Alkylamine-containing small molecule degraders of BCL6

Abstract

Compounds, compositions and methods for treating diseases or disorders characterized by aberrant B-cell lymphoma 6 (BCL6) activity are disclosed.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 416,736, filed October 17, 2022, which is incorporated herein 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 nascent substrates, 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 CRL4-DNA damage-binding protein 1 (DDB1) and CUL4-associated factor 15 (DCAF15) (CRL4 DCAF15 These include arylsulfonamides that promote the destruction of RNA-binding motif protein 39 (RBM39) in a ATP-dependent manner (Han et al., Science 356:eaal3755 (2017)).

[0003] Other types of small molecules include heterobifunctional degradation agents (also known as PROTACs) (Toure et al., Angew. Chem. Int. Ed. Engl. 55:1966-1973 (2016)), which have been developed for a wide range of targets, including kinases (Huang et al., Cell Chem. Biol. 25:88-99 (2018)), nuclear receptors (Bondeson et al., Nat. Chem. Biol. 11:611-617 (2015)), and epigenetic enzymes (Winter et al., Science 348:1376-1381 (2015)). These small molecule degraders 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 can demonstrate remarkable efficacy and sustained target depletion, some putative target 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 suppresses 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 lymphoma 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 family of proteins 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 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 are useful for combating BCL6-related diseases. Summary of the Invention [Means for solving the problem]

[0010] A first aspect of the present invention is a compound of formula (I): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, During the ceremony: X is CH2, S, CHF, CHCl, CHOH, or CF2; R1 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SON(R9)2, -N(R9)C(O)R9, -N(R9)SO2R9, -N(R9)C(O)N(R9)2, -P(O)(R9)2, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) hydroxyalkyl, (C3-C7) carbocyclyl, 4- to 7-membered heterocyclyl, (C6-C 10 ) aryl, monocyclic or bicyclic 5-10 membered heteroaryl, (C2-C6) alkenyl, or (C2-C6) alkynyl; said alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be selected from the group consisting of one or more identical or different R 10 may be further substituted by groups; Each R9 is independently selected from hydrogen, (C1-C6) alkyl, (C3-C7) carbocyclyl, 4- to 7-membered heterocyclyl, (C6-C 10 ) aryl, or monocyclic or bicyclic 5-10 membered heteroaryl; said alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl may be one or more of the same or different R 10 may be further substituted by groups; Each R 10are independently alkyl, alkenyl, alkynyl, halo, haloalkyl, carbocyclyl, heterocyclyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkylenyloxy, alkynyloxy, amino, alkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, aralkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-aralkylamino, hydroxyalkyl, aminoalkyl, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, N-alkyl-N-arylaminosulfonyl, N- alkyl-N-heteroarylaminosulfonyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylsulfonylamino, haloalkylsulfonylamino, cycloalkylsulfonylamino, heterocycloalkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, N-alkyl-N-heteroarylaminocarbonyl, cyano, nitro, azido, or phosphinyl; R2 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SON(R9)2, -N(R9)C(O)R9, -N(R9)SO2R9, -N(R9)C(O)N(R9)2, -P(O)(R9)2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl, (C6-C 10 ) aryl, monocyclic or bicyclic 5-10 membered heteroaryl, (C2-C6) alkenyl, or (C2-C6) alkynyl; said alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be selected from the group consisting of one or more of the same or different R 10 may be further substituted by a group, or R and R, together with the same carbon atom to which they are attached, are a spiro(C-C)carbocyclyl group or a 4- to 7-membered heterocyclyl group; said carbocyclyl or heterocyclyl may be one or more of the same or different R 10 may be further substituted by groups; R3 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SON(R9)2, -N(R9)C(O)R9, -N(R9)SO2R9, -N(R9)C(O)N(R9)2, -P(O)(R9)2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl, (C6-C 10 ) aryl, monocyclic or bicyclic 5-10 membered heteroaryl, (C2-C6) alkenyl, or (C2-C6) alkynyl; said alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be selected from the group consisting of one or more identical or different R 10 may be further substituted by groups; R4 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SON(R9)2, -N(R9)C(O)R9, -N(R9)SO2R9, -N(R9)C(O)N(R9)2, -P(O)(R9)2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl, (C6-C 10 ) aryl, monocyclic or bicyclic 5-10 membered heteroaryl, (C2-C6) alkenyl, or (C2-C6) alkynyl; said alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be selected from the group consisting of one or more of the same or different R 10 may be further substituted by groups; R5 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SON(R9)2, -N(R9)C(O)R9, -N(R9)SO2R9, -N(R9)C(O)N(R9)2, -P(O)(R9)2, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) hydroxyalkyl, (C3-C7) carbocyclyl, 4- to 7-membered heterocyclyl, (C6-C 10 ) aryl, monocyclic or bicyclic 5-10 membered heteroaryl, (C2-C6) alkenyl, or (C2-C6) alkynyl; said alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be selected from the group consisting of one or more identical or different R 10 may be further substituted by groups; R6 is absent, (C1-C6) alkylene, or (C3-C7) carbocyclyl; said alkylene or carbocyclyl may be joined by one or more of the same or different R 10 may be further substituted by a group, or R5 and R6, together with the same carbon atom to which they are attached, are a spiro(C3-C7)carbocyclyl group or a 4- to 7-membered heterocyclyl group; said carbocyclyl or heterocyclyl may be one or more of the same or different R 10 may be further substituted by a group, or R6 is (C2-C4) alkylene, which combines with R7 to form a 4- to 6-membered heterocyclyl group; R7 and R8 are each independently hydrogen, (C1-C6) alkyl, (C3-C7) carbocyclyl, 4- to 7-membered heterocyclyl, (C6-C 10 ) aryl, or monocyclic or bicyclic 5-10 membered heteroaryl; said alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl may be one or more of the same or different R 10 may be further substituted by a group, or R7 and R8 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclyl, said heterocyclyl being comprised of one or more of the same or different R 10 may be further substituted by groups; [ka] teeth [ka] and; X1 and X2 are independent of each other. 17 or N; R 17 is hydrogen, (C1-C4)alkyl, halo, hydroxy, amino, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C2-C4)alkenyl, (C2-C4)alkynyl, nitro, cyano, NH(C1-C4)alkyl, or N(C1-C4alkyl); X3 is CH or N; X4 is CR 17 or N; R 17 is hydrogen, fluorine, chloro, or methyl; R 11 is Cl or CN; R 12is hydrogen, (C-C)alkyl, (C-C)carbocyclyl, 4- to 7-membered heterocyclyl, (C-C)carbocyclyl(C-C)alkyl, or 4- to 7-membered heterocyclyl(C-C)alkyl; said alkyl, carbocyclyl, or heterocyclyl may be further substituted by one or more identical or different groups selected from (C-C)alkyl, (C-C)alkoxy, halo, amino, hydroxyl, haloalkyl, NH(C-C)alkyl, N((C-C)alkyl), (C-C)carbocyclyl, and 4- to 7-membered heterocyclyl; or R 12 is -LYZ or -LYZ; L is absent or (C1-C5) alkylene optionally substituted by one or more substituents selected from (C1-C2) alkyl and oxo; Y 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 hydrogen or (C1-C4) alkyl; Z is hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C 10 ) carbocyclyl, or 3- to 10-membered heterocyclyl; where Z is (C1-C4) alkyl, halo, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, amino, (C1-C4) aminoalkyl, cyano, hydroxy, 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 t are each independently hydrogen, (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, amino, cyano and hydroxy; R 13 is hydrogen, methyl, -(CH2) 1-3 W1W2, or [ka] and; W1 is CR 18 R 18 or C(O); R 18 and R 18’ are independently hydrogen, (C-C)alkyl, fluoro, hydroxy, cyano, nitro, (C-C)alkoxy, (C-C)haloalkyl, (C-C)haloalkoxy, amino, NH(C-C)alkyl, or N(C-Calkyl), or R 18 and R 18’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, amino, cyano and hydroxy; W2 is cyano, hydroxy, 5- or 6-membered heteroaryl, phenyl, C(O)-(C1-C2)alkyl, S(O)2-(C1-C2)alkyl, C(O)OCH3, C(O)NHCH3, CR 19 R 20 R 21 , amino, NH(C1-C2) alkyl, or N(C1-C2 alkyl)2; R 19 is hydrogen, (C1-C2)alkyl, fluoro, chloro, bromo, hydroxy, amino, cyano, nitro, (C1-C2)alkoxy, (C1-C2)haloalkyl, or (C1-C2)haloalkoxy; R 20 is hydrogen, (C1-C2)alkyl, fluoro, chloro, bromo, hydroxy, cyano, nitro, (C1-C2)alkoxy, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, or -Y2-L2-Z2; 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 hydrogen, (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, amino, cyano, hydroxy, C(O)R', C(O)OR', OC(O)R', C(O)NR'R', and N(R')C(O)R', where each R' is independently hydrogen or (C1-C4)alkyl; Or, R 19 and R 20 together with the carbon atoms to which they are attached form a (C3-C6)carbocyclyl or a 3- to 6-membered heterocyclyl optionally substituted by one or more substituents selected from (C1-C2)alkyl, halo, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, (C1-C2)alkoxy, (C1-C2)alkylamino, amino, cyano and hydroxy; R 21 is (C1-C2)alkyl, —C(O)OR″, OR″, —C(O)NR″, NR″R″, phenyl, or 5-membered heteroaryl, where each R″ is independently hydrogen or (C1-C2)alkyl; A'' is (C4-C6)carbocyclyl or 4- to 6-membered heterocyclyl optionally substituted by one or more substituents independently selected from (C1-C2)alkyl, halo, hydroxy, cyano, and (C1-C2)alkoxy; W3 is NR 22 or CR 23 R 23 and; R 22 is hydrogen, (C1-C2)alkyl, (C1-C4)haloalkyl, (C1-C4)hydroxyalkyl, —C(O)CH3, or —C(O)O—(C1-C4)alkyl; R 23 and R 23’are independently hydrogen, (C1-C2)alkyl, cyclopropyl, fluoro, chloro, bromo, hydroxy, amino, cyano, nitro, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, (C1-C2)alkoxy, —C(O)OR″, NR″R″, phenyl, or 5-membered heteroaryl; R 14 -L3CR 24 R 25 R 26 , or -CH=CH-R 26 and; L3 is absent, O, S, (C1-C4)alkylene, -O-(C1-C4)alkylene, or -S-(C1-C4)alkylene; R 24 is hydrogen or (C1-C4) alkyl; R 25 is hydrogen or (C1-C4) alkyl, or R 24 and R 25 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 26 is (C1-C6) alkyl, -NR 27 R 28 , -OR 27 , -C(O)R 27 , -C(O)OR 27 , -N(R 28 )C(O)R 27 , -C(O)NR 27 R 28 , -S(O)-(C1-C6)alkyl, -S(O)2-(C1-C6)alkyl, -P(O)-(C1-C6alkyl)2, -C(NH)NH2, or -(C1-C4)alkyl-NR 28 C(O)R 27 and; R 27is hydrogen, a 3- to 6-membered heterocyclyl, or (C1-C4)alkyl optionally substituted by 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 28 is hydrogen or (C1-C4) alkyl; R 15 is hydrogen, (C1-C4)alkyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, or cyano, wherein said alkyl or cycloalkyl is optionally substituted by one or more substituents selected from (C1-C4)alkyl, (C3-C6)cycloalkyl, hydroxy, (C1-C2)alkoxy, amino, NH(C1-C2)alkyl, N((C1-C2)alkyl), (C1-C2)aminoalkyl, and halo; R 15 ' is hydrogen, (C1-C4)alkyl, cyano, (C1-C4)haloalkyl, or -Y3-L4-Z3; Y3 is absent, C(O)O or C(O)N(R'); L4 is absent or (C1-C2) alkylene; Z3 is hydrogen, (C1-C6)alkyl, phenyl, (C3-C6)cycloalkyl, or 4- to 6-membered heterocyclyl, where Z3 is optionally substituted by one or more substituents independently selected from (C1-C2)alkyl, halo, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, (C1-C2)alkoxy, amino, nitro, cyano, and hydroxy; or R 15 and R 15 ' 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, and R 15 and R 15' 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, amino, cyano, and hydroxy; R 16 is hydrogen, (C1-C2) alkyl, (C3-C4) cycloalkyl, (C1-C2) haloalkyl, cyano, (C2-C4) alkenyl, or (C2-C4) alkynyl; R 16 ' is (C1-C4)alkyl, cyano, (C1-C4)haloalkyl, or -Y4-L5-Z4; Y4 is absent, C(O), C(O)O, OC(O), C(O)N(R'), or S(O)N(R'); L5 is absent or (C1-C2) alkylene optionally substituted by one or more substituents selected from (C1-C2) alkyl and oxo; Z4 is hydrogen, (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, amino, nitro, cyano, hydroxy, 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 wherein each R u are independently hydrogen, (C1-C4) alkyl, or (C3-C6) cycloalkyl; or Z4 is -Q-L6-W, where Q is absent, O, NH, or N(C1-C2)alkyl; L6 is absent or (C1-C2) alkylene optionally substituted by one or more substituents selected from oxo and (C1-C2) alkyl; W is (C-C)alkyl, phenyl, (C-C)cycloalkyl, (C-C)cycloalkenyl, or 5- or 6-membered heterocyclyl, where W is optionally substituted by one or more substituents independently selected from (C-C)alkyl, halo, (C-C)haloalkyl, (C-C)haloalkoxy, (C-C)alkoxy, (C-C)alkylamino, amino, nitro, cyano, or hydroxy; or R 16 and R 16 ', together with the carbon atoms to which they are attached, are optionally 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, amino, nitro, cyano, or hydroxy (C3-C 10 ) carbocyclyl or 4- to 10-membered heterocyclyl; or (C3-C 10 ) the carbocyclyl or 4- to 10-membered heterocyclyl may be fused to a 5- or 6-membered heteroaryl or phenyl ring, and the 5- or 6-membered heteroaryl or phenyl ring may be optionally substituted by (C1-C2) alkyl, halo, (C1-C2) haloalkyl, (C1-C2) haloalkoxy, (C1-C2) alkoxy, (C1-C2) alkylamino, amino, nitro, cyano, or hydroxy; and R 16" is hydrogen, (C1-C4) alkyl, (C1-C2) haloalkyl, (C1-C2) alkoxy, (C1-C2) haloalkoxy, cyano, nitro, acetylenyl, phenyl, or 5- or 6-membered heteroaryl, wherein said alkyl, phenyl, or heteroaryl is optionally substituted with one or more substituents independently selected from halo, hydroxy, and amino; provided that when R7 is (C1-C3) alkyl and R8 is (C1-C3) alkyl, then R6 is not (C1-C6) alkylene; and however, [ka] but [ka] and R 11 is Cl, X is CH or CF, and R is absent or an optionally substituted (C-C) alkylene, then R and R cannot a) independently be hydrogen or a (C-C) alkyl optionally substituted with an oxo group, or b) R and R cannot, together with the nitrogen atom to which they are attached, form a 4-membered heterocyclyl optionally substituted with a gem-difluoro group.

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

[0012] A further aspect of the present invention is directed to a method of treating a disease or disorder characterized by or mediated by aberrant 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.

[0013] In some embodiments, the disease or disorder 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. In some embodiments, the disease or disorder is cancer. 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 the invention.

[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 that is 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. 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 certain materials or steps "and those that do not materially affect the basic and novel characteristics" of the claimed invention.

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

[0019] As used herein, the term "alkyl" refers to a saturated straight-chain or branched-chain monovalent hydrocarbon radical. In some embodiments, the alkyl radical is a C1-C6 group. In some embodiments, unless otherwise disclosed for 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 (where 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 or to a radical group through a single bond. In some embodiments, unless otherwise disclosed for one or more groups of a compound 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 (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, or alternatively, "E" and "Z" orientations. In some embodiments, an alkenyl radical is a C2-C 15 In some embodiments, unless otherwise disclosed for one or more groups of the compound 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 radical 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 one or more groups of the compound 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, which is 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, such as 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 (e.g., an alkcarbocyclic group), alone or as part of a larger moiety. 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-C4). 10In 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 11 Representative examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and phenyl; bicyclic carbocyclyls having 7 to 11 ring atoms include [4,3], [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, naphthalene, and bicyclo[3.2.2]nonane. Representative examples of spirocarbocyclyl 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, bicyclic, or spirocarbocycles). The term carbocyclic group also includes carbocyclic rings 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 carbocyclic ring.

[0027] Thus, the term carbocyclic, as used herein, refers to a group of the formula —R c -carbocyclyl (wherein R c is an alkylene chain). The term carbocyclic, as used herein, also includes carbocyclylalkyl groups, which refer to groups of the formula --O--R c -carbocyclyl (wherein Rc is an alkylene chain).

[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. In some embodiments, the aralkyl group is an optionally substituted benzyl group. The term aryl, as used herein, refers to a group of the formula --OR. c --Aryl (R c also includes aralkoxy groups, which refers to groups attached through an oxygen atom of a alkylene chain such as methylene or ethylene.

[0030] As used herein, the term "heterocyclyl," used alone or as part of a larger moiety, refers to a "carbocyclyl" containing a saturated, partially unsaturated, or aromatic ring system 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, and combinations thereof. In some embodiments, heterocyclyl refers to a 3- to 12-membered heterocyclyl ring system. In some embodiments, heterocyclyl refers to a saturated ring system, such as a 3- to 12-membered saturated heterocyclyl ring system. In some embodiments, heterocyclyl refers to a 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, oxazinyl, and the like. nyl, 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, pyrimidine Azalidinyl, dithianyl, dithiolanyl, pyrimidinonyl, 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]heptanyl, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azaspiro[4.5]decan-2-one, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, and 1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclyls containing a sulfur or oxygen atom 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 benzo-fused 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 are 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 heterocyclic 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 heterocyclic ring, and in some embodiments, the point of attachment is at a heteroatom contained in the heterocyclic ring.

[0032] Thus, the term heterocyclic includes N-heterocyclyl groups, which as used herein refer to heterocyclyl groups containing at least one nitrogen atom, where the point of attachment of the heterocyclyl group to the rest of the molecule is 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 heterocyclic also includes C-heterocyclyl groups, which as used herein refer to heterocyclyl groups containing at least one heteroatom, where the point of attachment of the heterocyclyl group to the rest of the molecule is 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 heterocyclic also refers to groups of the formula --R, as disclosed above. c -heterocyclyl (wherein R c is an alkylene chain). The term "heterocyclic" as used herein also includes heterocyclylalkyl groups, which means groups where R c is an alkylene chain of the formula --O--R c -heterocyclylalkoxy, which means a group attached via an 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. Examples of heteroaryl include aryl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indolyl, 1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl, and 1,2,3-triazol-5-yl. The term "heteroaryl" also includes groups in which the heteroaryl is fused to one or more cyclic (e.g., carbocyclyl, or heterocyclyl) rings, where 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 encompasses N-heteroaryl groups, which as used herein refer to heteroaryl groups as defined above containing at least one nitrogen, where the point of attachment of the heteroaryl group to the rest of the molecule is through a nitrogen atom in the heteroaryl group. The term heteroaryl, 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 rest of the molecule is through a carbon atom in the heteroaryl group. The term heteroaryl, as disclosed above, refers to groups of the formula -R c Also included are heteroarylalkyl groups, which refer to the group -heteroaryl, where R c is an alkylene chain as defined above. The term heteroaryl, as used herein, also includes heteroaralkoxy groups of the formula --O--R c - refers to a group attached through an oxygen atom of a heteroaryl, where R c is an alkylene group as defined above.

[0035] Unless otherwise specified, 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., substituted 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 rings (e.g., substituted C3-C 12 , C5-C6), heterocycle (e.g., 3- to 12-membered, 5- to 6-membered), substituted heterocycle (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, carbamate, substituted carbamate, amino acid, and peptide groups.

[0036] In one aspect, the compound of the present invention has formula (I): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, During the ceremony: X is CH2, S, CHF, CHCl, CHOH, or CF2; R1 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SON(R9)2, -N(R9)C(O)R9, -N(R9)SO2R9, -N(R9)C(O)N(R9)2, -P(O)(R9)2, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) hydroxyalkyl, (C3-C7) carbocyclyl, 4- to 7-membered heterocyclyl, (C6-C 10 ) aryl, monocyclic or bicyclic 5-10 membered heteroaryl, (C2-C6) alkenyl, or (C2-C6) alkynyl; said alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be selected from the group consisting of one or more identical or different R 10 may be further substituted by groups; Each R9 is independently selected from hydrogen, (C1-C6) alkyl, (C3-C7) carbocyclyl, 4- to 7-membered heterocyclyl, (C6-C 10 ) aryl, or monocyclic or bicyclic 5-10 membered heteroaryl; said alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl may be one or more of the same or different R 10 may be further substituted by groups; Each R 10are independently alkyl, alkenyl, alkynyl, halo, haloalkyl, carbocyclyl, heterocyclyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkylenyloxy, alkynyloxy, amino, alkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, aralkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-aralkylamino, hydroxyalkyl, aminoalkyl, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, N-alkyl-N-arylaminosulfonyl, N- alkyl-N-heteroarylaminosulfonyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylsulfonylamino, haloalkylsulfonylamino, cycloalkylsulfonylamino, heterocycloalkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, N-alkyl-N-heteroarylaminocarbonyl, cyano, nitro, azido, or phosphinyl; R2 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SON(R9)2, -N(R9)C(O)R9, -N(R9)SO2R9, -N(R9)C(O)N(R9)2, -P(O)(R9)2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl, (C6-C 10 ) aryl, monocyclic or bicyclic 5-10 membered heteroaryl, (C2-C6) alkenyl, or (C2-C6) alkynyl; said alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be selected from the group consisting of one or more of the same or different R 10 may be further substituted by a group, or R and R, together with the same carbon atom to which they are attached, are a spiro(C-C)carbocyclyl group or a 4- to 7-membered heterocyclyl group; said carbocyclyl or heterocyclyl may be one or more of the same or different R 10 may be further substituted by groups; R3 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SON(R9)2, -N(R9)C(O)R9, -N(R9)SO2R9, -N(R9)C(O)N(R9)2, -P(O)(R9)2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl, (C6-C 10 ) aryl, monocyclic or bicyclic 5-10 membered heteroaryl, (C2-C6) alkenyl, or (C2-C6) alkynyl; wherein said alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be selected from the group consisting of one or more of the same or different R 10 may be further substituted by groups; R4 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SON(R9)2, -N(R9)C(O)R9, -N(R9)SO2R9, -N(R9)C(O)N(R9)2, -P(O)(R9)2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl, (C6-C 10 ) aryl, monocyclic or bicyclic 5-10 membered heteroaryl, (C2-C6) alkenyl, or (C2-C6) alkynyl; said alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be selected from the group consisting of one or more of the same or different R 10 may be further substituted by groups; R5 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SON(R9)2, -N(R9)C(O)R9, -N(R9)SO2R9, -N(R9)C(O)N(R9)2, -P(O)(R9)2, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) hydroxyalkyl, (C3-C7) carbocyclyl, 4- to 7-membered heterocyclyl, (C6-C 10 ) aryl, monocyclic or bicyclic 5-10 membered heteroaryl, (C2-C6) alkenyl, or (C2-C6) alkynyl; said alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be selected from the group consisting of one or more of the same or different R 10 may be further substituted by groups; R6 is absent, (C1-C6) alkylene, or (C3-C7) carbocyclyl; said alkylene or carbocyclyl may be joined by one or more of the same or different R 10 may be further substituted by a group, or R5 and R6, together with the same carbon atom to which they are attached, are a spiro(C3-C7)carbocyclyl group or a 4- to 7-membered heterocyclyl group; said carbocyclyl or heterocyclyl may be one or more of the same or different R 10 may be further substituted by a group, or R6 is (C2-C4) alkylene, which combines with R7 to form a 4- to 6-membered heterocyclyl group; R7 and R8 are each independently hydrogen, (C1-C6) alkyl, (C3-C7) carbocyclyl, 4- to 7-membered heterocyclyl, (C6-C 10 ) aryl, or monocyclic or bicyclic 5-10 membered heteroaryl; said alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl may be one or more of the same or different R 10 may be further substituted by a group, or R7 and R8 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclyl, said heterocyclyl being comprised of one or more of the same or different R 10 may be further substituted by groups; [ka] teeth [ka] and; X1 and X2 are independent of each other. 17 or N; R 17 is hydrogen, (C1-C4)alkyl, halo, hydroxy, amino, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C2-C4)alkenyl, (C2-C4)alkynyl, nitro, cyano, NH(C1-C4)alkyl, or N(C1-C4alkyl); X3 is CH or N; X4 is CR 17 or N; and R 17 is hydrogen, fluorine, chloro, or methyl; R 11 is Cl or CN; R 12is hydrogen, (C-C)alkyl, (C-C)carbocyclyl, 4- to 7-membered heterocyclyl, (C-C)carbocyclyl(C-C)alkyl, or 4- to 7-membered heterocyclyl(C-C)alkyl; said alkyl, carbocyclyl, or heterocyclyl is optionally further substituted by one or more identical or different groups selected from (C-C)alkyl, (C-C)alkoxy, halo, amino, hydroxyl, haloalkyl, NH(C-C)alkyl, N((C-C)alkyl), (C-C)carbocyclyl, and 4- to 7-membered heterocyclyl; or R 12 is -LYZ; L is absent or (C1-C5) alkylene optionally substituted by one or more substituents selected from (C1-C2) alkyl and oxo; Y 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 hydrogen or (C1-C4) alkyl; Z is hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C 10 ) carbocyclyl, or 3- to 10-membered heterocyclyl; where Z is (C1-C4) alkyl, halo, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, amino, (C1-C4) aminoalkyl, cyano, hydroxy, 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 Rr , 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 hydrogen, (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, amino, cyano and hydroxy; R 13 is hydrogen, methyl, -(CH2) 1-3 W1W2, or [ka] and; W1 is CR 18 R 18’ or C(O); R 18 and R 18’ are independently hydrogen, (C-C)alkyl, fluoro, hydroxy, cyano, nitro, (C-C)alkoxy, (C-C)haloalkyl, (C-C)haloalkoxy, amino, NH(C-C)alkyl, or N(C-Calkyl), or R 18 and R 18’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, amino, cyano and hydroxy; W2 is cyano, hydroxy, 5- or 6-membered heteroaryl, phenyl, C(O)-(C1-C2)alkyl, S(O)2-(C1-C2)alkyl, C(O)OCH3, C(O)NHCH3, CR 19 R 20 R 21 , amino, NH(C1-C2) alkyl, or N(C1-C2 alkyl)2; R 19 is hydrogen, (C1-C2)alkyl, fluoro, chloro, bromo, hydroxy, amino, cyano, nitro, (C1-C2)alkoxy, (C1-C2)haloalkyl, or (C1-C2)haloalkoxy; R 20 is hydrogen, (C1-C2)alkyl, fluoro, chloro, bromo, hydroxy, cyano, nitro, (C1-C2)alkoxy, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, or -Y2-L2-Z2; 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 hydrogen, (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, amino, cyano, hydroxy, C(O)R', C(O)OR', OC(O)R', C(O)NR'R', and N(R')C(O)R', where each R' is independently hydrogen or (C1-C4)alkyl; Or, R 19 and R 20 together with the carbon atoms to which they are attached form a (C3-C6)carbocyclyl or a 3- to 6-membered heterocyclyl optionally substituted by one or more substituents selected from (C1-C2)alkyl, halo, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, (C1-C2)alkoxy, (C1-C2)alkylamino, amino, cyano and hydroxy; R 21 is (C1-C2)alkyl, —C(O)OR″, OR″, —C(O)NR″, NR″R″, phenyl, or 5-membered heteroaryl, where each R″ is independently hydrogen or (C1-C2)alkyl; A'' is (C4-C6)carbocyclyl or 4- to 6-membered heterocyclyl optionally substituted by one or more substituents independently selected from (C1-C2)alkyl, halo, hydroxy, cyano, and (C1-C2)alkoxy; W3 is NR 22 or CR 23 R 23 and; R 22 is hydrogen, (C1-C2)alkyl, (C1-C4)haloalkyl, (C1-C4)hydroxyalkyl, —C(O)CH3, or —C(O)O—(C1-C4)alkyl; R 23 and R 23’are independently hydrogen, (C1-C2)alkyl, cyclopropyl, fluoro, chloro, bromo, hydroxy, amino, cyano, nitro, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, (C1-C2)alkoxy, —C(O)OR″, NR″R″, phenyl, or 5-membered heteroaryl; R 14 -L3CR 24 R 25 R 26 , or -CH=CH-R 26 and; L3 is absent, O, S, (C1-C4)alkylene, -O-(C1-C4)alkylene, or -S-(C1-C4)alkylene; R 24 is hydrogen or (C1-C4) alkyl; R 25 is hydrogen or (C1-C4) alkyl, or R 24 and R 25 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 26 is (C1-C6) alkyl, -NR 27 R 28 , -OR 27 , -C(O)R 27 , -C(O)OR 27 , -N(R 28 )C(O)R 27 , -C(O)NR 27 R 28 , -S(O)-(C1-C6)alkyl, -S(O)2-(C1-C6)alkyl, -P(O)-(C1-C6alkyl)2, -C(NH)NH2, or -(C1-C4)alkylNR 28 C(O)R 27 and; R 27is hydrogen, a 3- to 6-membered heterocyclyl, or (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 28 is hydrogen or (C1-C4) alkyl; R 15 is hydrogen, (C1-C4)alkyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, or cyano, wherein said alkyl or cycloalkyl is optionally substituted by one or more substituents selected from (C1-C4)alkyl, (C3-C6)cycloalkyl, hydroxy, (C1-C2)alkoxy, amino, NH(C1-C2)alkyl, N((C1-C2)alkyl), (C1-C2)aminoalkyl, and halo; R 15 ' is hydrogen, (C1-C4)alkyl, cyano, (C1-C4)haloalkyl, or -Y3-L4-Z3; Y3 is absent, C(O)O or C(O)N(R'); L4 is absent or (C1-C2) alkylene; Z3 is hydrogen, (C1-C6)alkyl, phenyl, (C3-C6)cycloalkyl, or 4- to 6-membered heterocyclyl, where Z3 is optionally substituted by one or more substituents independently selected from (C1-C2)alkyl, halo, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, (C1-C2)alkoxy, amino, nitro, cyano, and hydroxy; or R 15 and R 15 ' 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, and R 15 and R 15', 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, amino, cyano, and hydroxy; R 16 is hydrogen, (C1-C2) alkyl, (C3-C4) cycloalkyl, (C1-C2) haloalkyl, cyano, (C2-C4) alkenyl, or (C2-C4) alkynyl; R 16 ' is (C1-C4)alkyl, cyano, (C1-C4)haloalkyl, or -Y4-L5-Z4; Y4 is absent, C(O), C(O)O, OC(O), C(O)N(R'), or S(O)N(R'); L5 is absent or (C1-C2) alkylene optionally substituted by one or more substituents selected from (C1-C2) alkyl and oxo; Z4 is hydrogen, (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, amino, nitro, cyano, hydroxy, 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 wherein each R u are independently hydrogen, (C1-C4) alkyl, or (C3-C6) cycloalkyl; or Z4 is -Q-L6-W, where Q is absent, O, NH, or N(C1-C2)alkyl; L6 is absent or (C1-C2) alkylene optionally substituted by one or more substituents selected from oxo and (C1-C2) alkyl; W is (C-C)alkyl, phenyl, (C-C)cycloalkyl, (C-C)cycloalkenyl, or 5- or 6-membered heterocyclyl, where W is optionally substituted by one or more substituents independently selected from (C-C)alkyl, halo, (C-C)haloalkyl, (C-C)haloalkoxy, (C-C)alkoxy, (C-C)alkylamino, amino, nitro, cyano, or hydroxy; or R 16 and R 16 ', together with the carbon atoms to which they are attached, are optionally 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, amino, nitro, cyano, or hydroxy (C3-C 10 ) carbocyclyl or 4- to 10-membered heterocyclyl; or (C3-C 10 ) the carbocyclyl or 4- to 10-membered heterocyclyl may be fused to a 5- or 6-membered heteroaryl or phenyl ring, and the 5- or 6-membered heteroaryl or phenyl ring may be optionally substituted by (C1-C2) alkyl, halo, (C1-C2) haloalkyl, (C1-C2) haloalkoxy, (C1-C2) alkoxy, (C1-C2) alkylamino, amino, nitro, cyano, or hydroxy; and R 16" is hydrogen, (C1-C4) alkyl, (C1-C2) haloalkyl, (C1-C2) alkoxy, (C1-C2) haloalkoxy, cyano, nitro, acetylenyl, phenyl, or 5- or 6-membered heteroaryl, wherein said alkyl, phenyl, or heteroaryl is optionally substituted with one or more substituents independently selected from halo, hydroxy, and amino; provided that when R7 is (C1-C3) alkyl and R8 is (C1-C3) alkyl, then R6 is not (C1-C6) alkylene; and however [ka] but [ka] and R 11 is Cl, X is CH or CF, and R is absent or an optionally substituted (C-C) alkylene, then R and R cannot a) independently be hydrogen or a (C-C) alkyl optionally substituted with an oxo group, or b) R and R cannot, together with the nitrogen atom to which they are attached, form a 4-membered heterocyclyl optionally substituted with a gem-difluoro group.

[0037] In some embodiments, L and Y are absent and Z is methyl.

[0038] In some embodiments, R 11 is Cl.

[0039] In some embodiments, R 11 is CN.

[0040] In some embodiments, R1 is hydrogen, -OR9, or (C1-C6) alkyl.

[0041] In some embodiments, R1 is hydrogen, methyl, or -OH.

[0042] In some embodiments, R1 is hydrogen.

[0043] In some embodiments, R1 is methyl.

[0044] In some embodiments, R2 is hydrogen, -OR9, or (C1-C6) alkyl.

[0045] In some embodiments, R2 is hydrogen, methyl, or -OH.

[0046] In some embodiments, R2 is hydrogen.

[0047] In some embodiments, R2 is methyl.

[0048] In some embodiments, R1 and R2 together with the same carbon atom to which they are attached form a spiro(C3-C7)carbocyclyl group.

[0049] In some embodiments, R1 and R2 together with the same carbon atom to which they are attached form a spiro(C3)carbocyclyl.

[0050] In some embodiments, R3 is hydrogen.

[0051] In some embodiments, R4 is hydrogen.

[0052] In some embodiments, R5 is hydrogen, -OR9, or (C1-C6) alkyl.

[0053] In some embodiments, R5 is hydrogen, methyl, or -OH.

[0054] In some embodiments, R5 is hydrogen.

[0055] In some embodiments, R5 is methyl.

[0056] In some embodiments, R6 is absent.

[0057] In some embodiments, R6 is (C1-C6) alkyl or (C3-C7) carbocyclyl.

[0058] In some embodiments, R6 is (C1-C2) alkyl or (C3-C4) carbocyclyl.

[0059] In some embodiments, R6 is C1-alkylene. In some embodiments, R6 is C2-alkylene. In some embodiments, R6 is one or more of the same or different R 10 In some embodiments, R is a C-alkylene substituted with one or more of the same or different R 10 In some embodiments, each R 10 is independently methyl, fluoro, or cyclopropyl.

[0060] In some embodiments, R6 is C3-carbocyclyl. In some embodiments, R6 is C4-carbocyclyl.

[0061] In some embodiments, R5 and R6 together with the same carbon atom to which they are attached form a spiro(C3-C7)carbocyclyl group.

[0062] In some embodiments, R5 and R6 together with the same carbon atom to which they are attached form a spiro(C3)carbocyclyl.

[0063] In some embodiments, R6 is (C2-C4) alkylene, which is joined to R7 to form a 4-6 membered heterocyclyl group.

[0064] In some embodiments, R6 is (C2-C3) alkylene, which is joined to R7 to form a 4-membered heterocyclyl group.

[0065] In some embodiments, R7 is hydrogen or (C1-C6) alkyl.

[0066] In some embodiments, R7 is hydrogen or methyl.

[0067] In some embodiments, R8 is hydrogen or (C1-C6) alkyl.

[0068] In some embodiments, R8 is hydrogen or methyl.

[0069] In some embodiments, R7 and R8 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclyl.

[0070] In some embodiments, R7 and R8 together with the nitrogen atom to which they are attached form a 4-membered heterocyclyl.

[0071] In some embodiments, X is CH2.

[0072] In some embodiments, X is S.

[0073] In some embodiments, X is CHF.

[0074] In some embodiments, X is CHCl.

[0075] In some embodiments, X is CHOH.

[0076] In some embodiments, X is CF2.

[0077] In some embodiments [ka] teeth [ka] and the compound of formula (I) is represented by formula I-1 [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0078] In some embodiments of Formula I-1, X1 is N. In some embodiments of Formula I-1, X1 is CR 17 In some embodiments of Formula I-1, X1 is CH.

[0079] In some embodiments of Formula I-1, X2 is N. In some embodiments of Formula I-1, X2 is CR 17 In some embodiments of Formula I-1, X2 is CH.

[0080] In some embodiments of Formula I-1, X 1 and X 2 are both CH.

[0081] In some embodiments of Formula I-1, X is CH2.

[0082] In some embodiments of Formula I-1, X is CHF.

[0083] In some embodiments of Formula I-1, X is CF2.

[0084] In some embodiments of Formula I-1, R1 is hydrogen, -OR9, or (C1-C6) alkyl.

[0085] In some embodiments of Formula I-1, R 1 is hydrogen, methyl, or —OH.

[0086] In some embodiments of Formula I-1, R 1 is hydrogen.

[0087] In some embodiments of Formula I-1, R 1 is methyl.

[0088] In some embodiments of Formula I-1, R2 is hydrogen, -OR9, or (C1-C6) alkyl.

[0089] In some embodiments of Formula I-1, R2 is hydrogen, methyl, or -OH.

[0090] In some embodiments of Formula I-1, R2 is hydrogen.

[0091] In some embodiments of Formula I-1, R2 is methyl.

[0092] In some embodiments of Formula I-1, R 1 and R 2 together with the same carbon atom to which they are attached form a spiro(C 3 -C 7 )carbocyclyl group.

[0093] In some embodiments of Formula I-1, R 1 and R 2 together with the same carbon atom to which they are attached form a spiro(C 3 )carbocyclyl.

[0094] In some embodiments of Formula I-1, R3 is hydrogen.

[0095] In some embodiments of Formula I-1, R4 is hydrogen.

[0096] In some embodiments of Formula I-1, R5 is hydrogen, -OR9, or (C1-C6) alkyl.

[0097] In some embodiments of Formula I-1, R5 is hydrogen, methyl, or -OH.

[0098] In some embodiments of Formula I-1, R5 is hydrogen.

[0099] In some embodiments of Formula I-1, R5 is methyl.

[0100] In some embodiments of Formula I-1, R6 is (C1-C6) alkyl or (C3-C7) carbocyclyl.

[0101] In some embodiments of Formula I-1, R6 is (C1-C2) alkyl or (C3-C4) carbocyclyl.

[0102] In some embodiments of Formula I-1, R6 is C1-alkylene. In some embodiments of Formula I-1, R6 is C2-alkylene. In some embodiments of Formula I-1, R6 is selected from one or more of the same or different R 10 In some embodiments of Formula I-1, R6 is a C1-alkylene optionally substituted with one or more of the same or different R 10 In some embodiments of Formula I-1, each R is a C2-alkylene optionally substituted with a group. 10 is independently methyl, fluoro, or cyclopropyl.

[0103] In some embodiments of Formula I-1, R6 is C3-carbocyclyl. In some embodiments of Formula I-1, R6 is C4-carbocyclyl.

[0104] In some embodiments of Formula I-1, R5 and R6, together with the same carbon atom to which they are attached, form a spiro(C3-C7)carbocyclyl group.

[0105] In some embodiments of Formula I-1, R5 and R6 together with the same carbon atom to which they are attached form a spiro(C3)carbocyclyl.

[0106] In some embodiments of Formula I-1, R6 is (C2-C4) alkylene, which is joined to R7 to form a 4-6 membered heterocyclyl group.

[0107] In some embodiments of Formula I-1, R6 is (C2-C3) alkylene, which is joined to R7 to form a 4-membered heterocyclyl group.

[0108] In some embodiments of Formula I-1, R7 is hydrogen or (C1-C6) alkyl.

[0109] In some embodiments of Formula I-1, R7 is hydrogen or methyl.

[0110] In some embodiments of Formula I-1, R8 is hydrogen or (C1-C6) alkyl.

[0111] In some embodiments of Formula I-1, R8 is hydrogen or methyl.

[0112] In some embodiments of Formula I-1, R7 and R8 together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl.

[0113] In some embodiments of Formula I-1, R7 and R8 together with the nitrogen atom to which they are attached form a 3-membered heterocyclyl.

[0114] In some embodiments of Formula I-1, R 12 is methyl and R 11 is Cl. In some embodiments, R 12 is methyl and R 11 is CN.

[0115] In some embodiments of Formula I-1, R 12 is (C1-C2)alkyl, 4-membered heterocyclyl, (C3)carbocyclyl(C1)alkyl, or 4-membered heterocyclyl(C1)alkyl; wherein said alkyl, carbocyclyl, or heterocyclyl is optionally further substituted with one or more identical or different groups selected from (C1-C6)alkyl, (C1-C6)alkoxy, halo, amino, hydroxyl, haloalkyl, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl, and 4- to 7-membered heterocyclyl. In some embodiments, R 12is methyl. In some embodiments, R 12 is a 4-membered heterocyclyl, (C3)carbocyclyl(C1)alkyl, or a 4-membered heterocyclyl(C1)alkyl, where the heterocyclyl contains one heteroatom selected from N and O.

[0116] In some embodiments of Formula I-1, R 13 Ha-(CH2) 1-3 In some embodiments of Formula I-1, R 13 is -(CH2)2W1W2.

[0117] In some embodiments of Formula I-1, W1 is CR 18 R 18’ In some embodiments of Formula I-1, R 18 and R 18’ is independently hydrogen or (C-C) alkyl. In some embodiments of Formula I-1, R 18 and R 18’ are both (C1-C2) alkyl. In some embodiments of Formula I-1, R 18 and R 18’ are both methyl.

[0118] In some embodiments of Formula I-1, W2 is cyano, hydroxy, or amino. In some embodiments of Formula I-1, W2 is hydroxy.

[0119] In some embodiments, the compound of Formula I-1 has the formula I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f: [ka] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0120] In some embodiments, the compound of Formula I-1 has the formula I-1g, I-1h, I-1i, I-1j, I-1k, or I-1l: [ka] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0121] In some embodiments, the compound of formula I-1 has formula I-1m or I-1n: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0122] In some embodiments [ka] teeth [ka] and the compound of formula (I) is represented by formula I-2 [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0123] In some embodiments of Formula I-2, X1 is N. In some embodiments of Formula I-2, X1 is CR 17 In some embodiments of Formula I-2, X1 is CH.

[0124] In some embodiments of Formula I-2, X2 is N. In some embodiments of Formula I-2, X2 is CR 17 In some embodiments of Formula I-2, X2 is CH.

[0125] In some embodiments of Formula I-2, X 1 and X 2 are both CH.

[0126] In some embodiments of Formula I-2, X3 is N. In some embodiments of Formula I-2, X3 is CH.

[0127] In some embodiments of Formula I-2, X is CH2.

[0128] In some embodiments of Formula I-2, X is CHF.

[0129] In some embodiments of Formula I-2, X is CF2.

[0130] In some embodiments of Formula I-2, R1 is hydrogen, -OR9, or (C1-C6) alkyl.

[0131] In some embodiments of Formula I-2, R 1 is hydrogen, methyl, or —OH.

[0132] In some embodiments of Formula I-2, R 1 is hydrogen.

[0133] In some embodiments of Formula I-2, R1 is methyl.

[0134] In some embodiments of Formula I-2, R2 is hydrogen, -OR9, or (C1-C6) alkyl.

[0135] In some embodiments of Formula I-2, R2 is hydrogen, methyl, or -OH.

[0136] In some embodiments of Formula I-2, R2 is hydrogen.

[0137] In some embodiments of Formula I-2, R2 is methyl.

[0138] In some embodiments of Formula I-2, R 1 and R 2 together with the same carbon atom to which they are attached form a spiro(C 3 -C 7 )carbocyclyl group.

[0139] In some embodiments of Formula I-2, R 1 and R 2 together with the same carbon atom to which they are attached form a spiro(C 3 )carbocyclyl.

[0140] In some embodiments of Formula I-2, R3 is hydrogen.

[0141] In some embodiments of Formula I-2, R4 is hydrogen.

[0142] In some embodiments of Formula I-2, R5 is hydrogen, -OR9, or (C1-C6) alkyl.

[0143] In some embodiments of Formula I-2, R5 is hydrogen, methyl, or -OH.

[0144] In some embodiments of Formula I-2, R5 is hydrogen.

[0145] In some embodiments of Formula I-2, R5 is methyl.

[0146] In some embodiments of Formula I-2, R6 is (C1-C6) alkyl or (C3-C7) carbocyclyl.

[0147] In some embodiments of Formula I-2, R6 is (C1-C2) alkyl or (C3-C4) carbocyclyl.

[0148] In some embodiments of Formula I-2, R6 is C1-alkylene. In some embodiments of Formula I-2, R6 is C2-alkylene. In some embodiments of Formula I-2, R6 is selected from one or more of the same or different R 10 In some embodiments of Formula I-2, R6 is a C1-alkylene substituted with one or more of the same or different R10 In some embodiments of Formula I-2, each R is a C-alkylene substituted with a group. 10 is independently methyl, fluoro, or cyclopropyl.

[0149] In some embodiments of Formula I-2, R6 is C3-carbocyclyl. In some embodiments of Formula I-2, R6 is C4-carbocyclyl.

[0150] In some embodiments of Formula I-2, R5 and R6, together with the same carbon atom to which they are attached, form a spiro(C3-C7)carbocyclyl group.

[0151] In some embodiments of Formula I-2, R5 and R6 together with the same carbon atom to which they are attached form a spiro(C3)carbocyclyl.

[0152] In some embodiments of Formula I-2, R6 is (C2-C4) alkylene, which is joined to R7 to form a 4-6 membered heterocyclyl group.

[0153] In some embodiments of Formula I-2, R6 is (C2-C3) alkylene, which is joined to R7 to form a 4-membered heterocyclyl group.

[0154] In some embodiments of Formula I-2, R7 is hydrogen or (C1-C6) alkyl.

[0155] In some embodiments of Formula I-2, R7 is hydrogen or methyl.

[0156] In some embodiments of Formula I-2, R8 is hydrogen or (C1-C6) alkyl.

[0157] In some embodiments of Formula I-2, R8 is hydrogen or methyl.

[0158] In some embodiments of Formula I-2, R7 and R8 together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl.

[0159] In some embodiments of Formula I-2, R7 and R8 together with the nitrogen atom to which they are attached form a 3-membered heterocyclyl.

[0160] In some embodiments of Formula I-2, R 12 is methyl and R 11 is Cl. In some embodiments, R 12 is methyl and R 11 is CN.

[0161] In some embodiments of Formula I-2, R 12 is (C1-C2)alkyl, 4-membered heterocyclyl, (C3)carbocyclyl(C1)alkyl, or 4-membered heterocyclyl(C1)alkyl; said alkyl, carbocyclyl, or heterocyclyl may be further substituted with one or more identical or different groups selected from (C1-C6)alkyl, (C1-C6)alkoxy, halo, amino, hydroxyl, haloalkyl, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl, and 4- to 7-membered heterocyclyl. In some embodiments, R 12 is methyl. In some embodiments, R 12 is a 4-membered heterocyclyl, (C3)carbocyclyl(C1)alkyl, or a 4-membered heterocyclyl(C1)alkyl, where the heterocyclyl contains one heteroatom selected from N and O.

[0162] In some embodiments of Formula I-1, R 14 -L3CR 24 R 25 R 26In some embodiments of Formula I-2, L3 is (C1-C4) alkylene, -O-(C1-C4) alkylene, or -S-(C1-C4) alkylene. In some embodiments of Formula I-2, L3 is -O-(C1-C4) alkylene. In some embodiments of Formula I-2, L3 is -O-(C1) alkylene.

[0163] In some embodiments of Formula I-2, R 24 and R 25 together with the carbon atom to which they are attached form a (C-C)carbocyclyl, a 4- to 7-membered heterocyclyl, or C=O. In some embodiments of Formula I-2, R 24 and R 25 together with the same carbon atom to which they are attached to form C=O. In some embodiments of Formula I-2, R 24 and R 25 together with the same carbon atom to which they are attached to form a 4- to 7-membered heterocyclyl. In some embodiments of Formula I-2, R 24 and R 25 together with the same carbon atom to which they are attached to form an oxetane ring.

[0164] In some embodiments of Formula I-2, R 26 is (C1-C6) alkyl, -NR 27 R 28 -OR 27 In some embodiments of Formula I-2, R 26 is methyl, hydroxyl, amino, or NHMe. In some embodiments, R 26 is methyl. In some embodiments, R 26 is hydroxyl. In some embodiments, R 26 is amino. In some embodiments, R 26 is NHMe.

[0165] In some embodiments, the compound of Formula I-2 has formula I-2a, I-2b, I-2c, I-2d, I-2e, or I-2f: [ka] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0166] In some embodiments, the compound of formula I-2 has formula I-2g, I-2h, I-2i, I-2j, I-2k, or I-2l: [ka] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0167] In some embodiments, the compound of formula I-2 has formula I-2m or I-2n: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0168] In some embodiments, [ka] teeth [ka] and the compound of formula (I) is represented by formula I-3 [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, R 11 is Cl. In some embodiments, R 11 is CN.

[0169] In some embodiments of Formula I-3, X1 is CR 17 In some embodiments of Formula I-3, X1 is CH. In some embodiments of Formula I-3, X1 is N.

[0170] In some embodiments of Formula I-3, X2 is CR 17 In some embodiments of Formula I-3, X2 is CH. In some embodiments of Formula I-3, X2 is N.

[0171] In some embodiments of Formula I-3, R 12 is (C1-C2)alkyl, 4-membered heterocyclyl, (C3)carbocyclyl(C1)alkyl, or 4-membered heterocyclyl(C1)alkyl; said alkyl, carbocyclyl, or heterocyclyl may be further substituted with one or more identical or different groups selected from (C1-C6)alkyl, (C1-C6)alkoxy, halo, amino, hydroxyl, haloalkyl, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl, and 4- to 7-membered heterocyclyl. In some embodiments, R 12 is methyl. In some embodiments, R 12 is a 4-membered heterocyclyl, (C3)carbocyclyl(C1)alkyl, or a 4-membered heterocyclyl(C1)alkyl, where the heterocyclyl contains one heteroatom selected from N and O.

[0172] In some embodiments of Formula I-3, A' is a 7-membered heterocyclyl, where the heterocyclyl contains two heteroatoms selected from N and O, and R 15 and R 15 ', may be further substituted with one or more substituents independently selected from oxo, (C1-C2)alkyl, cyclopropyl, spiro-cyclopropyl, halo, (C1-C2)haloalkyl, (C1-C2)alkoxy, amino, cyano, and hydroxy.

[0173] In some embodiments, the compound of Formula I-3 has formula I-3a, I-3b, I-3c, I-3d, I-3e, I-3f, I-3g, I-3h, I-3i, I-3j, I-3k, or I-3l: [ka] [ka] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 29 are independently oxo, (C1-C2)alkyl, cyclopropyl, spiro-cyclopropyl, halo, (C1-C2)haloalkyl, (C1-C2)alkoxy, amino, cyano, and hydroxy; and n is 0 to 2.

[0174] In some embodiments, the compound of formula I-3 has formula I-3m or I-3n: [ka] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0175] In some embodiments, [ka] teeth [ka] and the compound of formula (I) is represented by formula I-4 [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0176] In some embodiments of Formula I-4, X1 is CR 17 In some embodiments of Formula I-4, X1 is CH. In some embodiments of Formula I-4, X1 is N.

[0177] In some embodiments of Formula I-4, X2 is CR 17 In some embodiments of Formula I-4, X2 is CH. In some embodiments of Formula I-4, X2 is N.

[0178] In some embodiments of Formula I-4, X4 is CH. In some embodiments of Formula I-4, X4 is N.

[0179] In some embodiments of Formula I-4, R 12 is (C1-C2)alkyl, 4-membered heterocyclyl, (C3)carbocyclyl(C1)alkyl, or 4-membered heterocyclyl(C1)alkyl; said alkyl, carbocyclyl, or heterocyclyl may be further substituted with one or more identical or different groups selected from (C1-C6)alkyl, (C1-C6)alkoxy, halo, amino, hydroxyl, haloalkyl, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl, and 4- to 7-membered heterocyclyl. In some embodiments, R 12 is methyl. In some embodiments, R 12 is a 4-membered heterocyclyl, (C3)carbocyclyl(C1)alkyl, or a 4-membered heterocyclyl(C1)alkyl, where the heterocyclyl contains one heteroatom selected from N and O.

[0180] In some embodiments, the compound of formula I-4 has formula I-4a or I-4b: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0181] In some embodiments, [ka] teeth [ka] and the compound of formula (I) is represented by formula I-5 [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0182] In some embodiments of Formula I-5, X1 is CR 17 In some embodiments of Formula I-5, X1 is CH. In some embodiments of Formula I-5, X1 is N.

[0183] In some embodiments of Formula I-5, X2 is CR 17 In some embodiments of Formula I-5, X2 is CH. In some embodiments of Formula I-5, X2 is N.

[0184] In some embodiments of Formula I-5, R 12 is (C1-C2)alkyl, 4-membered heterocyclyl, (C3)carbocyclyl(C1)alkyl, or 4-membered heterocyclyl(C1)alkyl; said alkyl, carbocyclyl, or heterocyclyl may be further substituted with one or more identical or different groups selected from (C1-C6)alkyl, (C1-C6)alkoxy, halo, amino, hydroxyl, haloalkyl, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl, and 4- to 7-membered heterocyclyl. In some embodiments, R 12 is methyl. In some embodiments, R 12 is a 4-membered heterocyclyl, (C3)carbocyclyl(C1)alkyl, or a 4-membered heterocyclyl(C1)alkyl, where the heterocyclyl contains one heteroatom selected from N and O.

[0185] In some embodiments of Formula I-5, R 12 is (C1-C6)alkyl, (C1-C6)alkyl-OH, (C1-C6)alkyl-NH(C1-C6)alkyl or (C1-C6)alkyl-N((C1-C6)alkyl)2.

[0186] In some embodiments of Formula I-5, R 14 -L3CR 24 R 25 R 26 In some embodiments of Formula I-5, L3 is (C1-C4) alkylene, -O-(C1-C4) alkylene, or -S-(C1-C4) alkylene. In some embodiments of Formula I-5, L3 is -O-(C1-C4) alkylene. In some embodiments of Formula I-5, L3 is -O-(C1) alkylene.

[0187] In some embodiments of Formula I-5, R 24 and R 25 together with the carbon atom to which they are attached form a (C-C) carbocyclyl, a 4- to 7-membered heterocyclyl, or C=O. In some embodiments of Formula I-5, R 24 and R 25 together with the same carbon atom to which they are attached to form C=O. In some embodiments of Formula I-5, R 24 and R 25 together with the same carbon atom to which they are attached to form a 4- to 7-membered heterocyclyl. In some embodiments of Formula I-5, R 24 and R 25 together with the same carbon atom to which they are attached to form an oxetane ring.

[0188] In some embodiments of Formula I-5, R 26 is (C1-C6) alkyl, -NR 27 R 28 , or -OR 27 In some embodiments of Formula I-5, R 26is methyl, hydroxyl, amino, or NHMe. In some embodiments, R 26 is methyl. In some embodiments, R 26 is hydroxyl. In some embodiments, R 26 is amino. In some embodiments, R 26 is NHMe.

[0189] In some embodiments, the compound of formula I-5 has formula I-5a, I-5b, I-5c, I-5d, I-5e, or I-5f: [ka] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0190] Representative examples of compounds of the present invention include: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0191] The compounds of the present disclosure may be in the form of a free acid or free base, or a 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. See, for example, Gould, PL, "Salt selection for basic drugs," International Journal of Pharmaceutics, 33:201-217 (1986); Bastin, RJ, et al., "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4:427-435 (2000); and Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66:1-19 (1977).

[0192] The compounds of the present disclosure may have at least one chiral center and therefore, as used herein, may be in the form of stereoisomers, which 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 multiple 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 the (R-) form of the compound is considered equivalent to administration of the (S-) form of the compound. Thus, the compounds of the present disclosure may be prepared and used in the form of a single isomer, substantially free of other isomers, or in the form of mixtures of various isomers, such as racemic mixtures of stereoisomers.

[0193] 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 a level above 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," i.e., H, refers to protium ( 1 H) and deuterium ( 2 It refers to all isotopes of hydrogen, including H. As used herein, the term "compound" encompasses isotopic derivatives.

[0194] 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.

[0195] 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 and then gradually or rapidly cooling it. 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.

[0196] 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 bound 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.

[0197] Synthesis method In another aspect, the present disclosure relates to methods for preparing 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. The compound of formula (I) will be better understood in connection with the synthetic schemes described in the various examples, which illustrate non-limiting methods by which the compound of formula (I) may be prepared.

[0198] Pharmaceutical Composition Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer, 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 can include, for example, liquids (both aqueous and non-aqueous, and combinations thereof), solids, encapsulating materials, gases, and combinations thereof (e.g., semi-solids), as well as gases, which function to carry or transport a compound from one organ or part of the body to another. 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 contain one or more pharmaceutically acceptable excipients.

[0199] In general, 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, wet-milling, 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, intracerebroventricular, 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 can also be advantageous in that the compound can be administered relatively quickly, such as in single-dose treatments and / or acute conditions.

[0200] In some embodiments, the compounds of formula (I) are formulated for oral or intravenous administration (eg, systemic intravenous injection).

[0201] 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); semi-solid 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.

[0202] Oral administration 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 additional carriers or excipients, such as a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) cross-linked polymers (e.g., cross-linked polyvinylpyrrolidone (crospovidone), cross-linked carbohydrates, The formulation may be mixed with disintegrating agents such as sodium hydroxymethylcellulose (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; 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. Similar types of solid compositions can also be used as fillers for 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 opacifying agents.

[0203] In some embodiments, the compound of formula (I) can be formulated into hard or soft gelatin capsules.Representative excipients that can be used include pregelatinized starch, magnesium stearate, mannitol, sodium stearyl fumarate, anhydrous lactose, microcrystalline cellulose, and croscarmellose sodium.The gelatin shell can contain gelatin, titanium dioxide, iron oxide, and coloring agents.

[0204] The liquid dosage form for oral administration includes solution, suspension, emulsion, microemulsion, syrup and elixir.In addition to the compound, the liquid dosage form can contain aqueous or non-aqueous carriers commonly used in the art (depending on the solubility of the compound), such as water or other solvents, solubilizers and emulsifiers, such as 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 esters of sorbitan, and their mixtures.The oral composition can also contain excipients such as wetting agents, suspending agents, coloring agents, sweeteners, flavoring agents and fragrances.

[0205] Injectable preparations for parenteral administration may include sterile aqueous or oily suspensions. These 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. Among the acceptable vehicles and solvents that may be used are 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 mild fixed oil, including synthetic mono- or diglycerides, can be used. Additionally, fatty acids, such as oleic acid, are used in the preparation of injections. Injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. The effect of a compound can be prolonged by delaying its absorption, which can be accomplished by using a liquid suspension or crystalline or amorphous material with poor water solubility. Prolonged absorption of a compound from a parenterally administered formulation can also be achieved by suspending the compound in an oil vehicle.

[0206] In certain embodiments, compounds of Formula (I) can be administered locally rather than systemically, for example, by injecting the conjugate directly into an organ, often in a depot or sustained-release formulation. In certain embodiments, long-acting formulations are administered by infusion (e.g., subcutaneously or intramuscularly) or 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 ratio of compound to polymer and the properties of the specific polymer used. Depot injectable formulations are also prepared by encapsulating 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.

[0207] The compositions may be formulated for buccal or sublingual administration and examples include tablets, lozenges and gels.

[0208] 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 an aerosol spray from a pressurized pack or nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas).In some embodiments, the dosage unit of the 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 an inhaler or insufflator can be formulated to contain a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0209] The compound of formula (I) can be formulated for topical administration, which 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.

[0210] 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). For example, 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.

[0211] In some embodiments, topical formulations can 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 improving the penetration rate of drugs through the skin.For example, see 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, octriphenyl 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.

[0212] Representative examples of other excipients that may be included in topical and other types of formulations (to the extent they are 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 citrate buffer, hydrochloric acid buffer, and lactate buffer. Suitable solubilizers include quaternary ammonium chloride, cyclodextrin, benzyl benzoate, lecithin, and polysorbate. Suitable skin protectants include vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, and zinc oxide.

[0213] Transdermal formulations typically use transdermal delivery devices and transdermal delivery patches, where the compound is formulated in a lipophilic emulsion or buffered aqueous solution and dissolved and / or dispersed in a polymer or adhesive. 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, and the absorption rate can be slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. Absorption enhancers can be used to increase absorption, and examples include pharmaceutically acceptable absorbable solvents that aid passage through the skin.

[0214] Ophthalmic preparations include eye drops.

[0215] Formulations 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, as well as synthetic polymers such as polyvinylpyrrolidone and PEG. 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 waxes, 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.

[0216] 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 effective to produce 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 an 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.

[0217] The total daily dosage of compound and its 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 condition); the subject's age, weight, general health, sex and diet; the administration time, administration route and excretion rate of the specific compound used; treatment period; the drug used in combination with or simultaneously with compound; and similar factors 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).

[0218] How to use In some embodiments, the present disclosure is directed to treating a disease or disorder associated with (e.g., characterized by or mediated by) aberrant (e.g., elevated levels of BCL6, or otherwise functionally aberrant, e.g., deregulated levels of BCL6) BCL6 activity relative to non-pathological conditions. The method involves 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.

[0219] 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 method is also applicable to companion animals such as dogs and cats. A subject "in need" of treatment according to the present disclosure may be "suffering from or suspected of having" a particular cancer, may have tested positive, or may otherwise exhibit a sufficient number of risk factors, or a sufficient number or combination of signs or symptoms, such that a medical professional can diagnose or suspect the subject has cancer. Thus, subjects suffering from a particular disease or disorder and subjects suspected of having the disease are not necessarily two distinct groups.

[0220] In some embodiments, the method is directed to treating a subject with cancer. The method includes treating adult tumors / cancers and pediatric tumors / cancers. The cancer may be a vascularized tumor, or a tumor that is not yet substantially vascularized or is not vascularized.

[0221] In some embodiments, the cancer is a lymphoid malignancy.

[0222] 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.

[0223] In some embodiments, the methods of the present disclosure involve treating a subject with a cell proliferative disease or disorder of the blood system.

[0224] In some embodiments, the methods are directed to treating a subject with an inflammatory disease or disorder.

[0225] 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.

[0226] The compounds of Formula (I) can be administered to cancer patients as monotherapy or in combination therapy. Therapy can be "front / first-line," as the initial treatment for patients who have not previously received an anticancer treatment regimen, alone or in combination with other treatments; "second-line," as the treatment for patients who have previously received an anticancer treatment regimen, alone or in combination with other treatments; or "third-line," "fourth-line," etc., treatment, alone or in combination with other treatments. Therapy can also be administered to patients who have previously received unsuccessful or partially successful treatments but who have become unresponsive or intolerant to a particular treatment. Therapy can also be administered as adjuvant treatment, 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.

[0227] 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 approximately once every 8 weeks. In some embodiments, the dosing frequency ranges from about once daily for 1, 2, 3, 4, 5, or 6 weeks, and in other embodiments, involves at least one 28-day cycle comprising daily administration for 3 weeks (21 days) followed by a 7-day "off" period. In other embodiments, the compound may be administered twice daily (BID) for 2.5 days (a total of 5 doses) or once daily (QD) for 2 days (a total of 2 doses). In other embodiments, the compound may be administered once daily (QD) for 5 days.

[0228] 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 "concurrently" mean that the agents are administered simultaneously, including substantially simultaneous administration, in the same or separate dosage form, by the same or separate administration modes, or sequentially, for example, as part of the same treatment regimen or by a continuous treatment regimen. 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 benefit than if 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 the active agents exactly at the same time.

[0229] In some embodiments, the treatment regimen may include administering a compound of Formula (I) in combination with one or more additional therapeutic agents known to be used in the treatment of 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 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 therein) and U.S. Patent No. 9,345,705 B2 (columns 12-18 therein). 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.

[0230] In some embodiments, the compound of Formula (I) and the additional (e.g., anticancer) therapeutic agent are 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 11 to about 12 hours apart, about 13 to about 14 hours apart, about 15 to about 16 hours apart, about 16 to about 18 hours apart, about 17 to about 19 hours apart, about 20 to about 22 hours apart, about 21 to about 24 hours apart, about 22 to about 26 hours apart, about 23 to about 28 hours apart, about 24 to about 28 hours apart, about 25 to about 29 hours apart, about 26 to about 30 hours apart, about 27 to about 31 hours apart, about 28 to about 32 hours apart, about 29 to about 33 hours apart, about 34 to about 34 hours apart, about 35 to about 35 hours apart, about 36 to about 37 hours apart, about 38 to about 39 hours apart, about 39 to about 40 hours apart, about 40 to about 42 hours apart, about 40 to about 44 hours apart, about 40 to about 45 hours apart, about 41 to about 46 hours apart, about 42 to about 47 hours apart, about 43 to about 48 hours apart, about 44 to about 49 hours apart, about 45 to about 49 hours apart, about 46 to about 48 hours apart, about 47 to about 49 hours apart, about 48 They may be administered at intervals of about 10 hours, about 10 to about 11 hours, about 11 to about 12 hours, about 12 to 18 hours, 18 to 24 hours, 24 to 36 hours, 36 to 48 hours, 48 ​​to 52 hours, 52 to 60 hours, 60 to 72 hours, 72 to 84 hours, 84 to 96 hours, or 96 to 120 hours. Two or more (e.g., anticancer) therapeutic agents may be administered during a single patient visit.

[0231] 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, the therapeutic agents are administered at intervals of 1 minute, 10 minutes, 30 minutes, less than 1 hour, 1 hour, 1-2 hours, 2-3 hours, 3-4 hours, 4-5 hours, 5-6 hours, 6-7 hours, 7-8 hours, 8-9 hours, 9-10 hours, 10-11 hours, 11-12 hours, 24 hours or less, or 48 hours or less. In one example, the (e.g., anti-cancer) therapeutic agents are administered during the same visit. In another example, the combination anti-cancer therapeutic agents may be administered at intervals of 1 minute to 24 hours.

[0232] In some embodiments, the compound of Formula (I) and the additional anticancer 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 occurrence of resistance to one or both of the anticancer therapeutic agents, to avoid or reduce the side effects of one or both of the anticancer therapeutic agents, and / or to improve the efficacy of the therapy. 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, and repeating this sequential administration, i.e., cycle, to reduce the occurrence of resistance to one or both of the anticancer therapeutic agents, to avoid or reduce the side effects of one or both of the anticancer therapeutic agents, and / or to improve the efficacy of the anticancer therapeutic agents.

[0233] 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).

[0234] 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.

[0235] These and other aspects of the present disclosure will be further understood in light 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]

[0236] Example 1 Synthesis of 5-((2-((3S,5R)-3-(2-aminoethyl)-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one (97a) and 5-((2-((3R,5S)-3-(2-aminoethyl)-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one (97b) [ka]

[0237] Methyl 2-(1-benzyl-5-methyl-4-oxo-3-piperidyl)acetate

[0238] To a solution of 1-benzyl-3-methyl-piperidin-4-one (30 g, 147.58 mmol, 1 equiv.) in THF (300 mL) was added LDA (2 M, 73.80 mL, 1 equiv.) dropwise at −78° C. After the addition, the mixture was stirred at −78° C. for 30 minutes, and then methyl 2-bromoacetate (33.86 g, 221.38 mmol, 20.90 mL, 1.5 equiv.) and HMPA (31.74 g, 177.10 mmol, 31.12 mL, 1.2 equiv.) were added dropwise at −78° C., and the mixture was stirred at −78° C. for 2.5 hours. The resulting mixture was then stirred at 20° C. for 9 hours. The reaction mixture was quenched by adding NH4Cl (100 mL, aq.), then diluted with HO (500 mL), and extracted with EtOAc (300 mL × 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure 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 yellow oil (8.3 g, 17%). LCMS: [M+1] + =276.2.

[0239] Methyl 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)acetate

[0240] To a solution of methyl 2-(1-benzyl-5-methyl-4-oxo-3-piperidyl)acetate (8.3 g, 30.14 mmol, 1 equiv) in DCM (85 mL) was added DAST (77.74 g, 482.31 mmol, 63.72 mL, 16 equiv). The mixture was stirred at 50 °C for 12 h. The residue was diluted with DCM (60 mL), and then the mixture was added dropwise to saturated aqueous NaHCO (200 mL). The resulting mixture was stirred at 20 °C for 20 min and then extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give the title compound as a yellow oil (3.7 g, 41%). 1H NMR(400MHz, CDCl3) δ=7.31-7.21(m,5H), 3.64-3.60(m,3H), 3.57-3.54(m,1H), 3.42(d,J=13.2Hz,1H), 2.97-2.87(m,1H ), 2.78-2.66(m,2H), 2.65-2.48(m,1H), 2.25-2.05(m,2H), 2.04-1.87(m,2H), 0.92(d,J=6.8Hz,3H).

[0241] 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)ethanol

[0242] To a solution of methyl 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)acetate (1 g, 3.36 mmol, 1 equiv.) in THF (10 mL) was added LiAlH (255.29 mg, 6.73 mmol, 2 equiv.) slowly dropwise at 0° C., and the mixture was then stirred at 20° C. for 1 h. The reaction mixture was quenched by the addition of NH Cl (10 mL, aq.) and then diluted with HO (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na SO , filtered, and concentrated under reduced pressure to give the title compound as a yellow oil (700 mg, 77%). LCMS: [M+1] + =270.1.

[0243] 2-[2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)ethyl]isoindoline-1,3-dione

[0244] To a solution of 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)ethanol (700 mg, 2.60 mmol, 1 equiv.) and isoindoline-1,3-dione (458.88 mg, 3.12 mmol, 1.2 equiv.) in DCM (7 mL) was added PPh3 (886.20 mg, 3.38 mmol, 1.3 equiv.) at 0 °C. Then, a solution of DEAD (588.43 mg, 3.38 mmol, 614.23 μL, 1.3 equiv.) in DCM (1 mL) was added dropwise at 0 °C. The resulting reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure, 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 colorless oil (600 mg, 58%). LCMS: [M+1] + =399.1.

[0245] 2-[2-(4,4-difluoro-5-methyl-3-piperidyl)ethyl]isoindoline-1,3-dione

[0246] To a solution of 2-[2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)ethyl]isoindoline-1,3-dione (200 mg, 501.95 μmol, 1 equiv.) in MeCN (8 mL) and HO (2 mL) was added ceric ammonium nitrate (2.75 g, 5.02 mmol, 2.50 mL, 10 equiv.). The mixture was stirred at 40 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC (80 g Agela C18 column; sample dissolution solvent: approximately 0.20 grams of sample dissolved in 2 mL of MeOH; flow rate: 40 mL / min; mobile phase: TFA; gradient B: 30-60% in 10 min; 60% in 5 min; instrument: Biotage) to give the title compound as a yellow solid (140 mg, 66%, TFA salt). LCMS: [M+1] + =309.2.

[0247] 2-[2-[1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidyl]ethyl]isoindoline-1,3-dione

[0248] To a solution of 5-[(2,5-dichloropyrimidin-4-yl)amino]-3-(3-hydroxy-3-methylbutyl)-1-methyl-benzimidazol-2-one (160 mg, 403.76 μmol, 1 equiv.) and 2-[2-(4,4-difluoro-5-methyl-3-piperidyl)ethyl]isoindoline-1,3-dione (139.21 mg, 403.76 μmol, 1 equiv., TFA) in DMF (3 mL) was added DIPEA (156.55 mg, 1.21 mmol, 210.99 μL, 3 equiv.). The mixture was stirred at 130 °C for 6 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40mm*3μm; mobile phase: [water (10mM NH4HCO3)-MeCN]; B%: 30%-60%, 8 min) to give the title compound as a yellow solid (200mg, 74%). LCMS: [M+1] + =668.1.

[0249] 2-[2-[(3S,5R)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidyl]ethyl]isoindoline-1,3-dione and 2-[2-[(3R,5S)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidyl]ethyl]isoindoline-1,3-dione

[0250] 200 mg of the mixture of enantiomers was separated by SFC (Supercritical Fluid Chromatography) on a column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH 3 H 2 O ETOH]; B%: 46%-46%, 7 min. 2-[2-[(3S,5R)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidyl]ethyl]isoindoline-1,3-dione (50 mg, 44% yield, 96% purity) was obtained as a white solid, and 2-[2-[(3R,5S)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidyl]ethyl]isoindoline-1,3-dione (60 mg, 54% yield, 99% purity) was obtained as a white solid.

[0251] 5-[[2-[(3S,5R)-3-(2-aminoethyl)-4,4-difluoro-5-methyl-1-piperidyl]-5-chloro-pyrimidin-4-yl]amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (97a)

[0252] To a solution of 2-[2-[(3S,5R)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidyl]ethyl]isoindoline-1,3-dione (50.00 mg, 74.84 μmol, 1 equiv.) in EtOH (0.5 mL) was added NH2NH2·HO (56.19 mg, 1.12 mmol, 54.56 μL, 15 equiv.). The mixture was stirred at 60 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 30%-55%, 8 min) to give the title compound as a white solid (15.2 mg, 37%). 1 H NMR(400MHz,MeOD) δ=7.94(s,1H), 7.39(dd,J=1.9,8.4Hz,1H), 7.34(d,J=1.6Hz,1H), 7.15(d,J=8.6Hz,1H), 4.66(br d,J=13.4Hz,1H), 4.53(br d,J=13.4Hz,1H), 4.07-3.98(m,2H), 3.44(s,3H), 2.82-2.55(m,4H), 2. 05-1.82(m,5H), 1.45-1.34(m,1H), 1.28(s,6H), 0.99(d,J=6.8Hz,3H). LCMS:[M+1] + =538.2.

[0253] 5-[[2-[(3R,5S)-3-(2-aminoethyl)-4,4-difluoro-5-methyl-1-piperidyl]-5-chloro-pyrimidin-4-yl]amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (97b)

[0254] To a solution of 2-[2-[(3R,5S)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidyl]ethyl]isoindoline-1,3-dione (50 mg, 74.84 μmol, 1 equiv.) in EtOH (0.5 mL) was added NH2NH2·HO (56.19 mg, 1.12 mmol, 54.56 μL, 15 equiv.). The mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 30%-55%, 8 min) to give the title compound as a white solid (20.1 mg, 49%). 1 H NMR(400MHz,MeOD) δ=7.94(s,1H), 7.39(dd,J=1.6,8.4Hz,1H), 7.34(s,1H), 7.15(d,J=8.0Hz,1H), 4.66(br d,J=14.0Hz,1H), 4.53(br d,J=13.2Hz,1H), 4.09-3.98(m,2H), 3.44(s,3H), 2.75-2.58(m,4H), 1. 99-1.79(m,5H), 1.44-1.34(m,1H), 1.28(s,6H), 0.99(d,J=6.8Hz,3H). LCMS:[M+1] + =538.2.

[0255] The absolute configurations of compounds 97a and 97b were randomly assigned based on the alkylamino and methyl groups being in the cis-conformation.

[0256] Example 2: Synthesis of 5-[[2-[(3S,5R)-3-(aminomethyl)-4,4-difluoro-5-methyl-1-piperidyl]-5-chloro-pyrimidin-4-yl]amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (2a) and 5-[[2-[(3R,5S)-3-(aminomethyl)-4,4-difluoro-5-methyl-1-piperidyl]-5-chloro-pyrimidin-4-yl]amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (2b) [ka]

[0257] Benzyl 3-methyl-4-oxo-piperidine-1-carboxylate

[0258] To a solution of 1-benzyl-3-methyl-piperidin-4-one (26 g, 127.90 mmol, 1 equiv.) in toluene (300 mL) was added CbzCl (33.38 g, 195.69 mmol, 27.82 mL, 1.53 equiv.). The mixture was stirred at 112 °C for 12 h. The residue was diluted with HO (200 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give the title compound as a yellow oil (25 g, 79%). LCMS: [M+1] + =248.2.

[0259] Benzyl 3-[(1,3-dioxoisoindolin-2-yl)methyl]-5-methyl-4-oxo-piperidine-1-carboxylate

[0260] To a solution of benzyl 3-methyl-4-oxo-piperidine-1-carboxylate (10 g, 40.44 mmol, 1 equiv.) in THF (200 mL) was added LiHMDS (1 M, 50.55 mL, 1.25 equiv.) dropwise over 30 min at −78° C. After the addition, the mixture was stirred at −78° C. for 90 min, and then 2-(chloromethyl)isoindoline-1,3-dione (11.86 g, 60.66 mmol, 1.5 equiv.) in THF (200 mL) was added dropwise at −78° C. The resulting mixture was stirred at −78° C. for 2 h. The reaction mixture was quenched by the addition of NH4Cl at 0° C., then diluted with HO (200 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by reverse-phase HPLC (Column: 800 g Agela C18; Sample Dissolution Solvent: approx. 8.50 grams of sample dissolved in 40 ml of MeOH; Flow Rate: 120 mL / min; Mobile Phase: water-MeCN; Gradient B%: 45-75% in 30 min; 75% in 30 min; Instrument: Biotage) to give the title compound as a white solid (5 g, 30%). LCMS: [M+1] + =407.1.

[0261] Benzyl 3-[(1,3-dioxoisoindolin-2-yl)methyl]-4,4-difluoro-5-methyl-piperidine-1-carboxylate

[0262] To a solution of benzyl 3-[(1,3-dioxoisoindolin-2-yl)methyl]-5-methyl-4-oxo-piperidine-1-carboxylate (4 g, 9.84 mmol, 1 equiv.) in DCM (50 mL) was added DAST (25.38 g, 157.47 mmol, 20.81 mL, 16 equiv.) at 0 °C. The resulting mixture was then stirred at 20 °C for 72 h. The residue was diluted with DCM (40 mL), and the mixture was then added dropwise to saturated aqueous NaHCO (100 mL). The resulting mixture was stirred at 20 °C for 20 min and then extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue which was purified by reverse-phase HPLC (Column: 330 g Agela C18; Sample dissolution solvent: approximately 5.00 grams of sample dissolved in 20 ml of MeOH; Flow rate: 70 ml / min; Mobile phase: water MeCN; Gradient B%: 45-75% in 25 min; 75% in 40 min; Instrument: Biotage) to give the title compound as a yellow oil (1.7 g, 40%). 1 H NMR(400MHz, CDCl3) δ=7.93-7.69(m,4H), 7.27(s,5H), 5.19-5.00(m,2H), 4.27-4.16(m,1H), 4.12-4.05(m,1 H), 3.83-3.70(m,1H), 2.98-2.61(m,2H), 2.56-2.30(m,1H), 2.05-1.84(m,1H), 1.59(br s,1H), 1.05(d,J=6.6Hz,3H).

[0263] 2-[(4,4-difluoro-5-methyl-3-piperidyl)methyl]isoindoline-1,3-dione

[0264] To a solution of benzyl 3-[(1,3-dioxoisoindolin-2-yl)methyl]-4,4-difluoro-5-methyl-piperidine-1-carboxylate (1.5 g, 3.50 mmol, 1 equiv.) in DCM (5 mL) was added TEA (1.06 g, 10.50 mmol, 1.46 mL, 3 equiv.), Pd(OAc) (314.42 mg, 1.40 mmol, 0.4 equiv.), and EtSiH (2.44 g, 21.01 mmol, 3.36 mL, 6 equiv.). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC (column: 330 g Agela C18; sample dissolution solvent: approximately 5.00 grams of sample dissolved in 20 ml of MeOH; flow rate: 70 ml / min; mobile phase: water-MeCN; gradient B%: 30-60% in 25 min, 60% in 10 min; instrument: Biotage) to give the title compound as a yellow solid (800 mg, 78%). LCMS: [M+1] + =295.0.

[0265] 2-[[1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidyl]methyl]isoindoline-1,3-dione

[0266] To a solution of 5-[(2,5-dichloropyrimidin-4-yl)amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (350 mg, 883.24 μmol, 1 equiv.) and 2-[(4,4-difluoro-5-methyl-3-piperidyl)methyl]isoindoline-1,3-dione (259.93 mg, 883.24 μmol, 1 equiv.) in DMF (2 mL) was added DIPEA (342.46 mg, 2.65 mmol, 461.53 μL, 3 equiv.). The reaction mixture was stirred at 50° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 μm; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 40%~60%, 8 min) to give the title compound as a yellow solid (170 mg, yield 28%, purity 95%). 1 H NMR(400MHz,MeOD) δ=7.86(s,1H), 7.71(br s,3H), 7.34(d,J=1.6Hz,1H), 7.25(br d,J=8.4Hz,1H), 6.95(br d,J=8.4Hz,1H), 4.66-4.50(m,2H), 4.09-3.86(m,3H), 3.73-3.67(m,1H), 3.45-3.36(m,3H), 2.89(br t,J=12.8Hz,1H), 2.74(br t,J=12.8Hz,1H), 2.47-2.28(m,1H), 2.11-1.90(m,1H), 1.86-1.75(m,1H), 1.89-1.74(m,2H), 1.28(d,J=1.2Hz,6H), 1.02(d,J=6.8Hz,3H).

[0267] 2-[[(3S,5S)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidyl]methyl]isoindoline-1,3-dione and 2-[[(3R,5R)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidyl]methyl]isoindoline-1,3-dione

[0268] 170 mg of the mixture of enantiomers was separated by SFC (Supercritical Fluid Chromatography) with column: REGIS(S,S)WHELK-O1 (250 mm*25 mm, 10 μm); mobile phase: [Neu-EtOH]; B%: 50%-50%, 8 min to give 2-[[(3S,5S)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl [3R,5R]-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidyl]methyl]isoindoline-1,3-dione as a white solid (70 mg, 40% yield, 96% purity) and 2-[[(3R,5R)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidyl]methyl]isoindoline-1,3-dione as a white solid (70 mg, 40% yield, 96% purity).

[0269] 5-[[2-[(3S,5R)-3-(aminomethyl)-4,4-difluoro-5-methyl-1-piperidyl]-5-chloro-pyrimidin-4-yl]amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (2a)

[0270] To a solution of 2-[[(3R,5R)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidyl]methyl]isoindoline-1,3-dione (80 mg, 122.30 μmol, 1 equiv.) in EtOH (2 mL) was added NH2NH2·HO (91.84 mg, 1.83 mmol, 89.16 μL, 15 equiv.). The mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (10mM NH4HCO3)-MeCN]; B%: 25%~55%, 8 min) to give the title compound as a white solid (16.7mg, 26.%). 1 H NMR(400MHz,MeOD) δ=7.95(s,1H), 7.44-7.29(m,2H), 7.12(br d,J=8.4Hz,1H), 4.75(br d,J=13.2Hz,1H), 4.52(br d,J=13.4Hz,1H), 4.07-3.97(m,2H), 3.43(s,3H), 3.03(br dd,J=4.4,13.4Hz,1H), 2.73(q,J=13.2Hz,2H), 2.59-2.54(m,1H), 2.03-1.83(m,4H), 1.28(s,6H), 0.99(br d,J=6.4Hz,3H). LCMS:[M+1] + =524.2.

[0271] 5-[[2-[(3R,5S)-3-(aminomethyl)-4,4-difluoro-5-methyl-1-piperidyl]-5-chloro-pyrimidin-4-yl]amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (2b)

[0272] To a solution of 2-[[(3S,5S)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidyl]methyl]isoindoline-1,3-dione (80 mg, 122.30 μmol, 1 equiv.) in EtOH (2 mL) was added NH2NH2·HO (91.84 mg, 1.83 mmol, 89.16 μL, 15 equiv.). The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (10mM NH4HCO3)-MeCN]; B%: 25%~55%, 8 min) to give the title compound as a white solid (16.6mg, 256%). 1 H NMR(400MHz,MeOD) δ=7.95(s,1H), 7.40(br d,J=8.4Hz,1H), 7.33(s,1H), 7.12(br d,J=8.4Hz,1H), 4.76(br d,J=13.2Hz,1H), 4.52(br d,J=13.4Hz,1H), 4.08-3.98(m,2H), 3.43(s,3H), 3.03(br dd,J=4.4,13.4Hz,1H), 2.73(q,J=13.2Hz,2H), 2.59-2.54(m,1H), 2.03-1.83(m,4H), 1.28(s,6H), 0.99(br d, J = 6.4 Hz, 3H). LCMS: [M+1] + =524.2.

[0273] The absolute configurations of compounds 2a and 2b were randomly assigned based on the alkylamino and methyl groups being in the cis-conformation.

[0274] Example 3 Synthesis of 2-((6-((2-((3S,5R)-3-(aminomethyl)-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (50a) and 2-((6-((2-((3R,5S)-3-(aminomethyl)-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (50b) [ka]

[0275] 2-((6-((5-chloro-2-(3-((1,3-dioxoisoindolin-2-yl)methyl)-4,4-difluoro-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0276] To a solution of 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (350 mg, 857.34 μmol, 1 equiv.) and 2-[(4,4-difluoro-5-methyl-3-piperidyl)methyl]isoindoline-1,3-dione (302.77 mg, 1.03 mmol, 1.2 equiv.) in DMF (3 mL) was added DIPEA (332.42 mg, 2.57 mmol, 448.00 μL, 3 equiv.). The reaction mixture was stirred at 130° C. for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40mm*3μm; mobile phase: [water (10mM NH4HCO3)-MeCN]; B%: 25%~55%, 8 min) to give the title compound as a yellow solid (260mg, 46%). 1H NMR(400MHz,DMSO-d6) δ=8.91(s,1H), 8.05(s,1H), 7.91(br d,J=4.0Hz,1H), 7.86(br d,J=2.0Hz,1H), 7.78(br s,3H), 7.71-7.63(m,1H), 7.38(br d,J=7.6Hz,1H), 7.15(s,1H), 4.66-4.44(m,4H), 3.94-3.89(m,1H), 3.64(s,3H), 3.60-3.50(m,1H), 2.84(br t,J=12.8Hz,1H), 2.72-2.66(m,2H), 2.64(d,J=4.8Hz,3H), 2.13(br s,1H), 0.94(br d,J=6.8Hz,3H).

[0277] 2-((6-((5-chloro-2-((3R,5R)-3-((1,3-dioxoisoindolin-2-yl)methyl)-4,4-difluoro-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide and 2-((6-((5-chloro-2-((3S,5S)-3-((1,3-dioxoisoindolin-2-yl)methyl)-4,4-difluoro-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0278] 260 mg of the mixture of enantiomers was separated by SFC (Supercritical Fluid Chromatography) using a column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [Neu-IPA]; B%: 42%-42%, 12 min to give 2-[[6-[[5-chloro-2-[(3R,5R)-3-[(1,3-dioxoisoindolin-2-yl)methyl]-4,4-difluoro-5-methyl-1-piperidyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolyl] oxy]-N-methyl-acetamide as a yellow solid (75 mg, 32%) and 2-[[6-[[5-chloro-2-[(3S,5S)-3-[(1,3-dioxoisoindolin-2-yl)methyl]-4,4-difluoro-5-methyl-1-piperidyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide as a yellow solid (65 mg, 29%).

[0279] 2-((6-((2-((3S,5R)-3-(aminomethyl)-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (50a)

[0280] To a solution of 2-[[6-[[5-chloro-2-[(3R,5R)-3-[(1,3-dioxoisoindolin-2-yl)methyl]-4,4-difluoro-5-methyl-1-piperidyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (70.00 mg, 105.09 μmol, 1 equiv) in EtOH (2 mL) was added NH2NH2·HO (78.92 mg, 1.58 mmol, 76.62 μL, 15 equiv). The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (0.04% HCl)-MeCN]; B%: 15% to 35%, 8 min) to give the title compound as a white solid (6.1 mg, 6%, HCl salt).1 H NMR(400MHz,MeOD) δ=8.03(s,1H), 7.81(d,J=2.4Hz,1H), 7.68-7.60(m,1H), 7.54(d,J=9.2Hz,1H), 7.29(s,1H), 4.57(br d,J=13.8Hz,1H), 4.50(s,2H), 4.30(br d,J=12.8Hz,1H), 3.73(s,3H), 3.28-3.22(m,1H), 3.03-2.79(m,3H), 2.77(s,3H), 2.43(br d,J=13.2Hz,1H), 2.18-2.11(m,1H), 0.97(d,J=6.8Hz,3H). LCMS:[M+1] + =536.2.

[0281] 2-((6-((2-((3R,5S)-3-(aminomethyl)-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (50b)

[0282] To a solution of 2-[[6-[[5-chloro-2-[(3S,5S)-3-[(1,3-dioxoisoindolin-2-yl)methyl]-4,4-difluoro-5-methyl-1-piperidyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (65 mg, 97.59 μmol, 1 equiv) in EtOH (2 mL) was added NHNH·HO (73.28 mg, 1.46 mmol, 71.14 μL, 15 equiv). The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water (0.04% HCl)-MeCN]; B%: 15%~35%, 8 min) to give the title compound as a white solid (13.7mg, 24%, HCl salt). 1H NMR(400MHz,MeOD) δ=8.16(s,1H), 7.96(d,J=2.4Hz,1H), 7.79-7.72(m,1H), 7.65(d,J=9.2Hz,1H), 7.43(s,1H), 4.73(br d,J=12.0Hz,1H), 4.61(s,2H), 4.41(br d,J=13.6Hz,1H), 3.79(s,3H), 3.40-3.34(m,1H), 3.15-2.91(m,3H), 2. 89(s,3H), 2.70-2.53(m,1H), 2.43-2.19(m,1H), 1.09(d,J=6.8Hz,3H). LCMS:[M+1] + =536.2.

[0283] The absolute configurations of compounds 50a and 50b were randomly assigned based on the alkylamino and methyl groups being in the cis-conformation.

[0284] Example 4 Synthesis of 2-((6-((2-((3S,5R)-3-(2-aminoethyl)-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (51a) and 2-((6-((2-((3R,5S)-3-(2-aminoethyl)-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (51b) [ka]

[0285] 2-((6-((2,5-dichloropyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0286] To a solution of 2-[(6-amino-1-methyl-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide (3 g, 11.48 mmol, 1 equiv.) and 2,4,5-trichloropyrimidine (3.16 g, 17.22 mmol, 1.5 equiv.) in DMF (30 mL) was added DIEA (2.23 g, 17.22 mmol, 3.00 mL, 1.5 equiv.). The reaction mixture was stirred at 15 °C for 12 h. Water (50 mL) was added, and the precipitated solid was filtered and washed with HO (150 mL) and ethyl acetate (200 mL). The solid was dried under reduced pressure to give the title compound (3.98 g, 85%). 1 H NMR(400MHz,DMSO-d6) δ 9.65(s,1H), 8.38(s,1H), 7.94(s,1H), 7.75(s,1H), 7.66(d,J=8.4Hz,1H), 7.53 (d,J=8.8Hz,1H), 7.23(s,1H), 4.58(s,2H), 3.69(s,3H), 2.67(d,J=3.6Hz,3H).

[0287] 2-((6-((5-chloro-2-(3-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-4,4-difluoro-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0288] A mixture of 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (600 mg, 1.47 mmol, 1 equiv.), 2-[2-(4,4-difluoro-5-methyl-3-piperidyl)ethyl]isoindoline-1,3-dione (931.10 mg, 2.20 mmol, 1.5 equiv., TFA), and DIEA (379.90 mg, 2.94 mmol, 512.00 μL, 2 equiv.) in DMSO (10 mL) was stirred at 120° C. under a N atmosphere for 6 hours. Water (15 mL) was added, and the precipitated solid was filtered and washed with HO (30 mL) and ethyl acetate (30 mL). The solid was dried under reduced pressure to give the title compound as a white solid (1 g, crude). 1H NMR(400MHz,DMSO-d6) δ 8.99(s,1H), 8.03(s,1H), 7.84(s,5H), 7.74(d,J=6.8Hz,2H), 7.46(d,J=8.8Hz,1H), 7.19(s,1H), 4.58-4.48 (m,4H), 3.56(s,3H), 3.30(s,2H), 2.69-2.64(m,5H), 2.05-1.90(m,3H), 1.42(s,1H), 0.94(d,J=6.8Hz,3H).

[0289] 2-((6-((2-(3-(2-aminoethyl)-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0290] To a mixture of 2-[[6-[[5-chloro-2-[3-[2-(1,3-dioxoisoindolin-2-yl)ethyl]-4,4-difluoro-5-methyl-1-piperidyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (400 mg, 588.15 μmol, 1 equiv) in NMP (5 mL) was added NH2NH2·HO (480.00 mg, 9.59 mmol, 466.02 μL, 16.30 equiv) and the mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Phenomenex Luna C18 (250*70 mm, 15 μm); mobile phase: [water (0.1% TFA)-MeCN]; B%: 12% to 35%, 21 min) to give the title compound as a white solid (250 mg, 77%). 1H NMR(400MHz,MeOD) δ 8.14(s,1H), 7.87(d,J=2.0Hz,1H), 7.76(dd,J=9.2,2.0Hz,1H), 7.62(d,J=9.2Hz,1H), 7.31(s,1H), 4.57(s,2H), 4.48(d,J=13.2Hz,1H), 4. 38(d,J=12.8Hz,1H), 3.83(s,3H), 3.06-2.96(m,3H), 2.85(s,3H), 2.2 1-2.06(m,3H), 2.03(s,1H), 1.68-1.58(m,1H), 1.03(d,J=6.4Hz,3H).

[0291] 2-((6-((2-((3S,5R)-3-(2-aminoethyl)-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (51a) and 2-((6-((2-((3R,5S)-3-(2-aminoethyl)-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (51b)

[0292] 2-[[6-[[2-[3-(2-aminoethyl)-4,4-difluoro-5-methyl-1-piperidyl]-5-chloro-pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (150 mg, 225.90 μmol, TFA) was separated by SFC (column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 μm); mobile phase: [0.1% NH3HO IPA]; B%: 30%-30%, 15 min) to give 51a and 51b as white solids, respectively. 51a: (12 mg, yield 10%, purity 100%); 1H NMR(400MHz,MeOD) δ 7.99(s,1H), 7.87(d,J=2.0Hz,1H), 7.80(dd,J=9.2,2.4Hz,3H), 7.57(d,J=9.2Hz,1H), 7.32(s,1H), 4.69(d,J=11.6Hz,1H), 4.59- 4.55(m,3H), 3.85(s,3H), 2.87(s,3H), 2.77-2.66(m,4H), 2.04-1.89(m,3H), 1.44-1.38(m,1H), 1.02(d,J=6.8Hz,3H);LCMS:[M+H + ]=550.2. 51b: (4 mg, 3% yield, 95% purity); 1 H NMR(400MHz,DMSO-d6) δ 8.96(s,1H), 8.08(s,1H), 8.00(s,1H), 7.81(s,1H), 7.72(d,J=9.6Hz,1H), 7.48(d,J=8.8Hz,1H), 7.22(s,1H), 4.65-4.47( LCMS:[M+H + ]=550.1.

[0293] The absolute configurations of compounds 51a and 51b were randomly assigned based on the alkylamino and methyl groups being in the cis-conformation.

[0294] Example 5 Synthesis of 2-((6-((5-chloro-2-(3-(2-(dimethylamino)ethyl)-4,4-difluoro-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (53) [ka]

[0295] 2-(1-benzyl-4,4-difluoro-5-methylpiperidin-3-yl)ethan-1-amine

[0296] To a solution of 2-[2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)ethyl]isoindoline-1,3-dione (2.6 g, 6.53 mmol, 1 equiv.) in EtOH (30 mL), NHNH·H0 (3.27 g, 65.25 mmol, 3.17 mL, 10 equiv.) was added and the reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was cooled to 20 °C and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a colorless oil (1.15 g, 64% yield, 98% purity). LCMS: [M+H] + =269.0.

[0297] 2-(1-benzyl-4,4-difluoro-5-methylpiperidin-3-yl)-N,N-dimethylethan-1-amine

[0298] To a solution of 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)ethanamine (1 g, 3.73 mmol, 1 equiv.) in MeOH (15 mL) was added aqueous HCHO (2.42 g, 29.81 mmol, 2.22 mL, 37% purity, 8 equiv.) and AcOH (111.89 mg, 1.86 mmol, 106.57 μL, 0.5 equiv.). The reaction mixture was stirred at 20 °C for 30 min, then NaBH CN (1.87 g, 29.81 mmol, 8 equiv.) was added, and the reaction mixture was stirred at 20 °C for 11.5 h. The reaction mixture was quenched by adding water (50 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na SO , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by p-HPLC (column: Phenomenex Luna C18 (250*70 mm, 15 μm); mobile phase: [water (HCl)-ACN]; B%: 1%-20%, 20 min) to give the title compound as a colorless oil (320 mg, yield 29%, purity 100%). 1 H NMR(400MHz,MeOD) δ=7.38-7.27(m,5H), 3.65-3.56(m,2H), 3.23-3.18(m,2H)2.86(s,7H), 2.22-2.01(m,6H)1.64-1.61(m,1H)0.97(d,J=6.63Hz,3H).

[0299] 2-(4,4-difluoro-5-methylpiperidin-3-yl)-N,N-dimethylethan-1-amine

[0300] To a solution of 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)-N,N-dimethyl-ethanamine (160 mg, 539.82 μmol, 1 equiv.) in DMF (3 mL) was added Pd / C (0.1 g, 67.48 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 60 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (100 mg, 90% yield). 1 H NMR(400MHz,DMSO-d6) δ ppm 3.57-3.49(m,1H), 2.37-2.31(m,2H), 2.06-2.05(m,6H), 1.72-1.69(m,2 H), 1.41-1.48(m,1H), 1.02-0.92(m,4H), 0.21(dd,J=6.50,1.75Hz,3H).

[0301] 2-((6-((5-chloro-2-(3-(2-(dimethylamino)ethyl)-4,4-difluoro-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (53)

[0302] A mixture of 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (100 mg, 244.96 μmol, 1 equiv.), 2-(4,4-difluoro-5-methyl-3-piperidyl)-N,N-dimethyl-ethanamine (100 mg, 484.79 μmol, 1.98 equiv.) and DIPEA (63.32 mg, 489.91 μmol, 85.33 μL, 2 equiv.) in DMSO (2 mL) was stirred at 100° C. for 12 h. The mixture was directly purified by p-HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (HCl)-ACN]; B%: 1%-30%, 8 min) to give the title compound as a white solid (12 mg, yield 8%, purity 94%, HCl salt). 1 H NMR (400 MHz,DMSO-d6) δ=10.43(br s,1H), 9.44(br s,1H), 8.18-8.11(m,1H), 8.02(br d,J=3.8Hz,1H), 7.82(br s,1H), 7.73(br d,J=7.9Hz,1H), 7.55(br d,J=8.9Hz,1H), 7.24(s,1H), 4.58(s,4H), 3.69(br s,3H), 3.18-3.01(m,3H), 2.85-2.74(m,2H), 2.73-2.65(m,8H), 2.04(br s,3H), 1.73-1.58(m,1H), 0.94(br d,J=6.6Hz,3H). LCMS:[M+H] + =578.2.

[0303] Example 6 Synthesis of 2-((6-((2-(3-(1-amino-2-methylpropan-2-yl)-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (57) [ka]

[0304] Methyl 2-(1-benzyl-4,4-difluoro-5-methylpiperidin-3-yl)propanoate and Methyl 2-(1-benzyl-4,4-difluoro-5-methylpiperidin-3-yl)-2-methylpropanoate

[0305] To a solution of methyl 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)acetate (2.00 g, 6.73 mmol, 1 equiv) in THF (30 mL) was added LiHMDS (1 M, 7.40 mL, 1.1 equiv) dropwise at −78° C. under N. After the addition, the reaction mixture was stirred at −78° C. for 15 minutes, and then MeI (1.05 g, 7.40 mmol, 460.53 μL, 1.1 equiv) was added dropwise at −78° C. The resulting mixture was warmed to 20° C. over 1 hour. The reaction mixture was cooled to −78° C., and LiHMDS (1 M, 7.40 mL, 1.1 equiv) was added dropwise at −78° C. under N. After the addition, the reaction mixture was stirred at −78° C. for 15 minutes, and then MeI (1.05 g, 7.40 mmol, 460.61 μL, 1.1 equiv) was added dropwise at −78° C. under N. The resulting mixture was warmed to 20° C. over 1 hour and then stirred at 20° C. for 9.5 hours. The reaction mixture was cooled to 0° C., quenched with saturated aqueous NH4Cl (100 mL), and extracted with ethyl acetate (80 mL × 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1, 2 / 1) to give the title compound mixture as a yellow oil (2.2 g). LCMS: [M+H] + =326.1.

[0306] 2-(1-benzyl-4,4-difluoro-5-methylpiperidin-3-yl)propan-1-ol and 2-(1-benzyl-4,4-difluoro-5-methylpiperidin-3-yl)-2-methylpropan-1-ol

[0307] To a mixture of 2 g of methyl 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)-2-methyl-propanoate (6.15 mmol, 1 equiv.) and methyl 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)propanoate (6.15 mmol, 1 equiv.) in THF (20 mL) was added LAH (279.91 mg, 7.38 mmol, 1.2 equiv.) at 0° C. After the addition, the reaction mixture was stirred at 20° C. for 1 hour, and then the reaction mixture was cooled to 0° C. and quenched with water (2 mL). 10 g of anhydrous NaSO was added, and the mixture was stirred for 2 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a mixture of the title compounds as a yellow oil (1.6 g). LCMS: [M+H] + =298.1.

[0308] 2-(2-(1-benzyl-4,4-difluoro-5-methylpiperidin-3-yl)propyl)isoindoline-1,3-dione and 2-(2-(1-benzyl-4,4-difluoro-5-methylpiperidin-3-yl)-2-methylpropyl)isoindoline-1,3-dione

[0309] To a solution of 1.1 g of 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)-2-methylpropan-1-ol (1.68 mmol, 1 equiv.) and 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)propan-1-ol (1.68 mmol, 1 equiv.), isoindoline-1,3-dione (321.59 mg, 2.19 mmol, 1.3 equiv.), and PPh3 (573.30 mg, 2.19 mmol, 1.3 equiv.) in THF (20 mL) was added DEAD (380.67 mg, 2.19 mmol, 397.36 μL, 1.3 equiv.) under N2 at 0 °C. The reaction mixture was slowly warmed to 20 °C and stirred at 20 °C for 12 h. The reaction mixture (combined with another 0.5 g batch) was quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase MPLC (neutral conditions) to give 2-[2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)-2-methyl-propyl]isoindoline-1,3-dione as a yellow oil (400 mg, purity 73.3%, LCMS: [M+H] + =427.1) and 2-[2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)propyl]isoindoline-1,3-dione as a yellow oil (600 mg, purity 89.4%, LCMS: [M+H]+ =413.1).

[0310] 2-(2-(4,4-difluoro-5-methylpiperidin-3-yl)-2-methylpropyl)isoindoline-1,3-dione

[0311] To a solution of 2-[2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)-2-methyl-propyl]isoindoline-1,3-dione (300 mg, 703.40 μmol, 1 equiv.) in ACN (12 mL) and HO (3 mL), CAN (3.86 g, 7.03 mmol, 3.51 mL, 10 equiv.) was added and stirred at 50 °C for 12 h. To the reaction mixture (combined with another batch on a 100 mg scale), saturated aqueous NaCO (approximately 10 mL) was added. The reaction mixture was filtered, and the filter cake was washed with water (15 mL × 2) and EtOAc (15 mL × 2). The filtrate was extracted with ethyl acetate (30 mL × 3). The combined organic phase was dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (silica flash column, eluent 0-30% MeOH / DCM) to give the title compound as a yellow solid (130 mg). LCMS: [M+H] + =337.1.

[0312] 2-((6-((5-chloro-2-(3-(1-(1,3-dioxoisoindolin-2-yl)-2-methylpropan-2-yl)-4,4-difluoro-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0313] To a solution of 2-[2-(4,4-difluoro-5-methyl-3-piperidyl)-2-methyl-propyl]isoindoline-1,3-dione (130 mg, 386.47 μmol, 1 equiv.) and 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (157.77 mg, 386.47 μmol, 1 equiv.) in DMSO (2 mL), DIPEA (99.90 mg, 772.95 μmol, 134.63 μL, 2 equiv.) was added, and the reaction mixture was stirred at 100° C. for 1 hour. The reaction mixture 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×2) and EtOAc (10 mL×2). The filter cake was dried to give the title compound as a white solid (40 mg, 13% yield, 90% purity). 1 H NMR(400MHz,DMSO-d6) δ=8.97(s,1H), 8.09(s,1H), 7.82-7.75(m,5H), 7.65-7.52(m,2H), 7.34(s,1H), 7.11(s,1H), 4.73-4.34(m,4H), 3.74-3.39(m,3H), 3.28-2.87(m,3H), 2.72-2.61(m,4H), 2.11-1.64(m,2H), 0.93(d,J=6.4Hz,3H), 0.77(s,6H).

[0314] 2-((6-((2-(3-(1-amino-2-methylpropan-2-yl)-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (57)

[0315] To a solution of 2-[[6-[[5-chloro-2-[3-[2-(1,3-dioxoisoindolin-2-yl)-1,1-dimethyl-ethyl]-4,4-difluoro-5-methyl-1-piperidyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (40 mg, 56.49 μmol, 1 equiv) in EtOH (1 mL) was added NH2NH2·H2O (42.41 mg, 847.28 μmol, 41.18 μL, 15 equiv) and the reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure and directly purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water (HCl)-ACN]; B%: 20%~40%, 8 min) to give the title compound as a white solid (5.8 mg, yield 14%, purity 99%, HCl). 1 H NMR(400MHz,DMSO-d6) δ=9.14(s,1H), 8.12(s,1H), 7.99(d,J=4.4Hz,1H), 7.78(s,1H), 7.78(br s,2H), 7.68(dd,J=2.4,9.2Hz,1H), 7.47(d,J=9.2Hz,1H), 7.26(s,1H), 4.69-4.43(m,4H), 3.68(s,3H), 2.94(br t,J=10.8Hz,2H), 2.74-2.66(m,5H), 2.03-1.92(m,2H), 1.07-0.71(m,9H). LCMS:[M+H] + =578.2.

[0316] Example 7 Synthesis of 2-((6-((2-(3-(1-aminopropan-2-yl)-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (56) [ka]

[0317] 2-(2-(4,4-difluoro-5-methylpiperidin-3-yl)propyl)isoindoline-1,3-dione

[0318] To a solution of 2-[2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)propyl]isoindoline-1,3-dione (500 mg, 1.21 mmol, 1 equiv.) in MeCN (20 mL) and HO (5 mL) was added CAN (6.65 g, 12.12 mmol, 6.04 mL, 10 equiv.). The reaction mixture was stirred at 50 °C for 12 h. The pH of the reaction mixture (combined with another 100 mg batch) was adjusted to 9-10 by adding saturated aqueous NaCO solution. The reaction mixture was then filtered and washed with EtOAc (15 mL × 2). Water (20 mL) was added to the filtrate and extracted with ethyl acetate (20 mL × 3). The combined organic phase was dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (silica flash column, eluent 0-50% ethyl acetate / MeOH) to give the title compound as a yellow solid (250 mg, purity 73%). LCMS: [M+H] + =323.0.

[0319] 2-((6-((5-chloro-2-(3-(1-(1,3-dioxoisoindolin-2-yl)propan-2-yl)-4,4-difluoro-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0320] To a solution of 2-[2-(4,4-difluoro-5-methyl-3-piperidyl)propyl]isoindoline-1,3-dione (200 mg, 620.45 μmol, 1 equiv.) and 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (253.29 mg, 620.45 μmol, 1 equiv.) in DMSO (2 mL), DIPEA (160.38 mg, 1.24 mmol, 216.14 μL, 2 equiv.) was added, and the reaction mixture was stirred at 100° C. for 1 hour. Water (5 mL) was added to the reaction mixture, which was then filtered. The filter cake was washed with water (15 mL×2) and EtOAc (15 mL×2). The solid was dried under reduced pressure to give the title compound as a white solid (200 mg, 98% purity). 1 H NMR(400MHz,DMSO-d6) δ=9.04-8.92(m,1H), 8.12-8.02(m,1H), 7.99-7.75(m,5H), 7.73(d,J=8.0Hz,1H), 7.45(d,J=9.2Hz,1H), 7.16(d,J=21.6Hz,1H), 4.74-4. 29(m,4H), 3.81-3.40(m,4H), 3.31-3.00(m,2H), 2.91-2.84(m,1H), 2 .73-2.64(m,4H), 2.54(s,1H), 2.13-1.80(m,2H), 1.07-0.67(m,6H). LCMS: [M+H] + =694.2.

[0321] 2-((6-((2-(3-(1-aminopropan-2-yl)-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (56)

[0322] To a solution of 2-[[6-[[5-chloro-2-[3-[2-(1,3-dioxoisoindolin-2-yl)-1-methyl-ethyl]-4,4-difluoro-5-methyl-1-piperidyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (150 mg, 216.10 μmol, 1 equiv.) in EtOH (2 mL) and NMP (2 mL), NH2NH2·HO (162.27 mg, 3.24 mmol, 157.55 μL, 15 equiv.) was added, and the reaction mixture was stirred at 60 °C for 12 h. Water (5 mL) was added to the reaction mixture, which was then filtered. The filter cake was washed with water (15 mL × 2), EtOAc (15 mL × 2), and EtOH (15 mL × 2). The solid was dried under reduced pressure to give the title compound as a white solid (75.4 mg, 46.% yield, 92% purity). 1 H NMR(400MHz,DMSO-d6) δ=8.95(s,1H), 8.07(m,1H), 8.02-7.89(m,1H), 7.82(br d,J=5.6Hz,1H), 7.71(dd,J=2,9.2Hz,1H), 7.47(d,J=9.2Hz,1H), 7.30-7.11(m,1H), 4.63-4.42( m,4H), 3.68(s,3H), 2.83-2.73(m,1H), 2.69-2.61(m,5H), 2.04-1.70(m,2H), 0.95-0.83(m,6H). LCMS:[M+H] + =564.2.

[0323] Example 8 Synthesis of 2-((6-((5-chloro-2-((3S,5R)-3-(2-(3,3-difluoroazetidin-1-yl)ethyl)-4,4-difluoro-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (54a) and 2-((6-((5-chloro-2-((3R,5S)-3-(2-(3,3-difluoroazetidin-1-yl)ethyl)-4,4-difluoro-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (54b) [ka]

[0324] 2-(1-benzyl-4,4-difluoro-5-methylpiperidin-3-yl)acetaldehyde

[0325] To a solution of 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)ethanol (3 g, 11.14 mmol, 1 equiv.) in DCM (30 mL) was added PCC (4.80 g, 22.28 mmol, 2 equiv.), and the reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (silica flash column, eluent: 10-50% ethyl acetate / petrol) to give the title compound as a yellow oil (1 g, 34% yield). LCMS: [M+H] + =268.0.

[0326] 1-benzyl-3-(2-(3,3-difluoroazetidin-1-yl)ethyl)-4,4-difluoro-5-methylpiperidine

[0327] To a solution of 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)acetaldehyde (1 g, 3.74 mmol, 1 equiv.) and 3,3-difluoroazetidine (969.17 mg, 7.48 mmol, 2 equiv., HCl) in MeOH (10 mL), DIPEA (1.93 g, 14.96 mmol, 2.61 mL, 4 equiv.) was added and the reaction mixture was stirred at 20 °C for 1 h. NaBH CN (470.17 mg, 7.48 mmol, 2 equiv.) was then added and the reaction mixture was stirred at 40 °C for 11 h. Saturated NaHCO (40 mL) was added and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na SO , filtered, and concentrated under reduced pressure. 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 yellow oil (300 mg, 22% yield, 96% purity). 1 H NMR(400MHz,MeOD) δ=7.33-7.25(m,5H), 3.59-3.51(m,6H), 2.96-2.93(m,1H), 2.81-2.77(m,1H), 2.65-2.53(m,2H), 2.19-2.02(m,2H), 2.00-1.93(m,2H), 1.83-1.74(m,1H), 1.29-1.18(m,1H), 0.94(d,J=6.8Hz,3H). LCMS:[M+H] + =345.1.

[0328] 3-(2-(3,3-difluoroazetidin-1-yl)ethyl)-4,4-difluoro-5-methylpiperidine

[0329] A mixture of 1-benzyl-3-[2-(3,3-difluoroazetidin-1-yl)ethyl]-4,4-difluoro-5-methylpiperidine (200 mg, 580.74 μmol, 1 equiv.), CAN (3.18 g, 5.81 mmol, 2.89 mL, 10 equiv.) in MeCN (8 mL) and HO (2 mL) was stirred at 40° C. for 12 hours. The pH of the reaction mixture (combined with another batch on a 100 mg scale) was adjusted to 10 by adding saturated aqueous NaCO (20 mL). The reaction mixture was concentrated under reduced pressure, and the concentrate was washed with THF (80 mL×2) and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (230 mg, crude). LCMS: [M+H] + =255.2.

[0330] 2-((6-((5-chloro-2-(3-(2-(3,3-difluoroazetidin-1-yl)ethyl)-4,4-difluoro-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0331] A mixture of 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (50 mg, 122.48 μmol, 1 equiv.), 3-[2-(3,3-difluoroazetidin-1-yl)ethyl]-4,4-difluoro-5-methyl-piperidine (152.66 mg, 306.19 μmol, 51% purity, 2.5 equiv.), DIPEA (31.66 mg, 244.96 μmol, 42.67 μL, 2 equiv.) in DMSO (1 mL) was stirred at 100° C. for 3 h. The mixture (combined with another batch on a 20 mg scale) was directly purified by p-HPLC (column: Phenomenex C18 80*40 mm*3 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 50%-80%, 8 min) to give the title compound as a white solid (50 mg, purity 100%). 1H NMR(400MHz,DMSO-d6) δ=8.99(s,1H), 8.08(s,1H), 7.95(br d,J=4.0Hz,1H), 7.85(br s,1H), 7.69(dd,J=2.0,8.8Hz,1H), 7.47(d,J=9.2Hz,1H), 7.23(s,1H), 4.68-4.44(m,4H), 3.68(s,3H), 2.67-2.6 2(m,5H), 2.54-2.52(m,4H), 2.39-2.18(m,2H), 2.05-1.86(m,2H), 1.70-1.62(m,1H), 1.23-1.15(m,1H), 0.94(br d,J=6.4Hz,3H).

[0332] 2-((6-((5-chloro-2-((3S,5R)-3-(2-(3,3-difluoroazetidin-1-yl)ethyl)-4,4-difluoro-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (54a) and 2-((6-((5-chloro-2-((3R,5S)-3-(2-(3,3-difluoroazetidin-1-yl)ethyl)-4,4-difluoro-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (54b)

[0333] 2-[[6-[[5-chloro-2-[3-[2-(3,3-difluoroazetidin-1-yl)ethyl]-4,4-difluoro-5-methyl-1-piperidyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (50 mg, 79.87 μmol) was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O ​​ETOH]; B%: 50%-50%, 10 min) to give compound 54a as a white solid (13.9 mg, 27% yield, 99% purity); 1H NMR(400MHz,DMSO-d6) δ=8.99(s,1H), 8.08(s,1H), 7.96(br d,J=4.4Hz,1H), 7.85(s,1H), 7.69(dd,J=2.0,8.8Hz,1H), 7.47(d,J=9.2Hz,1H), 7.23(s,1H), 4.59-4.52(m,4H), 3.68(s,3H), 2.67-2. 62(m,5H), 2.52(m,4H), 2.38-2.32(m,2H), 2.04-1.86(m,2H), 1.70-1.62(m,1H), 1.23-1.15(m,1H), 0.94(d,J=6.4Hz,3H);LCMS:[M+H] + = 626.1; and compound 54b was obtained as a white solid (12.2 mg, 24% yield, 99% purity); 1 H NMR(400MHz,DMSO-d6) δ=8.99(s,1H), 8.08(s,1H), 7.96(br d,J=4.4Hz,1H), 7.85(s,1H), 7.69(dd,J=2.0,8.8Hz,1H), 7.47(d,J=9.2Hz,1H), 7.23(s,1H), 4.69-4.42(m,4H), 3.68(s,3H), 2.68-2.62 (m,5H), 2.54-2.52(m,4H), 2.35-2.17(m,2H), 2.04-1.86(m,2H), 1.70-1.62(m,1H), 1.23-1.15(m,1H), 0.94(d,J=6.4Hz,3H);LCMS:[M+H] + =626.1

[0334] Example 9: 5-[[2-[(3S,5R)-3-amino-4,4-difluoro-5-methyl-1-piperidyl]-5-chloro-pyrimidin-4-yl]amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (1) [ka]

[0335] 2-[(3S,5R)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidyl]isoindoline-1,3-dione

[0336] To a solution of 5-[(2,5-dichloropyrimidin-4-yl)amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (100 mg, 252.35 μmol, 1 equiv.) in DMSO (1 mL) was added DIEA (65.22 mg, 504.7 μmol, 87.92 μL, 2 equiv.) and 2-[(3S,5R)-4,4-difluoro-5-methyl-3-piperidyl]isoindoline-1,3-dione (70.73 mg, 252.35 μmol, 1 equiv.). The reaction mixture was stirred under N at 100° C. for 12 hours. The reaction mixture was diluted with water (10 mL), filtered, and the filter cake was dried under reduced pressure to give the title compound as a yellow solid (120 mg, 59% yield, 79% purity). LCMS: [M+H] + =640.3.

[0337] 5-[[2-[(3S,5R)-3-amino-4,4-difluoro-5-methyl-1-piperidyl]-5-chloro-pyrimidin-4-yl]amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (1)

[0338] To a solution of 2-[(3S,5R)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidyl]isoindoline-1,3-dione (120 mg, 187.48 μmol, 1 equiv.) in EtOH (6 mL), MeNH (6 mL, 40% purity in water) was added, and the reaction mixture was stirred at 70 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 80*40 mm*3 μm; mobile phase: [water (FA)-MeCN]; B%: 1%-40%, 8 min) to give the title compound as a white solid (35 mg, 33% yield, 98% purity). 1 H NMR(400MHz,MeOD) δ=7.99(s,1H), 7.40(d,J=1.6Hz,1H), 7.34(dd,J=1.9,8.4Hz,1H), 7.15(d,J=8.4Hz,1H), 4.82(br d,J=2.0Hz,1H), 4.57(br d,J=13.2Hz,1H), 4.08-3.97(m,2H), 3.43(s,3H), 3.24-3.11(m,1H), 2.86(t,J=12.4Hz,1H), 2. 71(t,J=12.8Hz,1H), 2.17-1.98(m,1H), 1.89-1.83(m,2H), 1.28(s,6H), 1.04(d,J=6.8Hz,3H). LCMS:[M+H] + =510.3.

[0339] Example 10: Degradation activity in SU-DHL-4 cells HiBiT Protocol

[0340] DC 50The concentration required to achieve 50% degradation was determined from a cell degradation assay (HiBiT, Promega™) in Su-DHL-4 cells (Table 1). Endogenous B-cell lymphoma 6 (BCL6) was tagged with the 11-amino acid Small BiT (SmBiT) via clustered regularly interspaced short palindromic repeats (CRISPR) / CRISPR-associated protein 9 (Cas9) gene editing and single-cell clonal selection. After 24 hours of compound treatment, cells were lysed and incubated with Large BiT (LgBiT) protein to reconstitute intact nanoluciferase. Substrate was then added, and relative luciferase units were measured. The degradation level for each treatment was expressed as a percentage compared to the control, 100% DMSO (Prism).

[0341] Example 11: Kinetic Solubility

[0342] Preparation of 50 mM phosphate buffer (PB) with a pH of 7.4: a) Preparation of 50 mM NaH2PO4: 3.00 g of NaH2PO4 was dissolved in 500 mL of water, and the measured pH was about 4.5; b) Preparation of 50 mM Na2HPO4: 3.55 g of Na2HPO4 was dissolved in 500 mL of water, and the measured pH was about 9.4; c) Preparation of 50 mM PB (pH 7.4): 15 mL of 50 mM NaHPO was added to a 50 mL tube, and then the pH was adjusted to 7.4 with 50 mM NaHPO.

[0343] protocol: a) 10 μL of 10 mM test compound and control compound in DMSO were each added to the lower chamber of a Whatman® Mini-UniPrep® vial; b) 490 μL of 50 mM PB (pH 7.4) was added to the lower chamber of each Whatman® Mini-UniPrep® vial; c) the soluble sample was vortexed for at least 2 minutes; d) The Mini-UniPrep® vials were shaken on a Barnstead shaker at 800 rpm at room temperature for 24 hours, then centrifuged (e.g., 4000 rpm) for 20 minutes; e) The Mini-UniPrep® vial was compressed to prepare the filtrate for injection into the UPLC system and the concentration was calculated using the standard curve.

[0344] Example 12: Metabolic stability in human liver microsomes

[0345] Preparation of solutions a) Phosphate buffer solution K2HPO4 was dissolved in water to a final concentration of 50 mM, then the pH was adjusted to 7.4 with HCl and filtered through a 0.22 μm filter. b) Quenching Solution A 1 mg / mL stock of terfenadine / tolbutamide with DMSO was prepared and then canned to make the quenching solution (5 / 10 ng / mL terfenadine / tolbutamide). c) Test compound working solution 10 mM test compound stocks were prepared in DMSO and then made up to 200 μM working solutions with DMSO. d) Control compound working solution A 10 mM control compound (dextromethorphan) stock was prepared in DMSO and then made up to a 200 μM working solution with DMSO. e) Liver microsome working solution Liver microsomes were thawed in a 37°C water bath and then made up to a 0.63 mg / mL liver microsome working solution with phosphate buffer. f)NADPH solution A 5 mM NADPH working solution was prepared in phosphate buffer.

[0346] Sample preparation a) 1.5 μL of test compound / control compound working solution was added to 238.5 μL of liver microsomes (n=1). b) The solution was pre-incubated at 37°C for 5 minutes. c) The reaction was initiated by adding 60 μL of NADPH working solution. d) At each time point (0, 5, 15, 30 and 60 minutes), 30 μL of the reaction mixture was removed and added to 300 μL of quenching solution. e) All samples were centrifuged at 4,000 rpm at 4°C for 15 minutes, and then 100 μL of the supernatant was transferred to 100 μL of water for LC-MS / MS analysis.

[0347] Table 1. Potency and solubility data [Table 1]

[0348] Structures of known compounds: [ka]

[0349] The results shown in Table 1 demonstrate that polar or charged moieties on the piperidine ring (compounds 1, 50, 51, and 97) resulted in degraders of BCL6. These results were surprising and unexpected, given reports that polar or charged moieties generally result in non-degraders (Kerres, et al., Cell Rep. 20(12):2860-2875 (2017)). Introduction of a basic center resulted in maintaining or improving the potency of the compounds and / or improving their kinetic solubility.

[0350] 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.

[0351] 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 many modifications can be made to the illustrative embodiments and that other arrangements can be devised without departing from the spirit and scope of the 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 is CH ２ , S, CHF, CHCl, CHOH, or CF ２ and R １ is hydrogen, cyano, halo, -OR ９ , -N(R ９ ) ２ , -C(O)N(R ９ ) ２ , -SO ２ N (R ９ ) ２ , -N(R ９ ) C(O)R ９ , -N(R ９ ) SO ２ R ９ , -N(R ９ )C(O)N(R ９ ) ２ , -P(O)(R ９ ) ２ , (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) hydroxyalkyl, (C ３ -C ７ ) carbocyclyl, 4- to 7-membered heterocyclyl, (C ６ -C １０ ) aryl, monocyclic or bicyclic 5-10 membered heteroaryl, (C ２ -C ６ ) alkenyl, or (C ２ -C ６ ) alkynyl; said alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be one or more of the same or different R １０ may be further substituted by groups; Each R ９ are independently hydrogen, (C １－ C ６ ) alkyl, (C ３ -C ７ ) carbocyclyl, 4- to 7-membered heterocyclyl, (C ６ -C １０ ) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl; said alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl may be one or more of the same or different R １０ may be further substituted by groups; Each R １０ are independently alkyl, alkenyl, alkynyl, halo, haloalkyl, carbocyclyl, heterocyclyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkylenyloxy, alkynyloxy, amino, alkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, aralkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-aralkylamino, hydroxyalkyl, aminoalkyl, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, N-alkyl-N-arylaminosulfonyl, N- alkyl-N-heteroarylaminosulfonyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylsulfonylamino, haloalkylsulfonylamino, cycloalkylsulfonylamino, heterocycloalkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, N-alkyl-N-heteroarylaminocarbonyl, cyano, nitro, azido, or phosphinyl; R ２ is hydrogen, cyano, halo, -OR ９ , -N(R ９ ) ２ , -C(O)N(R ９ ) ２ , -SO ２ N (R ９ ) ２ , -N(R ９ ) C(O)R ９ , -N(R ９ ) SO ２ R ９ , -N(R ９ )C(O)N(R ９ ) ２ , -P(O)(R ９ ) ２ , (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) hydroxyalkyl, (C ３ -C ７ ) carbocyclyl, 4- to 7-membered heterocyclyl, (C ６ -C １０ ) aryl, monocyclic or bicyclic 5-10 membered heteroaryl, (C ２ -C ６ ) alkenyl, or (C ２ -C ６ ) alkynyl; said alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be one or more of the same or different R １０ may be further substituted by a group, or R １ and R ２ together with the same carbon atom to which they are attached to form spiro (C ３ -C ７ ) a carbocyclyl group or a 4- to 7-membered heterocyclyl group; said carbocyclyl or heterocyclyl may be one or more of the same or different R １０ may be further substituted by groups; R ３ is hydrogen, cyano, halo, -OR ９ , -N(R ９ ) ２ , -C(O)N(R ９ ) ２ , -SO ２ N (R ９ ) ２ , -N(R ９ ) C(O)R ９ , -N(R ９ ) SO ２ R ９ , -N(R ９ )C(O)N(R ９ ) ２ , -P(O)(R ９ ) ２ , (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) hydroxyalkyl, (C ３ -C ７ ) carbocyclyl, 4- to 7-membered heterocyclyl, (C ６ -C １０ ) aryl, monocyclic or bicyclic 5-10 membered heteroaryl, (C ２ -C ６ ) alkenyl, or (C ２ -C ６ ) alkynyl; said alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be one or more of the same or different R １０ may be further substituted by groups; R ４ is hydrogen, cyano, halo, -OR ９ , -N(R ９ ) ２ , -C(O)N(R ９ ) ２ , -SO ２ N (R ９ ) ２ , -N(R ９ ) C(O)R ９ , -N(R ９ ) SO ２ R ９ , -N(R ９ )C(O)N(R ９ ) ２ , -P(O)(R ９ ) ２ , (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) hydroxyalkyl, (C ３ -C ７ ) carbocyclyl, 4- to 7-membered heterocyclyl, (C ６ -C １０ ) aryl, monocyclic or bicyclic 5-10 membered heteroaryl, (C ２ -C ６ ) alkenyl, or (C ２ -C ６ ) alkynyl; said alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be one or more of the same or different R １０ may be further substituted by groups; R ５ is hydrogen, cyano, halo, -OR ９ , -N(R ９ ) ２ , -C(O)N(R ９ ) ２ , -SO ２ N (R ９ ) ２ , -N(R ９ ) C(O)R ９ , -N(R ９ ) SO ２ R ９ , -N(R ９ )C(O)N(R ９ ) ２ , -P(O)(R ９ ) ２ , (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) hydroxyalkyl, (C ３ -C ７ ) carbocyclyl, 4- to 7-membered heterocyclyl, (C ６ -C １０ ) aryl, monocyclic or bicyclic 5-10 membered heteroaryl, (C ２ -C ６ ) alkenyl, or (C ２ -C ６ ) alkynyl; said alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be one or more of the same or different R １０ may be further substituted by groups; R ６ does not exist or (C １ -C ６ ) alkylene, or (C ３ -C ７ ) carbocyclyl; said alkylene or carbocyclyl may be one or more of the same or different R １０ may be further substituted by a group, or R ５ and R ６ together with the same carbon atom to which they are attached to form spiro (C ３ -C ７ ) a carbocyclyl group or a 4- to 7-membered heterocyclyl group; said carbocyclyl or heterocyclyl may be one or more of the same or different R １０ may be further substituted by a group, or R ６ is R ７ and combine to form a 4- to 6-membered heterocyclyl group, (C ２ -C ４ ) alkylene; R ７ and R ８ are each independently hydrogen, (C １ -C ６ ) alkyl, (C ３ -C ７ ) carbocyclyl, 4- to 7-membered heterocyclyl, (C ６ -C １０ ) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl; said alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl may be one or more of the same or different R １０ may be further substituted by a group, or R ７ and R ８ together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclyl, said heterocyclyl being comprised of one or more of the same or different R １０ may be further substituted by groups; 【Chemistry 2】 teeth 【Chemistry 3】 and X １ and X ２ is independent, CR １７ or N; R １７ is hydrogen, (C １ -C ４ ) alkyl, halo, hydroxy, amino, (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, nitro, cyano, NH(C １ -C ４ ) alkyl, or N(C １ -C ４ alkyl) ２ and X ３ is CH or N; X ４ is CR １７ or N; R １７ is hydrogen, fluorine, chloro, or methyl; R １１ is Cl or CN; R １２ is hydrogen, (C １ -C ６ ) alkyl, (C ３ -C ６ ) carbocyclyl, 4- to 7-membered heterocyclyl, (C ３ -C ７ ) carbocyclyl (C １ -C ６ ) alkyl, or 4- to 7-membered heterocyclyl (C １ -C ６ ) alkyl; said alkyl, carbocyclyl, or heterocyclyl is (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, halo, amino, hydroxyl, haloalkyl, NH(C １ -C ６ ) alkyl, N((C １ -C ６ ) alkyl) ２ , (C ３ -C ６ ) carbocyclyl, and 4- to 7-membered heterocyclyl, or R １２ is -LYZ or -LYZ; 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 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) ２ N(R'), or N(R')S(O) ２ and Each R' is independently hydrogen or (C １ -C ４ ) alkyl; Z is hydrogen, (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; １ -C ４ ) alkyl, halo, (C １ -C ４ ) haloalkyl, (C １ -C ４ ) haloalkoxy, amino, (C １ -C ４ ) aminoalkyl, cyano, hydroxy, 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 where R ｒ , R ｓ and R ｔ are each independently hydrogen, (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 ) forming a 4- to 9-membered heterocyclyl optionally substituted by one or more substituents selected from alkylamino, amino, cyano, and hydroxy; R １３ is hydrogen, methyl, -(CH ２ ) １－３ W １ W ２ ,or 【Chemistry 4】 and W １ is CR １８ R １８ or C(O); R １８ and R １８’ are independently hydrogen, (C １ -C ２ ) alkyl, fluoro, hydroxy, cyano, nitro, (C １ -C ２ ) alkoxy, (C １ -C ２ ) haloalkyl, (C １ -C ２ ) haloalkoxy, amino, NH(C １ -C ２ ) alkyl, or N(C １ -C ２ alkyl) ２ and R １８ and R １８’ 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 represented by (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 ) optionally substituted with one or more substituents independently selected from alkylamino, amino, cyano, and hydroxy; W ２ is cyano, hydroxy, 5- or 6-membered heteroaryl, phenyl, C(O)—(C １ -C ２ ) alkyl, S(O) ２ -(C １ -C ２ ) alkyl, C(O)OCH ３ , C(O)NHCH ３ , C.R. １９ R ２０ R ２１ , amino, NH(C １ -C ２ ) alkyl, or N(C １ -C ２ alkyl) ２ and: R １９ is hydrogen, (C １ -C ２ ) alkyl, fluoro, chloro, bromo, hydroxy, amino, cyano, nitro, (C １ -C ２ ) alkoxy, (C １ -C ２ ) haloalkyl, or (C １ -C ２ ) haloalkoxy; R ２０ is hydrogen, (C １ -C ２ ) alkyl, fluoro, chloro, bromo, hydroxy, cyano, nitro, (C １ -C ２ ) alkoxy, (C １ -C ２ ) haloalkyl, (C １ -C ２ ) haloalkoxy, or -Y ２ -L ２ -Z ２ and 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 hydrogen, (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 and N(R')C(O)R', wherein each R' is independently selected from hydrogen or (C １ -C ４ ) alkyl; Or, R １９ and R ２０ 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 ) optionally substituted with one or more substituents selected from alkylamino, amino, cyano and hydroxy (C ３ -C ６ ) forming a carbocyclyl or a 3- to 6-membered heterocyclyl; R ２１ 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 hydrogen or (C １ -C ２ ) alkyl; A'' is (C １ -C ２ ) alkyl, halo, hydroxy, cyano, and (C １ -C ２ ) alkoxy (C ４ -C ６ ) carbocyclyl or 4- to 6-membered heterocyclyl; W ３ is NR ２２ or CR ２３ R ２３ and R ２２ is hydrogen, (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 ２３ and R ２３’ are independently hydrogen, (C １ -C ２ ) alkyl, cyclopropyl, fluoro, chloro, bromo, hydroxy, amino, cyano, nitro, (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 １４ Is, -L ３ CR ２４ R ２５ R ２６ or —CH═CH—R ２６ and L ３ 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 ２４ is hydrogen or (C １ -C ４ ) alkyl; R ２５ is hydrogen or (C １ -C ４ ) alkyl, or R ２４ and R ２５ 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 ２６ is (C １ -C ６ ) alkyl, —NR ２７ R ２８ , -OR ２７ , -C(O)R ２７ , -C(O)OR ２７ , -N(R ２８ ) C(O)R ２７ , —C(O)NR ２７ R ２８ , —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 , or -(C １ -C ４ ) alkyl-NR ２８ C(O)R ２７ and R ２７ is hydrogen, 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 ２８ is hydrogen or (C １ -C ４ ) alkyl; R １５ is hydrogen, (C １ -C ４ ) alkyl, (C ３ -C ６ ) cycloalkyl, (C １ -C ４ ) haloalkyl, or cyano, wherein the alkyl or cycloalkyl is (C １ -C ４ ) alkyl, (C ３ -C ６ ) cycloalkyl, hydroxy, (C １ -C ２ ) alkoxy, amino, 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 １５ ' is hydrogen, (C １ -C ４ ) alkyl, cyano, (C １ -C ４ ) haloalkyl, or -Y ３ -L ４ -Z ３ and Y ３ is absent, C(O)O or C(O)N(R'); L ４ does not exist or (C １ -C ２ ) alkylene; Z ３ is hydrogen, (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 ) optionally substituted with one or more substituents independently selected from alkoxy, amino, nitro, cyano, and hydroxy; or R １５ and R １５ ', 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, and R １５ and R １５ 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 ) may be further substituted with one or more substituents independently selected from alkoxy, amino, cyano, and hydroxy; R １６ is hydrogen, (C １ -C ２ ) alkyl, (C ３ -C ４ ) cycloalkyl, (C １ -C ２ ) haloalkyl, cyano, (C ２ -C ４ ) alkenyl, or (C ２ -C ４ ) alkynyl; R １６ ' is (C １ -C ４ ) alkyl, cyano, (C １ -C ４ ) haloalkyl, or -Y ４ -L ５ -Z ４ and Y ４ is absent, C(O), C(O)O, OC(O), C(O)N(R'), or S(O) ２ N(R'), L ５ 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 hydrogen, (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, wherein 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, amino, nitro, cyano, hydroxy, 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 hydrogen, (C １ -C ４ ) alkyl, or (C ３ -C ６ ) cycloalkyl, or Z ４ Is -Q-L ６ -W, where Q is absent, O, NH, or N(C １ -C ２ ) alkyl; L ６ is absent or is oxo and (C １ -C ２ ) alkyl (C １ -C ２ ) alkylene; W 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 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 ) optionally substituted with one or more substituents independently selected from alkylamino, amino, nitro, cyano, or hydroxy; or R １６ and R １６ ', together with the carbon atom to which they are attached, form 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 ) optionally substituted by one or more substituents independently selected from alkylamino, amino, nitro, cyano, or hydroxy (C ３ -C １０ ) forming a carbocyclyl or a 4- to 10-membered heterocyclyl; or (C ３ -C １０ ) carbocyclyl or 4- to 10-membered heterocyclyl is optionally fused to a 5- or 6-membered heteroaryl or phenyl ring, and the 5- or 6-membered heteroaryl or phenyl ring 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 ) optionally substituted by alkylamino, amino, nitro, cyano, or hydroxy; and R １６ '' is hydrogen, (C １ -C ４ ) alkyl, (C １ -C ２ ) haloalkyl, (C １ -C ２ ) alkoxy, (C １ -C ２ ) haloalkoxy, cyano, nitro, acetylenyl, phenyl, or 5- or 6-membered heteroaryl, wherein said alkyl, phenyl, or heteroaryl is optionally substituted with one or more substituents independently selected from halo, hydroxy, and amino; However, R ７ However, (C １ -C ３ ) alkyl, and R ８ However, (C １ -C ３ ) alkyl, R ６ is (C １ -C ６ ) is not alkylene, and however, 【Chemistry 5】 but 【Chemistry 6】 and R １１ is Cl and X is CH ２ or CF ２ and R ６ may be absent or substituted (C １ -C ２ ) alkylene, R ７ and R ８ a) may be independently substituted with hydrogen or an oxo group (C １ -C ２ a) cannot be alkyl, or b) R ７ and R ８ cannot be taken together with the nitrogen atom to which they are attached to form a 4-membered heterocyclyl optionally substituted with a gem-difluoro group. 【Request 2】 【Chemical 7】 but 【Chemistry 8】 and the compound is of formula I-1 【Chemistry 9】 2. The compound of claim 1 having the structure: 【Request 3】 【Chemical 10】 but 【Chemistry 11】 and the compound is of formula I-2 【Chemistry 12】 2. The compound of claim 1 having the structure: 【Request 4】 【Chemical 13】 but 【Chemistry 14】 and the compound is of formula I-3 【Chemistry 15】 2. The compound of claim 1 having the structure:

5. 【Catalog 16】 but 【Chemistry 17】 and the compound is of formula I-4 【Chemistry 18】 2. The compound of claim 1 having the structure:

6. 【Chemical 19】 but 【Chemistry 20】 and the compound is of formula I-5 【Chemical 21】 2. The compound of claim 1 having the structure:

7. R １１ The compound of claim 1 , wherein is Cl.

8. R １１ The compound of claim 1 , wherein is CN.

9. R １ is hydrogen, -OR ９ , or (C １ -C ６ ) alkyl.

10. R １ The compound of claim 9, wherein is hydrogen, methyl, or —OH.

11. R １ The compound of claim 10, wherein is hydrogen.

12. R １ The compound of claim 10, wherein is methyl.

13. R ２ is hydrogen, -OR ９ , or (C １ -C ６ ) alkyl.

14. R ２ The compound of claim 13, wherein is hydrogen, methyl, or —OH.

15. R ２ 15. The compound of claim 14, wherein is hydrogen.

16. R ２ The compound of claim 14, wherein is methyl.

17. R １ and R ２ together with the same carbon atom to which they are attached to form spiro (C ３ -C ７ ) forming a carbocyclyl group.

18. R １ and R ２ together with the same carbon atom to which they are attached to form spiro (C ３ ) forming a carbocyclyl.

19. R ３ The compound of claim 1 , wherein is hydrogen.

20. R ４ The compound of claim 1 , wherein is hydrogen.

21. R ５ is hydrogen, -OR ９ , or (C １ -C ６ ) alkyl.

22. R ５ 22. The compound of claim 21, wherein is hydrogen, methyl, or -OH.

23. R ５ 23. The compound of claim 22, wherein is hydrogen.

24. R ５ 23. The compound of claim 22, wherein is methyl.

25. R ６ is optionally substituted (C １ -C ６ ) alkylene or optionally substituted (C ３ -C ７ 2. The compound of claim 1, wherein:

26. R ６ is optionally substituted (C １ -C ２ ) alkylene or optionally substituted (C ３ -C ４ 26. The compound of claim 25, wherein:

27. R ６ is C １ - alkylene.

28. R ６ is C ２ - alkylene.

29. R ６ may contain one or more identical or different R １０ C substituted with a group １ - alkylene.

30. R ６ may contain one or more identical or different R １０ C substituted with a group ２ - alkylene.

31. Each R １０ 30. The compound of claim 29, wherein is methyl, fluoro, or cyclopropyl.

32. R ６ is C ３ -carbocyclyl.

33. R ６ is C ４ -carbocyclyl.

34. R ５ and R ６ together with the same carbon atom to which they are attached to form spiro (C ３ -C ７ ) forming a carbocyclyl group.

35. R ５ and R ６ together with the same carbon atom to which they are attached to form spiro (C ３ ) forming a carbocyclyl.

36. R ６ But, R ７ to form a 4- to 6-membered heterocyclyl group (C ２ -C ４ ) alkylene.

37. R ６ But, R ７ to form a 4-membered heterocyclyl group (C ２ -C ３ ) alkylene.

38. R ７ is hydrogen or (C １ -C ６ ) alkyl.

39. R ７ 39. The compound of claim 38, wherein is hydrogen or methyl.

40. R ８ is hydrogen or (C １ -C ６ ) alkyl.

41. R ８ 41. The compound of claim 40, wherein is hydrogen or methyl.

42. R ７ and R ８ The compound of claim 1, wherein, together with the nitrogen atom to which they are attached, form a 3- to 7-membered heterocyclyl.

43. R ７ and R ８ 43. The compound of claim 42, wherein, together with the nitrogen atom to which they are attached, form a three-membered heterocyclyl.

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

45. 2. The compound of claim 1, wherein X is CHF.

46. X is CF ２ 2. The compound of claim 1, wherein:

47. The following structure: 【Chemical 22】 【Chemical 23】 【Chemistry 24】 【Chemistry 25】 【Chemical formula 26】 【Chemical 27】 【Chemical formula 28】 【Chemical formula 29】 【Chemistry 30】 【Chemical 31】 【Chemical Formula 32】 【Chemical 33】 【Chemical 34】 【Chemistry 35】 【Chemical 36】 【Chemical 37】 【Chemical 38】 【Chemical 39】 【Chemistry 40】 2. The compound of claim 1, wherein:

48. 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

49. 49. The pharmaceutical composition of claim 48, in liquid or solid form.

50. 10. A method for treating a disease or disorder characterized by aberrant B-cell lymphoma 6 (BCL6) activity, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof.

51. 51. The method of claim 50, wherein the disease or disorder is a lymphoid malignancy.

52. 52. The method of claim 51, 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.

53. 51. The method of claim 50, further comprising administering an additional anti-cancer agent.

54. 54. The method of claim 53, wherein the additional anticancer agent is an enhancer of zeste homolog 2 (EZH2) inhibitor.

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