655.61 μmol, 1 equiv.) and 2,4,5-trichloropyrimidine (240.51 mg, 1.31 mmol, 2 equiv.) in DMF (3.5 mL) was added DIPEA (169.46 mg, 1.31 mmol, 228.39 μL, 2 equiv.). The mixture was stirred at 20 °C for 12 h. The mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (silica flash column, eluent: 10–100% EtOH / ethyl acetate) to give approximately 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 give the title compound as a yellow solid (220 mg, 324.93 μmol, 50% yield, 98% purity). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.60 (s, 1H), 8.40 (s, 1H), 7.93 (br d, J = 4.40 Hz, 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 = 4.52 Hz, 3H), 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).

[0241] 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-8-[2-[[(3S,5R)-5-methyl-3-piperidyl]oxy]ethoxy]-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide

[0242] A solution of tert-butyl (3S,5R)-3-[2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-8-quinolyl]oxy]ethoxy]-5-methyl-piperidine-1-carboxylate (180 mg, 270.45 μmol, 1 equiv) in DCM (2 mL) and TFA (0.5 mL) was stirred at 20° C. for 1 h. 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.

[0243] 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)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 3 -yl)oxy)-N-methylacetamide (7)

[0244] To a solution of 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-8-[2-[[(3S,5R)-5-methyl-3-piperidyl]oxy]ethoxy]-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (200 mg, 294.35 μmol, 1 equiv., TFA) in DMSO (8 mL) was added DIPEA (380.42 mg, 2.94 mmol, 512.70 μL, 10 equiv.). The mixture was stirred at 80° C. for 12 hours. The mixture was filtered, and the filtrate was directly purified without further workup. The filtrate (combined with another batch at 25 mg) was purified by p-HPLC (column: Waters Xbridge™ BEH C18 100*30 mm*10 μm; mobile phase: [water (NH4HCO3)-CAN]; B%: 35%-65%, 8 min) to give the title compound as a yellow solid (25 mg, purity 95%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.66 - 9.21 (m, 1H), 8.06 (s, 1H), 7.99 (br d, J = 1.63 Hz, 1H), 7.88 (s, 1H), 7.05 (s, 1H), 6.91 (br s, 1H), 4.63 (br d, J = 10.01 Hz, 2H), 4.54 (s, 2H), 4.36 (br d, J = 9.38 Hz, 1H), 4.11 - 4.24 (m, 1H), 3.84 - 3.92 (m, 1H), 3.67 - 3.84 (m, 5H), 2.66 (br d, J = 4.13 Hz, 3H), 2.32 - 2.47 (m, 2H), 1.96 (br d, J = 10.38 Hz, 1H), 1.54 - 1.67 (m, 1H), 1.10 (q, J = 11.51 Hz, 1H), 0.87 (br d, J = 6.38 Hz, 3H). LCMS: [M+H] += 529.3.

[0245] 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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 Synthesis of -one (10) [ka]

[0246] 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

[0247] 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 equiv.) 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 equiv.) and CsCO (1.60 g, 4.90 mmol, 2 equiv.). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture (combined with another 500 mg batch) was treated with water (20 mL) and then extracted with EtOAc (25 mL × 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered and concentrated in vacuo to give a residue, which was purified by preparative HPLC (column: Welch Xtimate® C18 180*70 mm*10 μm; mobile phase: [water (NHHCO)-ACN]; B%: 50%-80%, 15 min) to give the title compound as a white solid (1 g, 1.82 mmol, yield 66%, purity 99%). 1 H NMR (400 MHz, DMSO-d6) δ = 10.35 (br s, 1H), 7.37 - 7.27 (m, 4H), 7.23 - 7.18 (m, 1H), 6.03 (d, J = 1.6 Hz, 1H), 5.93 (t, J = 6.0 Hz, 1H), 5.82 (d, J = 1.6 Hz, 1H), 4.22 (d, J = 6.0 Hz, 2H), 4.15 - 3.99 (m, 1H), 3.95 (t, J = 5.4 Hz, 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 = 6.4 Hz, 3H).

[0248] tert-Butyl (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-carboxylate

[0249] 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 equiv.) in THF (10 mL) was added Pd / C (300 mg, 10% purity) under Ar. The suspension was degassed under vacuum and purged with H2 several times. The reaction mixture was stirred under H2 (15 psi) at 25 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound as a brown solid (800 mg, 1.60 mmol, 87% yield, 91% purity). 1 H NMR (400 MHz, DMSO-d6) δ = 9.13 (s, 1H), 7.99 (s, 1H), 7.98 - 7.92 (d, J = 4.4 Hz, 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 = 7.0 Hz, 2H), 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 = 4.8 Hz, 3H), 2.15 - 1.97 (m, 2H), 0.84 (d, J = 6.4 Hz, 6H).

[0250] 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

[0251] To a solution of tert-butyl (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-carboxylate (500 mg, 1.10 mmol, 1 equiv.) in DMF (5 mL) were added 2,4,5-trichloropyrimidine (403.56 mg, 2.20 mmol, 2 equiv.) and DIPEA (355.45 mg, 2.75 mmol, 479.04 μL, 2.5 equiv.). The reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was treated with water (8 mL), and then the suspension was filtered. The precipitate was filtered, and the solid was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to give the title compound as a yellow solid (530 mg, 793.05 μmol, yield 72%, purity 90%). 1 H NMR (400 MHz, DMSO-d6) δ = 10.90 (s, 1H), 9.39 (s, 1H), 8.34 (s, 1H), 6.97 (s, 2H), 4.06 (t, J = 4.8 Hz, 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 = 6.8 Hz, 3H).

[0252] 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

[0253] A solution of 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 (500 mg, 831.29 μmol, 1 equiv) 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.

[0254] (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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 -On(26)

[0255] 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 equiv., TFA) in DMSO (30 mL) was added DIPEA (1.05 g, 8.13 mmol, 1.42 mL, 10 equiv.). The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was treated with water (30 mL), and the suspension was then filtered to obtain a residue. The residue was purified by column chromatography (SiO2, 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). 1H NMR (400 MHz, DMSO-d6) 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 = 12.6 Hz, 1H), 4.58 (d, J = 12.8 Hz, 1H), 4.41 (t, J = 11.6 Hz, 1H), 3.42 (s, 3H), 2.76 - 2.68 (m, 2H), 2.40 - 2.24 (m, 1H), 2.17 (t, J = 6.8 Hz, 1H), 2.04 - 1.81 (m, 3H), 1.70 - 1.57 (m, 2H), 0.97 (br d, J = 6.0 Hz, 3H). LCMS: [M+H] + = 465.2. 30mg of yellow solid was separated by HPLC (カラム: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 40%~70%, 8 minutes) によりThe title compound was purified by さらに and obtained as a white solid (10 mg, 21.30 μmol, yield 33%, purity 99%). 1 H NMR (400 MHz, DMSO-d6) δ = 10.80 (s, 1H), 8.76 (s, 1H), 8.06 (s, 1H), 7.49 (s, 1H), 6.63 (d, J = 1.0 Hz, 1H), 4.70 (d, J = 13.0 Hz, 1H), 4.59 (d, J = 12.5 Hz, 1H), 4.46 - 4.36 (m, 1H), 4.14 - 4.00 (m, 1H), 3.42 (s, 3H), 2.73 (br t, J = 12.7 Hz, 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, 12.6 Hz, 1H), 0.97 (d, J = 6.7 Hz, 3H). LCMS: [M+H] + = 465.3.

[0256] (1 3 S,1 5R)-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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 -On(10)

[0257] 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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphan-42-one (150 mg, 322.65 μmol, 1 equiv.) and (3-hydroxy-3-methyl-butyl) 4-methylbenzenesulfonate (166.70 mg, 645.31 μmol, 2 equiv.) in DMSO (2 mL) was added KI (26.78 mg, 161.33 μmol, 0.5 equiv.) and CsCO (210.25 mg, 645.31 μmol, 2 equiv.). The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was treated with water, and the suspension was filtered. The solid was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 60%~90%, 8 min) to give the title compound as a white solid (30mg, 53.90μmol, yield 17%, purity 99%). 1H NMR (400 MHz, DMSO-d6) δ = 8.84 (s, 1H), 8.07 (s, 1H), 7.54 (s, 1H), 6.76 (s, 1H), 4.70 (br d, J = 12.0 Hz, 1H), 4.59 (d, J = 12.0 Hz, 1H), 4.49 - 4.37 (m, 2H), 4.14 - 4.04 (m, 1H), 3.82 (dd, J = 6.0, 9.6 Hz, 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 = 6.8 Hz, 3H). LCMS: [M+H] + = 551.4.

[0258] 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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 Synthesis of -one (11) [ka]

[0259] 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

[0260] 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 equiv.) 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 equiv.) and CsCO (1.21 g, 3.71 mmol, 2 equiv.). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture (combined with another batch of the same scale) was treated with water (20 mL) and then extracted with EtOAc (25 mL × 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered and concentrated in vacuo to give a residue, which was purified by preparative HPLC (column: Welch Xtimate® C18 180*70 mm#10 μm; mobile phase: [water (NHHCO)-ACN]; B%: 50%-80%, 15 min) to give the title compound as a white solid (850 mg, 1.51 mmol, yield 59%, purity 97%). 1 H NMR (400 MHz, DMSO-d6) δ = 10.35 (s, 1H), 7.38 - 7.26 (m, 4H), 7.24 - 7.17 (m, 1H), 6.03 (d, J = 1.6 Hz, 1H), 5.93 (t, J = 6.0 Hz, 1H), 5.82 (d, J = 1.6 Hz, 1H), 4.21 (d, J = 6.0 Hz, 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 = 6.8 Hz, 3H).

[0261] tert-Butyl (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-carboxylate

[0262] 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 equiv) in THF (10 mL) was added Pd / C (300 mg, 10% purity) under Ar. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound as a brown solid (680 mg, crude). 1 H NMR (400 MHz, DMSO-d6) δ = 10.37 (s, 1H), 5.96 (d, J = 1.6 Hz, 1H), 5.90 (d, J = 1.6 Hz, 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 = 6.6 Hz, 3H).

[0263] 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

[0264] To a solution of tert-butyl (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-carboxylate (500 mg, 1.10 mmol, 1 equiv.) in DMF (8 mL) were added 2,4,5-trichloropyrimidine (403.56 mg, 2.20 mmol, 2 equiv.) and DIPEA (355.44 mg, 2.75 mmol, 479.03 μL, 2.5 equiv.). 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 the precipitate was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to give the title compound as a yellow solid (500 mg, 656.72 μmol, yield 60%). 1 H NMR (400 MHz, DMSO-d6) 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, 1H), 3.45 (s, 3H), 2.66 - 2.52 (m, 2H), 2.03 - 1.80 (m, 5H), 1.39 (s, 10H), 0.94 (d, J = 6.8 Hz, 3H).

[0265] 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

[0266] A solution of 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 (500.00 mg, 831.29 μmol, 1 equiv) 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.

[0267] (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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 -On(27)

[0268] 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 equiv., TFA) in DMSO (20 mL) was added DIPEA (1.05 g, 8.13 mmol, 1.42 mL, 10 equiv.). The reaction mixture was stirred at 80° C. for 12 hours. The reaction mixture was then treated with water (30 mL). The suspension was filtered to give a residue, which was purified by column chromatography (SiO, 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). 1H NMR (400 MHz, DMSO-d6) 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 = 6.0 Hz, 3H). LCMS: [M+H] + = 465.2. 30 mg of the residue was fractionated by HPLC (カラム: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 40%~70%, 8 minutes) purified by によりさらにして, and the title compound was obtained as a white solid (10 mg, purity 99%). 1 H NMR (400 MHz, DMSO-d6) δ = 10.81 (s, 1H), 8.77 (s, 1H), 8.06 (s, 1H), 7.49 (d, J = 1.2 Hz, 1H), 6.63 (d, J = 1.3 Hz, 1H), 4.70 (br d, J = 12.8 Hz, 1H), 4.58 (br d, J = 11.4 Hz, 1H), 4.48 - 4.35 (m, 1H), 4.07 (dt, J = 7.0, 11.4 Hz, 1H), 3.41 (s, 3H), 2.73 (br t, J = 12.6 Hz, 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, 12.8 Hz, 1H), 0.97 (d, J = 6.7 Hz, 3H). LCMS: [M+H] + = 465.3.

[0269] (1 3R,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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 -On(11)

[0270] in DMSO (5 mL) 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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 To a mixture of 4-methyl-3-methylbutyl 4-methylbenzenesulfonate (166.70 mg, 645.31 μmol, 2 equiv.) and 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (150 mg, 322.65 μmol, 1 equiv.), KI (26.78 mg, 161.33 μmol, 0.5 equiv.) and CsCO (210.25 mg, 645.31 μmol, 2 equiv.) were added. The reaction mixture was stirred at 80 °C under N for 12 h. The reaction mixture was treated with water, and the suspension was filtered. The solid was purified by preparative HPLC (column: Waters Xbridge™ Prep OBD C18 150*40 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 45%-75%, 8 min) to give the title compound as a white solid (65 mg, 115.60 μmol, yield 36%, purity 98%). 1H NMR (400 MHz, DMSO-d6) δ = 8.84 (s, 1H), 8.07 (s, 1H), 7.53 (s, 1H), 6.76 (s, 1H), 4.69 (d, J = 12.4 Hz, 1H), 4.58 (d, J = 12.6 Hz, 1H), 4.47 - 4.37 (m, 2H), 4.13 - 4.03 (m, 1H), 3.82 (dd, J = 6.4, 9.2 Hz, 2H), 3.46 (s, 3H), 2.72 (t, J = 12.4 Hz, 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 = 6.4 Hz, 3H). LCMS: [M+H] + = 551.4.

[0271] 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-3-aza-4(6,4)-benzo[d]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 Synthesis of -one (29) [ka]

[0272] in DMSO (1 mL) 3 S,1 5 R)-2 5 -chloro-1 4 ,1 4 -difluoro-1 5 ,43 -dimethyl-4 2 ,4 3 -dihydro-4 1 A mixture of H-5-oxa-3-aza-4(6,4)-benzo[d]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphan-42-one (70 mg, 150.57 μmol, 1 equiv.), MeI (23.51 mg, 165.63 μmol, 10.31 μL, 1.1 equiv.), and CsCO (73.59 mg, 225.86 μmol, 1.5 equiv.) was stirred at 15 °C for 2 h. The mixture was filtered, and the filtrate was purified by preparative HPLC (column: Waters Xbridge™ Prep OBD C18 150*40 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 45%-75%, 8 min) to give the title compound as a white solid (30 mg, 62.01 μmol, yield 41%, purity 99%). 1 H NMR (400 MHz, DMSO-d6) δ = 8.82 (s, 1H), 8.07 (s, 1H), 7.55 (s, 1H), 6.75 (s, 1H), 4.68 (br d, J = 12.5 Hz, 1H), 4.58 (br d, J = 13.4 Hz, 1H), 4.42 (br t, J = 11.8 Hz, 1H), 4.15 - 4.04 (m, 1H), 3.46 (s, 3H), 3.26 (s, 3H), 2.72 (br t, J = 12.6 Hz, 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 = 6.7 Hz, 3H), 1.00 - 0.91 (m, 1H), 0.60 - 0.35 (m, 1H). LCMS: [M+H] + = 479.2.

[0273] Example 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-3-aza-4(6,4)-benzo[d]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 Synthesis of -one (30) [ka]

[0274] (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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 To a solution of 30 mg of methyl-1-one (34.53 μmol, 1 equiv.) in DMSO (0.5 mL) was added CsCO (31.54 mg, 96.80 μmol, 1.5 equiv.) and iodomethane (10.08 mg, 70.98 μmol, 4.42 μL, 1.1 equiv.). The reaction mixture was stirred at 15° C. for 2 hours. The reaction mixture (combined with the 10 mg and 30 mg scales) was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by p-HPLC (column: Waters Xbridge™ Prep OBD C18 150*40 mm*10 μm; mobile phase: [water (NHHCO)-ACN]; B%: 50%-80%, 8 min) to give the title compound as a white solid (20 mg, 41.59 μmol, 99% yield, 99% purity). 1H NMR (400 MHz, DMSO-d6) δ = 8.82 (s, 1H), 8.07 (s, 1H), 7.55 (d, J = 1.1 Hz, 1H), 6.75 (d, J = 1.3 Hz, 1H), 4.69 (br d, J = 13.4 Hz, 1H), 4.59 (br d, J = 13.1 Hz, 1H), 4.43 (br t, J = 11.8 Hz, 1H), 4.09 (dt, J = 7.5, 11.3 Hz, 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 = 6.8 Hz, 3H). LCMS: [M+H] + = 479.3.

[0275] Example 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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 Synthesis of -one (14) [ka]

[0276] 2-((6-(benzylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetic acid ethyl ester

[0277] A flask containing a mixture of 6-(benzylamino)-4-hydroxy-3-methyl-1H-benzimidazol-2-one (15 g, 55.71 mmol, 1 equiv.), ethyl 2-bromoacetate (8.35 g, 50.15 mmol, 5.55 mL, 0.9 equiv.), and CsCO (36.32 g, 111.43 mmol, 2 equiv.) in DMSO (100 mL) was degassed and purged with N three times. The reaction mixture was stirred under a N atmosphere at 20 °C for 12 h. 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-d6) δ ppm 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 = 6.0 Hz, 2H), 4.18 - 4.13 (m, 2H), 3.38 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H).

[0278] 2-((6-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetic acid ethyl ester

[0279] 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 equiv.) and Pd / C (300 mg, 10% purity) in THF (100 mL) was degassed and purged with H three times. The reaction mixture was stirred under an atmosphere of H at 20° C. for 12 h. 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.

[0280] 2-((6-((2,5-dichloropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetic acid ethyl ester

[0281] 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 equiv.), 2,4,5-trichloropyrimidine (6.22 g, 33.93 mmol, 2 equiv.), and DIPEA (4.38 g, 33.93 mmol, 5.91 mL, 2 equiv.) in DMF (30 mL) was degassed and purged with N three times. The reaction mixture was stirred under a N atmosphere 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 provide the title compound as a pink solid (4 g, 9.70 mmol, 57% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 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 = 7.2 Hz, 3H).

[0282] 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 ethyl ester

[0283] 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 equiv.) and (3S,5R)-4,4-difluoro-5-methyl-piperidin-3-amine (1.65 g, 6.26 mmol, 1.72 equiv., TFA) in DMSO (30 mL) and DIPEA (6 mL) was degassed and purged with N three times. The reaction mixture was stirred at 130° C. under a N atmosphere for 12 hours. 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-d6) δ ppm 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 = 7.2 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H).

[0284] 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

[0285] A flask containing 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 equiv.) and LiOH·HO (191.49 mg, 4.56 mmol, 2 equiv.) in EtOH (10 mL) and HO (2 mL) was degassed and purged with N three times. The reaction mixture was stirred under a N atmosphere at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was adjusted to pH = 4 with 1 N 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.

[0286] (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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 ,7-dione

[0287] 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 equiv), HATU (534.59 mg, 1.41 mmol, 1 equiv), and DIPEA (363.42 mg, 2.81 mmol, 489.78 μL, 2 equiv) in DMF (10 mL) was degassed and purged with N three times. The reaction mixture was stirred under a N atmosphere at 20° C. for 2 hours. The reaction mixture was poured into water and filtered. The precipitate was washed with water, then 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-d6) δ ppm 10.82 (s, 1H), 8.69 (s, 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.00 (s, 1H), 7.08 (s, 1H), 6.57 (s, 1H), 4.95 (d, J = 14.8 Hz, 1H), 4.61 (d, J = 14.4 Hz, 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 = 6.8 Hz, 3H). LCMS: [M+H] + = 480.1.

[0288] (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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2-On(31)

[0289] (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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 To a solution of ,7-dione in THF (5 mL) was added BH3·THF (1 M, 3.33 mL, 4 equiv.) under N2 at 0 °C. The reaction mixture was stirred at 60 °C for 12 h. Saturated aqueous NH4Cl (40 mL) was added slowly under N2, and after the addition, the reaction mixture was stirred for 20 min. 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 (SiO2, 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-d6) δ ppm 10.80 (s, 1H), 8.78 (s, 1H), 8.06 (s, 1H), 7.55 (s, 1H), 6.64 (s, 1H), 4.71 (d, J = 12.4 Hz, 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 = 12.6 Hz, 1H), 2.58 - 2.52 (m, 1H), 2.25 - 2.15 (m, 1H), 2.05 - 1.88 (m, 1H), 0.96 (d, J = 6.8 Hz, 3H). LCMS: [M+H] + = 466.3.

[0290] (13 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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 -On(14)

[0291] in DMSO (5 mL) 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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2A flask containing a mixture of 4-methyl-3-methyl-butyl-4-methylbenzenesulfonate (83.18 mg, 321.97 μmol, 1.5 equiv.), KI (17.82 mg, 107.32 μmol, 0.5 equiv.), and CsCO (139.87 mg, 429.29 μmol, 2 equiv.) was degassed and purged with N three times. The reaction mixture was stirred under N atmosphere at 80 °C for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue (combined with two other batches) was purified by preparative HPLC. (Column: Waters Xbridge™ Prep OBD C18 150*40 mm*10 μm; Mobile phase: [HO (10 mM NHHCO)-ACN]; Gradient: 35% to 60% B over 8.0 min) to give 80 mg of product. The product (80 mg) was further purified by SFC (Column: DAICEL CHIRALPAK AD (250 mm*30 mm*10 μm); Mobile phase: [CO-MeOH (0.1% NHHO)]; B%: 46%, isocratic elution mode) to give the title compound as a white solid (47.7 mg, 86.41 μmol). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.87 (s, 1H), 8.08 (s, 1H), 7.60 (s, 1H), 6.76 (s, 1H), 4.71 (d, J = 12.4 Hz, 1H), 4.52 (d, J = 13.6 Hz, 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 = 12.8 Hz, 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 = 6.4 Hz, 3H). LCMS: [M+H] + = 552.3. The stereochemistry of compound 14 was confirmed by the crystal structure of BCL6 / compound 14.

[0292] Example 10: (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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 Synthesis of -one (15) [ka]

[0293] 4-Bromo-2-methoxy-6-nitroaniline

[0294] To a solution of 2-methoxy-6-nitroaniline (100 g, 594.71 mmol, 100 mL, 1 equiv.) in DCM (2 L) was added NBS (137.60 g, 773.12 mmol, 1.3 equiv.). The reaction mixture was stirred at 25° C. for 12 h. The reaction mixture (combined with four other batches of the same scale) was concentrated under vacuum, and the residue was triturated with water (1 L) at 25° C. for 30 min and filtered. The filter cake was dried, triturated with petroleum ether / ethyl acetate = 4 / 1 (500 mL) at 25° C. for 30 min, filtered, and the filter cake was dried to give the title compound as a yellow solid (500 g, purity 95%, yield 68%). 1 H NMR (400 MHz, MeCN-d3) δ = 7.77 (d, J = 2.1 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.64 (br s, 2H), 3.90 (s, 3H).

[0295] 4-Bromo-2-methoxy-N-methyl-6-nitroaniline

[0296] A solution of 4-bromo-2-methoxy-6-nitroaniline (50 g, 202.39 mmol, 1 equiv.) in DMF (2 L) was stirred at 0 °C for 10 min. CsCO (131.89 g, 404.78 mmol, 2 equiv.) was added, and the reaction mixture was stirred at 0 °C for 10 min. MeI (34.47 g, 242.87 mmol, 15.12 mL, 1.2 equiv.) was added dropwise, and the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was washed with water (5 L). The red solid was filtered, and the filter cake was washed with water (1500 mL × 3). The solid was then dried under reduced pressure to give the title compound as a red solid (375 g, 93% purity, 70% yield). 1 H NMR (400 MHz, CDCl3) δ = 7.59 (d, J = 1.6 Hz, 1H), 7.24 (d, J = 5.2 Hz, 1H), 7.18 (s, 1H), 3.87 (s, 3H), 2.86 (d, J = 5.2 Hz, 3H). LCMS: [M+H] + = 261.1.

[0297] 4-Bromo-6-methoxy-N1-methylbenzene-1,2-diamine

[0298] A mixture of 4-bromo-2-methoxy-N-methyl-6-nitroaniline (75 g, 287.28 mmol, 1 equiv.) and SnCl (259.30 g, 1.15 mol, 4 equiv.) in EtOH (1.5 L) was stirred at 75 °C under a N atmosphere for 2 h. The reaction mixture (combined with four other batches of the same scale) was concentrated in vacuo. The residue was treated with water (2 L) and the pH was adjusted to 14 with NaOH. The solid was filtered, and the filter cake was washed with EtOAc (4 L). The filtrate was extracted with EtOAc (1 L × 3). The combined organic phase was washed with brine (3 L), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue, which was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 50 / 1 to 2 / 1) to give the title compound as a colorless oil (260 g, 1.08 mol, yield 75%, purity 96%). 1H NMR (400 MHz, CDCl3) δ = 6.54 (d, J = 1.8 Hz, 1H), 6.45 (d, J = 2.0 Hz, 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.

[0299] 5-Bromo-7-methoxy-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0300] To a solution of 4-bromo-6-methoxy-N1-methylbenzene-1,2-diamine (45 g, 194.73 mmol, 1 equiv.) in DMF (450 mL) was added CDI (63.15 g, 389.46 mmol, 2 equiv.). The reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was diluted with water (500 mL) and then filtered. The filter cake was washed with water (500 mL) followed by EtOAc (500 mL). The solid was dried under vacuum to give the title compound as a white solid (64 g, 221.56 mmol, 57% yield, 89% purity). 1 H NMR (400 MHz, DMSO-d6) δ = 11.95 (br s, 1H), 7.00 (s, 1H), 6.93 (d, J = 1.9 Hz, 1H), 3.86 (d, J = 1.8 Hz, 3H), 3.63 (d, J = 1.9 Hz, 3H).

[0301] 5-(benzylamino)-7-methoxy-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0302] 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 equiv.) and phenylmethanamine (16.01 g, 149.37 mmol, 16.28 mL, 1.2 equiv.) in THF (320 mL), LiHMDS (1 M, 298.74 mL, 2.4 equiv.) was added dropwise at 15 °C. The reaction mixture was degassed and purged with N for 5 min. BrettPhos (2.67 g, 4.98 mmol, 0.04 equiv.) and BrettPhos Pd G3 (2.26 g, 2.49 mmol, 0.02 equiv.) were added to the reaction mixture, which was stirred at 80 °C under N for 2 h. The reaction mixture (combined with another batch of the same scale) was quenched with saturated aqueous NH4Cl (50 mL), filtered, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 2 / 1) to give 65 g of approximately 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 H NMR (400 MHz, DMSO-d6) δ = 10.37 (s, 1H), 7.37 - 7.29 (m, 4H), 7.24 - 7.18 (m, 1H), 6.06 (d, J = 1.8 Hz, 1H), 5.96 (t, J = 6.0 Hz, 1H), 5.83 (d, J = 2.0 Hz, 1H), 4.23 (d, J = 6.0 Hz, 2H), 3.73 (s, 3H), 3.32 (s, 3H).

[0303] 5-(benzylamino)-7-hydroxy-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0304] 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 equiv.) in DCM (1.1 L) was added a solution of BBr3 (153.86 g, 614.14 mmol, 59.18 mL, 3 equiv.) in DCM (100 mL) at −70° C. The reaction mixture was warmed to 40° C. and stirred at 40° C. for 2 h. The reaction mixture was quenched with CHCl:MeOH (10:1, 1.1 L), and then the reaction mixture was concentrated in vacuo to give a residue. The residue was treated with 4 N HCl (150 mL) and stirred at 40° C. for 30 min. The resulting mixture was treated with saturated aqueous NaCO3 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-d6) δ = 10.23 (s, 1H), 9.26 (s, 1H), 7.36 - 7.27 (m, 4H), 7.23 - 7.17 (m, 1H), 5.89 - 5.83 (m, 2H), 5.72 (d, J = 2.0 Hz, 1H), 4.17 (d, J = 6.0 Hz, 2H), 3.33 (s, 3H). LCMS: [M+H] + = 270.2.

[0305] tert-Butyl (7-hydroxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate

[0306] 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 equiv) in MeOH (300 mL) was added Pd / C (5 g, 10% purity) under Ar. The suspension was degassed and purged with H three times. The reaction mixture was stirred under H (50 psi) at 50 °C for 12 h. BocO (9.74 g, 44.65 mmol, 10.26 mL, 1 equiv) was then added, and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue that 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-d6) 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.

[0307] tert-Butyl (7-(2-chloroethoxy)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate

[0308] 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 equiv.) and 2-chloroethyl 4-methylbenzenesulfonate (8.40 g, 35.80 mmol, 1 equiv.) in ACN (20 mL) and DMF (20 mL) was added K2CO3 (12.37 g, 89.51 mmol, 2.5 equiv.). The reaction mixture was stirred at 70 °C under N2 for 12 h. The reaction was quenched with water (100 mL) and then extracted with ethyl acetate (80 mL × 3). The organic phase was separated, washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was triturated with petroleum ether:ethyl acetate=1:1 (20 mL) at 25° C. for 5 minutes, filtered, and the filter cake was dried in vacuo to give the title compound as a white solid (7.8 g, 19.63 mmol, 55% yield, 86% purity). 1 H NMR (400 MHz, DMSO-d6) δ = 10.73 (s, 1H), 9.19 (s, 1H), 6.89 (s, 1H), 6.84 (s, 1H), 4.24 (t, J = 4.8 Hz, 2H), 4.00 (t, J = 4.8 Hz, 2H), 3.43 (s, 3H), 1.46 (s, 9H).

[0309] 5-Amino-7-(2-chloroethoxy)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0310] 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 equiv.) 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.

[0311] 7-(2-chloroethoxy)-5-((2,5-dichloropyrimidin-4-yl)amino)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0312] 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 equiv., TFA), 2,4,5-trichloropyrimidine (7.03 g, 38.32 mmol, 2 equiv.), and DIEA (7.43 g, 57.48 mmol, 10.01 mL, 3 equiv.) in DMF (90 mL) was degassed and purged with N three times. The reaction mixture was stirred under N at 25 °C for 2 h. Water (30 mL) was added, and a solid precipitate formed. The mixture was filtered, and the filter cake was washed with petroleum ether:ethyl acetate = 1:1 (50 mL) and dried under vacuum to give the title compound as a yellow solid (5.7 g, 13.93 mmol, 73% yield, 95% purity). It was used directly in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ = 10.94 (s, 1H), 9.40 (s, 1H), 8.34 (s, 1H), 6.98 (br d, J = 14.8 Hz, 2H), 4.36 - 4.28 (m, 2H), 4.07 - 3.99 (m, 2H), 3.49 (s, 3H). LCMS: [M+H] + = 388.1.

[0313] 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

[0314] 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 equiv.), (3R,5S)-4,4-difluoro-5-methylpiperidin-3-amine (1.95 g, 5.15 mmol, 2 equiv., TFA), and DIEA (3.33 g, 25.73 mmol, 4.48 mL, 10 equiv.) in DMSO (10 mL) was degassed and purged with N2 three times. The reaction mixture was stirred at 80 °C under a N2 atmosphere for 12 h. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue, which was purified by column chromatography (SiO2, 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, yield 38%, purity 90%). 1 H NMR (400 MHz, DMSO-d6) 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, 3H), 2.97 - 2.83 (m, 1H), 2.63 (dt, J = 7.0, 12.1 Hz, 2H), 2.35 - 1.86 (m, 4H), 0.98 (br d, J = 6.5 Hz, 3H).

[0315] (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 1H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 -On(32)

[0316] 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 equiv.) in anhydrous DMF (30 mL) was added KCO (99.04 mg, 716.64 μmol, 2 equiv.) and NaI (537.10 mg, 3.58 mmol, 10 equiv.). The reaction mixture was stirred at 100° C. in a glove box 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 dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue, which was purified by column chromatography (SiO2, petroleum ether:THF = 1 / 0 to 1:1) to give the title compound as a white solid (100 mg, 158.84 μmol, yield 15%, purity 74%). 1 H NMR (400 MHz, DMSO-d6) δ = 10.80 (s, 1H), 8.78 (s, 1H), 8.07 (s, 1H), 7.55 (s, 1H), 6.63 (d, J = 1.3 Hz, 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 = 6.8 Hz, 3H). LCMS: [M+1] + = 466.2.

[0317] (1 3 R,15 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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 -On(15)

[0318] (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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 To a solution of 4-methyl-3-methylbutyl 4-methylbenzenesulfonate (77.63 mg, 300.50 μmol, 2 equiv.) in DMSO (1 mL), KI (12.47 mg, 75.13 μmol, 0.5 equiv.) and CsCO (97.91 mg, 300.50 μmol, 2 equiv.) were added. The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (Column: Waters Xbridge™ BEH C18 100*30 mm*10 μm; Mobile phase: [water (NHHCO)-ACN]; B%: 35%-55%, 8 min) to give the title compound as a white solid (19 mg, 33.73 μmol, 22% yield, 98% purity). 1H NMR (400 MHz, DMSO-d6) δ = 8.88 (s, 1H), 8.08 (s, 1H), 7.60 (s, 1H), 6.76 (d, J = 1.0 Hz, 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, 10.3 Hz, 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, 9.2 Hz, 2H), 1.18 (s, 6H), 0.97 (d, J = 6.8 Hz, 3H). LCMS: [M+H] + = 552.4.

[0319] 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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 Synthesis of -one (12) [ka]

[0320] 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

[0321] 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 equiv.) and tert-butyl (3S,5R)-3-methyl-5-(2-(tosyloxy)ethoxy)piperidine-1-carboxylate (1.54 g, 3.71 mmol, 1 equiv.) in DMSO (15 mL) was added KCO (1.03 g, 7.43 mmol, 2 equiv.). The reaction mixture was stirred at 70 °C under a N atmosphere for 1.5 h. The reaction mixture was treated with water (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic phase was washed with brine (80 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue, which was purified by column chromatography (SiO, 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-d6) 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 = 1.8 Hz, 1H), 4.21 (d, J = 5.5 Hz, 2H), 4.04 - 4.00 (m, 2H), 3.85 - 3.72 (m, 3H), 3.34 (br s, 5H), 2.05 (br d, J = 6.1 Hz, 1H), 1.37 (s, 11H), 0.94 - 0.87 (m, 2H), 0.86 (d, J = 6.6 Hz, 3H).

[0322] 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

[0323] 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 equiv.) in THF (20 mL) was added Pd / C (400 mg, 10% purity) under Ar. The suspension was degassed under vacuum and purged with H2 several times. The reaction mixture was stirred under H2 (15 psi) at 60°C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give the title compound as a black oil (0.9 g, crude). LCMS: [M-100+H] + = 321.3.

[0324] 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

[0325] To a solution of 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 (900.00 mg, 2.14 mmol, 1 equiv) in DMF (10 mL) was added 2,4,5-trichloropyrimidine (785.16 mg, 4.28 mmol, 2 equiv) and DIPEA (691.55 mg, 5.35 mmol, 932.01 μL, 2.5 equiv). 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). 1H NMR (400 MHz, DMSO-d6) δ = 10.90 (s, 1H), 9.38 (s, 1H), 8.33 (s, 1H), 6.96 (d, J = 3.2 Hz, 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 = 11.6 Hz, 1H), 1.55 - 1.44 (m, 1H), 1.37 (s, 9H), 0.99 - 0.88 (m, 1H), 0.85 (d, J = 6.8 Hz, 3H).

[0326] 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

[0327] 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 equiv) in DCM (12 mL) was added TFA (3.23 g, 28.36 mmol, 2.10 mL, 22.99 equiv). The reaction mixture was stirred at 25° C. for 30 minutes. 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

[0328] (1 3 R,1 5 S)-2 5 -chloro-1 5 ,4 3 -dimethyl-4 2 ,4 3 -dihydro-4 1H-5,8-dioxa-3-aza-4(6,4)-benzo[d]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 -on

[0329] 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 equiv., TFA) in DMSO (75 mL) was added DIPEA (1.78 g, 13.76 mmol, 2.40 mL, 10 equiv.). The reaction mixture was stirred at 80° C. for 12 hours. The reaction was quenched with water (100 mL), filtered, and the solid was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to give the title compound as a white solid (190 mg, 176.38 μmol, 13% yield). LCMS: [M+H] + = 431.2.

[0330] (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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 -On(12)

[0331] in DMSO (3 mL) 3 R,1 5 S)-2 5 -chloro-1 5 ,4 3 -dimethyl-4 2 ,4 3 -dihydro-4 1H-5,8-dioxa-3-aza-4(6,4)-benzo[d]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 To a mixture of methyl-3-methylbutyl 4-methylbenzenesulfonate (227.82 mg, 881.90 μmol, 2 equiv.) and 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (190 mg, 440.95 μmol, 1 equiv.), CsCO (287.34 mg, 881.90 μmol, 2 equiv.) and KI (36.60 mg, 220.48 μmol, 0.5 equiv.) were added. The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered, and the residue was purified by preparative HPLC (column: Phenomenex C18 80*40 mm*3 μm; mobile phase: [water (NHHCO)-ACN]; B%: 25%-55%, 8 min) to give the title compound as a white solid (50 mg, 95.74 μmol, 22% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d6) 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 = 6.4 Hz, 3H). LCMS: [M+H] + = 517.4.

[0332] 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 1H-5,8-dioxa-3-aza-4(6,4)-benzo[d]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 Synthesis of -one (13) [ka]

[0333] 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

[0334] 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 equiv.) and tert-butyl (3R,5S)-3-methyl-5-(2-(tosyloxy)ethoxy)piperidine-1-carboxylate (1.44 g, 3.49 mmol, 1 equiv.) in DMSO (10 mL) was added KCO (964.86 mg, 6.98 mmol, 2 equiv.). The reaction mixture was stirred at 70 °C for 1.5 h. The reaction was quenched with water (30 mL) and then extracted with EtOAc (20 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. Column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) gave the title compound as a yellow solid (900 mg, 1.73 mmol, 49% yield). LCMS: [M+H] + = 511.3.

[0335] 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

[0336] 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 equiv) in THF (8 mL) was added Pd / C (400 mg, 10% purity) under Ar. The suspension was degassed under vacuum and purged with H2 several times. The reaction mixture was stirred under H2 (15 psi) at 60°C for 1 h. The reaction mixture was filtered through a Celite® pad and the filtrate was concentrated under vacuum to give the title compound as a black solid (900 mg, crude). LCMS: [M-100+H] + = 321.2.

[0337] 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

[0338] To a solution of 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 (900 mg, 2.14 mmol, 1 equiv.) and 2,4,5-trichloropyrimidine (785.16 mg, 4.28 mmol, 2 equiv.) in DMF (9 mL) was added DIEA (553.23 mg, 4.28 mmol, 745.59 μL, 2 equiv.). 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 minutes to give the title compound as a yellow solid (800 mg, 1.38 mmol, 65% yield, 98% purity). 1H NMR (400 MHz, DMSO-d6) δ = 10.90 (s, 1H), 9.39 (s, 1H), 8.33 (s, 1H), 6.97 (d, J = 2.9 Hz, 2H), 4.14 (br t, J = 4.4 Hz, 2H), 3.88 - 3.82 (m, 2H), 3.47 (s, 3H), 2.45 - 2.16 (m, 3H), 2.06 (br d, J = 11.9 Hz, 1H), 1.55 - 1.44 (m, 2H), 1.37 (s, 11H), 0.85 (d, J = 6.5 Hz, 3H).

[0339] 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

[0340] To a solution of tert-butyl (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-carboxylate (800 mg, 1.41 mmol, 1 equiv.) in DCM (8 mL) was added TFA (2 mL). The reaction mixture was stirred at 25° C. for 30 minutes. 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.

[0341] (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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 -on

[0342] To a solution of tert-butyl (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-carboxylate (800 mg, 1.38 mmol, 1 equiv., TFA) in DMSO (36 mL) was added DIEA (1.78 g, 13.76 mmol, 2.40 mL, 10 equiv.). The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated in vacuo to give a residue, which was purified by column chromatography (SiO2, 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 H NMR (400 MHz, DMSO-d6) δ = 10.83 (s, 1H), 8.77 (s, 1H), 8.03 (s, 1H), 7.65 (d, J = 0.9 Hz, 1H), 6.66 (d, J = 1.3 Hz, 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 = 11.2 Hz, 1H), 0.87 (d, J = 6.8 Hz, 3H).

[0343] (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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 -On(13)

[0344] 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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphan-42-one (90 mg, 208.87 μmol, 1 equiv.) in DMSO (1 mL) was added KI (17.34 mg, 104.44 μmol, 0.5 equiv.), CsCO (136.11 mg, 417.74 μmol, 2 equiv.), and 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (107.92 mg, 417.74 μmol, 2 equiv.). The reaction mixture was stirred at 80°C for 12 hours, then cooled to 25°C and purified by preparative HPLC (column: Waters Xbridge™ BEH C18 100*30mm*10μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 40%-70%, 8 min) to give the title compound as a white solid (20mg, 38.30μmol, yield 18%, purity 96%). 1 H NMR (400 MHz, DMSO-d6) δ = 8.85 (s, 1H), 8.05 (s, 1H), 7.70 (s, 1H), 6.79 (d, J = 1.1 Hz, 1H), 4.69 - 4.58 (m, 2H), 4.39 (br dd, J = 3.6, 12.8 Hz, 1H), 4.20 - 4.09 (m, 1H), 3.82 (br dd, J = 5.3, 9.8 Hz, 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, 10.4 Hz, 2H), 1.65 - 1.56 (m, 1H), 1.18 (s, 6H), 1.12 (br d, J = 11.3 Hz, 1H), 0.88 (d, J = 6.5 Hz, 3H). LCMS: [M+H] + = 517.4.

[0345] Example 13: (1 3 R,1 5S)-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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 Synthesis of -one (16) [ka]

[0346] tert-Butyl (5-methylpyridin-3-yl)carbamate

[0347] To a solution of 5-methylpyridin-3-amine (12.5 g, 115.59 mmol, 1 equiv.) in THF (100 mL) was added NaHMDS (1 M, 254.30 mL, 2.2 equiv.) at 25 °C, and the reaction mixture was stirred for 30 min. Then, a solution of BocO (26.99 g, 123.68 mmol, 28.41 mL, 1.07 equiv.) in THF (25 mL) was added, and the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture (combined with another batch of the same scale) was quenched with water (50 mL) and treated with 0.2 M HCl (300 mL). The mixture was extracted with EtOAc (500 mL × 3). The combined organic phase was washed with brine (500 mL), dried over anhydrous NaSO, filtered, and concentrated 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, yield 56%, purity 99%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.49 (s, 1 H), 8.39 (s, 1 H), 8.01 (s, 1 H), 7.74 (s, 1 H), 2.24 (s, 3 H), 1.47 (s, 9 H).

[0348] tert-Butyl (5-methylpiperidin-3-yl)carbamate

[0349] To a solution of tert-butyl (5-methylpyridin-3-yl)carbamate (17 g, 81.63 mmol, 1 equiv.) in AcOH (340 mL) was added Pd / C (14 g, 10% purity) and PtO2 (1.85 g, 8.16 mmol, 0.1 equiv.) under Ar. The suspension was degassed under vacuum and purged with H2 several times. The reaction mixture was stirred under H2 (3 MPa) at 80 °C for 12 h. The reaction mixture was filtered, and the filter cake was washed with MeOH (500 mL × 3). The filtrate was concentrated under vacuum to give a residue, which was adjusted to pH 8 with saturated aqueous NaHCO3. The mixture was treated with water (400 mL) and then extracted with EtOAc (200 mL × 3). The combined organic phase was washed with brine (400 mL), dried over anhydrous NaSO, filtered, and concentrated 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-d6) δ = 6.64 (br d, J = 7.9 Hz, 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 = 12.3 Hz, 1H), 1.69 - 1.41 (m, 1H), 1.39 - 1.36 (m, 9H), 0.76 (d, J = 6.7 Hz, 3H).

[0350] tert-Butyl (1-benzyl-5-methylpiperidin-3-yl)carbamate

[0351] A mixture of tert-butyl (5-methylpiperidin-3-yl)carbamate (10 g, 46.66 mmol, 1 equiv), benzaldehyde (5.94 g, 56.00 mmol, 5.66 mL, 1.2 equiv), and AcOH (1.40 g, 23.33 mmol, 1.33 mL, 0.5 equiv) in DMF (250 mL) was stirred at 15° C. for 2 h. Sodium triacetoxyborohydride (19.78 g, 93.33 mmol, 2 equiv) was then added, and the reaction mixture was stirred at 15° C. for 10 h. 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), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC (column: Agela DuraShell C18 250*70 mm*10 μm; mobile phase: [water (NHHCO)-ACN]; B%: 50%-75%, 20 min) to give the title compound as a white solid (5 g, 16.26 mmol, yield 35%, purity 99%). 1 H NMR (400 MHz, DMSO-d6) δ = 7.34 - 7.22 (m, 5H), 6.73 (br d, J = 8.1 Hz, 1H), 3.50 - 3.39 (m, 3H), 2.81 (br d, J = 7.4 Hz, 1H), 2.67 (br d, J = 9.2 Hz, 1H), 1.73 (br d, J = 12.0 Hz, 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 = 6.7 Hz, 3H).

[0352] tert-Butyl ((3R,5S)-1-benzyl-5-methylpiperidin-3-yl)carbamate and tert-butyl ((3S,5R)-1-benzyl-5-methylpiperidin-3-yl)carbamate

[0353] tert-Butyl (1-benzyl-5-methylpiperidin-3-yl)carbamate (5 g, 16.42 mmol, 1 equiv.) was purified 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-d6) 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 (br d, J = 6.7Hz, 3H). tert-Butyl ((3S,5R)-1-benzyl-5-methylpiperidin-3-yl)carbamate: 1 H NMR (400 MHz, DMSO-d6) δ = 7.34 - 7.22 (m, 5H), 6.74 (br d, J = 8.2 Hz, 1H), 3.44 (br d, J = 3.7 Hz, 3H), 2.84 - 2.76 (m, 1H), 2.67 (br d, J = 8.9 Hz, 1H), 1.72 (br d, J = 12.0 Hz, 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).

[0354] tert-Butyl ((3R,5S)-5-methylpiperidin-3-yl)carbamate

[0355] To a solution of tert-butyl ((3S,5R)-1-benzyl-5-methylpiperidin-3-yl)carbamate (1.30 g, 4.27 mmol, 1 equiv) in THF (13 mL) was added Pd / C (700 mg, 10% purity) under Ar. The suspension was degassed under vacuum and purged with H2 several times. The reaction mixture was stirred under H2 (15 psi) at 25 °C 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-d4) δ = 3.41 (ddd, J = 4.5, 7.1, 11.3 Hz, 1H), 3.11 - 3.03 (m, 1H), 2.87 (br dd, J = 3.5, 12.4 Hz, 1H), 2.14 (t, J = 11.6 Hz, 1H), 2.05 - 1.97 (m, 1H), 1.97 - 1.90 (m, 1H), 1.68 - 1.54 (m, 1H), 1.43 (s, 9H), 1.40 (s, 1H), 0.87 (d, J = 6.6 Hz, 3H).

[0356] 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

[0357] 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 equiv.) and tert-butyl ((3R,5S)-5-methylpiperidin-3-yl)carbamate (992.57 mg, 4.63 mmol, 1.2 equiv.) in DMSO (15 mL) was added DIPEA (997.67 mg, 7.72 mmol, 1.34 mL, 2 equiv.). 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 under vacuum to give a residue, which was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to give the title compound as a yellow solid (1.1 g, 1.84 mmol, 48% yield, 95% purity). LCMS: [M+H] + = 510.2.

[0358] 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

[0359] 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 equiv) 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.

[0360] (1 3 R,1 5 S)-2 5 -chloro-1 5 ,4 3 -dimethyl-4 2 ,43 -dihydro-4 1 H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 -on

[0361] In a glove box, a mixture of 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 equiv.), KCO (296.35 mg, 2.14 mmol, 5 equiv.), and NaI (642.82 mg, 4.29 mmol, 10 equiv.) in DMF (30 mL) was stirred at 100° C. for 36 h. 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 dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue, which was purified by column chromatography (SiO2, petroleum ether / THF=4 / 1 to 1 / 1) to give the title compound as a yellow solid (320 mg). 1H NMR (400 MHz, DMSO-d6) 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 (br d, J = 11.1 Hz, 1H), 4.49 (br d, J = 10.8 Hz, 1H), 4.36 (br t, J = 10.9 Hz, 1H), 4.07 - 3.96 (m, 1H), 3.40 (br s, 3H), 3.01 (br t, J = 11.1 Hz, 1H), 2.94 - 2.75 (m, 2H), 2.39 (br t, J = 12.1 Hz, 1H), 2.16 - 2.10 (m, 1H), 1.90 (s, 1H), 1.82 (br d, J = 11.9 Hz, 1H), 1.57 (br d, J = 3.1 Hz, 1H), 0.85 (br d, J = 6.4 Hz, 3H). LCMS: [M+1] + = 430.2.

[0362] (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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 -On(16)

[0363] in DMSO (3 mL) 3 R,1 5 S)-2 5 -chloro-1 5 ,4 3 -dimethyl-4 2 ,4 3 -dihydro-4 1H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 A mixture of 3-methyl-4-methylbenzenesulfonate (348.53 mg, 1.35 mmol, 2 equiv.), KI (55.99 mg, 337.29 μmol, 0.5 equiv.), and CsCO (439.58 mg, 1.35 mmol, 2 equiv.) was degassed and purged with N three times. The reaction mixture was stirred at 80 °C under N atmosphere for 12 h. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (column: Waters Xbridge™ BEH C18 100*30 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 35%-55%, 8 min) to give the title compound as a white solid (23 mg, 44.12 μmol, 7% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d6) δ = 8.74 (s, 1H), 8.02 (s, 1H), 7.70 (s, 1H), 6.79 (d, J = 1.1 Hz, 1H), 4.79 (br d, J = 11.6 Hz, 1H), 4.52 - 4.45 (m, 2H), 4.42 - 4.34 (m, 1H), 4.02 (dt, J = 8.1, 11.1 Hz, 1H), 3.82 (br dd, J = 5.2, 9.7 Hz, 2H), 3.45 (s, 3H), 3.05 - 2.97 (m, 1H), 2.91 - 2.78 (m, 2H), 2.40 (t, J = 12.3 Hz, 1H), 2.15 (br t, J = 11.4 Hz, 1H), 1.82 (br d, J = 12.5 Hz, 1H), 1.69 (br dd, J = 5.1, 9.4 Hz, 2H), 1.63 - 1.54 (m, 1H), 1.18 (s, 6H), 1.13 (dd, J = 2.8, 18.5 Hz, 1H), 1.02 - 0.92 (m, 1H), 0.86 (d, J = 6.6 Hz, 3H). LCMS: [M+H] + = 516.4.

[0364] 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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 Synthesis of -one (17) [ka]

[0365] tert-Butyl ((3S,5R)-5-methylpiperidin-3-yl)carbamate

[0366] To a solution of tert-butyl N-[(3S,5R)-1-benzyl-5-methyl-3-piperidyl]carbamate (1.30 g, 4.27 mmol, 1 equiv) in THF (13 mL) was added Pd / C (700 mg, 10% purity) under Ar. The suspension was degassed under vacuum and purged with H2 several times. The reaction mixture was stirred under H2 (15 psi) at 25 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give the title compound as a white solid (0.8 g, crude). 1 H NMR (400 MHz, MeOD-d4) δ = 3.41 (tt, J = 4.3, 11.3 Hz, 1H), 3.11 - 3.03 (m, 1H), 2.87 (br dd, J = 3.5, 12.5 Hz, 1H), 2.14 (t, J = 11.6 Hz, 1H), 2.05 - 1.90 (m, 2H), 1.61 (dtd, J = 3.8, 7.3, 14.7 Hz, 1H), 1.43 (s, 9H), 1.40 (s, 1H), 0.87 (d, J = 6.6 Hz, 3H).

[0367] 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

[0368] 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 equiv.) and tert-butyl N-[(3S,5R)-5-methyl-3-piperidyl]carbamate (992.57 mg, 4.63 mmol, 1.2 equiv.) in DMSO (20 mL) was added DIPEA (997.64 mg, 7.72 mmol, 1.34 mL, 2 equiv.). The reaction mixture was stirred at 100° C. for 2 hours. The reaction was quenched with water (20 mL), and the solid was filtered and dried. The product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) 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.

[0369] 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

[0370] To a solution of tert-butyl N-[(3S,5R)-1-[5-chloro-4-[[7-(2-chloroethoxy)-1-methyl-2-oxo-3H-benzimidazol-5-yl]amino]pyrimidin-2-yl]-5-methyl-3-piperidyl]carbamate (600 mg, 1.06 mmol, 1 equiv.) in DCM (6 mL) was added TFA (1.5 mL). The reaction mixture was stirred at 25° C. for 30 minutes. 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.

[0371] (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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 -on

[0372] To a solution of 6-[[2-[(3S,5R)-3-amino-5-methyl-1-piperidyl]-5-chloro-pyrimidin-4-yl]amino]-4-(2-chloroethoxy)-3-methyl-1H-benzimidazol-2-one (200 mg, 344.60 μmol, 1 equiv., TFA) in DMF (30 mL) was added KCO (238.13 mg, 1.72 mmol, 5 equiv.) and NaI (516.53 mg, 3.45 mmol, 10 equiv.) in a glovebox. The reaction mixture was stirred at 100 °C under a N atmosphere for 36 h. The reaction mixture was concentrated in vacuo, and water (50 mL) was added. The solution was extracted with ethyl acetate (35 mL × 3). The combined organic phase was dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue, which was purified by column chromatography (SiO, 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-d6) 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 = 11.3 Hz, 1H), 4.51 - 4.45 (m, 1H), 4.40 - 4.31 (m, 1H), 4.01 (br d, J = 7.6 Hz, 1H), 3.42 - 3.39 (m, 3H), 3.08 - 2.94 (m, 1H), 2.92 - 2.78 (m, 2H), 2.40 (br t, J = 12.2 Hz, 1H), 2.15 (br s, 1H), 1.82 (br d, J = 12.2 Hz, 1H), 1.63 - 1.52 (m, 1H), 1.02 - 0.94 (m, 1H), 0.86 (br d, J = 6.4 Hz, 3H). LCMS: [M+H] + = 430.2.

[0373] (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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 -On(17)

[0374] in DMSO (2 mL) 3 S,1 5 R)-2 5 -chloro-1 5 ,4 3 -dimethyl-4 2 ,4 3 -dihydro-4 1H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 A mixture of CsCO (303.16 mg, 930.44 μmol, 2 equiv.), 3-hydroxy-3-methyl-butyl 4-methylbenzenesulfonate (240.36 mg, 930.44 μmol, 2 equiv.), KI (38.61 mg, 232.61 μmol, 0.5 equiv.), and CsCO (303.16 mg, 930.44 μmol, 2 equiv.) was degassed and purged with N three times. The reaction mixture was stirred at 80 °C under N atmosphere for 12 h. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (column: Waters Xbridge™ Prep OBD C18 150*40 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 30%-60%, 8 min) to give the title compound as a white solid (35 mg, 67.15 μmol, yield 14%, purity 99%). 1 H NMR (400 MHz, DMSO-d6) δ = 8.73 (s, 1H), 8.02 (s, 1H), 7.70 (s, 1H), 6.79 (d, J = 1.3 Hz, 1H), 4.80 (br d, J = 12.4 Hz, 1H), 4.49 (br dd, J = 4.0, 12.6 Hz, 1H), 4.45 (s, 1H), 4.42 - 4.33 (m, 1H), 4.02 (dt, J = 8.0, 11.2 Hz, 1H), 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 = 12.2 Hz, 1H), 2.15 (br t, J = 11.4 Hz, 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 = 11.8 Hz, 1H), 0.86 (d, J = 6.6 Hz, 3H). LCMS: [M+H] + = 516.1.

[0375] Example 15: (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 ,4 4 -Tetrahydro-5-oxa-3-aza-4(7,5)-quinoxalina-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 ,4 3 -Zion (18-1) and (1 3 S,1 5 R)-2 5 -chloro-1 4 ,1 4 -difluoro-4 1 -(((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)-quinoxalina-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 ,4 3 Synthesis of -dione (18-2) [ka]

[0376] 6-Bromo-8-methoxy-1-methyl-1,4-dihydroquinoxaline-2,3-dione

[0377] 4-Bromo-6-methoxy-N 1To a solution of 30 g (129.82 mmol, 1 equiv.) of 1,2-methylbenzene-1,2-diamine in 350 mL of THF was added dropwise oxalyl dichloride (32.96 g, 259.64 mmol, 22.73 mL, 2 equiv.) at 25° C. The reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture (combined with another batch of the same scale) was filtered, and the filter cake was washed with ethyl acetate (300 mL) and dried under vacuum. The residue was triturated with 200 mL of EtOAc at 25° C. for 30 minutes to give the title compound as a white solid (40 g, 97% purity). 1 H NMR (400 MHz, DMSO-d6) δ = 11.95 (s, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 3.87 (s, 3H), 3.63 (s, 3H).

[0378] 6-(benzylamino)-8-methoxy-1-methyl-1,4-dihydroquinoxaline-2,3-dione

[0379] To a solution of 6-bromo-8-methoxy-1-methyl-1,4-dihydroquinoxaline-2,3-dione (18 g, 63.14 mmol, 1 equiv.) and BnNH (8.12 g, 75.76 mmol, 8.26 mL, 1.2 equiv.) in THF (180 mL), LiHMDS (1 M, 151.53 mL, 2.4 equiv.) was added dropwise at 25 °C and purged with N for 5 min. BrettPhos (1.69 g, 3.16 mmol, 0.04 equiv.) and BrettPhos Pd G (1.43 g, 1.58 mmol, 0.02 equiv.) were then added at 25 °C, and the resulting mixture was stirred at 80 °C under N for 12 h. The reaction mixture (combined with two other batches of the same scale) was slowly quenched with saturated aqueous NH4Cl (200 mL) at 0° C. The solution was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo to give a residue that was purified by flash silica gel chromatography (silica flash column, eluent: 20-100% THF / petroleum ether gradient) to give the title compound as a yellow solid (20 g, 94% purity). 1H NMR (400 MHz, DMSO-d6) δ = 11.62 (br s, 1H), 7.39 - 7.29 (m, 4H), 7.27 - 7.19 (m, 1H), 6.45 (t, J = 6.0 Hz, 1H), 6.19 (d, J = 2.4 Hz, 1H), 5.99 (d, J = 2.4 Hz, 1H), 4.23 (d, J = 6.0 Hz, 2H), 3.73 (s, 3H), 3.63 - 3.57 (m, 3H).

[0380] 6-(benzylamino)-8-hydroxy-1-methyl-1,4-dihydroquinoxaline-2,3-dione

[0381] 6-(Benzylamino)-8-methoxy-1-methyl-1,4-dihydroquinoxaline-2,3-dione (20 g, 64.24 mmol, 1 equiv.) was dissolved in DCM (400 mL) and cooled to -70 °C. BBr (80.47 g, 321.20 mmol, 30.95 mL, 5 equiv.) in DCM (50 mL) was added dropwise to the reaction mixture under N. The reaction mixture was warmed to 40 °C and stirred for 12 h. The reaction was quenched with CHCl / MeOH solution (10:1, 600 mL) at 0 °C and then concentrated in vacuo. The residue was stirred in 4 N aqueous HCl at 40 °C for 30 min and then filtered. The filter cake was triturated with (EtOAc, 100 mL) at 25° C. for 30 min to afford the title compound as a yellow solid (11 g, 34.04 mmol, 53% yield, 92% purity). 1 H NMR (400 MHz, DMSO-d6) 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).

[0382] 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

[0383] To a solution of 6-(benzylamino)-8-hydroxy-1-methyl-1,4-dihydroquinoxaline-2,3-dione (1 g, 3.03 mmol, 90% purity, 1 equiv.) in ACN (10 mL) and DMF (10 mL) was added KCO (836.77 mg, 6.05 mmol, 2 equiv.) and tert-butyl (3R,5S)-4,4-difluoro-3-methyl-5-(3-(tosyloxy)propyl)piperidine-1-carboxylate (1.35 g, 3.03 mmol, 1 equiv.). The reaction mixture was stirred at 60 °C for 6 h. Water (50 mL) was added, and the solution (combined with another batch on a 1.5 g scale) was extracted with EtOAc (50 mL × 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue which was purified by flash silica gel chromatography (silica flash column, eluent 33-100% ethyl acetate / petroleum ether gradient) to give the title compound as a yellow solid (1 g). 1 H NMR (400 MHz, DMSO-d6) 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 = 6.0 Hz, 1H), 6.17 (d, J = 2.4 Hz, 1H), 5.99 (d, J = 2.4 Hz, 1H), 4.23 (br d, J = 6.0 Hz, 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 = 6.8 Hz, 4H).

[0384] (3S,5R)-tert-butyl 3-[3-[(7-amino-4-methyl-2,3-dioxo-1H-quinoxalin-5-yl)oxy]propyl]-4,4-difluoro-5-methyl-piperidine-1-carboxylate

[0385] 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 equiv.) in THF (4 mL) was added Pd / C (150 mg, 10% purity) under Ar. The suspension was degassed under vacuum and purged with H three times. The reaction mixture was stirred under H (15 psi) at 25° C. for 12 h. The reaction mixture (combined with another batch of the same scale) was filtered through a pad of Celite®, and the filtrate was concentrated under vacuum to give the title compound as a red solid (800 mg, crude). 1 H NMR (400 MHz, DMSO-d6) δ = 11.67 (br d, J = 13.6 Hz, 1H), 7.95 (s, 1H), 6.13 (d, J = 2.0 Hz, 1H), 5.99 (d, J = 2.0 Hz, 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 = 6.8 Hz, 3H).

[0386] tert-Butyl (3S,5R)-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

[0387] To a solution of tert-butyl (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-carboxylate (800 mg, 1.66 mmol, 1 equiv.) in DMF (8 mL) was added DIPEA (428.55 mg, 3.32 mmol, 577.56 μL, 2 equiv.) and 2,4,5-trichloropyrimidine (608.22 mg, 3.32 mmol, 2 equiv.). 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 phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo to give a residue which was purified by flash silica gel chromatography (silica flash column, eluent of 20-100% THF / petroleum ether gradient) to give the title compound as a gray solid (750 mg, 83% purity). 1 H NMR (400 MHz, DMSO-d6) 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 = 6.8 Hz, 3H).

[0388] 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

[0389] A solution of tert-butyl (3S,5R)-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 equiv) 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.

[0390] (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)-quinoxalina-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 ,4 3 -Zeon (28)

[0391] 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 equiv., TFA) in DMSO (28 mL) was added DIPEA (1.41 g, 10.88 mmol, 1.90 mL, 10 equiv.). The reaction mixture was stirred at 80° C. for 12 h. Water (50 mL) was added and the solution (combined with another 50 mg scale) was extracted with EtOAc (50 mL×3). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo to give a residue which was purified by flash silica gel chromatography (silica flash column, eluent of 50-100% THF / petroleum ether gradient) to give the title compound as a yellow solid (250 mg, purity 77%). 1 H NMR (400 MHz, DMSO-d6) 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 = 11.6 Hz, 1H), 4.21 - 4.10 (m, 1H), 3.67 (s, 3H), 2.74 (br t, J = 12.7 Hz, 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 = 6.5 Hz, 3H). LCMS: [M+H] + = 493.2.

[0392] 3-(hydroxymethyl)cyclobutan-1-ol

[0393] To a mixture of 3-oxocyclobutane-1-carboxylic acid (10 g, 87.64 mmol, 1 equiv.) in THF (500 mL) was added BH3-Me2S (10 M, 26.29 mL, 3 equiv.) in one portion at −70° C. under N2. The reaction mixture was stirred at 15° C. for 3 h. The reaction (combined with two other batches of the same scale) was cooled to 0° C. in an ice bath. MeOH (100 mL) 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, 217.17 mmol, 83% yield, 85% purity). 1 H NMR (400 MHz, CDCl3) 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).

[0394] (3-Hydroxycyclobutyl)methyl 4-methylbenzenesulfonate

[0395] To a solution of 3-(hydroxymethyl)cyclobutan-1-ol (26 g, 254.57 mmol, 1 equiv.) in DCM (300 mL) was added TEA (51.52 g, 509.15 mmol, 70.87 mL, 2 equiv.) and DMAP (3.11 g, 25.46 mmol, 0.1 equiv.) at 15 °C. TosCl (48.53 g, 254.57 mmol, 1 equiv.) was then added slowly at 0 °C under N2, and the reaction mixture was stirred at 15 °C for 12 h. The reaction mixture was poured into water (400 mL), and the aqueous phase was extracted with DCM (300 mL × 2). The combined organic phase was washed with brine (800 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give the title compound as a white solid (33 g, 122.80 mmol, 48% yield, 95% purity). 1H NMR (400 MHz, DMSO-d6) 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).

[0396] (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)-quinoxalina-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 ,4 3 -Zeon

[0397] (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)-quinoxalina-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 ,4 3To a solution of 150 mg of 4-methyl-2-benzothiazolinone (304.32 μmol, 1 equiv.) in 2 mL of DMSO was added (3-hydroxycyclobutyl)methyl 4-methylbenzenesulfonate (156.00 mg, 608.64 μmol, 2 equiv.), CsCO (198.31 mg, 608.64 μmol, 2 equiv.), and KI (25.26 mg, 152.16 μmol, 0.5 equiv.). The reaction mixture was stirred at 80 °C under N for 12 h. The reaction mixture (combined with another batch on a 100 mg scale) was filtered, and the filtrate was concentrated under vacuum to give a residue, which was purified by preparative HPLC (column: Phenomenex C18 80*40 mm*3 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 35%-65%, 8 min) to give the title compound as a white solid (60 mg, purity 97%). LCMS: [M+H] + = 577.3.

[0398] (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 ,4 4 -Tetrahydro-5-oxa-3-aza-4(7,5)-quinoxalina-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 ,4 3 -Zion (18-1) and (1 3 S,1 5 R)-2 5 -chloro-1 4 ,1 4 -difluoro-4 1 -(((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)-quinoxalina-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 ,4 3 -Zeon (18-2)

[0399] (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)-quinoxalina-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 ,4 3 The -dione (combined with another 20 mg scale) was purified by SFC (column: DAICEL CHIRALPAK IC (250 mm * 30 mm, 10 μm); mobile phase: [ACN / EtOH (0.1% NH3H2O)]; B%: 70% ~ 70%, 13 min) to give 18-1 as a white solid (7 mg, 98% pure) and 18-2 as a white solid (20 mg, 97.8% pure).

[0400] 18-1: 1H NMR (400 MHz, DMSO-d6) δ = 9.01 (s, 1H), 8.15 (s, 1H), 7.77 (d, J = 1.4 Hz, 1H), 7.05 (d, J = 1.4 Hz, 1H), 5.04 (d, J = 6.0 Hz, 1H), 4.70 (br d, J = 14.0 Hz, 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, 14.1 Hz, 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 = 13.2 Hz, 1H), 1.39 - 1.31 (m, 3H), 0.98 (d, J = 6.6 Hz, 3H)。LCMS: [M+H] + = 577.4。

[0401] 18-2: 1H NMR (400 MHz, DMSO-d6) δ = 9.00 (s, 1H), 8.15 (s, 1H), 7.77 (d, J = 1.4 Hz, 1H), 7.05 (d, J = 1.4 Hz, 1H), 5.01 (d, J = 6.8 Hz, 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, 13.9 Hz, 1H), 3.90 - 3.77 (m, 1H), 3.63 (s, 3H), 2.76 (br t, J = 12.8 Hz, 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, 12.5 Hz, 1H), 0.98 (d, J = 6.8 Hz, 3H). LCMS: [M+H] + = 577.4.

[0402] 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)-quinoxalina-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 ,4 3 -Zion (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)-quinoxalina-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 ,4 3 Synthesis of -dione (19-2) [ka]

[0403] 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

[0404] To a solution of 6-(benzylamino)-8-hydroxy-1-methyl-1,4-dihydroquinoxaline-2,3-dione (2.5 g, 8.41 mmol, 1 equiv.) and tert-butyl (3S,5R)-4,4-difluoro-3-methyl-5-[3-(p-tolylsulfonyloxy)propyl]piperidine-1-carboxylate (3.76 g, 8.41 mmol, 1 equiv.) in ACN (25 mL) and DMF (25 mL) was added KCO (2.91 g, 21.02 mmol, 2.5 equiv.). The reaction mixture was stirred at 60 °C for 6 h. The reaction was quenched with water (40 mL) and extracted with EtOAc (30 mL × 3). The combined organic phase was washed with brine (40 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue, which was purified by column chromatography (SiO, 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). 1H NMR (400 MHz, DMSO-d6) δ = 11.71 - 11.52 (m, 1H), 7.42 - 7.18 (m, 5H), 6.42 (br t, J = 5.9 Hz, 1H), 6.17 (d, J = 1.4 Hz, 1H), 5.99 (s, 1H), 4.22 (br d, J = 5.9 Hz, 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 = 6.6 Hz, 3H).

[0405] (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

[0406] 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 equiv.) in DMF (15 mL) was added Pd / C (600 mg, 10% purity) under Ar. The suspension was degassed under vacuum and purged with H2 three times. The reaction mixture was stirred under H2 (15 psi) at 60°C for 12 h. The reaction mixture (combined with another batch on a 200 mg scale) was filtered and the filtrate was concentrated under vacuum to give the title compound as a black oil (1.5 g). LCMS: [M-56+H] + = 427.2.

[0407] tert-Butyl (3R,5S)-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

[0408] To a solution of tert-butyl (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-carboxylate (1.5 g, 3.11 mmol, 1 equiv.) and 2,4,5-trichloropyrimidine (1.14 g, 6.22 mmol, 2 equiv.) in DMF (16 mL) was added DIPEA (803.55 mg, 6.22 mmol, 1.08 mL, 2 equiv.). 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 phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue, which was purified by column chromatography (SiO, petroleum ether / ethyl acetate / MeOH=4 / 1 / 0 to 0 / 0 / 1) 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.

[0409] 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

[0410] A solution of tert-butyl (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-carboxylate (1 g, 1.59 mmol, 1 equiv) in DCM (10 mL) and TFA (2.5 mL) was stirred at 25° C. for 30 minutes. 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.

[0411] (1 3 R,1 5 S)-25-chloro-14,14-difluoro-15,44-dimethyl-4 1 ,4 2 ,4 3 ,4 4 -Tetrahydro-5-oxa-3-aza-4(7,5)-quinoxalina-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 ,4 3 -Zeon

[0412] 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 equiv., TFA) in DMSO (40 mL) was added DIEA (2.01 g, 15.54 mmol, 2.71 mL, 10 equiv.). The reaction mixture was stirred at 80° C. for 12 hours. The reaction (combined with another batch on a 100 mg scale) was quenched with water (60 mL) and extracted with EtOAc (30 mL×3). The combined organic phase was washed with brine (60 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by column chromatography (SiO, ethyl acetate / MeOH=1 / 0 to 0 / 1) to give the title compound as a yellow solid (380 mg). 1H NMR (400 MHz, DMSO-d6) δ = 12.25 - 11.79 (m, 1H), 9.08 (s, 1H), 8.10 (s, 1H), 7.60 (s, 1H), 6.76 (d, J = 1.9 Hz, 1H), 4.73 - 4.64 (m, 1H), 4.59 (br d, J = 14.1 Hz, 1H), 4.46 (br t, J = 11.8 Hz, 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 = 6.6 Hz, 3H).

[0413] (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)-quinoxalina-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 ,4 3 -Zeon

[0414] (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)-quinoxalina-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 ,4 3 To a solution of 260 mg (527.48 μmol, 1 equiv.) of 4-methyl-3-methylbenzenesulfonate (270.41 mg, 1.05 mmol, 2 equiv.) in DMSO (2.6 mL) was added CsCO (343.73 mg, 1.05 mmol, 2 equiv.) and KI (43.78 mg, 263.74 μmol, 0.5 equiv.). The reaction mixture was stirred at 80 °C for 12 h. 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), dried over anhydrous NaSO, filtered and concentrated under vacuum to give a residue, which was purified by preparative HPLC (column: Waters Xbridge™ BEH C18 100*30 mm*10 μm; mobile phase: [water (NHHCO)-ACN]; B%: 45%-65%, 8 min) to give the title compound as a white solid (60 mg, 102.94 μmol, yield 20%, purity 99%). 1H NMR (400 MHz, DMSO-d6) δ = 9.05 - 8.95 (m, 1H), 8.15 (s, 1H), 7.77 (d, J = 1.3 Hz, 1H), 7.05 (s, 1H), 5.05 - 4.97 (m, 1H), 4.70 (br d, J = 12.5 Hz, 1H), 4.64 - 4.56 (m, 1H), 4.46 (br t, J = 11.4 Hz, 1H), 4.27 - 4.15 (m, 2H), 4.03 (br dd, J = 6.6, 13.9 Hz, 1H), 3.88 - 3.79 (m, 1H), 3.63 (s, 3H), 2.76 (br t, J = 12.8 Hz, 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, 7.4 Hz, 2H), 1.82 - 1.59 (m, 4H), 1.44 - 1.31 (m, 1H), 0.98 (d, J = 6.6 Hz, 3H).

[0415] (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)-quinoxalina-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 ,4 3 -Zion (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)-quinoxalina-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 ,4 3 -Zion (19-2)

[0416] (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)-quinoxalina-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 ,4 3 The -dione (90 mg) was separated by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3HO IPA]; B%: 50%-50%, 17 min) to give 19-1 as a white solid (7 mg, 12% yield, 99% pure) and 19-2 as a white solid (15 mg, 25% yield, 99% pure).

[0417] 19-1: 1H NMR (400 MHz, DMSO-d6) δ = 9.01 (s, 1H), 8.15 (s, 1H), 7.77 (s, 1H), 7.05 (s, 1H), 5.04 (br d, J = 5.8 Hz, 1H), 4.70 (br d, J = 12.6 Hz, 1H), 4.60 (br d, J = 12.5 Hz, 1H), 4.46 (br t, J = 12.1 Hz, 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 = 5.6 Hz, 3H), 1.81 - 1.57 (m, 2H), 1.44 - 1.31 (m, 1H), 0.98 (br d, J = 6.6 Hz, 3H)。LCMS: [M+H] + = 577.4。

[0418] 19-2: 1H NMR (400 MHz, DMSO-d6) δ = 9.00 (s, 1H), 8.15 (s, 1H), 7.77 (br s, 1H), 7.05 (br s, 1H), 5.01 (br d, J = 6.8 Hz, 1H), 4.70 (br d, J = 12.3 Hz, 1H), 4.60 (br d, J = 12.6 Hz, 1H), 4.45 (br t, J = 11.6 Hz, 1H), 4.26 - 4.13 (m, 2H), 4.08 - 3.98 (m, 1H), 4.03 (br dd, J = 6.4, 13.6 Hz, 1H), 3.83 (br dd, J = 7.3, 14.3 Hz, 1H), 3.63 (s, 3H), 2.76 (br t, J = 12.5 Hz, 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 = 6.4 Hz, 3H). LCMS: [M+H] + = 577.4.

[0419] 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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 Synthesis of -one (33): [ka]

[0420] tert-Butyl (3S,5R)-3-(2-(benzyloxy)ethoxy)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0421] To a solution of tert-butyl 4,4-difluoro-3-hydroxy-5-methyl-piperidine-1-carboxylate (13.00 g, 51.74 mmol, 1 equiv.) in DMF (100 mL) was added NaH (4.14 g, 103.47 mmol, 60% purity, 2 equiv.) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes, and then 2-bromoethoxymethylbenzene (13.35 g, 62.08 mmol, 9.82 mL, 1.2 equiv.) was added. The reaction mixture was heated to 90 °C and stirred under N for 12 hours. The reaction mixture was slowly quenched with saturated NH Cl (100 mL) and then extracted with ethyl acetate (150 mL × 2). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na SO , filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; SepaFlash® silica flash column, eluent: 5-50% ethyl acetate / petroleum ether gradient) to give the title compound as a colorless oil (5.7 g, 11.53 mmol, 22% yield, 78% purity). 1 H NMR (400 MHz, CDCl3) 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 = 10.4 Hz, 1H), 2.70 (s, 1H), 2.07 - 1.88 (m, 1H), 1.46 (s, 9H), 1.07 (d, J = 6.8 Hz, 3H).

[0422] tert-Butyl (3S,5R)-4,4-difluoro-3-(2-hydroxyethoxy)-5-methylpiperidine-1-carboxylate

[0423] To a solution of tert-butyl 3-(2-benzyloxyethoxy)-4,4-difluoro-5-methyl-piperidine-1-carboxylate (5.70 g, 14.79 mmol, 1 equiv.) in MeOH (60 mL) was added Pd / C (2 g, 10% purity) under Ar. The suspension was degassed under vacuum and purged with H2 several times. The reaction mixture was stirred under H2 (50 psi) at 60 °C for 12 h. The reaction mixture was filtered and concentrated under vacuum to give the title compound as a colorless oil (4.3 g, crude). 1 H NMR (400 MHz, CDCl3) 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 = 6.8 Hz, 3H).

[0424] (3R,5S)-tert-Butyl 4,4-difluoro-3-methyl-5-(2-(tosyloxy)ethoxy)piperidine-1-carboxylate

[0425] To a solution of tert-butyl 4,4-difluoro-3-(2-hydroxyethoxy)-5-methyl-piperidine-1-carboxylate (4.3 g, 14.56 mmol, 1 equiv.) in DCM (40 mL) was added DMAP (177.88 mg, 1.46 mmol, 0.1 equiv.) and TEA (2.95 g, 29.12 mmol, 4.05 mL, 2 equiv.). 4-Methylbenzenesulfonyl chloride (4.16 g, 21.84 mmol, 1.5 equiv.) was then 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), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 8 / 1 to 1 / 1) to give the title compound as a colorless oil (5 g, 11.01 mmol, yield 76%, purity 99%). 1H NMR (400 MHz, CDCl3) δ = 7.81 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.0 Hz, 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 = 6.8 Hz, 3H).

[0426] tert-Butyl (3R,5S)-4,4-difluoro-3-methyl-5-(2-(tosyloxy)ethoxy)piperidine-1-carboxylate and tert-butyl (3S,5R)-4,4-difluoro-3-methyl-5-(2-(tosyloxy)ethoxy)piperidine-1-carboxylate

[0427] The cis mixture of tert-butyl (3R,5S)-4,4-difluoro-3-methyl-5-(2-(tosyloxy)ethoxy)piperidine-1-carboxylate was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 15%, isocratic elution mode) to give tert-butyl (3R,5S)-4,4-difluoro-3-methyl-5-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate as a white solid (2.2 g, 4.85 mmol, yield 44%, purity 99%); 1 H NMR (400 MHz, CDCl3) δ = 7.81 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.2 Hz, 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 = 6.8 Hz, 3H);LCMS: [M-Boc+H]+ = 350.2; and (3S,5R)-4,4-difluoro-3-methyl-5-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate tert-butyl ester was obtained as a white solid (2.2 g, 4.85 mmol, 44% yield, 99% purity); 1 H NMR (400 MHz, CDCl3) δ = 7.73 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 4.11 - 3.99 (m, 3H), 3.92 - 3.72 (m, 3H), 3.40 - 3.28 (m, LCMS: [M-Boc+H] + = 350.2.

[0428] 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

[0429] A mixture of 6-(benzylamino)-4-hydroxy-3-methyl-1H-benzimidazol-2-one (800 mg, 2.97 mmol, 1 equiv.), tert-butyl (3R,5S)-4,4-difluoro-3-methyl-5-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate (1.34 g, 2.97 mmol, 1 equiv.), and K2CO3 (821.13 mg, 5.94 mmol, 2 equiv.) in DMSO (10 mL) was degassed and purged with N2 three times. The reaction mixture was stirred under N2 at 70 °C for 2 hours. The reaction mixture was poured into water and filtered. The filter cake was washed with water and dried under vacuum to give the title compound as a yellow solid (800 mg, 1.46 mmol, 49% yield). 1H NMR (400 MHz, DMSO-d6) δ = 10.36 (s, 1H), 7.40 - 7.15 (m, 5H), 6.03 (s, 1H), 5.93 (t, J = 6.0 Hz, 1H), 5.84 (s, 1H), 4.21 (d, J = 5.6 Hz, 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 = 6.8 Hz, 3H).

[0430] 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

[0431] 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 equiv.) in DMF (10 mL) was added Pd / C (400.00 mg, 375.87 μmol, 10% purity) under Ar. The suspension was degassed under vacuum and purged with H2 several times. The reaction mixture was stirred under H2 (15 psi) at 20 °C for 24 h. The reaction mixture was filtered and then concentrated under reduced pressure to give the title compound as a yellow solid (600 mg, crude). 1H NMR (400 MHz, DMSO-d6) δ = 10.36 (s, 1H), 5.96 (d, J = 1.2 Hz, 1H), 5.91 (d, J = 1.6 Hz, 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 = 6.8 Hz, 3H).

[0432] 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

[0433] 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 equiv.), 2,4,5-trichloropyrimidine (337.53 mg, 1.84 mmol, 1.4 equiv.), and DIPEA (339.75 mg, 2.63 mmol, 457.89 μL, 2 equiv.) in DMF (8 mL) was degassed and purged with N three times. The reaction mixture was stirred under N atmosphere at 20° C. for 2 hours. The reaction mixture was poured into water and filtered. The filter cake was washed with water and dried under vacuum to give the title compound as a yellow solid (600 mg, 994.29 μmol, 76% yield). 1H NMR (400 MHz, DMSO-d6) 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 = 6.8 Hz, 3H).

[0434] 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

[0435] A solution of 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 (800 mg, 1.33 mmol, 1 equiv) in HCl / EtOAc (10 mL) was stirred at 20° C. under N atmosphere for 1 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in MeOH (50 mL) and basic resin was added to achieve 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.

[0436] (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-5,8-dioxa-3-aza-4(6,4)-benzo[d]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 -on

[0437] 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 equiv.) and DIPEA (1.03 g, 7.95 mmol, 1.38 mL, 10 equiv.) in DMSO (40 mL) was degassed and purged with N2 three times. The reaction mixture was stirred at 80 °C under N2 atmosphere for 24 h. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (SiO2, 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-d6) 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), 4.24 - 4.10 (m, 2H), 3.88 (t, J = 6.4 Hz, 2H), 3.41 (s, 3H), 3.00 - 2.75 (m, 2H), 2.10 - 1.94 (m, 1H), 0.97 (d, J = 6.8Hz, 3H).

[0438] (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-5,8-dioxa-3-aza-4(6,4)-benzo[d]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 -On(33)

[0439] in DMSO (3 mL) 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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 A mixture of CsCO3 (167.49 mg, 514.07 μmol, 2 equiv.), 3-hydroxy-3-methyl-butyl 4-methylbenzenesulfonate (99.60 mg, 385.55 μmol, 1.5 equiv.), KI (21.33 mg, 128.52 μmol, 0.5 equiv.), and CsCO3 (167.49 mg, 514.07 μmol, 2 equiv.) was degassed and purged with N2 three times. The reaction mixture was stirred at 80 °C under N2 atmosphere for 12 h. The reaction mixture was concentrated under vacuum, and the residue was purified by p-HPLC (column: Waters™ Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [HO (10 mm NH4HCO3)-ACN]; gradient: 35% to 65% B over 8.0 min) to give the title compound as a white solid (50 mg, purity 98.9%). 1H NMR (400 MHz, DMSO-d6) 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.

[0440] 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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 Synthesis of -one (34): [ka]

[0441] 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

[0442] 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 equiv.) and tert-butyl (3S,5R)-4,4-difluoro-3-methyl-5-(2-(tosyloxy)ethoxy)piperidine-1-carboxylate (1.27 g, 2.82 mmol, 0.95 equiv.) in DMSO (10 mL) was added KCO (821.13 mg, 5.94 mmol, 2 equiv.). The reaction mixture was stirred at 70 °C under N 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-d6) δ = 10.36 (s, 1H), 7.38 - 7.27 (m, 4H), 7.24 - 7.18 (m, 1H), 6.03 (d, J = 1.5 Hz, 1H), 5.93 (t, J = 6.0 Hz, 1H), 5.83 (d, J = 1.5 Hz, 1H), 4.22 (d, J = 6.0 Hz, 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 = 6.7 Hz, 3H).

[0443] 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

[0444] 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 equiv) in DMF (12 mL) was added Pd / C (0.1 g, 10% purity) under Ar. The suspension was degassed under vacuum and purged with H2 several times. The reaction mixture was stirred under H2 (15 psi) at 15 °C for 12 h. 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.

[0445] 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

[0446] To a solution of 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 (500 mg, 1.10 mmol, 1 equiv.) in DMF (5 mL) was added DIEA (283.13 mg, 2.19 mmol, 381.57 μL, 2 equiv.) and 2,4,5-trichloropyrimidine (401.82 mg, 2.19 mmol, 2 equiv.). The reaction mixture was stirred at 15° C. for 2 hours. Water (10 mL) was then added, and the reaction mixture was filtered. The filter cake was washed with EtOAc (10 mL). The solid was concentrated under vacuum to give the title compound as a grey solid (550 mg, 902.32 μmol, 82% yield, 99% purity). 1H NMR (400 MHz, DMSO-d6) 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).

[0447] 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

[0448] A mixture 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)-4,4-difluoro-5-methylpiperidine-1-carboxylate (550 mg, 911.43 μmol, 1 equiv.) in DCM (11 mL) and TFA (2.75 mL) was stirred at 15° C. under N atmosphere for 30 min. The reaction mixture was concentrated in vacuo and the residue was dissolved in MeOH (10 mL). Then, 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.

[0449] (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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 -on

[0450] 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 equiv.) in DMSO (16 mL) was added DIPEA (2.05 g, 15.89 mmol, 2.77 mL, 20 equiv.). 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×2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel 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-d6) δ = 10.81 (s, 1H), 8.90 (s, 1H), 8.08 (s, 1H), 7.65 (d, J = 1.3 Hz, 1H), 6.64 (d, J = 1.4 Hz, 1H), 4.68 (td, J = 6.4, 12.4 Hz, 1H), 4.51 - 4.29 (m, 2H), 4.14 (td, J = 6.7, 12.9 Hz, 2H), 3.88 (br t, J = 6.8 Hz, 2H), 3.41 (s, 3H), 2.98 - 2.81 (m, 2H), 2.12 - 1.93 (m, 1H), 0.97 (d, J = 6.8 Hz, 3H).

[0451] (1 3 R,1 5 S)-2 5 -chloro-1 4 ,14 -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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 -On(34)

[0452] (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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 To a solution of 4-methyl-3-methyl-butyl-4-methylbenzenesulfonate (74.70 mg, 289.16 μmol, 1.5 equiv.) and 4-methyl-3-methyl-1-methyl-2 ... The reaction mixture (combined with another batch on a 30 mg scale) was concentrated under vacuum and the residue was purified by preparative HPLC (column: Waters™ Xbridge BEH C18 100*30 mm 5 μm; mobile phase: [HO (10 mm NH4HCO3)-ACN]; gradient: 33% to 59% B over 8.0 min) to give the title compound as a white solid (25 mg, 99% purity). 1H NMR (400 MHz, DMSO-d6) 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, 10.0 Hz, 2H), 1.18 (s, 6H), 0.97 (br d, J = 6.8 Hz, 3H). LCMS: [M+H] + = 552.21.

[0453] 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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 -on (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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 Synthesis of -one (36) [ka]

[0454] tert-Butyl 3-(1,3-dioxoisoindolin-2-yl)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0455] To a solution of 2-(4,4-difluoro-5-methylpiperidin-3-yl)isoindoline-1,3-dione (10 g, 35.68 mmol, 1 equiv.) in DCM (20 mL) was added BocO (7.79 g, 35.68 mmol, 8.20 mL, 1 equiv.) and TEA (7.22 g, 71.36 mmol, 9.93 mL, 2 equiv.) at 0 °C. The reaction mixture was stirred at 15 °C for 12 h. 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), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (silica flash column, eluent of 0-50% ethyl acetate / petroleum ether gradient) to give the title compound as a yellow oil (9 g, 23.19 mmol, 88% yield, 98% purity). 1 H NMR (400 MHz, CDCl3) δ = 7.93 - 7.86 (m, 2H), 7.79 - 7.73 (m, 2H), 4.57 - 4.37 (m, 1H), 4.36 - 4.00 (m, 3H), 2.97 - 2.66 (m, 1H), 2.32 - 2.08 (m, 1H), 1.48 (s, 9H), 1.08 (d, J = 6.7 Hz, 3H).

[0456] tert-Butyl 3-amino-4,4-difluoro-5-methylpiperidine-1-carboxylate

[0457] 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 equiv.) in EtOH (90 mL), MeNH (90 mL, 40% purity) was added. The reaction mixture was stirred at 70° C. for 1 hour. The reaction mixture was concentrated in vacuo to give the title compound as a yellow oil (5.6 g, 22.37 mmol, 95% yield). 1 H NMR (400 MHz, CDCl3) δ = 4.40 - 3.82 (m, 2H), 3.00 - 2.83 (m, 1H), 2.59 (br d, J = 9.3 Hz, 2H), 2.09 - 1.85 (m, 1H), 1.46 (s, 9H), 1.41 - 1.27 (m, 2H), 1.05 (d, J = 6.8 Hz, 3H).

[0458] 4,4-Difluoro-5-methylpiperidin-3-amine

[0459] To a solution of tert-butyl 3-amino-4,4-difluoro-5-methylpiperidine-1-carboxylate (5.6 g, 22.37 mmol, 1 equivalent) 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, 2 TFA). 1 H NMR (400 MHz, DMSO-d6) δ = 9.38 (br s, 4H), 4.14 - 3.93 (m, 1H), 3.66 (br d, J = 12.5 Hz, 1H), 3.46 (br d, J = 12.9 Hz, 1H), 3.13 (t, J = 12.5 Hz, 1H), 2.86 (t, J = 12.9 Hz, 1H), 2.58 - 2.50 (m, 1H), 1.04 (d, J = 6.8 Hz, 3H).

[0460] 2-((6-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)acetic acid ethyl ester

[0461] 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 equiv.) and 2,4-dichloro-5-fluoro-pyrimidine (11.33 g, 67.86 mmol, 2 equiv.) in DMF (72 mL) was added DIPEA (8.77 g, 67.86 mmol, 11.82 mL, 2 equiv.). The reaction mixture was stirred under N at 15° C. for 2 h. Water (100 mL) was added, the mixture was filtered, and the filter cake was washed with EtOAc (100 mL) and dried under vacuum to give the title compound as a white solid (10 g, 23.25 mmol, 69% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.94 (s, 1H), 9.84 (s, 1H), 8.27 (d, J = 3.3 Hz, 1H), 7.18 (s, 1H), 7.01 (d, J = 1.0 Hz, 1H), 4.82 (s, 2H), 4.19 (q, J = 7.2 Hz, 2H), 3.49 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H).

[0462] 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 ethyl ester

[0463] 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 equiv.) and 4,4-difluoro-5-methyl-piperidin-3-amine (6.12 g, 16.17 mmol, 1.6 equiv., TFA) in DMSO (80 mL) and DIPEA (16 mL) was stirred at 130° C. for 12 hours under N2. The reaction mixture (combined with another batch on a 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 in vacuo to give the title compound as a yellow solid (4.3 g, 66% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.91 (s, 1H), 9.17 (s, 1H), 7.99 (d, J = 3.5 Hz, 1H), 7.11 (d, J = 7.6 Hz, 2H), 4.83 (s, 2H), 4.62 - 4.46 (m, 2H), 4.18 (q, J = 7.1 Hz, 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 = 6.6 Hz, 3H).

[0464] 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

[0465] To a solution of 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 equiv.) in EtOH (30 mL) and HO (6 mL) was added LiOH·HO (543.61 mg, 12.95 mmol, 2 equiv.). The reaction mixture was stirred at 15 °C for 2 h. The reaction mixture (combined with another batch of 1 g scale) was concentrated in vacuo, and water (20 mL) was added. The solution was acidified to pH = 4 with 1 N HCl. The mixture was filtered, and the filter cake was dried under vacuum to give the title compound as a yellow solid (2.8 g, 68% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.78 (s, 1H), 9.08 (s, 1H), 7.96 (d, J = 3.5 Hz, 1H), 6.77 (s, 1H), 6.53 (br s, 1H), 4.84 - 4.75 (m, 1H), 4.63 (br d, J = 10.6 Hz, 1H), 4.44 (d, J = 15.7 Hz, 1H), 4.24 (br d, J = 15.7 Hz, 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 = 6.7 Hz, 3H).

[0466] 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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 ,7-dione

[0467] To a solution of 2-[[6-[[2-(3-amino-4,4-difluoro-5-methyl-1-piperidyl)-5-fluoropyrimidin-4-yl]amino]-3-methyl-2-oxo-1H-benzimidazol-4-yl]oxy]acetic acid (2 g, 4.15 mmol, 1 equiv.) in DMF (28 mL) was added HATU (1.58 g, 4.15 mmol, 1 equiv.) and DIPEA (1.07 g, 8.31 mmol, 1.45 mL, 2 equiv.). The reaction mixture was stirred under N2 at 15 °C for 2 h. The reaction mixture (combined with another 0.8 g batch) was poured into water (100 mL), filtered, and washed with water (50 mL). The filter cake was dried under vacuum, and the residue was triturated with MeOH (10 mL) at 15 °C for 10 min. The mixture was filtered and the filter cake was dried in vacuo to give the title compound as a yellow solid (2 g, 74% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.78 (s, 1H), 9.18 (s, 1H), 8.51 (br d, J = 8.1 Hz, 1H), 7.95 (br d, J = 3.5 Hz, 1H), 7.19 (s, 1H), 6.49 (s, 1H), 4.92 (br d, J = 14.8 Hz, 1H), 4.63 (br d, J = 14.7 Hz, 2H), 4.45 (br d, J = 14.3 Hz, 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 = 4.8 Hz, 1H), 1.09 (br d, J = 6.8 Hz, 3H).

[0468] 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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2-on

[0469] 1 4 ,1 4 ,2 5 -Trifluor-1 5 ,4 3 -dimethyl-4 2 ,4 3 -dihydro-4 1 H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 To a solution of ,7-dione (1.4 g, 3.02 mmol, 1 equiv.) in THF (27 mL) was added BH3·THF (1 M, 12.08 mL, 4 equiv.) under N2 at 0 °C. The reaction mixture was stirred at 50 °C for 5 h. The reaction mixture was slowly quenched with saturated NH4Cl (50 mL) under N2. After stirring at 15 °C for 30 min, the mixture was extracted with ethyl acetate (40 mL × 3). The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated in vacuo. The residue (combined with another 600 mg batch) was triturated with EtOAc (5 mL) and filtered. The filtrate was dried in vacuo to give the title compound as a yellow solid (870 mg, 44% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 10.77 (br d, J = 3.5 Hz, 1H), 9.30 (br s, 1H), 8.03 (br t, J = 3.8 Hz, 1H), 7.69 (br s, 1H), 6.61 - 6.52 (m, 1H), 4.76 - 4.23 (m, 3H), 4.08 (br d, J = 8.7 Hz, 1H), 3.41 (br d, J = 3.9 Hz, 3H), 3.25 (br dd, J = 4.9, 8.5 Hz, 1H), 2.98 (br d, J = 1.5 Hz, 2H), 2.74 (br t, J = 11.1 Hz, 1H), 2.62 - 2.53 (m, 1H), 2.32 - 2.08 (m, 1H), 2.03 - 1.86 (m, 1H), 0.96 (br d, J = 6.0 Hz, 3H).

[0470] 14 ,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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 -on

[0471] 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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 To a solution of 290 mg (645.26 μmol, 1 equiv.) and (3-hydroxy-3-methyl-butyl) 4-methylbenzenesulfonate (250.04 mg, 967.90 μmol, 1.5 equiv.) in DMSO (5 mL) was added CsCO (420.48 mg, 1.29 mmol, 2 equiv.) and KI (53.56 mg, 322.63 μmol, 0.5 equiv.). The reaction mixture was stirred at 80 °C under N for 10 h. The reaction mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (column: Waters™ Xbridge BEH C18 250*50 mm*10 μm; mobile phase: [HO (10 mM NHHCO)-ACN]; gradient: 30% to 60% B over 10 min) to give the title compound as a white solid (350 mg, 640.45 μmol, 33% yield). 1H NMR (400 MHz, DMSO-d6) δ = 9.40 (s, 1H), 8.04 (d, J = 3.7 Hz, 1H), 7.74 (s, 1H), 6.67 (d, J = 1.2 Hz, 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 (br dd, J = 6.1, 10.1 Hz, 2H), 3.46 (s, 3H), 3.31 - 3.19 (m, 1H), 3.03 - 2.93 (m, 2H), 2.74 (br t, J = 12.6 Hz, 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, 9.7 Hz, 2H), 1.18 (s, 6H), 0.96 (d, J = 6.7 Hz, 3H).

[0472] (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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 -on (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 1H-5-oxa-3,8-diaza-4(6,4)-benzo[d]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 -On(36)

[0473] 1 4 ,1 4 ,2 5 -Trifluor-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]imidazola-2(2,4)-pyrimidina-1(1,3)-piperidinacyclooctaphane-4 2 The 3-one (350 mg, 653.52 μmol, 1 equivalent) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: [CO2-MeOH (0.1% NH3HO)]; B%: 40%, isocratic elution mode) to give compound 35 as a white solid (120 mg, 224.06 μmol, yield 34%) and compound 36 as a white solid (125 mg, 233.40 μmol, yield 36%). Compound 35: 11H NMR (400 MHz, DMSO-d6) δ = 9.39 (s, 1H), 8.04 (d, J = 3.8 Hz, 1H), 7.74 (s, 1H), 6.67 (s, 1H), 4.69 (br d, J = 12.9 Hz, 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, 9.7 Hz, 2H), 3.46 (s, 3H), 3.30 - 3.19 (m, 1H), 3.04 - 2.92 (m, 2H), 2.74 (br t, J = 12.6 Hz, 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, 9.7 Hz, 2H), 1.18 (s, 6H), 0.96 (d, J = 6.6 Hz, 3H). LCMS: [M+H] + = 536.2. Compound 36: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.40 (s, 1H), 8.04 (d, J = 3.6 Hz, 1H), 7.74 (s, 1H), 6.67 (d, J = 1.0 Hz, 1H), 4.69 (br d, J = 13.0 Hz, 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, 9.9 Hz, 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, 9.6 Hz, 2H), 1.18 (s, 6H), 0.96 (d, J = 6.8 Hz, 3H). LCMS: [M+H] + = 536.2.

[0474] Example 20: Degradation activity

[0475] HiBiT Protocol

[0476] DC 50 The concentration required to achieve 50% degradation was determined from a cell degradation assay (HiBiT, Promega™) in Su-DHL-4 cells (Table 1). Endogenous BCL6 was tagged with the 11-amino acid residue SmBiT through CRISPR / Cas9 gene editing and single-cell clonal selection. After 24 hours of compound treatment, cells were lysed and incubated with LgBiT protein to reconstitute intact nanoluciferase. Substrate was then added, and relative luciferase units were measured. The degradation level for each treatment was given as a percentage compared to the 100% DMSO (Prism) control.

[0477] Table 1. Degradation activity of compounds [Table 1-1]

[0478] [Table 1-2]

[0479] [Table 1-3]

[0480] [Table 1-4]

[0481] [Table 1-5]

[0482] [Table 1-6]

[0483] [Table 1-7]

[0484] [Table 1-8]

[0485] [Table 1-9]

[0486] [Table 1-10]

[0487] [Table 1-11]

[0488] All patent and non-patent publications are indicative of the level of skill of those skilled in the art to which this invention pertains, and all such publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

[0489] Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications can be made to the illustrative embodiments and other arrangements can be devised without departing from the spirit and scope of the present invention as defined by the appended claims.

Claims

1. Formula I: 【Chemical 1】 or a pharmaceutically acceptable salt or stereoisomer thereof, (In the formula, X １ is N, CH, CCl, CF, or CCN; X ２ is N or CR ４ and R ４ is H, (C １ -C ４ ) alkyl, halo, 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 -C ４ ) alkyl, or N(C １ -C ４ alkyl) ２ and R １ is H, OH, or halo; R ２ is H, OH, or halo; R ３ is H, halo, or CN; Y is CH ２ , NH, or O; Z is CH ２ , NH, S, or O; n is 0, 1, or 2; A is, 【Chemistry 2】 and X ３ is CH or N; R ５ is H, (C １ -C ６ ) alkyl, (C １ -C ６ ) hydroxyalkyl, (C １ -C ６ ) aminoalkyl, (C ３ -C ６ ) carbocyclyl, 4- to 7-membered heterocyclyl, (C １ -C ６ ) alkyl-(C ３ -C ７ ) carbocyclyl, or (C ３ -C ７ ) carbocyclyl-4 to 7-membered heterocyclyl; said alkyl, carbocyclyl, or heterocyclyl may be one or more of the same or different R １３ may be further substituted by a group, R １３ is (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, halo, NH ２ , OH, (C １ -C ６ ) haloalkyl, NH(C １ -C ６ ) alkyl, or N((C １ -C ６ ) alkyl) ２ , (C ３ -C ６ ) carbocyclyl, 4- to 7-membered heterocyclyl, or R ５ Is -L-Y １ -Z １ where L is absent or (C １ -C ２ ) optionally substituted by one or more substituents selected from alkyl and oxo (C １ -C ５ ) alkylene; Y １ does not exist, 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) ２ N(R'), or N(R')S(O) ２ and Each R' is independently H or (C １ -C ４ ) alkyl; Z １ is H, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C ３ -C １０ ) carbocyclyl, or 3- to 10-membered heterocyclyl, wherein Z １ is (C １ -C ４ ) alkyl, halo, (C １ -C ４ ) haloalkyl, (C １ -C ４ ) haloalkoxy, NH ２ , (C １ -C ４ ) Aminoalkyl, CN, OH, carboxy, carbamoyl, sulfamoyl, mercapto, ureido, NR ｒ R ｓ , OR ｒ , C(O)R ｒ , C(O)OR ｒ , O.C.(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 optionally substituted with one or more substituents independently selected from ｒ , R ｓ and R ｔ are each independently 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, (C １ -C ４ ) alkyl, halo, (C １ -C ４ ) haloalkyl, (C １ -C ４ ) haloalkoxy, (C １ -C ４ ) alkoxy, (C １ -C ４ ) alkylamino, NH ２ forming a 4- to 9-membered heterocyclyl optionally substituted by one or more substituents selected from , CN and OH; R ６ Is, -L １ CR １４ R １５ R １６ or —CH═CH—R １６ where L １ does not exist or O,S,(C １ -C ４ ) alkylene, —O—(C １ -C ４ ) alkylene, or —S—(C １ -C ４ ) alkylene; R １４ is H or (C １ -C ４ ) alkyl; R １５ is H or (C １ -C ４ ) alkyl, or R １４ and R １５ together with the carbon atoms to which they are attached, (C ３ -C ５ ) forming a carbocyclyl, a 4- to 7-membered heterocyclyl, or C═O; R １６ is (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 ) alkylNR １８ C(O)R １７ or 4- to 7-membered heterocyclyl, R １７ is H, 3- to 6-membered heterocyclyl, or OH, Cl, F, CF ３ , N(C １ -C ４ alkyl) ２ , (C ３ -C ６ ) carbocyclyl, 3- to 6-membered heterocyclyl, (C ２ -C ４ ) alkenyl, and (C ２ -C ４ ) alkynyl (C １ -C ４ ) alkyl; R １８ is H or (C １ -C ４ ) alkyl; R ７ is H, methyl, -(CH ２ ) １－３ W １ W ２ ,or 【Chemistry 3】 where W １ is CR １９ R １９ or C(O); 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 and R １９ and R １９’ together with the carbon atoms to which they are attached, form C(O), (C ３ -C ６ ) carbocyclyl or 3- to 6-membered heterocyclyl, which is (C １ -C ２ ) alkyl, halo, (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; 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 , C.R. ２０ R ２１ R ２２ , N.H. ２ , NH(C １ -C ２ ) alkyl, or N(C １ -C ２ alkyl) ２ where R ２０ is H, (C １ -C ２ ) Alkyl, F, Cl, Br, OH, NH ２ , C.N., N.O. ２ , (C １ -C ２ ) alkoxy, (C １ -C ２ ) haloalkyl, or (C １ -C ２ ) haloalkoxy; 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 where Y ２ does not exist, 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) ２ N(R'), or N(R')SO ２ and L ２ does not exist or (C １ -C ２ ) alkylene; Z ２ is H, (C １ -C ６ ) alkyl, (C ２ -C ４ ) alkenyl, (C ２ -C ４ ) alkynyl, phenyl, (C ３ -C ６ ) carbocyclyl, or 4- to 6-membered heterocyclyl, wherein Z ２ is (C １ -C ４ ) alkyl, halo, (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', where each R' is independently H or (C １ -C ４ ) alkyl; or R ２０ and R ２１ together with the carbon atoms to which they are attached, (C １ -C ２ ) alkyl, halo, (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 (C ３ -C ６ ) forming a carbocyclyl or a 3- to 6-membered heterocyclyl; R ２２ is (C １ -C ２ ) alkyl, —C(O)OR″, OR″, —C(O)NR″, NR″R″, phenyl, or 5-membered heteroaryl, where each R″ is independently H or (C １ -C ２ ) alkyl; A'' is (C １ -C ２ ) alkyl, halo, OH, oxo, CN, and (C １ -C ２ ) optionally substituted with one or more substituents independently selected from alkoxy; (C ４ -C ６ ) carbocyclyl or 4- to 6-membered heterocyclyl; W ３ is NR ２３ or CR ２４ R ２４ where 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; R ２４ and R ２４’ are independently H, (C １ -C ２ ) Alkyl, cyclopropyl, F, Cl, Br, OH, NH ２ , C.N., N.O. 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; R ８ is H, (C １ -C ４ ) alkyl, (C ３ -C ６ ) cycloalkyl, (C １ -C ４ ) haloalkyl, or CN, wherein said alkyl or cycloalkyl is (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 ) optionally substituted with one or more substituents selected from aminoalkyl, and halo; R ８ ' is H, (C １ -C ４ ) alkyl, CN, (C １ -C ４ ) haloalkyl, or -Y ３ -L ３ -Z ３ where Y ３ is absent, C(O)O or C(O)N(R''); L ３ does not exist or (C １ -C ２ ) alkylene; Z ３ is H, (C １ -C ６ ) alkyl, phenyl, (C ３ -C ６ ) cycloalkyl, or 4- to 6-membered heterocyclyl, where Z ３ is (C １ -C ２ ) alkyl, halo, (C １ -C ２ ) haloalkyl, (C １ -C ２ ) haloalkoxy, (C １ -C ２ ) alkoxy, NH ２ , NO ２ optionally substituted with one or more substituents independently selected from: R ８ and R ８ ', together with the carbon atoms to which they are attached, form (C ４ -C ６ ) forming a carbocyclyl or a 4- to 6-membered heterocyclyl; A' is a 6- or 7-membered heterocyclyl, which is R ８ and R ８ In addition to ', oxo, (C １ -C ２ ) alkyl, cyclopropyl, spiro-cyclopropyl, halo, (C １ -C ２ ) haloalkyl, (C １ -C ２ ) haloalkoxy, (C １ -C ２ ) alkoxy, NH ２ may be further substituted by one or more substituents independently selected from , CN, and OH; X ４ is CR ２５ or N, where R ２５ is H, F, Cl, or methyl; 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; R ９ ' is (C １ -C ４ ) alkyl, CN, (C １ -C ４ ) haloalkyl, or -Y ４ -L ４ -Z ４ where Y ４ is absent or is C(O), C(O)O, OC(O), C(O)N(R″) or S(O) ２ N(R″); L ４ does not exist or (C １ -C ２ ) optionally substituted by one or more substituents selected from alkyl and oxo (C １ -C ２ ) alkylene; Z ４ is H, (C １ -C ６ ) alkyl, (C ２ -C ４ ) alkenyl, (C ２ -C ４ ) alkynyl, phenyl, (C ３ -C ６ ) carbocyclyl, (C ３ -C ６ ) cycloalkenyl, or 4- to 6-membered heterocyclyl, where Z ４ is oxo, (C １ -C ４ ) alkyl, (C ３ -C ６ ) cycloalkyl, halo, (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 , O.C.(O.)R ｕ , C(O)NR ｕ R ｕ , and N(R ｕ ) C(O)R ｕ and optionally substituted with one or more substituents independently selected from ｕ are independently H, (C １ -C ４ ) alkyl, (C ３ -C ６ ) cycloalkyl, or Z ４ Is -Q-L ５ -W ４ where Q is absent, O, NH, or N(C １ -C ２ ) alkyl; L ５ is absent or is oxo and (C １ -C ２ ) alkyl, optionally substituted by one or more substituents selected from １ -C ２ ) alkylene; W ４ is (C １ -C ４ ) alkyl, phenyl, (C ３ -C ６ ) cycloalkyl, (C ３ -C ６ ) cycloalkenyl, or 5- or 6-membered heterocyclyl, where W ４ is (C １ -C ４ ) alkyl, halo, (C １ -C ４ ) haloalkyl, (C １ -C ４ ) haloalkoxy, (C １ -C ４ ) alkoxy, (C １ -C ４ ) alkylamino, NH ２ , NO ２ optionally substituted with one or more substituents independently selected from , CN, or OH; or R ９ and R ９ ', together with the carbon atoms to which they are attached, form (C ３ -C １０ ) carbocyclyl or 4- to 10-membered heterocyclyl, which is oxo, (C １ -C ２ ) alkyl, halo, (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 ３ -C １０ ) carbocyclyl or 4- to 10-membered heterocyclyl may be fused to a 5- or 6-membered heteroaryl or phenyl ring, said 5- or 6-membered heteroaryl or phenyl ring being (C １ -C ２ ) alkyl, halo, (C １ -C ２ ) haloalkyl, (C １ -C ２ ) haloalkoxy, (C １ -C ２ ) alkoxy, (C １ -C ２ ) alkylamino, NH ２ , NO ２ , optionally substituted with CN or OH; 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 , acetylenyl, phenyl, or 5- or 6-membered heteroaryl, wherein said alkyl, phenyl, or heteroaryl is selected from halo, OH, and NH ２ and optionally substituted by one or more substituents independently selected from X ５ does not exist or (C ３ -C ６ ) carbocyclyl, (C ３ -C ６ ) carbocyclyl (C=O), or SO ２ and R １０ and R １０ ' are each independently H, (C １ -C ３ ) alkyl, (C １ -C ３ ) hydroxyalkyl, (C １ -C ３ ) aminoalkyl, or R １０ and R １０ ' together with the same carbon atom to which they are attached (C ３ -C ６ ) carbocyclyl or 4- to 6-membered heterocyclyl; said alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl or heterocyclyl may be one or more of the same or different R １０ａ may be substituted by a group, R １０ａ is (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkyl-(C １ -C ３ ) alkoxy, halo, 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 ) carbocyclyl, 4- to 6-membered heterocyclyl, or R １０ ' and R １１ ', together with the carbon atoms to which they are attached, form (C ３ -C ６ ) forming a carbocyclyl or a 4- to 6-membered heterocyclyl; R １１ and R １１ ' are each independently H, (C １ -C ３ ) alkyl, (C １ -C ３ ) hydroxyalkyl, (C １ -C ３ ) aminoalkyl, or R １１ and R １１ ' together with the same carbon atom to which they are attached form C=O, (C ３ -C ６ ) carbocyclyl, or 4- to 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is one or more of the same or different R １１ａ groups, and each R １１ａ are independently １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkyl-(C １ -C ３ ) alkoxy, halo, 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 ) carbocyclyl, or 4- to 6-membered heterocyclyl, or two R １１ａ groups taken together with the same carbon atom to which they are attached form C=O; R １２ 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 ) carbocyclyl, NH-4- to 6-membered heterocyclyl, NH-(C １ -C ６ ) alkyl-(C ３ -C ６ ) carbocyclyl, or NH—(C １ -C ６ ) alkyl-4 to 6-membered heterocyclyl, wherein said alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl, or heterocyclyl is selected from one or more of the same or different R １２ａ groups, where each R １２ａ are independently １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkyl-(C １ -C ３ ) alkoxy, halo, 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 ) carbocyclyl, or 4- to 6-membered heterocyclyl; m is 0, 1, or 2; and o is 0 or 1.

2. The compound of claim 1 , wherein Z is O.

3. Z is CH ２ 2. The compound of claim 1, wherein:

4. Y is CH ２ 2. The compound of claim 1, wherein:

5. The compound of claim 1 , wherein Y is O.

6. 2. The compound of claim 1, wherein Y is NH.

7. The compound of claim 1 , wherein n is 0.

8. 2. The compound of claim 1, wherein n is 1.

9. 2. The compound of claim 1, wherein n is 2.

10. R １ and R ２ 10. The compound of claim 1, wherein each is H.

11. R １ and R ２ The compound of claim 1 , wherein each is halo.

12. R １ and R ２ and each is F.

13. X １ The compound of claim 1 , wherein is N.

14. R ３ The compound of claim 1 , wherein is halo.

15. R ３ 15. The compound of claim 14, wherein is Cl or F.

16. X ２ The compound of claim 1 , wherein is CH.

17. A is, 【Chemistry 4】 and the compound of formula (I) is of formula I-1 【Chemistry 5】 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt or stereoisomer thereof.

18. R ５ 18. The compound of claim 17, wherein is methyl.

19. X ３ 18. The compound of claim 17, wherein is CH.

20. R ６ Ga-L １ CR １４ R １５ R １６ 18. The compound of claim 17, wherein:

21. L １ -O-(C １ 21. The compound of claim 20, wherein:

22. R １４ and R １５ taken together with the same carbon atom to which they are attached to form C=O.

23. R １６ But methyl, OH, NH ２ or NHMe.

24. Formula I-1a 【Chemistry 6】 18. The compound of claim 17, having the structure: or a pharmaceutically acceptable salt or stereoisomer thereof.

25. A is, 【Chemistry 7】 and the compound of formula (I) is of formula I-2 【Chemistry 8】 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt or stereoisomer thereof.

26. R ５ 26. The compound of claim 25, wherein is methyl.

27. R ７ Ga-(CH ２ ) ２ W １ W ２ 26. The compound of claim 25, wherein:

28. W １ is CR １９ R １９ 28. The compound of claim 27, wherein:

29. R １９ and R １９ and R are both methyl.

30. W ２ is CN, OH, or NH ２ 28. The compound of claim 27, wherein:

31. R ７ 26. The compound of claim 25, wherein is H or methyl.

32. Formula I-2a, I-2b, or I-2c: 【Chemistry 9】 26. The compound of claim 25, having the structure: or a pharmaceutically acceptable salt or stereoisomer thereof.

33. A is, 【Chemistry 10】 and the compound of formula (I) is of formula I-3 【Chemistry 11】 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt or stereoisomer thereof.

34. R ５ 34. The compound of claim 33, wherein is methyl.

35. R ８ However, (C ３ -C ６ ) cycloalkyl, and R ８ 34. The compound of claim 33, wherein ' is H.

36. A' is a 7-membered heterocyclyl containing two heteroatoms selected from N and O, and R ８ and R ８ In addition to ', oxo, (C １ -C ２ ) alkyl, cyclopropyl, spiro-cyclopropyl, halo, (C １ -C ２ ) haloalkyl, (C １ -C ２ ) alkoxy, NH ２ 34. The compound of claim 33, optionally further substituted with one or more substituents independently selected from: , CN, and OH.

37. Formula I-3a 【Chemistry 12】 34. The compound of claim 33, having the structure: or a pharmaceutically acceptable salt or stereoisomer thereof.

38. A is, 【Chemistry 13】 and the compound of formula (I) is of formula I-4 【Chemistry 14】 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt or stereoisomer thereof.

39. A is, 【Chemistry 15】 and the compound of formula (I) is of formula I-5 【Chemistry 16】 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt or stereoisomer thereof.

40. A is, 【Chemistry 17】 and the compound of formula (I) is of formula I-6 【Chemistry 18】 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt or stereoisomer thereof.

41. R ５ 41. The compound of claim 40, wherein is methyl.

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

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

44. X ５ 41. The compound of claim 40, wherein is absent.

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

46. R １０ and R １１ are H and R １０ ' and R １１ 46. The compound of claim 45, wherein ' together with the carbon atom to which they are attached form a cyclobutyl.

47. R １２ 41. The compound of claim 40, wherein is OH.

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

49. R １２ 49. The compound of claim 48, wherein is H.

50. Formula I-6a or I-6b 【Chemistry 19】 41. The compound of claim 40, having the structure: or a pharmaceutically acceptable salt or stereoisomer thereof.

51. The following structure: 【Chemistry 20】 【Chemical 21】 【Chemical 22】 【Chemical 23】 【Chemistry 24】 【Chemistry 25】 2. The compound of claim 1, wherein:

52. 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. 52. A method for treating a disease or disorder associated with 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 to 51 or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of claim 52.

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

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

56. 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 lymphoblastic leukemia / lymphoma (ALL), or cutaneous T-cell lymphoma.

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

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

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

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

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

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