BCL6 micromolecule degradation agent containing alkylamine

Abstract

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

Description

[0001] Related Applications

[0002] This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 416,736, filed on October 17, 2022, which is incorporated herein by reference in its entirety. Background Art

[0003] 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, regulate Cullin Really Interesting New Gene (RING) ligase 4-cereblon (CRBN) (CRL4 CRBN ) E3 ubiquitin ligase activity to recruit and ubiquitinate new substrates, including Ikaros family zinc finger protein 1 (IKZF1), IKZF3, and casein kinase 1-α (CK1α), which leads to their proteasomal degradation (Kronke et al., Science 343:301-305 (2014); Lu et al., Science 343:305-309 (2014); Kronke et al., Nature 523:183-188 (2015)). Other small molecules that induce protein degradation include arylsulfonamides, which bind to CRL4-DNA damage binding protein 1 (DDB1) and CUL4-associated factor 15 (DCAF15) (CRL4 DCAF15 )-dependent manner to promote the destruction of RNA-binding motif protein 39 (RBM39) (Han et al., Science 356:eaa13755 (2017)).

[0004] Other types of small molecules include heterobifunctional degraders (also known as PROTACs) (Toure et al., Angew. Chem. Int. Ed. Engl. 55: 1966-1973 (2016)), which have been developed for a wide range of targets, including kinases (Huang et al., Cell Chem. Biol. 25: 88-99 (2018)), nuclear receptors (Bondeson et al., Nat. Chem. Biol. 11: 611-617 (2015)), and epigenetic enzymes (Winter et al., Science 348: 1376-1381 (2015)). These small molecule degraders bind 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)).

[0005] Although degraders can show significant 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)).

[0006] BCL6 was originally identified as a locus affected by chromosomal translocation in diffuse large B-cell lymphoma (DLBCL). It is now known that it is widely expressed in many lymphomas. Its role in lymphomagenesis stems from its function in the humoral immune system, where, during the humoral immune response, the formation of germinal centers (GCs) requires upregulation of BCL6 (Ye et al., Nat. Genet. 16: 161-170 (1997); Dent et al., Science 276: 89-92 (1997)). GC is a transient structure formed in response to antigenic stimulation. In GC, B cells tolerate massive proliferation and the mutagenic effects of the DNA editing enzyme AICDA to undergo immunoglobulin affinity maturation (Klein et al., Nat. Rev. Immunol. 8: 22-33 (2008)). These activities are regulated by and depend 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 exit from GC reaction and plasma cell differentiation (e.g., IRF4, PRDM1). This ensures that GC B cells have sufficient time to acquire somatic hypermutations of their immunoglobulin genes. Therefore, dysregulated repression of these target genes may lead to malignant transformation of B cells.

[0007] BCL6 also represses many oncogenes in GC B cells, including MYC, BCL2, BCL1, and CCND1 (Ci et al., Blood 113: 5536-5548 (2009)). Through this function, BCL6 can alleviate its own pro-oncogenic checkpoint repressive effects, thereby reducing the likelihood of malignant transformation of GC B cells. This effect is abolished in the presence of BCL2 or MYC translocations, which drive the expression of these oncogenes through abnormal regulatory elements. The presence of MYC and / or BCL2 together with BCL6 (regardless of the presence of translocations) is clearly harmful because it provides simultaneous inhibition of checkpoints for B cells through BCL6, while also providing the growth-promoting and survival effects of MYC and BCL6 (Cardenas et al., Clin. Cancer Res. BCL6: 885-893 (2017)). In normal immune responses, BCL6 function is terminated by disruption of the BCL6 transcription complex through 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 exit the GC response.

[0008] BCL6 is a promising drug target for non-Hodgkin lymphoma, such as diffuse large B-cell lymphoma (DLBCL) (Cerchietti et al., Cancer Cell 77: 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 increased BCL6 expression caused by somatic BCL6 translocation, exonic mutation, promoter mutation or regulatory pathway mutation is a common driver of B-cell malignancies (Hatzi et al., Trends Mol. Med. 20: 343-352 (2014)). In genetically engineered mice, overexpression of BCL6 is sufficient to drive the development of lymphoma (Cattoretti et al., Cancer Cell 7: 445-455 (2005)). BCL6 acts as a major transcriptional repressor, enabling rapid expression of germinal center (GC) B cells and tolerance to genomic instability caused by hypermutation and class switch recombination of immunoglobulin genes (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. 13: 1158-1165 (2004)) and differentiation (Phan et al., Nat. Immunol. 6: 1054-1060 (2005)). As expected, knockout of BCL6 in lymphoma cells resulted 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 limits their translation into clinical therapeutics (Cerchietti et al., Cancer Cell 17: 400-411 (2010); Cardenas et al., J. Clin. Invest. 126: 3351-3362 (2016)).

[0009] Broad complex / Tramtrack / Bric-a-brac (BTB) proteins are a diverse family of proteins characterized by the presence of a common protein-protein interaction domain, referred to as the BTB domain. BTB proteins have a variety of functions ranging from transcriptional regulation and chromatin remodeling to protein degradation and cytoskeletal regulation. The specificity of function depends in part on the presence of other domains and interacting partners in a given BTB protein. Studies of BTB proteins in Drosophila and mammalian systems have revealed the importance of these proteins in a variety of developmental contexts as well as in cancer and neurological and musculoskeletal diseases. BTB proteins play key roles in transcriptional regulation and chromatin remodeling (Chaharbakhshi et al., Genesis 54: 505-518 (2016)).

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

[0011] The first aspect of the present invention relates to a compound having a structure represented by formula (I):

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

[0013] in:

[0014] X is CH2, S, CHF, CHC1, CHOH or CF2;

[0015] R1 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SO2N(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 to 10 membered heteroaryl, (C2-C6)alkenyl or (C2-C6)alkynyl; wherein the alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is further optionally replaced by one or more identical or different R 10 Group substitution;

[0016] Each R9 is independently hydrogen, (C1-C6) alkyl, (C3-C7) carbocyclyl, 4- to 7-membered heterocyclyl, (C6-C 10 ) aryl or monocyclic or bicyclic 5 to 10 membered heteroaryl; wherein the alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is further optionally replaced by one or more identical or different R 10 Group substitution;

[0017] Each R 10 and alkyl, alkenyl, alkynyl, halo, haloalkyl, carbocyclyl, heterocyclyl, hydroxy, alkoxy, cycloalkyloxy, heterocycloalkyloxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkenyloxy, 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-aryl alkylaminosulfonyl, N-alkyl-N-heteroarylaminosulfonyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxyl, 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;

[0018] R2 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SO2N(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 to 10 membered heteroaryl, (C2-C6)alkenyl or (C2-C6)alkynyl; wherein the alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is further optionally replaced by one or more identical or different R 10 Group substitution, or

[0019] R1 and R2 together with the same carbon atom to which they are attached form a spiro (C3-C7) carbocyclyl or a 4- to 7-membered heterocyclyl; wherein the carbocyclyl or heterocyclyl is further optionally replaced by one or more identical or different R 10 Group substitution;

[0020] R3 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SO2N(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 to 10 membered heteroaryl, (C2-C6)alkenyl or (C2-C6)alkynyl; wherein the alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is further optionally replaced by one or more identical or different R 10 Group substitution;

[0021] R4 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SO2N(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 to 10 membered heteroaryl, (C2-C6)alkenyl or (C2-C6)alkynyl; wherein the alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is further optionally replaced by one or more identical or different R 10 Group substitution;

[0022] R5 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SO2N(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-C10 )aryl, monocyclic or bicyclic 5 to 10 membered heteroaryl, (C2-C6)alkenyl or (C2-C6)alkynyl; wherein the alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is further optionally replaced by one or more identical or different R 10 Group substitution;

[0023] R6 is absent and is (C1-C6) alkylene or (C3-C7) carbocyclyl; wherein the alkylene or carbocyclyl is further optionally replaced by one or more identical or different R 10 Group substitution, or

[0024] R5 and R6 together with the same carbon atom to which they are attached form a spiro (C3-C7) carbocyclyl or a 4- to 7-membered heterocyclyl; wherein the carbocyclyl or heterocyclyl is further optionally replaced by one or more identical or different R 10 Group substitution, or

[0025] R6 is a (C2-C4)alkylene group bonded to R7 to form a 4- to 6-membered heterocyclic group;

[0026] 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 to 10 membered heteroaryl; wherein the alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is further optionally replaced by one or more identical or different R 10 Group substitution, or

[0027] R7 and R8 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic group, wherein the heterocyclic group is further optionally substituted by one or more identical or different R 10 Group substitution;

[0028]

[0029] X1 and X2 are CR independently 17 or N;

[0030] 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)2;

[0031] X3 is CH or N;

[0032] X4 is CR 17’ or N;

[0033] R 17’ is hydrogen, fluorine, chlorine or methyl;

[0034] R 11 is C1 or CN;

[0035] R 12 is hydrogen, (C1-C6)alkyl, (C3-C6)carbocyclyl, 4 to 7 membered heterocyclyl, (C3-C7)carbocyclyl(C1-C6)alkyl or 4 to 7 membered heterocyclyl(C1-C6)alkyl; wherein the alkyl, carbocyclyl or heterocyclyl is further optionally substituted by one or more identical or different groups selected from (C1-C6)alkyl, (C1-C6)alkoxy, halo, amino, hydroxy, haloalkyl, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl and 4 to 7 membered heterocyclyl, or

[0036] R 12 is -LYZ or -LYZ;

[0037] L is absent or is (C1-C5)alkylene optionally substituted with one or more substituents selected from (C1-C2)alkyl and oxo;

[0038] Y does not exist and is O, S, S(O), S(O)2, NR', C(O), C(O)O, OC(O), C(O)N(R'), N(R')C(O), N(R')C(O)N(R'), N(R')C(O)O, OC(O)N(R'), S(O)2N(R') or N(R')S(O)2;

[0039] Each R' is independently hydrogen or (C1-C4) alkyl;

[0040] Z is hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C 10 ) carbocyclyl or 3 to 10 membered heterocyclyl; wherein Z is optionally substituted by one or more substituents independently selected from the group consisting of (C1-C4) alkyl, halo, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, amino, (C1-C4) aminoalkyl, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, thiol, urea, NR r R s , OR r 、C(O)R r 、C(O)OR r 、OC(O)R r 、C(O)NR r R s 、N(R r )C(O)R r、S(O) 0-2 R r 、S(O)2NR r R s 、N(R r )SO2R r 、Si(R r )(R s )R t and (CH2) 1-3 NR r R s ; where R r , R s and R t are each independently hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl; or R r and R s Together with the nitrogen atom to which they are attached, they form a 4- to 9-membered heterocyclic group, which is optionally substituted with one or more substituents selected from the group consisting of (C1-C4)alkyl, halo, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C1-C4)alkoxy, (C1-C4)alkylamino, amino, cyano and hydroxy;

[0041] R 13 is hydrogen, methyl, -(CH2) 1-3 W1W2 or

[0042] W1 is CR 18 R 18’ or C(O);

[0043] R 18 and R 18’ are independently hydrogen, (C1-C2)alkyl, fluorine, hydroxy, cyano, nitro, (C1-C2)alkoxy, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, amino, NH(C1-C2)alkyl or N(C1-C2alkyl)2, or

[0044] 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 with one or more substituents independently selected from the group consisting of (C1-C2)alkyl, halo, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, (C1-C2)alkoxy, (C1-C2)alkylamino, amino, cyano and hydroxy;

[0045] W2 is cyano, hydroxyl, 5-membered 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-C2alkyl)2:

[0046] R 19 is hydrogen, (C1-C2)alkyl, fluorine, chlorine, bromine, hydroxy, amino, cyano, nitro, (C1-C2)alkoxy, (C1-C2)haloalkyl or (C1-C2)haloalkoxy;

[0047] R 20 is hydrogen, (C1-C2)alkyl, fluorine, chlorine, bromine, hydroxy, cyano, nitro, (C1-C2)alkoxy, (C1-C2)haloalkyl, (C1-C2)haloalkoxy or -Y2-L2-Z2;

[0048] Y2 is absent and is O, S, S(O), S(O)2, NR', C(O), C(O)O, OC(O), C(O)N(R'), N(R')C(O), S(O)2N(R') or N(R')SO2;

[0049] L2 does not exist or is (C1-C2) alkylene;

[0050] Z2 is hydrogen, (C1-C6)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, phenyl, (C3-C6)carbocyclyl, or 4- to 6-membered heterocyclyl, wherein Z2 is optionally substituted with one or more substituents independently selected from the group consisting of (C1-C4)alkyl, 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', wherein each R' is independently hydrogen or (C1-C4)alkyl;

[0051] or R 19 and R 20 Together with the carbon atoms to which they are attached, they form a (C3-C6) carbocyclyl or a 3- to 6-membered heterocyclyl, which is optionally substituted with one or more substituents selected from the group consisting of (C1-C2) alkyl, halo, (C1-C2) haloalkyl, (C1-C2) haloalkoxy, (C1-C2) alkoxy, (C1-C2) alkylamino, amino, cyano and hydroxy;

[0052] R 21is (C1-C2)alkyl, -C(O)OR", OR", -C(O)NR", NR"R"phenyl or 5-membered heteroaryl, wherein each R" is independently hydrogen or (C1-C2)alkyl;

[0053] A" is a (C4-C6)carbocyclyl or a 4- to 6-membered heterocyclyl, which is optionally substituted by one or more substituents independently selected from the group consisting of (C1-C2)alkyl, halo, hydroxy, cyano and (C1-C2)alkoxy;

[0054] W3 is NR 22 or CR 23 R 23’ ;

[0055] R 22 is hydrogen, (C1-C2)alkyl, (C1-C4)haloalkyl, (C1-C4)hydroxyalkyl, -C(O)CH3 or -C(O)O-(C1-C4)alkyl;

[0056] R 23 and R 23’ are independently hydrogen, (C1-C2)alkyl, cyclopropyl, fluorine, chlorine, bromine, hydroxy, amino, cyano, nitro, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, (C1-C2)alkoxy, -C(O)OR", NR"R", phenyl or 5-membered heteroaryl;

[0057] R 14 Yes - L3CR 24 R 25 R 26 or -CH=CH-R 26 ;

[0058] L3 does not exist and is O, S, (C1-C4) alkylene, -O-(C1-C4) alkylene or -S-(C1-C4) alkylene;

[0059] R 24 is hydrogen or (C1-C4)alkyl;

[0060] R 25 is hydrogen or (C1-C4)alkyl, or

[0061] R 24 and R 25 Together with the carbon atoms to which they are attached, they form a (C3-C5) carbocyclyl, a 4- to 7-membered heterocyclyl, or C=O;

[0062] R 26 is (C1-C6) alkyl, -NR 27 R 28 、-OR 27 、-C(O)R27 、-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 ;

[0063] R 27 is hydrogen, 3- to 6-membered heterocyclyl or (C1-C4)alkyl, which is optionally substituted by one or more identical or different groups selected from the group consisting of OH, C1, F, CF3, N(C1-C4alkyl)2, (C3-C6)carbocyclyl, 3- to 6-membered heterocyclyl, (C2-C4)alkenyl and (C2-C4)alkynyl;

[0064] R 28 is hydrogen or (C1-C4)alkyl;

[0065] R 15 is hydrogen, (C1-C4)alkyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl or cyano, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of (C1-C4)alkyl, (C3-C6)cycloalkyl, hydroxy, (C1-C2)alkoxy, amino, NH(C1-C2)alkyl, N((C1-C2)alkyl)2, (C1-C2)aminoalkyl and halo;

[0066] R 15 ' is hydrogen, (C1-C4) alkyl, cyano, (C1-C4) haloalkyl or -Y3-L4-Z3;

[0067] Y3 is absent and is C(O)O or C(O)N(R');

[0068] L4 does not exist or is (C1-C2) alkylene;

[0069] Z3 is hydrogen, (C1-C6)alkyl, phenyl, (C3-C6)cycloalkyl or 4 to 6 membered heterocyclyl, wherein Z3 is optionally substituted by one or more substituents independently selected from the group consisting of (C1-C2)alkyl, halo, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, (C1-C2)alkoxy, amino, nitro, cyano and hydroxy, or

[0070] R 15 and R 15'Together with the carbon atoms to which they are attached, they form a (C4-C6) carbocyclyl or a 4- to 6-membered heterocyclyl;

[0071] A' is a 6-membered or 7-membered heterocyclic group, which, except for R 15 and R 15 ', optionally further substituted by one or more substituents independently selected from the group consisting of oxo, (C1-C2) alkyl, cyclopropyl, spiro-cyclopropyl, halo, (C1-C2) haloalkyl, (C1-C2) haloalkoxy, (C1-C2) alkoxy, amino, cyano and hydroxy;

[0072] R 16 is hydrogen, (C1-C2)alkyl, (C3-C4)cycloalkyl, (C1-C2)haloalkyl, cyano, (C2-C4)alkenyl or (C2-C4)alkynyl;

[0073] R 16 ' is (C1-C4) alkyl, cyano, (C1-C4) haloalkyl or -Y4-L5-Z4;

[0074] Y4 is absent and is C(O), C(O)O, OC(O), C(O)N(R') or S(O)2N(R');

[0075] L5 is absent or is (C1-C2)alkylene optionally substituted by one or more substituents selected from (C1-C2)alkyl and oxo;

[0076] 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, wherein Z4 is optionally substituted by one or more substituents independently selected from the group consisting of 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 , where each R u are independently hydrogen, (C1-C4)alkyl or (C3-C6)cycloalkyl, or

[0077] Z4 is -Q-L6-W, where

[0078] Q does not exist and is O, NH or N(C1-C2)alkyl;

[0079] L6 is absent or is (C1-C2)alkylene optionally substituted by one or more substituents selected from oxo and (C1-C2)alkyl;

[0080] W is (C1-C4)alkyl, phenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5-membered or 6-membered heterocyclyl, wherein W is optionally substituted by one or more substituents independently selected from the group consisting of (C1-C4)alkyl, halo, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C1-C4)alkoxy, (C1-C4)alkylamino, amino, nitro, cyano or hydroxy, or

[0081] R 16 and R 16 'Together with the carbon atoms to which they are attached, they form (C3-C 10 ) carbocyclic group or 4 to 10 membered heterocyclic group, which is optionally substituted by one or more substituents independently selected from the following: oxo, (C1-C2) alkyl, halo, (C1-C2) haloalkyl, (C1-C2) haloalkoxy, (C1-C2) alkoxy, (C1-C2) alkylamino, amino, nitro, cyano or hydroxy; or the (C3-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 optionally substituted with (C1-C2)alkyl, halo, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, (C1-C2)alkoxy, (C1-C2)alkylamino, amino, nitro, cyano or hydroxy; and

[0082] R 16 ” is hydrogen, (C1-C4) alkyl, (C1-C2) haloalkyl, (C1-C2) alkoxy, (C1-C2) haloalkoxy, cyano, nitro, ethynyl, phenyl or 5-membered or 6-membered heteroaryl, wherein said alkyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy and amino;

[0083] Provided that when R7 is (C1-C3)alkyl and R8 is (C1-C3)alkyl, R6 is not (C1-C6)alkylene, and

[0084] The premise is that yes R 11When it is Cl, X is CH2 or CF2, and R6 is absent or is optionally substituted (C1-C2)alkylene, R7 and R8 cannot a) independently be hydrogen or (C1-C2)alkyl optionally substituted with oxo, or b) R7 and R8 together with the nitrogen atom to which they are attached form a 4-membered heterocyclyl optionally substituted with gem-difluoro.

[0085] 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.

[0086] Another aspect of the present invention relates to a method for treating a disease or condition characterized by or mediated by aberrant BCL6 activity, which method requires 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.

[0087] 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

[0088] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which the subject matter of this article belongs. As used in the specification and the appended claims, unless otherwise indicated, the following terms have the indicated meanings to facilitate understanding of the present invention.

[0089] 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 a mixture of two or more such compositions, reference to "an inhibitor" includes a mixture of two or more such inhibitors, and so forth.

[0090] Unless otherwise indicated, the term "about" means within 10% (eg, within 5%, 2%, or 1%) of the particular value modified by the term "about."

[0091] The transitional term "comprising," which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. In contrast, the transitional phrase "consisting of" excludes any elements, steps, or ingredients not specified in the claim. The transitional phrase "consisting essentially of" limits the scope of the claim to the specified materials or steps, "and those that do not materially affect one or more of the basic and novel characteristics of the claimed invention."

[0092] With respect to the compounds of the present invention, and to the extent the following terminology is used herein to further describe them, the following definitions apply.

[0093] As used herein, the term "alkyl" refers to a saturated straight or branched monovalent hydrocarbon group. In some embodiments, the alkyl group is a C1-C6 group. In some embodiments, and to the extent that any one or more groups of the compound of formula (I) are not otherwise disclosed, the alkyl group is a C0-C6, C0-C5, C0-C3, C1-C6, C1-C5, C1-C4 or C1-C3 group (wherein the C0 alkyl group refers to a bond). Examples of alkyl groups include methyl, ethyl, 1-propyl, 2-propyl, isopropyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 1-pentyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and 3,3-dimethyl-2-butyl. In some embodiments, the alkyl group is 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.

[0094] As used herein, the term "alkylene" refers to a straight or branched divalent hydrocarbon chain, such as methylene, ethylene, propylene, n-butylene, etc., that is connected to the rest of the molecule by a group, consisting only of carbon and hydrogen, unsaturated and having 1 to 6 carbon atoms. The alkylene chain can be connected to the rest of the molecule by a single bond and is connected to the group by a single bond. In some embodiments, and to the extent that there is no additional disclosure for any one or more groups of formula (I) compounds, alkylene contains 1 to 4 carbon atoms (C1-C4 alkylene). In other embodiments, alkylene contains 1 to 3 carbon atoms (C1-C3 alkylene). In other embodiments, alkylene contains 1 to 2 carbon atoms (C1-C2 alkylene). In other embodiments, alkylene contains one carbon atom (C1 alkylene).

[0095] As used herein, the term "alkenyl" refers to a straight or branched monovalent hydrocarbon radical having at least one carbon-carbon double bond. Alkenyl includes groups having "cis" and "trans" orientations or alternatively "E" and "Z" orientations. In some embodiments, alkenyl is C2-C 15 In some embodiments, and to the extent not otherwise disclosed for any one or more groups of the compounds of formula (I), alkenyl is C2-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, but-1,3-dienyl, 2-methylbut-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hex-1,3-dienyl.

[0096] As used herein, the term "alkynyl" refers to a straight or branched monovalent hydrocarbon group having at least one carbon-carbon triple bond. In some embodiments, the alkynyl group is C2-C 15 In some embodiments, and to the extent not otherwise disclosed for any one or more groups of the compounds of formula (I), alkynyl is C2-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.

[0097] As used herein, the term "alkoxyl" or "alkoxy" refers to an alkyl group as defined above with an oxy group connected thereto and the oxy group being a point of attachment. In some embodiments, the alkoxy group is a methoxy group, an ethoxy group, a propoxy group or a tert-butoxy group. An "ether" is two hydrocarbon groups covalently connected by oxygen. Therefore, the substituent of an alkyl group that makes the alkyl group an ether is or is similar to an alkoxy group, such as can be represented by one of -O-alkyl, -O-alkenyl and -O-alkynyl.

[0098] As used herein, the term "halogen" (or "halo" or "halide") refers to fluorine, chlorine, bromine or iodine.

[0099] As used herein, the term "cyclic group" broadly refers to any group containing a saturated, partially saturated or aromatic ring system, used alone or as part of a larger moiety, for example, carbocyclic (cycloalkyl, cycloalkenyl), heterocyclic (heterocycloalkyl, heterocycloalkenyl), aryl and heteroaryl. The cyclic group may have one or more (e.g., fused) ring systems. Thus, for example, the cyclic group may contain one or more carbocyclic, heterocyclic, aryl or heteroaryl groups.

[0100] As used herein, the term "carbocycle" (also referred to as "carbocyclyl") refers to a group used alone or as part of a larger portion, which contains a saturated, partially unsaturated or aromatic ring system with 3 to 12 carbon atoms, which is a part of a single or larger portion (e.g., an alkyl carbocyclic group). The term carbocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged and spirocyclic systems, and combinations thereof. In one embodiment, the carbocyclyl contains 3 to 10 carbon atoms (C3-C 10 In one embodiment, the carbocyclyl contains 3 to 6 carbon atoms (C3-C6). In one embodiment, the carbocyclyl contains 5 to 6 carbon atoms (C5-C6). In some embodiments, the carbocyclyl that is a bicyclic ring contains C6-C 10 In another embodiment, the spiro carbocyclic group comprises 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, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, naphthalene, and bicyclo[3.2.2]nonane. Representative examples of spiro carbocyclyl include spiro [2.2] pentane, spiro [2.3] hexane, spiro [2.4] heptane, spiro [2.5] octane and spiro [4.5] decane. The term carbocyclyl includes an aryl ring system as defined herein. The term carbocyclyl also includes a cycloalkyl ring (e.g., a saturated or partially unsaturated mono-, di- or spiro carbocycle). The term carbocyclic group also includes a carbocycle fused to one or more (e.g., 1, 2 or 3) different cyclic groups (e.g., aryl rings or heterocycles), wherein the connecting group or point of attachment is on the carbocycle.

[0101] Thus, the term carbocycle also encompasses carbocyclylalkyl, which, as used herein, refers to radicals of the formula --R c -Carbocyclic group, where R c The term carbocycle also encompasses carbocyclylalkoxy, which as used herein refers to a carbocyclylalkoxy group of the formula --O--R c - a group bonded to the oxygen atom of a carbocyclic group, wherein R c An alkylene chain.

[0102] As used herein, the term "aryl", used alone or as part of a larger moiety (e.g., "aralkyl", where the terminal carbon atom on the alkyl group is the point of attachment, e.g., benzyl; "aralkyloxy", where the oxygen atom is the point of attachment; or "aryloxyalkyl", where the point of attachment is on the aryl group), refers to a group comprising a monocyclic, bicyclic or tricyclic carbon ring system (including fused rings), wherein at least one ring in the system is aromatic. In some embodiments, the aralkyloxy group is benzyloxy. The term "aryl" can be used interchangeably with the term "aryl ring". In one embodiment, aryl includes groups having 6-12 carbon atoms. In another embodiment, aryl includes groups having 6-10 carbon atoms. Examples of aryl include phenyl, naphthyl, biphenyl, 1,2,3,4-tetrahydronaphthyl, etc., which can be substituted or independently substituted by one or more substituents described herein. A specific aryl is phenyl. In some embodiments, aryl groups include an aryl ring fused to one or more (eg, 1, 2, or 3) different cyclic groups (eg, carbocyclic or heterocyclic) wherein the radical or point of attachment is on the aryl ring.

[0103] Thus, the term aryl encompasses aralkyl (e.g., benzyl), which, as disclosed above, refers to a group of the formula --Rc-aryl, where Rc is an alkylene chain, such as methylene or ethylene. In some embodiments, the aralkyl is an optionally substituted benzyl. The term aryl also encompasses aralkoxy, which, as used herein, refers to a substituted alkyl group of the formula --O--R c - a group bonded to the oxygen atom of an aryl group, wherein Rc is an alkylene chain such as methylene or ethylene.

[0104] As used herein, the term "heterocyclyl" refers to a "carbocyclyl" used alone or as part of a larger portion containing a saturated, partially unsaturated or aromatic ring system, in which one or more (e.g., 1, 2, 3, 4 or 5) carbon atoms have been replaced by heteroatoms or groups containing heteroatoms (e.g., O, N, N(O), S, S(O) or S(O)2). The term heterocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged and spirocyclic systems, and combinations thereof. In some embodiments, heterocyclyl refers to a 3- to 12-membered heterocyclyl ring system. In some embodiments, heterocyclyl refers to a saturated ring system, such as a 3- to 12-membered saturated heterocyclyl ring system. In some embodiments, heterocyclyl refers to a heteroaryl ring system, such as a 5- to 12-membered heteroaryl ring system. The term heterocyclyl also includes C2-C8 heterocycloalkyl, which is a saturated or partially unsaturated mono-, bi- or spiro ring system containing 2-8 carbons and one or more (eg, 1, 2 or 3) heteroatoms.

[0105] In some embodiments, heterocyclic radical includes 3-12 ring atoms and includes monocyclic, bicyclic, tricyclic and spirocyclic systems, wherein the ring atoms are carbon, and 1 to 5 ring atoms are heteroatoms, such as nitrogen, sulfur or oxygen. In some embodiments, heterocyclic radical includes 3 to 7-membered monocyclic rings with one or more heteroatoms selected from O, N and S. In some embodiments, heterocyclic radical includes 4 to 6-membered monocyclic rings with one or more heteroatoms selected from O, N and S. In some embodiments, heterocyclic radical includes 3-membered monocyclic rings. In some embodiments, heterocyclic radical includes 4-membered monocyclic rings. In some embodiments, heterocyclic radical includes 5 to 6-membered monocyclic rings. In some embodiments, heterocyclic radical includes 0 to 3 double bonds. In any of the foregoing embodiments, heterocyclic radical includes 1, 2, 3 or 4 heteroatoms. Any nitrogen or sulfur heteroatom may be optionally oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatom may be optionally substituted (e.g., methyl, isopropyl) and / or quaternized (e.g., [NR4] + Cl - 、[NR4] + OH - Representative examples of heterocyclic groups include oxirane, aziridinyl, thiirane, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydropyranyl, dihydrothiophenyl, tetrahydrothiophenyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, Azinyl, thiazinyl, thiazinyl alkyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepinyl, thiepanyl, oxazepine 1,4-diazepanyl, ... Thiazepine thiazepanyl, tetrahydrothiopyranyl, Oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinone, oxazolidinone, imidazolidinone, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, 1,6-dihydroimidazo 1[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, thienyl, Azine, thiadiazine, diazine, dithiazine, di Azine Thiazino, thiatriazine, triazine, dithiadiazine, imidazolinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolyl, thiopyranyl, 2H-pyranyl, 4H-pyran ... alkyl, 1,3-dioxolanyl, pyrazolyl, pyrazolidinyl, dithiolanyl, dithiolanyl, pyrimidinyl, pyrimidinedione, pyrimidine-2,4-dione, piperazinyl, piperazindione, 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[3.1.0]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, heterobicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]heptanyl, 1-azaspiro[4.5]decan-2-one, azaspiro[5.5]undecyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclic groups containing sulfur or oxygen atoms and 1 to 3 nitrogen atoms are thiazolyl (e.g., thiazol-2-yl), thiadiazolyl (e.g., 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl), Azolyl (e.g. oxazol-2-yl) and Oxazolyl (e.g., 1,3,4- oxadiazole-5-yl and 1,2,4- Examples of 5-membered heterocyclic groups containing 2 to 4 nitrogen atoms include imidazolyl (e.g., imidazolyl-2-yl), triazolyl (e.g., 1,3,4-triazol-5-yl, 1,2,3-triazol-5-yl, and 1,2,4-triazol-5-yl), and tetrazolyl (e.g., 1H-tetrazolyl). Representative examples of benzo-fused 5-membered heterocyclic groups include benzo The example of 6 yuan heterocyclic radical containing 1 to 3 nitrogen atoms and optionally sulphur or oxygen atoms is pyridyl (for example, pyridyl-2-yl, pyridyl-3-yl and pyridyl-4-yl), pyrimidyl (for example, pyrimidine-2-yl and pyrimidine-4-yl), triazine (for example, 1,3,4-triazine-2-yl and 1,3,5-triazine-4-yl), pyridazine (for example, pyridazine-3-yl) and pyrazinyl.In some embodiments, heterocyclic group includes the heterocycle fused to one or more (for example, 1 or 2) different cyclic groups (for example, carbocycle or heterocycle), wherein connecting group or connection point are on heterocycle, and in some embodiments, wherein connection point is the heteroatom contained in heterocycle.

[0106] Thus, the term heterocycle encompasses N-heterocyclyl, as used herein, which refers to a heterocyclyl containing at least one nitrogen atom, and wherein the point at which the heterocyclyl is connected to the rest of the molecule is through a nitrogen atom in the heterocyclyl. Representative examples of N-heterocyclyls include 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, 1-pyrazolidinyl, 1-imidazolinyl, and 1-imidazolidinyl. The term heterocycle also encompasses C-heterocyclyl, as used herein, which refers to a heterocyclyl containing at least one heteroatom, and wherein the point at which the heterocyclyl is connected to the rest of the molecule is through a carbon atom in the heterocyclyl. Representative examples of C-heterocyclyls include 2- or 3-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, and 2- or 3-pyrrolidinyl. The term heterocycle also encompasses heterocyclylalkyl, as disclosed above, which refers to a group of formula --Rc-heterocyclyl, wherein R c An alkylene chain.

[0107] The term heterocycle also encompasses heterocyclylalkoxy, which, as used herein, refers to a heterocyclyl alkoxy radical of the formula --O--R c - a group bonded to the oxygen atom of a heterocyclic group, wherein R c An alkylene chain.

[0108] As used herein, the term "heteroaryl", either alone or as part of a larger moiety (e.g., "heteroarylalkyl" (also referred to as "heteroaralkyl") or "heteroarylalkoxy" (also referred to as "heteroaralkoxy")), refers to a monocyclic, bicyclic, or tricyclic ring system having 5 to 12 ring atoms, wherein at least one ring is aromatic and contains at least one heteroatom. In one embodiment, heteroaryl includes 5 to 6 membered monocyclic aromatic groups wherein one or more of the ring atoms is O, N, or S. Representative examples of heteroaryl include thienyl, furanyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, Azolyl, iso Azolyl, triazolyl, thiadiazolyl, Oxazolyl, tetrazolyl, thiatriazolyl, triazolyl, pyridinyl, pyrimidinyl, imidazopyridinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazo[1,5-b]pyridazinyl, purinyl, deazapurinyl, benzo[1,5-b] oxazolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indolyl, 1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 1,3- Oxazol-2-yl, 1,3,4- oxadiazole-5-yl, 1,2,4- The term "heteroaryl" also includes groups in which a heteroaryl group is fused to one or more cyclic (e.g., carbocyclyl or heterocyclyl) rings, wherein the linking group or point of attachment is on the heteroaryl ring. Non-limiting examples include indolyl, indolizinyl, isoindolyl, benzothienyl, benzothiophenyl, methylenedioxyphenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzodiphenyl oxazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phen oxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido[2,3-b]-1,4- Oxazine-3 (4H) -one. The heteroaryl group can be monocyclic, bicyclic or tricyclic. In some embodiments, the heteroaryl group includes a heteroaryl ring fused to one or more (e.g., 1 or 2) different cyclic groups (e.g., carbocyclic or heterocyclic), wherein the attachment group or point of attachment is on the heteroaryl ring, and in some embodiments, wherein the point of attachment is a heteroatom contained in the heterocyclic ring.

[0109] Thus, the term heteroaryl encompasses N-heteroaryl, as used herein, which refers to a heteroaryl as defined above containing at least one nitrogen, and wherein the point of attachment of the heteroaryl to the rest of the molecule is through a nitrogen atom in the heteroaryl. The term heteroaryl also encompasses C-heteroaryl, as used herein, which refers to a heteroaryl as defined above, and wherein the point of attachment of the heteroaryl to the rest of the molecule is through a carbon atom in the heteroaryl. The term heteroaryl also encompasses heteroarylalkyl, as disclosed above, which refers to a heteroaryl of the formula --R c -heteroaryl radical, wherein R c is an alkylene chain as defined above. The term heteroaryl also encompasses heteroaralkoxy (or heteroarylalkoxy), which, as used herein, refers to a heteroarylalkyl group of the formula --O--R c - a group bonded to the oxygen atom of a heteroaryl group, wherein R c is an alkylene group as defined above.

[0110] Unless otherwise indicated, and to the extent that no specific group or groups in the compounds of formula (I) are further defined, any group described herein may be substituted or unsubstituted. For any specific group or groups, to the extent that no specific group or groups are further disclosed, representative examples of substituents may 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), C1-C4, C1-C3, C1-C2, C1), haloalkyl (e.g., CF3), alkenyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), substituted alkenyl (e.g., substituted C2-C6, C2-C5, C2-C4, C2-C3, C2), alkynyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), substituted alkynyl (e.g., substituted C2-C6, C2-C5, C2-C4, C2-C3, C2), cyclic (e.g., C3-C 12 , C5-C6), substituted cyclic groups (e.g., substituted C3-C 12 , C5-C6), carbocyclic rings (e.g., C3-C 12 , C5-C6), substituted carbocyclic rings (e.g., substituted C3-C 12 , C5-C6), heterocyclic (e.g., 3-12 membered, 5-6 membered), substituted heterocyclic (e.g., substituted 3-12 membered, 5-6 membered), aryl (e.g., benzyl and phenyl), substituted aryl (e.g., substituted benzyl or substituted phenyl), heteroaryl (e.g., pyridyl or pyrimidinyl), substituted heteroaryl (e.g., substituted pyridyl or substituted pyrimidinyl), aralkyl (e.g., benzyl), substituted aralkyl (e.g., substituted benzyl), halo, hydroxy, aryloxy (e.g., C6-C6), aryl ... 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, acylamino, substituted acylamino, thio, substituted thio, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfinamide, substituted sulfinamide, sulfonamide, substituted sulfonamide, urea, substituted urea, carbamate, substituted carbamate, amino acid, and peptidyl.

[0111] In one aspect, the compounds of the present invention are represented by formula (1):

[0112] or a pharmaceutically acceptable salt or stereoisomer thereof,

[0113] in:

[0114] X is CH2, S, CHF, CHCl, CHOH or CF2;

[0115] R1 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SO2N(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 to 10 membered heteroaryl, (C2-C6)alkenyl or (C2-C6)alkynyl; wherein the alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is further optionally replaced by one or more identical or different R 10 Group substitution;

[0116] Each R9 is independently hydrogen, (C1-C6) alkyl, (C3-C7) carbocyclyl, 4- to 7-membered heterocyclyl, (C6-C 10 ) aryl or monocyclic or bicyclic 5 to 10 membered heteroaryl; wherein the alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is further optionally replaced by one or more identical or different R 10 Group substitution;

[0117] Each R 10and alkyl, alkenyl, alkynyl, halo, haloalkyl, carbocyclyl, heterocyclyl, hydroxy, alkoxy, cycloalkyloxy, heterocycloalkyloxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkenyloxy, 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-aryl alkylaminosulfonyl, N-alkyl-N-heteroarylaminosulfonyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxyl, 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;

[0118] R2 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SO2N(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 to 10 membered heteroaryl, (C2-C6)alkenyl or (C2-C6)alkynyl; wherein the alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is further optionally replaced by one or more identical or different R 10 Group substitution, or

[0119] R1 and R2 together with the same carbon atom to which they are attached form a spiro (C3-C7) carbocyclyl or a 4- to 7-membered heterocyclyl; wherein the carbocyclyl or heterocyclyl is further optionally replaced by one or more identical or different R 10 Group substitution;

[0120] R3 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SO2N(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 to 10 membered heteroaryl, (C2-C6)alkenyl or (C2-C6)alkynyl; wherein the alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is further optionally replaced by one or more identical or different R 10 Group substitution;

[0121] R4 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SO2N(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 to 10 membered heteroaryl, (C2-C6)alkenyl or (C2-C6)alkynyl; wherein the alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is further optionally replaced by one or more identical or different R 10 Group substitution;

[0122] R5 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SO2N(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 to 10 membered heteroaryl, (C2-C6)alkenyl or (C2-C6)alkynyl; wherein the alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is further optionally replaced by one or more identical or different R 10 Group substitution;

[0123] R6 is absent and is (C1-C6) alkylene or (C3-C7) carbocyclyl; wherein the alkylene or carbocyclyl is further optionally replaced by one or more identical or different R 10 Group substitution, or

[0124] R5 and R6 together with the same carbon atom to which they are attached form a spiro (C3-C7) carbocyclyl or a 4- to 7-membered heterocyclyl; wherein the carbocyclyl or heterocyclyl is further optionally replaced by one or more identical or different R 10 Group substitution, or

[0125] R6 is a (C2-C4)alkylene group bonded to R7 to form a 4- to 6-membered heterocyclic group;

[0126] 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 to 10 membered heteroaryl; wherein the alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is further optionally replaced by one or more identical or different R 10 Group substitution, or

[0127] R7 and R8 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic group, wherein the heterocyclic group is further optionally substituted by one or more identical or different R 10 Group substitution;

[0128]

[0129] X1 and X2 are CR independently 17 or N;

[0130] 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)2;

[0131] X3 is CH or N;

[0132] X4 is CR 17’ or N; and

[0133] R 17’ is hydrogen, fluorine, chlorine or methyl;

[0134] R 11 is Cl or CN;

[0135] R 12is hydrogen, (C1-C6)alkyl, (C3-C6)carbocyclyl, 4 to 7 membered heterocyclyl, (C3-C7)carbocyclyl(C1-C6)alkyl or 4 to 7 membered heterocyclyl(C1-C6)alkyl; wherein the alkyl, carbocyclyl or heterocyclyl is further optionally substituted by one or more identical or different groups selected from (C1-C6)alkyl, (C1-C6)alkoxy, halo, amino, hydroxy, haloalkyl, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl and 4 to 7 membered heterocyclyl, or

[0136] R 12 YES-LYZ;

[0137] L is absent or is (C1-C5)alkylene optionally substituted with one or more substituents selected from (C1-C2)alkyl and oxo;

[0138] Y does not exist and is O, S, S(O), S(O)2, NR', C(O), C(O)O, OC(O), C(O)N(R'), N(R')C(O), N(R')C(O)N(R'), N(R')C(O)O, OC(O)N(R'), S(O)2N(R') or N(R')S(O)2;

[0139] Each R' is independently hydrogen or (C1-C4) alkyl;

[0140] Z is hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C 10 ) carbocyclyl or 3 to 10 membered heterocyclyl; wherein Z is optionally substituted by one or more substituents independently selected from the group consisting of (C1-C4) alkyl, halo, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, amino, (C1-C4) aminoalkyl, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, thiol, urea, NR r R s , OR r 、C(O)R r 、C(O)OR r 、OC(O)R r 、C(O)NR r R s 、N(R r )C(O)R r 、S(O) 0-2 R r 、S(O)2NR r R s 、N(R r )SO2R r 、Si(R r)(R s )R t and (CH2) 1-3 NR r R s ; where R r , R s and R t are each independently hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl; or R r and R s Together with the nitrogen atom to which they are attached, they form a 4- to 9-membered heterocyclic group, which is optionally substituted with one or more substituents selected from the group consisting of (C1-C4)alkyl, halo, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C1-C4)alkoxy, (C1-C4)alkylamino, amino, cyano and hydroxy;

[0141] R 13 is hydrogen, methyl, -(CH2) 1-3 W1W2 or

[0142] W1 is CR 18 R 18’ or C(O);

[0143] R 18 and R 18’ are independently hydrogen, (C1-C2)alkyl, fluorine, hydroxy, cyano, nitro, (C1-C2)alkoxy, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, amino, NH(C1-C2)alkyl or N(C1-C2alkyl)2, or

[0144] 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 with one or more substituents independently selected from the group consisting of (C1-C2)alkyl, halo, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, (C1-C2)alkoxy, (C1-C2)alkylamino, amino, cyano and hydroxy;

[0145] W2 is cyano, hydroxyl, 5-membered 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-C2alkyl)2:

[0146] R 19is hydrogen, (C1-C2)alkyl, fluorine, chlorine, bromine, hydroxy, amino, cyano, nitro, (C1-C2)alkoxy, (C1-C2)haloalkyl or (C1-C2)haloalkoxy;

[0147] R 20 is hydrogen, (C1-C2)alkyl, fluorine, chlorine, bromine, hydroxy, cyano, nitro, (C1-C2)alkoxy, (C1-C2)haloalkyl, (C1-C2)haloalkoxy or -Y2-L2-Z2;

[0148] Y2 is absent and is O, S, S(O), S(O)2, NR', C(O), C(O)O, OC(O), C(O)N(R'), N(R')C(O), S(O)2N(R') or N(R')SO2;

[0149] L2 does not exist or is (C1-C2) alkylene;

[0150] Z2 is hydrogen, (C1-C6)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, phenyl, (C3-C6)carbocyclyl, or 4- to 6-membered heterocyclyl, wherein Z2 is optionally substituted with one or more substituents independently selected from the group consisting of (C1-C4)alkyl, 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', wherein each R' is independently hydrogen or (C1-C4)alkyl;

[0151] or R 19 and R 20 Together with the carbon atoms to which they are attached, they form a (C3-C6) carbocyclyl or a 3- to 6-membered heterocyclyl, which is optionally substituted with one or more substituents selected from the group consisting of (C1-C2) alkyl, halo, (C1-C2) haloalkyl, (C1-C2) haloalkoxy, (C1-C2) alkoxy, (C1-C2) alkylamino, amino, cyano and hydroxy;

[0152] R 21 is (C1-C2)alkyl, -C(O)OR", OR", -C(O)NR", NR"R"phenyl or 5-membered heteroaryl, wherein each R" is independently hydrogen or (C1-C2)alkyl;

[0153] A" is a (C4-C6)carbocyclyl or a 4- to 6-membered heterocyclyl, which is optionally substituted by one or more substituents independently selected from the group consisting of (C1-C2)alkyl, halo, hydroxy, cyano and (C1-C2)alkoxy;

[0154] W3 is NR 22 or CR 23 R 23’ ;

[0155] R 22 is hydrogen, (C1-C2)alkyl, (C1-C4)haloalkyl, (C1-C4)hydroxyalkyl, -C(O)CH3 or -C(O)O-(C1-C4)alkyl;

[0156] R 23 and R 23 , are independently hydrogen, (C1-C2)alkyl, cyclopropyl, fluorine, chlorine, bromine, hydroxyl, amino, cyano, nitro, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, (C1-C2)alkoxy, -C(O)OR", NR"R", phenyl or 5-membered heteroaryl;

[0157] R 14 Yes - L3CR 24 R 25 R 26 or -CH=CH-R 26 ;

[0158] L3 does not exist and is O, S, (C1-C4) alkylene, -O-(C1-C4) alkylene or -S-(C1-C4) alkylene;

[0159] R 24 is hydrogen or (C1-C4)alkyl;

[0160] R 25 is hydrogen or (C1-C4)alkyl, or

[0161] R 24 and R 25 Together with the carbon atoms to which they are attached, they form a (C3-C5) carbocyclyl, a 4- to 7-membered heterocyclyl, or C=O;

[0162] 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 28C(O)R 27 ;

[0163] R 27 is hydrogen, 3- to 6-membered heterocyclyl or (C1-C4)alkyl, which is optionally substituted by one or more identical or different groups selected from OH, Cl, F, CF3, N(C1-C4alkyl)2, (C3-C6)carbocyclyl, 3- to 6-membered heterocyclyl, (C2-C4)alkenyl and (C2-C4)alkynyl;

[0164] R 28 is hydrogen or (C1-C4)alkyl;

[0165] R 15 is hydrogen, (C1-C4)alkyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl or cyano, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of (C1-C4)alkyl, (C3-C6)cycloalkyl, hydroxy, (C1-C2)alkoxy, amino, NH(C1-C2)alkyl, N((C1-C2)alkyl)2, (C1-C2)aminoalkyl and halo;

[0166] R 15 ' is hydrogen, (C1-C4) alkyl, cyano, (C1-C4) haloalkyl or -Y3-L4-Z3;

[0167] Y3 is absent and is C(O)O or C(O)N(R');

[0168] L4 does not exist or is (C1-C2) alkylene;

[0169] Z3 is hydrogen, (C1-C6)alkyl, phenyl, (C3-C6)cycloalkyl or 4 to 6 membered heterocyclyl, wherein Z3 is optionally substituted by one or more substituents independently selected from the group consisting of (C1-C2)alkyl, halo, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, (C1-C2)alkoxy, amino, nitro, cyano and hydroxy, or

[0170] R 15 and R 15 'Together with the carbon atoms to which they are attached, they form a (C4-C6) carbocyclyl or a 4- to 6-membered heterocyclyl;

[0171] A' is a 6-membered or 7-membered heterocyclic group, which, except for R 15 and R 15', optionally further substituted by one or more substituents independently selected from the following: oxo, (C1-C2) alkyl, cyclopropyl, spiro-cyclopropyl, halo, (C1-C2) haloalkyl, (C1-C2) haloalkoxy, (C1-C2) alkoxy, amino, cyano and hydroxy;

[0172] R 16 is hydrogen, (C1-C2)alkyl, (C3-C4)cycloalkyl, (C1-C2)haloalkyl, cyano, (C2-C4)alkenyl or (C2-C4)alkynyl;

[0173] R 16 ' is (C1-C4) alkyl, cyano, (C1-C4) haloalkyl or -Y4-L5-Z4;

[0174] Y4 is absent and is C(O), C(O)O, OC(O), C(O)N(R') or S(O)2N(R');

[0175] L5 is absent or is (C1-C2)alkylene optionally substituted by one or more substituents selected from (C1-C2)alkyl and oxo;

[0176] 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, wherein Z4 is optionally substituted by one or more substituents independently selected from the group consisting of 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 , where each R u are independently hydrogen, (C1-C4)alkyl or (C3-C6)cycloalkyl, or

[0177] Z4 is -Q-L6-W, where

[0178] Q does not exist and is O, NH or N(C1-C2)alkyl;

[0179] L6 is absent or is (C1-C2)alkylene optionally substituted by one or more substituents selected from oxo and (C1-C2)alkyl;

[0180] W is (C1-C4)alkyl, phenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5-membered or 6-membered heterocyclyl, wherein W is optionally substituted by one or more substituents independently selected from the group consisting of (C1-C4)alkyl, halo, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C1-C4)alkoxy, (C1-C4)alkylamino, amino, nitro, cyano or hydroxy, or

[0181] R 16 and R 16 'Together with the carbon atoms to which they are attached, they form (C3-C 10 ) carbocyclic group or 4 to 10 membered heterocyclic group, which is optionally substituted by one or more substituents independently selected from the following: oxo, (C1-C2) alkyl, halo, (C1-C2) haloalkyl, (C1-C2) haloalkoxy, (C1-C2) alkoxy, (C1-C2) alkylamino, amino, nitro, cyano or hydroxyl; or the (C3-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 optionally substituted with (C1-C2)alkyl, halo, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, (C1-C2)alkoxy, (C1-C2)alkylamino, amino, nitro, cyano or hydroxy; and

[0182] R 16 ” is hydrogen, (C1-C4) alkyl, (C1-C2) haloalkyl, (C1-C2) alkoxy, (C1-C2) haloalkoxy, cyano, nitro, ethynyl, phenyl or 5-membered or 6-membered heteroaryl, wherein said alkyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy and amino;

[0183] Provided that when R7 is (C1-C3)alkyl and R8 is (C1-C3)alkyl, R6 is not (C1-C6)alkylene, and

[0184] The premise is that yes R 11 When it is Cl, X is CH2 or CF2, and R6 is absent or is optionally substituted (C1-C2)alkylene, R7 and R8 cannot a) independently be hydrogen or (C1-C2)alkyl optionally substituted with oxo, or b) R7 and R8 together with the nitrogen atom to which they are attached form a 4-membered heterocyclyl optionally substituted with gem-difluoro.

[0185] In some embodiments, L and Y are absent and Z is methyl.

[0186] In some embodiments, R 11 It is Cl.

[0187] In some embodiments, R 11 It is CN.

[0188] In some embodiments, R1 is hydrogen, -OR9, or (C1-C6)alkyl.

[0189] In some embodiments, R1 is hydrogen, methyl, or -OH.

[0190] In some embodiments, R1 is hydrogen.

[0191] In some embodiments, R1 is methyl.

[0192] In some embodiments, R2 is hydrogen, -OR9, or (C1-C6)alkyl.

[0193] In some embodiments, R2 is hydrogen, methyl, or -OH.

[0194] In some embodiments, R2 is hydrogen.

[0195] In some embodiments, R2 is methyl.

[0196] In some embodiments, R1 and R2 together with the same carbon atom to which they are attached form a spiro (C3-C7) carbocyclyl.

[0197] In some embodiments, R1 and R2 together with the same carbon atom to which they are attached form a spiro (C3) carbocyclyl.

[0198] In some embodiments, R3 is hydrogen.

[0199] In some embodiments, R4 is hydrogen.

[0200] In some embodiments, R5 is hydrogen, -OR9, or (C1-C6)alkyl.

[0201] In some embodiments, R5 is hydrogen, methyl, or -OH.

[0202] In some embodiments, R5 is hydrogen.

[0203] In some embodiments, R5 is methyl.

[0204] In some embodiments, R6 is absent.

[0205] In some embodiments, R6 is (C1-C6)alkyl or (C3-C7)carbocyclyl.

[0206] In some embodiments, R6 is (C1-C2)alkyl or (C3-C4)carbocyclyl.

[0207] In some embodiments, R6 is C1-alkylene. In some embodiments, R6 is C2-alkylene. In some embodiments, R6 is replaced by one or more identical or different R 10 In some embodiments, R6 is a C1-alkylene group substituted with one or more identical or different R 10 In some embodiments, each R 10 are independently methyl, fluoro or cyclopropyl.

[0208] In some embodiments, R6 is C3-carbocyclyl.In some embodiments, R6 is C4-carbocyclyl.

[0209] In some embodiments, R5 and R6 together with the same carbon atom to which they are attached form a spiro (C3-C7) carbocyclyl.

[0210] In some embodiments, R5 and R6 together with the same carbon atom to which they are attached form a spiro (C3) carbocyclyl.

[0211] In some embodiments, R6 is (C2-C4)alkylene bonded to R7 to form a 4- to 6-membered heterocyclyl.

[0212] In some embodiments, R6 is a (C2-C3)alkylene group bonded to R7 to form a 4-membered heterocyclyl.

[0213] In some embodiments, R7 is hydrogen or (C1-C6)alkyl.

[0214] In some embodiments, R7 is hydrogen or methyl.

[0215] In some embodiments, R8 is hydrogen or (C1-C6)alkyl.

[0216] In some embodiments, R8 is hydrogen or methyl.

[0217] In some embodiments, R7 and R8 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclyl.

[0218] In some embodiments, R7 and R8 together with the nitrogen atom to which they are attached form a 4-membered heterocyclyl.

[0219] In some embodiments, X is CH2.

[0220] In some embodiments, X is S.

[0221] In some embodiments, X is CHF.

[0222] In some embodiments, X is CHCl.

[0223] In some embodiments, X is CHOH.

[0224] In some embodiments, X is CF2.

[0225] In some embodiments, yes And the structure of the compound of formula (I) is formula I-1, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0226] 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.

[0227] 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.

[0228] In some embodiments of Formula I-1, X1 and X2 are both CH.

[0229] In some embodiments of Formula I-1, X is CH2.

[0230] In some embodiments of Formula 1-1, X is CHF.

[0231] In some embodiments of Formula I-1, X is CF2.

[0232] In some embodiments of Formula I-1, R1 is hydrogen, -OR9 or (C1-C6)alkyl.

[0233] In some embodiments of Formula 1-1, R1 is hydrogen, methyl, or -OH.

[0234] In some embodiments of Formula 1-1, R1 is hydrogen.

[0235] In some embodiments of Formula 1-1, R1 is methyl.

[0236] In some embodiments of Formula I-1, R2 is hydrogen, -OR9 or (C1-C6)alkyl.

[0237] In some embodiments of Formula 1-1, R2 is hydrogen, methyl, or -OH.

[0238] In some embodiments of Formula 1-1, R2 is hydrogen.

[0239] In some embodiments of Formula 1-1, R2 is methyl.

[0240] In some embodiments of Formula I-1, R1 and R2 together with the same carbon atom to which they are attached form a spiro (C3-C7) carbocyclyl.

[0241] In some embodiments of Formula I-1, R1 and R2 together with the same carbon atom to which they are attached form a spiro (C3) carbocyclyl.

[0242] In some embodiments of Formula 1-1, R3 is hydrogen.

[0243] In some embodiments of Formula 1-1, R4 is hydrogen.

[0244] In some embodiments of Formula I-1, R5 is hydrogen, -OR9 or (C1-C6)alkyl.

[0245] In some embodiments of Formula 1-1, R5 is hydrogen, methyl, or -OH.

[0246] In some embodiments of Formula 1-1, R5 is hydrogen.

[0247] In some embodiments of Formula 1-1, R5 is methyl.

[0248] In some embodiments of Formula I-1, R6 is (C1-C6)alkyl or (C3-C7)carbocyclyl.

[0249] In some embodiments of Formula I-1, R6 is (C1-C2)alkyl or (C3-C4)carbocyclyl.

[0250] 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 replaced by one or more identical or different R 10 In some embodiments of Formula I-1, R6 is replaced by one or more identical or different R 10 In some embodiments of Formula I-1, each R 10 are independently methyl, fluoro or cyclopropyl.

[0251] In some embodiments of formula 1-1, R6 is C3-carbocyclyl. In some embodiments of formula 1-1, R6 is C4-carbocyclyl.

[0252] 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.

[0253] 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.

[0254] In some embodiments of Formula I-1, R6 is a (C2-C4)alkylene group bonded to R7 to form a 4- to 6-membered heterocyclyl.

[0255] In some embodiments of Formula 1-1, R6 is a (C2-C3)alkylene group bonded to R7 to form a 4-membered heterocyclyl.

[0256] In some embodiments of Formula I-1, R7 is hydrogen or (C1-C6)alkyl.

[0257] In some embodiments of Formula 1-1, R7 is hydrogen or methyl.

[0258] In some embodiments of Formula I-1, R8 is hydrogen or (C1-C6)alkyl.

[0259] In some embodiments of Formula 1-1, R8 is hydrogen or methyl.

[0260] In some embodiments of formula I-1, R7 and R8 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclyl.

[0261] 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.

[0262] 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 It is CN.

[0263] 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 the alkyl, carbocyclyl or heterocyclyl is further optionally substituted by one or more identical or different groups selected from (C1-C6) alkyl, (C1-C6) alkoxy, halo, amino, hydroxy, haloalkyl, NH (C1-C6) alkyl, N ((C1-C6) alkyl) 2, (C3-C6) carbocyclyl and 4 to 7-membered heterocyclyl. In some embodiments, R 12 In some embodiments, R 12 It is a 4-membered heterocyclyl, a (C3)carbocyclyl(C1)alkyl or a 4-membered heterocyclyl(C1)alkyl, wherein the heterocyclyl contains 1 heteroatom selected from N and O.

[0264] In some embodiments of Formula I-1, R 13 Yes - (CH2) 1-3 W1W2. In some embodiments of Formula I-1, R 13 It is -(CH2)2W1W2.

[0265] 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 , are independently hydrogen or (C1-C2) alkyl. In some embodiments of Formula I-1, R 18 and R 18’ Both are (C1-C2) alkyl. In some embodiments of Formula I-1, R 18 and R 18’ Both are methyl.

[0266] In some embodiments of formula 1-1, W2 is cyano, hydroxyl, or amino. In some embodiments of formula 1-1, W2 is hydroxyl.

[0267] In some embodiments, the compound of formula I-1 is formula I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f:

[0268]

[0269]

[0270] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0271] In some embodiments, the compound of formula I-1 is formula I-1g, I-1h, I-1i, I-1j, I-1k or I-11:

[0272]

[0273] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0274] In some embodiments, the compound of formula I-1 is formula I-1m or I-1n:

[0275] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0276] In some embodiments, And the structure of the compound of formula (I) is formula I-2, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0277] 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.

[0278] 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.

[0279] In some embodiments of Formula 1-2, both X1 and X2 are CH.

[0280] In some embodiments of formula 1-2, X3 is N. In some embodiments of formula 1-2, X3 is CH.

[0281] In some embodiments of Formula 1-2, X is CH2.

[0282] In some embodiments of Formula 1-2, X is CHF.

[0283] In some embodiments of Formula 1-2, X is CF2.

[0284] In some embodiments of Formula I-2, R1 is hydrogen, -OR9 or (C1-C6)alkyl.

[0285] In some embodiments of Formula 1-2, R1 is hydrogen, methyl, or -OH.

[0286] In some embodiments of Formula 1-2, R1 is hydrogen.

[0287] In some embodiments of Formula 1-2, R1 is methyl.

[0288] In some embodiments of Formula I-2, R2 is hydrogen, -OR9 or (C1-C6)alkyl.

[0289] In some embodiments of Formula 1-2, R2 is hydrogen, methyl, or -OH.

[0290] In some embodiments of Formula 1-2, R2 is hydrogen.

[0291] In some embodiments of Formula 1-2, R2 is methyl.

[0292] In some embodiments of Formula I-2, R1 and R2 together with the same carbon atom to which they are attached form a spiro (C3-C7) carbocyclyl.

[0293] In some embodiments of Formula I-2, R1 and R2 together with the same carbon atom to which they are attached form a spiro (C3) carbocyclyl.

[0294] In some embodiments of Formula 1-2, R3 is hydrogen.

[0295] In some embodiments of Formula 1-2, R4 is hydrogen.

[0296] In some embodiments of Formula I-2, R5 is hydrogen, -OR9 or (C1-C6)alkyl.

[0297] In some embodiments of Formula 1-2, R5 is hydrogen, methyl, or -OH.

[0298] In some embodiments of Formula 1-2, R5 is hydrogen.

[0299] In some embodiments of Formula 1-2, R5 is methyl.

[0300] In some embodiments of Formula I-2, R6 is (C1-C6)alkyl or (C3-C7)carbocyclyl.

[0301] In some embodiments of Formula I-2, R6 is (C1-C2)alkyl or (C3-C4)carbocyclyl.

[0302] 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 replaced by one or more identical or different R 10 In some embodiments of Formula I-2, R6 is replaced by one or more identical or different R 10 In some embodiments of Formula I-2, each R 10 are independently methyl, fluoro or cyclopropyl.

[0303] In some embodiments of formula 1-2, R6 is C3-carbocyclyl. In some embodiments of formula 1-2, R6 is C4-carbocyclyl.

[0304] 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.

[0305] 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.

[0306] In some embodiments of Formula 1-2, R6 is a (C2-C4)alkylene group bonded to R7 to form a 4- to 6-membered heterocyclyl.

[0307] In some embodiments of Formula 1-2, R6 is a (C2-C3)alkylene group bonded to R7 to form a 4-membered heterocyclyl.

[0308] In some embodiments of Formula I-2, R7 is hydrogen or (C1-C6)alkyl.

[0309] In some embodiments of Formula 1-2, R7 is hydrogen or methyl.

[0310] In some embodiments of Formula I-2, R8 is hydrogen or (C1-C6)alkyl.

[0311] In some embodiments of Formula 1-2, R8 is hydrogen or methyl.

[0312] In some embodiments of formula 1-2, R7 and R8 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclyl.

[0313] In some embodiments of formula 1-2, R7 and R8 together with the nitrogen atom to which they are attached form a 3-membered heterocyclyl.

[0314] In some embodiments of Formula I-2, R 12 is methyl and R 11 In some embodiments, R 12 is methyl and R 11 It is CN.

[0315] 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; wherein the alkyl, carbocyclyl or heterocyclyl is further optionally substituted by one or more identical or different groups selected from (C1-C6) alkyl, (C1-C6) alkoxy, halo, amino, hydroxy, haloalkyl, NH (C1-C6) alkyl, N ((C1-C6) alkyl) 2, (C3-C6) carbocyclyl and 4 to 7-membered heterocyclyl. In some embodiments, R 12 In some embodiments, R 12 It is a 4-membered heterocyclyl, a (C3)carbocyclyl(C1)alkyl or a 4-membered heterocyclyl(C1)alkyl, wherein the heterocyclyl contains 1 heteroatom selected from N and O.

[0316] In some embodiments of Formula I-1, R 14 Yes - 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.

[0317] In some embodiments of Formula I-2, R 24 and R 25 Together with the carbon atoms to which they are attached, they form a (C3-C5) 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, they 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, they form a 4-7 membered heterocyclic group. 24 and R 25 Together with the same carbon atom to which they are attached, they form an oxetane ring.

[0318] 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 In some embodiments, R 26 In some embodiments, R 26 In some embodiments, R 26 It's NHMe.

[0319] In some embodiments, the compound of formula I-2 is formula I-2a, I-2b, I-2c, I-2d, I-2e or I-2f:

[0320]

[0321]

[0322] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0323] In some embodiments, the compound of formula I-2 is formula I-2g, I-2h, I-2i, I-2j, I-2k or I-21:

[0324]

[0325]

[0326] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0327] In some embodiments, the compound of formula I-2 is formula I-2m or I-2n:

[0328] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0329] In some embodiments, yes And the structure of the compound of formula (I) is formula I-3, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, R 11 In some embodiments, R 11 It is CN.

[0330] 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.

[0331] 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.

[0332] 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; wherein the alkyl, carbocyclyl or heterocyclyl is further optionally substituted by one or more identical or different groups selected from (C1-C6) alkyl, (C1-C6) alkoxy, halo, amino, hydroxy, haloalkyl, NH (C1-C6) alkyl, N ((C1-C6) alkyl) 2, (C3-C6) carbocyclyl and 4 to 7-membered heterocyclyl. In some embodiments, R 12 In some embodiments, R 12 It is a 4-membered heterocyclyl, a (C3)carbocyclyl(C1)alkyl or a 4-membered heterocyclyl(C1)alkyl, wherein the heterocyclyl contains 1 heteroatom selected from N and O.

[0333] In some embodiments of formula I-3, A' is a 7-membered heterocyclyl, wherein the heterocyclyl contains 2 heteroatoms selected from N and O, and in addition to R 15 and R15 ', which is optionally further substituted by one or more substituents independently selected from the following: oxo, (C1-C2) alkyl, cyclopropyl, spiro-cyclopropyl, halo, (C1-C2) haloalkyl, (C1-C2) alkoxy, amino, cyano and hydroxy.

[0334] In some embodiments, the compound of formula I-3 is 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-31:

[0335]

[0336]

[0337]

[0338] 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 0-2.

[0339] In some embodiments, the compound of formula I-3 is formula I-3m or I-3n:

[0340]

[0341] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0342] In some embodiments, yes And the structure of the compound of formula (I) is formula I-4, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0343] 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.

[0344] In some embodiments of Formula I-4, X2 is CR 17 In some embodiments of Formula 1-4, X2 is CH. In some embodiments of Formula 1-4, X2 is N.

[0345] In some embodiments of formula 1-4, X4 is CH. In some embodiments of formula 1-4, X4 is N.

[0346] 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; wherein the alkyl, carbocyclyl or heterocyclyl is further optionally substituted by one or more identical or different groups selected from (C1-C6) alkyl, (C1-C6) alkoxy, halo, amino, hydroxy, haloalkyl, NH (C1-C6) alkyl, N ((C1-C6) alkyl) 2, (C3-C6) carbocyclyl and 4 to 7-membered heterocyclyl. In some embodiments, R 12 In some embodiments, R 12 It is a 4-membered heterocyclyl, a (C3)carbocyclyl(C1)alkyl or a 4-membered heterocyclyl(C1)alkyl, wherein the heterocyclyl contains 1 heteroatom selected from N and O.

[0347] In some embodiments, the compound of formula I-4 is formula I-4a or I-4b:

[0348]

[0349] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0350] In some embodiments, yes And the structure of the compound of formula (I) is formula I-5, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0351] 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.

[0352] 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.

[0353] 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; wherein the alkyl, carbocyclyl or heterocyclyl is further optionally substituted by one or more identical or different groups selected from (C1-C6) alkyl, (C1-C6) alkoxy, halo, amino, hydroxy, haloalkyl, NH (C1-C6) alkyl, N ((C1-C6) alkyl) 2, (C3-C6) carbocyclyl and 4 to 7-membered heterocyclyl. In some embodiments, R12 In some embodiments, R 12 It is a 4-membered heterocyclyl, a (C3)carbocyclyl(C1)alkyl or a 4-membered heterocyclyl(C1)alkyl, wherein the heterocyclyl contains 1 heteroatom selected from N and O.

[0354] In some embodiments of Formula I-5, R 12 It is (C1-C6)alkyl, (C1-C6)alkyl-OH, (C1-C6)alkyl-NH(C1-C6)alkyl or (C1-C6)alkyl-N((C1-C6)alkyl)2.

[0355] In some embodiments of Formula I-5, R 14 Yes - 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.

[0356] In some embodiments of Formula I-5, R 24 and R 25 Together with the carbon atoms to which they are attached, they form a (C3-C5) 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, they 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, they form a 4-7 membered heterocyclic group. 24 and R 25 Together with the same carbon atom to which they are attached, they form an oxetane ring.

[0357] In some embodiments of Formula I-5, R 26 is (C1-C6) alkyl, -NR 27 R 28 OR 27 In some embodiments of Formula I-5, R 26 is methyl, hydroxyl, amino or NHMe. In some embodiments, R 26 In some embodiments, R 26 In some embodiments, R 26 In some embodiments, R 26 It's NHMe.

[0358] In some embodiments, the compound of formula I-5 is formula I-5a, I-5b, I-5c, I-5d, I-5e or I-5f:

[0359]

[0360] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0361] Representative examples of compounds of the present invention include:

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0382] The compounds of the present disclosure may be in the form of free acids or free bases or pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of the present disclosure may be formed, for example, by reacting an appropriate free base of the compounds of the present invention with an appropriate pharmaceutically acceptable acid in a suitable solvent under standard conditions well known in the art. See, for example, Gould, PL, "Salt selection for basic drugs", International Journal of Pharmaceutics, 1: 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).

[0383] The compounds of the present disclosure may have at least one chiral center and may therefore be in the form of stereoisomers, which, as used herein, encompass all isomers of a single compound that differ only in the orientation of its atoms in space. The term stereoisomer includes mirror image isomers (including enantiomers of the (R-) or (S-) configuration of the compound), mirror image isomer mixtures of compounds (physical mixtures and racemates or racemic mixtures of enantiomers), geometric (cis / trans or E / Z, R / S) isomers of compounds, and compound isomers (diastereomers) that have more than one chiral center and are not mirror images of each other. The chiral center of the compound may undergo epimerization in vivo; therefore, for these compounds, administration of the compound in its (R-) form is considered equivalent to administration of the compound in its (S-) form. Therefore, the compounds of the present disclosure may be made and used in the form of a single isomer and substantially free of other isomers, or in the form of a mixture of various isomers (e.g., a racemic mixture of stereoisomers).

[0384] In some embodiments, the compound of formula (I) is an isotopic derivative because it has at least one desired isotopic substitution of an atom in an amount greater than the natural abundance of the isotope, i.e., enriched. In one embodiment, the compound comprises tritium or a plurality of tritium atoms. As used herein, the term "hydrogen", i.e., H, refers to all isotopes of hydrogen, including protium ( 1 As used herein, the term "compound" encompasses isotopic derivatives.

[0385] The compound of formula (I) may also be in the form of N-oxides, crystalline forms (also known as polymorphs), co-crystals, active metabolites, prodrugs, tautomers and non-solvated forms of the compound having the same type of activity, and solvated (e.g., hydrated) forms with pharmaceutically acceptable solvents such as water, ethanol, etc. As used herein, the term "compound" encompasses all these forms.

[0386] Formula (I) compound can be prepared by crystallization under different conditions, and can exist as a kind of polymorph of compound or the combination of polymorph.For example, by crystallization at different temperatures, or by using various cooling modes from very fast to very slow cooling range during crystallization, different solvents or different solvent mixtures can be used to recrystallize to identify and / or prepare different polymorphs.Polymorphs can also be obtained by heating or melting the compound, then gradually or rapidly cooling.The presence of polymorphs can be determined by solid probe NMR spectrum, IR spectrum, differential scanning calorimetry, powder X-ray diffraction pattern and / or other known technologies.

[0387] In some embodiments, the pharmaceutical composition comprises a co-crystal of a compound of formula (I). As used herein, the term "co-crystal" refers to a stoichiometric multi-component system comprising a compound of formula (I) and a co-crystal former, wherein the compound of formula (I) and the co-crystal former are linked by non-covalent interactions. As used herein, the term "co-crystal former" refers to a compound that can form intermolecular interactions with a compound of formula (I) and co-crystal therewith. Representative examples of co-crystal formers include benzoic acid, succinic acid, fumaric acid, glutaric acid, trans-cinnamic acid, 2,5-dihydroxybenzoic acid, glycolic acid, trans-2-hexanoic acid, 2-hydroxyhexanoic acid, lactic acid, sorbic acid, tartaric acid, ferulic acid, suberic acid, picolinic acid, salicylic acid, maleic acid, saccharin, 4,4'-bipyridyl para-aminosalicylic acid, nicotinamide, urea, isonicotinamide, methyl 4-hydroxybenzoate, adipic acid, terephthalic acid, resorcinol, pyrogallol, phloroglucinol, pyrogallol, isoniazid, theophylline, adenine, theobromine, phenacetin, phenazone, etofylline, and phenobarbital.

[0388] Synthesis method

[0389] On the other hand, the present disclosure relates to a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof. In a broad sense, a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof can be prepared by any method known to be suitable for preparing chemically related compounds. The compound of formula (I) will be better understood in conjunction with the synthesis schemes described in the various working examples, which illustrate non-limiting methods for preparing the compound of formula (I).

[0390] Pharmaceutical composition

[0391] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier. As known in the art, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle suitable for administering a compound of the present disclosure to a mammal. Suitable carriers may include, for example, liquids (aqueous and non-aqueous analogs, and combinations thereof), solids, encapsulating materials, gases and combinations thereof (e.g., semisolids) and gases, the function of which is to carry or transport a compound from one organ or part of a body to another organ or part of a body. The carrier is "acceptable" in the sense that it is physiologically inert and compatible with the other ingredients of the formulation, and is harmless to a subject or patient. Depending on the type of formulation, the composition may also include one or more pharmaceutically acceptable excipients.

[0392] In a broad sense, the compounds of formula (I) and their pharmaceutically acceptable salts and stereoisomers can be formulated into a composition of a given type according to conventional pharmaceutical practices, such as conventional mixing, dissolving, granulating, preparing dragees, levigating, emulsifying, encapsulating, entrapping and compression processes (see, for example, Remington: The Science and Practice of Pharmacy (20th ed.), A.R. Gennaro, ed., Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, J. Swarbrick and J.C. Boylan, eds., 1988-1999, Marcel Dekker, New York). The type of formulation depends on the mode of administration, which may include enteral (e.g., oral, buccal, sublingual, and rectal), parenteral (e.g., subcutaneous (sc), intravenous (iv), intramuscular (im), and intrasternal injection, or infusion techniques, intraocular, intraarterial, intramedullary, intrathecal, intraventricular, transdermal, interdermal, intravaginal, intraperitoneal, mucosal, nasal, intratracheal instillation, bronchial instillation, and inhalation), and topical (e.g., transdermal). In general, the most appropriate route of administration will depend on a variety of factors, including, for example, the nature of the medicament (e.g., its stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). For example, parenteral (e.g., intravenous) administration may also be advantageous because the compound can be administered relatively quickly, such as in the case of single-dose treatment and / or acute conditions.

[0393] In some embodiments, the compounds of Formula (I) are formulated for oral or intravenous administration (eg, systemic intravenous injection).

[0394] Thus, the compounds of formula (I) can be formulated into solid compositions (e.g., powders, tablets, dispersible granules, capsules, cachets and suppositories), liquid compositions (e.g., solutions in which the compound is dissolved, suspensions in which solid particles of the compound are dispersed, emulsions and solutions containing liposomes, micelles or nanoparticles, syrups and elixirs); semisolid compositions (e.g., gels, suspensions and creams); and gases (e.g., propellants for aerosol compositions). The compounds can also be formulated for rapid, immediate or extended release.

[0395] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with a carrier 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, for example, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrants such as cross-linked polymers (e.g., cross-linked Polyvinyl pyrrolidone (crospovidone), cross-linked sodium carboxymethyl cellulose (croscarmellose sodium), sodium starch glycolate, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retardants such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glyceryl monostearate, h) absorbents such as kaolin and bentonite clays, 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 include a buffer. Similar types of solid compositions may also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (lactose or milk sugar) and high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings. They may further contain sunscreens.

[0396] 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 cross-linked sodium carboxymethyl cellulose. The gelatin shell can contain gelatin, titanium dioxide, iron oxide, and a colorant.

[0397] Liquid dosage forms for oral administration include solutions, emulsions, emulsions, microemulsions, syrups and elixirs. In addition to the compound, the liquid dosage form may also contain aqueous or non-aqueous carriers commonly used in the art (depending on the solubility of the compound), such as, for example, water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (particularly 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 mixtures thereof. Oral compositions may also include excipients, such as wetting agents, suspending agents, coloring agents, sweeteners, flavoring agents and aromatics.

[0398] Injectable preparations for parenteral administration may include sterile aqueous solutions or oily suspensions. They can be prepared using suitable dispersants or wetting agents and suspending agents according to standard techniques. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in nontoxic parenterally acceptable diluents or solvents, for example, in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution (USP) and isotonic sodium chloride solution. In addition, sterile fixed oils are routinely used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used to prepare injectables. Injectable preparations can be sterilized, for example, by filtering with a filter that retains bacteria or by incorporating a sterilizing agent in the form of a sterile solid composition, which can be dissolved or dispersed in sterile water or other sterile injectable media before use. The effect of the compound may be prolonged by slowing its absorption, which can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. Prolonged absorption of the compound from a parenterally administered formulation may also be achieved by suspending the compound in an oil vehicle.

[0399] In certain embodiments, the compound of formula (I) can be applied in a local rather than systemic manner, for example, by injecting the conjugate directly into an organ, usually in the form of a depot preparation or a sustained release formulation. In a specific embodiment, a long-acting formulation is applied by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. An injectable depot form is prepared by forming a microcapsule matrix of a compound in a biodegradable polymer (e.g., polylactide-polyglycolide, poly(orthoester) and poly(anhydride)). The release rate of the compound can be controlled by changing the ratio of the compound to the polymer and the properties of the specific polymer used. Depot injectable formulations are also prepared by embedding the compound in a liposome or microemulsion compatible with body tissues. In addition, in other embodiments, in a targeted drug delivery system, for example, a compound is delivered in a liposome coated with an organ-specific antibody. In such embodiments, the liposome targets an organ and is selectively absorbed by the organ.

[0400] The composition may be formulated for buccal or sublingual administration, examples of which include tablets, lozenges, and gels.

[0401] The compound of formula (I) can be formulated for administration by inhalation. Various forms suitable for administration by inhalation include aerosols, mists or powders. Suitable propellants (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases) can be used to deliver the pharmaceutical composition in the form of an aerosol spray from a pressurized package or a nebulizer. In some embodiments, the dosage unit of the pressurized aerosol can be determined by providing a valve for delivering a metered amount. In some embodiments, capsules and cartridges containing, for example, gelatin for use in an inhaler or insufflator can be prepared, which contain a powder mixture of the compound and a suitable powder base (such as lactose or starch).

[0402] The compounds of formula (I) may be formulated for topical administration, which as used herein means 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.

[0403] Representative examples of carriers that can be used to prepare compounds for topical application include solvents (e.g., alcohols, polyols, water), creams, lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffered solutions (e.g., hypotonic or buffered saline). For example, saturated or unsaturated fatty acids (such as stearic acid, palmitic acid, oleic acid, palmitoleic acid, cetyl alcohol, or oleyl alcohol) can be used to prepare creams. Creams can also contain nonionic surfactants, such as polyoxy-40-stearate.

[0404] In some embodiments, topical formulations may also include excipients, an example of which is a penetration enhancer. These agents are capable of transporting pharmacologically active compounds through the stratum corneum and preferably enter the epidermis or dermis with little or no systemic absorption. The effectiveness of numerous compounds in improving the penetration rate of drugs through the skin has been evaluated. See, for example, percutaneous penetration enhancers, Maibach HI and Smith HE (editor), CRC Press, Boca Raton, Fla. (1995), which investigates 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 (editor), Interpharm Press, Buffalo Grove, Ill. (1997). Representative examples of penetration enhancers include triglycerides (e.g., soybean oil), aloe compositions (e.g., aloe-vera gel), ethanol, isopropyl alcohol, octolyphenylpolyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decyl methyl sulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate), and N-methylpyrrolidone.

[0405] Representative examples of other excipients that may be included in topical formulations and other types of formulations (to the extent that they are compatible) include preservatives, antioxidants, humectants, emollients, buffers, solubilizers, skin protectants and surfactants. Suitable preservatives include alcohols, quaternary amines, organic acids, parabens and 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 humectants include glycerol, sorbitol, polyethylene glycol, urea and propylene glycol. Suitable buffers include citric acid, hydrochloric acid and lactic acid buffers. Suitable solubilizers include quaternary ammonium chlorides, cyclodextrins, benzyl formate, lecithin and polysorbate. Suitable skin protectants include vitamin E oil, allantoin, dimethicone, glycerol, petrolatum and zinc oxide.

[0406] Transdermal formulations generally use transdermal delivery devices and transdermal delivery patches, wherein the compound is formulated into a lipophilic emulsion or a buffered aqueous solution, dissolved and / or dispersed in a polymer or adhesive. The patch can be configured to deliver a medicament continuously, pulsatingly or on demand. The transdermal delivery of a compound can be achieved by means of an iontophoresis patch. A transdermal patch can provide controlled delivery of a compound, wherein the absorption rate is slowed down by using a rate-controlled membrane or by trapping the compound in a polymer matrix or a gel. Absorption enhancers can be used to increase absorption, and examples thereof include pharmaceutically acceptable solvents that contribute to the absorbability of the compound through the skin.

[0407] Ophthalmic formulations include eye drops.

[0408] 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, and synthetic polymers such as polyvinyl pyrrolidone, PEG, etc. Compositions for rectal or vaginal administration may also be formulated as suppositories which may be prepared by mixing the compound with suitable non-irritating carriers and excipients (such as cocoa butter, mixtures of fatty acid glycerides, polyethylene glycols, suppository waxes, and combinations thereof) which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compound.

[0409] Dosage

[0410] As used herein, the term "therapeutically effective amount" refers to an amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof that is effective in producing a desired therapeutic response in a specific patient suffering from a disease or condition mediated by abnormal BCL6 activity. Therefore, the term "therapeutically effective amount" includes an amount of a compound or a pharmaceutically acceptable salt or stereoisomer thereof that, when administered, induces a positive change in the disease or condition to be treated in the subject, or is sufficient to prevent the development or progression of the disease or condition, or to alleviate one or more symptoms of the disease or condition to be treated to some extent, or simply kills or inhibits the growth of diseased cells or reduces the amount of BCL6 in diseased (e.g., cancer) cells.

[0411] The total daily dose of the compound and its usage can be determined according to standard medical practice, for example, by the attending physician using sound medical judgment. The specific therapeutically effective dose for any particular subject may depend on a variety of factors, including the following: the disease or condition being treated and its severity (e.g., its current state); the age, weight, general health, sex and diet of the subject; the administration time, route of administration and excretion rate of the specific compound employed; the duration of treatment; drugs used in combination or concomitantly with the compound; and similar factors well known in the medical field (see, for example, Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th edition, A. Gilman, J. Hardman and L. Limbird eds., McGraw-Hill Press, 155-173, 2001).

[0412] How to use

[0413] In some aspects, the present disclosure relates to treating a disease or condition (e.g., a disease or condition characterized by or mediated by elevated BCL6 levels) involving abnormal (e.g., elevated BCL6 levels or otherwise dysfunctional, e.g., dysregulated BCL6 levels) BCL6 activity relative to a non-pathological state. The method requires administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof to a subject in need thereof.

[0414] The term "subject" (or "patient") as used herein includes all members of the animal kingdom susceptible to or suffering from cancer. In some embodiments, the subject is a mammal, e.g., a human or non-human mammal. The methods are also applicable to companion animals, such as dogs and cats. A subject who "needs" treatment according to the present disclosure may "suffer from or be suspected of suffering from" a particular cancer, may have been diagnosed or otherwise present with a sufficient number of risk factors, or a sufficient number of signs or symptoms, or a combination of signs or symptoms, such that a medical professional can diagnose or suspect that the subject suffers from the cancer. Therefore, subjects suffering from a particular disease or condition and subjects suspected of suffering from a particular disease or condition are not necessarily two different groups.

[0415] In some embodiments, the method relates to treating a subject with cancer. The method encompasses treatment of adult tumors / cancers and pediatric tumors / cancers. The cancer may be a vascularized or not substantially vascularized or a non-vascularized tumor.

[0416] In some embodiments, the cancer is a lymphoid malignancy.

[0417] 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.

[0418] In some embodiments, the methods of the present disclosure entail treating a subject suffering from a cell proliferative disease or disorder of the hematological system.

[0419] In some embodiments, the methods relate to treating a subject having an inflammatory disease or disorder.

[0420] In some embodiments, the inflammatory disease or condition is inflammatory bowel disease, myocarditis, endometriosis, atherosclerosis, an allergic disease or condition, or an autoimmune disease or condition. In some embodiments, the allergic disease or condition is asthma or hay fever. In some embodiments, the autoimmune disease is noninfectious meningitis, autoimmune encephalitis, transverse myelitis, or acute disseminated encephalomyelitis.

[0421] The compound of formula (I) can be administered to cancer patients as a monotherapy or by combination therapy. The therapy can be "frontline / first line", that is, as the initial treatment for patients who have not undergone previous anticancer treatment regimens, alone or in combination with other treatments; or "second line", as the treatment of patients who have undergone previous anticancer treatment regimens, alone or in combination with other treatments; or as "third line", "fourth line" and other treatments, alone or in combination with other treatments. Therapy can also be given to patients who have previously received unsuccessful or partially successful treatments but are unresponsive or intolerant to a particular treatment. Therapy can also be given as an adjuvant therapy, that is, to prevent cancer recurrence in patients who currently have no detectable disease or surgery to remove the tumor. Therefore, in some embodiments, the compound can be administered to patients who have received another therapy, such as chemotherapy, radioimmunotherapy, surgical therapy, immunotherapy, radiotherapy, targeted therapy, or any combination thereof.

[0422] The method of the present disclosure may need to administer a compound of formula (I) or its pharmaceutical composition to a patient in a single dose or multiple doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 20 or more doses). For example, the frequency of administration may be once daily up to about once every eight weeks. In some embodiments, the frequency of administration is about once daily for 1, 2, 3, 4, 5 or 6 weeks, and in other embodiments, at least one 28-day cycle is required, which includes daily administration for 3 weeks (21 days), followed by a 7-day "disabled" period. In other embodiments, the compound may be administered twice daily (BID) (a total of 5 doses) or once daily (QD) (a total of 2 doses) in a two-day schedule. In other embodiments, the compound may be administered once daily (QD) in a 5-day schedule.

[0423] Combination therapy

[0424] Formula (I) compounds and their pharmaceutically acceptable salts and stereoisomers can be combined with at least one other active agent (e.g., anticancer agent) or regimen or used simultaneously to treat cancer. The terms "combined with..." and "simultaneously" herein mean co-administration of medicaments, which include substantially concurrent administration by the same or separate dosage form and by the same or different modes of administration, or sequential administration, for example, as part of the same treatment regimen, or by continuous treatment regimens. Therefore, if given sequentially, at the beginning of administration of the second compound, the first of the two compounds can still detect effective concentrations at the treatment site in some cases. The order and time interval can be determined so that they can work together (e.g., collaboratively) to provide an increased benefit than when administered in other ways. For example, therapeutic agents can be administered sequentially in any order simultaneously or at different time points; however, if not administered simultaneously, they can be administered at sufficiently close times to provide the desired therapeutic effect, which can be administered in a collaborative manner. Therefore, the term is not limited to administering active agents at exactly the same time.

[0425] In some embodiments, the treatment regimen may include administering a compound of formula (I) in combination with one or more additional therapeutic agents known to treat cancer. The dosage of the additional therapeutic agent may be the same as or even lower than the known or recommended dosage. See Hardman et al., eds., Goodman and Gilman's The Pharmacological Basis of Basis of Therapeutics, 10th edition, McGraw-Hill, New York, 2001; Physician's Desk Reference 60th edition, 2006. Anticancer agents that may be suitable for use in combination with the compounds are known in the art. See, for example, U.S. Pat. No. 9,101,622 (Section 5.2 thereof) and U.S. Pat. No. 9,345,705 B2 (Columns 12-18 thereof). Representative examples of additional anti-cancer agents and treatment regimens include radiation therapy, chemotherapeutic agents (e.g., mitotic inhibitors, angiogenesis inhibitors, anti-hormones, autophagy inhibitors, alkylating agents, intercalating antibiotics, growth factor inhibitors, anti-androgens, signal transduction pathway inhibitors, anti-microtubule agents, platinum coordination complexes, HDAC inhibitors, proteasome inhibitors, and topoisomerase inhibitors), immunomodulators, therapeutic antibodies (e.g., monospecific and bispecific antibodies), and CAR-T therapy.

[0426] In some embodiments, the compound of Formula (I) and the additional (e.g., anticancer) therapeutic agent may be administered less than 5 minutes apart, less than 30 minutes apart, less than 1 hour apart, about 1 hour apart, about 1 to about 2 hours apart, about 2 hours to about 3 hours apart, about 3 hours to about 4 hours apart, about 4 hours to about 5 hours apart, about 5 hours to about 6 hours apart, about 6 hours to about 7 hours apart, about 7 hours to about 8 hours apart, about 8 hours to about 9 hours apart, about 9 hours to about 10 hours apart, about 10 hours to about 11 hours apart, about 11 hours to about 12 hours apart, about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours apart. Two or more (eg, anti-cancer) therapeutic agents can be administered within the same patient visit.

[0427] When the active components of the combination are not administered in the same pharmaceutical composition, it will be understood that they can be administered to a subject in need in any order. For example, the compounds of the present disclosure can be administered to a subject in need before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks before) administering another therapeutic agent, simultaneously or thereafter (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks afterwards). In various aspects, the therapeutic agent is administered at intervals of 1 minute, 10 minutes, 30 minutes, less than 1 hour, 1 hour, 1 to 2 hours, 2 to 3 hours, 3 to 4 hours, 4 to 5 hours, 5 to 6 hours, 6 to 7 hours, 7 to 8 hours, 8 to 9 hours, 9 to 10 hours, 10 to 11 hours, 11 to 12 hours, no more than 24 hours, or no more than 48 hours. In one example, (e.g., anticancer) therapeutic agents are administered within the same clinic visit. In another example, the combined anticancer therapeutic agent can be administered at intervals of 1 minute to 24 hours.

[0428] In some embodiments, the compound of formula (I) and the additional anticancer agent or therapeutic agent are administered periodically. Cyclic therapy involves administering an anticancer therapeutic agent for a period of time, followed by administering a second anticancer therapeutic agent for a period of time, and repeating the sequential administration, i.e., cycling, in order to reduce resistance to one or both anticancer therapeutic agents, to avoid or reduce the side effects of one or both anticancer therapeutic agents, and / or improve the efficacy of the therapy. In one example, cyclic therapy involves administering a first anticancer therapeutic agent for a period of time, followed by administering a second anticancer therapeutic agent for a period of time, optionally, followed by administering a third anticancer therapeutic agent for a period of time, and so on, and repeating the sequential administration, i.e., cycling, in order to reduce resistance to an anticancer therapeutic agent, to avoid or reduce the side effects of an anticancer therapeutic agent, and / or improve the efficacy of an anticancer therapeutic agent.

[0429] In some embodiments, the compounds of the present disclosure can be used in combination with other anticancer agents, examples of which include Etoposide (e.g., lymphoma and non-lymphocytic leukemia), Vincristine (e.g., leukemia), Daunorubicin (e.g., acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), and Kaposi's sarcoma), Rituximab (e.g., non-Hodgkin's lymphoma), Alemtuzumab (e.g., chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL), and T-cell lymphoma), Bortezomib (e.g., multiple myeloma and mantle cell lymphoma), Pegaspargase (e.g., acute lymphoblastic leukemia), (e.g., Hodgkin lymphoma) and dexamethasone (e.g., acute multiple myeloma).

[0430] 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.

[0431] These and other aspects of the disclosure will be further understood upon consideration of the following examples, which are intended to illustrate certain specific embodiments of the disclosure, but are not intended to limit the scope of the disclosure as defined by the claims.

[0432] Example

[0433] Example 1: 5-((2-((3S,5R)-3-(2-aminoethyl)-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloro pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one (97a) and 5- ((2-((3R,5-S)-3-(2-aminoethyl)-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-3- Synthesis of (3-hydroxy-3-methylbutyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one (97b)

[0434]

[0435] 2-(1-Benzyl-5-methyl-4-oxo-3-piperidinyl)acetic acid methyl ester

[0436] At -78 ° C, LDA (2M, 73.80 mL, 1 eq) was added dropwise to a solution of 1-benzyl-3-methyl-piperidin-4-one (30 g, 147.58 mmol, 1 eq) in THF (300 mL) at -78 ° C. After addition, the mixture was stirred at -78 ° C for 30 min, then 2-bromoacetic acid methyl ester (33.86 g, 221.38 mmol, 20.90 mL, 1.5 eq) and HMPA (31.74 g, 177.10 mmol, 31.12 mL, 1.2 eq) were added dropwise at -78 ° C, and the mixture was stirred at -78 ° C for 2.5 hr. The resulting mixture was then stirred at 20 ° C for 9 hr. The reaction mixture was quenched by adding NH4Cl (100 mL, aq.), then diluted with H2O (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 (8-3 g, 17%) as a yellow oil. LCMS: [M+1] + =276.2.

[0437] 2-(1-Benzyl-4,4-difluoro-5-methyl-3-piperidinyl)acetic acid methyl ester

[0438] DAST (77.74 g, 482.31 mmol, 63.72 mL, 16 eq) was added to a solution of 2-(1-benzyl-5-methyl-4-oxo-3-piperidinyl)acetic acid methyl ester (8-3 g, 30.14 mmol, 1 eq) in DCM (85 mL). The mixture was stirred at 50 ° C for 12 hr. The residue was diluted with DCM (60 mL), and the mixture was then added dropwise to a saturated NaHCO aqueous solution (200 mL). The resulting mixture was stirred at 20 ° C for 20 min and then extracted with EtOAc (100 mL × 3). The combined organic layer was washed with brine (50 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 (3.7 g, 41%) as a yellow oil. 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).

[0439] 2-(1-Benzyl-4,4-difluoro-5-methyl-3-piperidinyl)ethanol

[0440] To a solution of 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidinyl)acetic acid methyl ester (1 g, 3.36 mmol, 1 eq) in THF (10 mL) was slowly added dropwise LiAlH4 (255.29 mg, 6.73 mmol, 2 eq) at 0 ° C, and the mixture was stirred at 20 ° C for 1 hr. The reaction mixture was quenched by adding NH4Cl (10 mL, aq.), then diluted with H2O (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (700 mg, 77%) as a yellow oil. LCMS: [M+1] + =270.1.

[0441] 2-[2-(1-Benzyl-4,4-difluoro-5-methyl-3-piperidinyl)ethyl]isoindoline-1,3-dione

[0442] To a solution of 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidinyl)ethanol (700 mg, 2.60 mmol, 1 eq) and isoindoline-1,3-dione (458.88 mg, 3.12 mmol, 1.2 eq) in DCM (7 mL) was added PPh3 (886.20 mg, 3-38 mmol, 1.3 eq) at 0 ° C. A solution of DEAD (588.43 mg, 3.38 mmol, 614.23 μL, 1.3 eq) in DCM (1 mL) was then added dropwise at 0 ° C. The resulting reaction mixture was stirred at 20 ° C for 12 hr. 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 (600 mg, 58%) as a colorless oil. LCMS: [M+1] + =399.1.

[0443] 2-[2-(4,4-difluoro-5-methyl-3-piperidinyl)ethyl]isoindoline-1,3-dione

[0444] To a solution of 2-[2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidinyl)ethyl]isoindoline-1,3-dione (200 mg, 501.95 μmol, 1 eq) in MeCN (8 mL) and H2O (2 mL) was added ceric ammonium nitrate (2.75 g, 5.02 mmol, 2.50 mL, 10 eq). The mixture was stirred at 40°C for 12 hr. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (column: 80 g Agela C18; solvent for sample dissolution: about 0.20 grams of sample dissolved in 2 ml MeOH; flow rate: 40 ml / min; mobile phase: TFA; gradient B%: 30-60% 10 min; 60% 5 min; instrument: Biotage) to give the title compound (140 mg, 66%, TFA salt) as a yellow solid. LCMS: [M+1] + =309.2.

[0445] 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-piperidinyl]ethyl]isoindoline-1,3-dione

[0446] To a solution of 5-[(2,5-dichloropyrimidin-4-yl)amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (160 mg, 403.76 μmol, 1 eq) and 2-[2-(4,4-difluoro-5-methyl-3-piperidinyl)ethyl]isoindoline-1,3-dione (139.21 mg, 403.76 μmol, 1 eq, TFA) in DMF (3 mL) was added DIPEA (156.55 mg, 1.21 mmol, 210.99 μL, 3 eq). The mixture was stirred at 130° C. for 6 hr. 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 (10mMNH4HCO3)-MeCN]; B%: 30%-60%, 8min) to give the title compound (200mg, 74.%) as a yellow solid. LCMS: [M+1] + =668.1.

[0447] 2-[2-[(3S,5R)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzoimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidinyl]ethyl]isoindoline-1,3-dione and 2-[2-[(3R,5S)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzoimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidinyl]ethyl]isoindoline-1.3-dione

[0448] The enantiomer mixture was separated in an amount of 200 mg 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-benzoimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidinyl]ethyl]isoindoline-1,3-dione was obtained as a white solid (50 mg, 44% yield, 96% purity) and 2-[2-[(3R,5S)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzoimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidinyl]ethyl]isoindoline-1,3-dione was obtained as a white solid (60 mg, 54% yield, 99% purity).

[0449] 5-[[2-[(3S,5R)-3-(2-aminoethyl)-4,4-difluoro-5-methyl-1-piperidinyl]-5-chloro-pyrimidin-4-yl][amino][-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (97a)

[0450] To a solution of 2-[2-[(3S,5R)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzoimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidinyl]ethyl]isoindoline-1,3-dione (50.00 mg, 74.84 μmol, 1 eq) in EtOH (0.5 mL) was added NH2NH2·H2O (56.19 mg, 1.12 mmol, 54.56 μL, 15 eq). The mixture was stirred at 60° C. for 1 hr. 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%: 30%-55%, 8min) to give the title compound (15.2mg, 37%) as a white solid. 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.

[0451] 5-[[2-[(3R,5S)-3-(2-aminoethyl)-4,4-difluoro-5-methyl-1-piperidinyl]-5-chloro-pyrimidin-4-yl]amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (97b)

[0452] To a solution of 2-[2-[(3R,5S)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzoimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidinyl]ethyl]isoindoline-1,3-dione (50 mg, 74.84 μmol, 1 eq) in EtOH (0.5 mL) was added NH2NH2·H2O (56.19 mg, 1.12 mmol, 54.56 μL, 15 eq). The mixture was stirred at 60° C. for 2 hr. 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 NH 4 HCO 3 )-MeCN]; B%: 30%-55%, 8 min) to give the title compound (20.1 mg, 49%) as a white solid. 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.

[0453] The absolute configurations of compounds 97a and 97b were randomly assigned based on the cis-configuration of the alkylamino and methyl groups.

[0454] Example 2: 5-[[2-[(3S,5R)-3-(aminomethyl)-4,4-difluoro-5-methyl-1-piperidinyl]-5-chloro-pyrimidine [(3R,5S)-4-pyridin-4-yl]amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzoimidazol-2-one (2a) 3-(aminomethyl)-4,4-difluoro-5-methyl-1-piperidinyl]-5-chloro-pyrimidin-4-yl]amino]-3-(3-hydroxy-3-methyl- Synthesis of 1-methyl-2-benzimidazol-2-one (2b)

[0455]

[0456] 3-Methyl-4-oxo-piperidine-1-carboxylic acid benzyl ester

[0457] To a solution of 1-benzyl-3-methyl-piperidin-4-one (26 g, 127.90 mmol, 1 eq) in toluene (300 mL) was added CbzCl (33.38 g, 195.69 mmol, 27.82 mL, 1.53 eq). The mixture was stirred at 112 ° C for 12 hr. The residue was diluted with H2O (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, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 0 / 1) to give the title compound (25 g, 79%) as a yellow oil. LCMS: [M+I] + =248.2.

[0458] 3-[(1,3-dioxoisoindolin-2-yl)methyl]-5-methyl-4-oxo-piperidine-1-carboxylic acid benzyl ester

[0459] To a solution of 3-methyl-4-oxo-piperidine-1-carboxylic acid benzyl ester (10 g, 40.44 mmol, 1 eq) in THF (200 mL) was added LiHMDS (1 M, 50.55 mL, 1.25 eq) dropwise at -78 ° C over 30 min. 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 eq) in THF (200 mL) was added dropwise at -78 ° C. The resulting mixture was stirred at -78 ° C for 2 hr. The reaction mixture was quenched by adding NH4Cl (200 mL, aq.) at 0 ° C, then diluted with H2O (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, which was purified by reverse phase HPLC (column: 800 g Agela C18; solvent for sample dissolution: about 8.50 grams of sample dissolved in 40 ml MeOH; flow rate: 120 ml / min; mobile phase: water-MeCN; gradient B%: 45-75% 30 min; 75% 30 min; instrument: Biotage) to give the title compound (5 g, 30%) as a white solid. LCMS: [M+1] + =407.1.

[0460] 3-[(1,3-dioxoisoindolin-2-yl)methyl]-4,4-difluoro-5-methyl-piperidine-1-carboxylic acid benzyl ester

[0461] To a solution of 3-[(1,3-dioxoisoindolin-2-yl)methyl]-5-methyl-4-oxo-piperidine-1-carboxylic acid benzyl ester (4 g, 9.84 mmol, 1 eq) in DCM (50 mL) was added DAST (25.38 g, 157.47 mmol, 20.81 mL, 16 eq) at 0°C. The resulting mixture was then stirred at 20°C for 72 hr. The residue was diluted with DCM (40 mL), and the mixture was then added dropwise to a saturated aqueous NaHCO solution (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 Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by reverse phase HPLC (column: 330 g Agela C18; solvent for sample dissolution: about 5.00 grams of sample dissolved in 20 ml MeOH; flow rate: 70 ml / min; mobile phase: water MeCN; gradient B%: 45-75% 25 min; 75% 40 min; instrument: Biotage) to give the title compound (1.7 g, 40%) as a yellow oil. 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, 1H), 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 (brs, 1H), 1.05 (d, J=6.6Hz, 3H).

[0462] 2-[(4,4-difluoro-5-methyl-3-piperidinyl)methyl]isoindoline-1,3-dione

[0463] To a solution of 3-[(1,3-dioxoisoindolin-2-yl)methyl]-4,4-difluoro-5-methyl-piperidine-1-carboxylic acid benzyl ester (1.5 g, 3.50 mmol, 1 eq) in DCM (5 mL) was added TEA (1.06 g, 10.50 mmol, 1.46 mL, 3 eq), Pd(OAc)2 (314.42 mg, 1.40 mmol, 0.4 eq) and Et3SiH (2.44 g, 21.01 mmol, 3.36 mL, 6 eq). The mixture was stirred at 20°C for 1 hr. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (column: 330 g Agela C18; solvent for sample dissolution: about 5.00 grams of sample dissolved in 20 ml MeOH; flow rate: 70 ml / min; mobile phase: water-MeCN; gradient B%: 30-60% 25 min; 60% 10 min; instrument: Biotage) to give the title compound (800 mg, 78%) as a yellow solid. LCMS: [M+1] + =295.0.

[0464] 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-piperidinyl]methyl]isoindoline-1,3-dione

[0465] 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 eq) and 2-[(4,4-difluoro-5-methyl-3-piperidinyl)methyl]isoindoline-1,3-dione (259.93 mg, 883.24 μmol, 1 eq) in DMF (2 mL) was added DIPEA (342.46 mg, 2.65 mmol, 461.53 μL, 3 eq). The reaction mixture was stirred at 50 °C for 12 hr. 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 (170 mg, 28% yield, 95% purity) as a yellow solid. 1H 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).

[0466] 2-[[(3S,5S)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzoimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidinyl]methyl]isoindoline-1,3-dione and 2-[[(3R,5R)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzoimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidinyl]methyl]isoindoline-1,3-dione

[0467] 170 mg of the enantiomeric mixture was separated by SFC (supercritical fluid chromatography) on a 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-benzoimidazol-5-yl]amino]pyrimidin-2-yl] -4,4-difluoro-5-methyl-3-piperidinyl]methyl]isoindoline-1,3-dione (70 mg, 40% yield, 96% purity) and 2-[[(3R,5R)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzoimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidinyl]methyl]isoindoline-1,3-dione (70 mg, 40% yield, 96% purity) as a white solid.

[0468] 5-[[2-[(3S,5R)-3-(Aminomethyl)-4,4-difluoro-5-methyl-1-piperidinyl]-5-chloro-pyrimidin-4-yl]amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (2a)

[0469] To a solution of 2-[[(3R,5R)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzoimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidinyl]methyl]isoindoline-1,3-dione (80 mg, 122.30 μmol, 1 eq) in EtOH (2 mL) was added NH2NH2·H2O (91.84 mg, 1.83 mmol, 89.16 μL, 15 eq). The mixture was stirred at 60° C. for 2 hr. 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 NH 4 HCO 3 )-MeCN]; B%: 25%-55%, 8 min) to give the title compound (16.7 mg, 26.%) as a white solid. 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.

[0470] 5-[[2-[(3R,5S)-3-(Aminomethyl)-4,4-difluoro-5-methyl-1-piperidinyl]-5-chloro-pyrimidin-4-yl]amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (2b)

[0471] To a solution of 2-[[(3S,5S)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzoimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidinyl]methyl]isoindoline-1,3-dione (80 mg, 122.30 μmol, 1 eq) in EtOH (2 mL) was added NH2NH2·H2O (91.84 mg, 1.83 mmol, 89.16 μL, 15 eq). The reaction mixture was stirred at 60° C. for 2 hr. 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 NH 4 HCO 3 )-MeCN]; B%: 25%-55%, 8 min) to give the title compound (16.6 mg, 256%) as a white solid. 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=6.4Hz, 3H). LCMS:[M+1] + =524.2.

[0472] The absolute configurations of compounds 2a and 2b were randomly assigned based on the cis-configuration of the alkylamino and methyl groups.

[0473] Example 3: 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) 2- ((6-((2-((3R,5S)-3-(aminomethyl)-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidin-4-yl)amino)- Synthesis of 1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (50b)

[0474]

[0475] 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

[0476] 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 eq) and 2-[(4,4-difluoro-5-methyl-3-piperidinyl)methyl]isoindoline-1,3-dione (302.77 mg, 1.03 mmol, 1.2 eq) in DMF (3 mL) was added DIPEA (332.42 mg, 2.57 mmol, 448.00 μL, 3 eq). The reaction mixture was stirred at 130° C. for 12 hr. 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 NH 4 HCO 3 )-MeCN]; B%: 25%-55%, 8 min) to give the title compound (260 mg, 46%) as a yellow solid. 1 HNMR (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).

[0477] 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

[0478] 260 mg of the enantiomeric mixture was separated by SFC (supercritical fluid chromatography) on 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-piperidinyl]pyrimidin-4-yl]amino]-1-methyl as a yellow solid -2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (75 mg, 32%) and 2-[[6-[[5-chloro-2-[(3S,5S)-3-[(1,3-dioxoisoindolin-2-yl)methyl]-4,4-difluoro-5-methyl-1-piperidinyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (65 mg, 29%) as a yellow solid.

[0479] 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)

[0480] To a solution of 2-[[6-[[5-chloro-2-[(3R,5R)-3-[(1,3-dioxoisoindolin-2-yl)methyl]-4,4-difluoro-5-methyl-1-piperidinyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide (70.00 mg, 105.09 μmol, 1 eq) in EtOH (2 mL) was added NH2NH2H2O (78.92 mg, 1.58 mmol, 76.62 μL, 15 eq). The reaction mixture was stirred at 60° C. for 2 hr. 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%-35%, 8 min) to give the title compound (6.1 mg, 6%, HCl salt) as a white solid. 1H 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.

[0481] 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)

[0482] To a solution of 2-[[6-[[5-chloro-2-[(3S,5S)-3-[(1,3-dioxoisoindolin-2-yl)methyl]-4,4-difluoro-5-methyl-1-piperidinyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide (65 mg, 97.59 μmol, 1 eq) in EtOH (2 mL) was added NH2NH2H2O (73.28 mg, 1.46 mmol, 71.14 μL, 15 eq). The reaction mixture was stirred at 60° C. for 2 hr. 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%-35%, 8 min) to give the title compound (13.7 mg, 24%, HCl salt) as a white solid. 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.

[0483] The absolute configurations of compounds 50a and 50b were randomly assigned based on the cis-configuration of the alkylamino and methyl groups.

[0484] Example 4: 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 Synthesis of 1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (51b)

[0485]

[0486] 2-((6-((2,5-dichloropyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0487] To a solution of 2-[(6-amino-1-methyl-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide (3 g, 11.48 mmol, 1 eq) and 2,4,5-trichloropyrimidine (3.16 g, 17.22 mmol, 1.5 eq) in DMF (30 mL) was added DIEA (2.23 g, 17.22 mmol, 3.00 mL, 1.5 eq). The reaction mixture was stirred at 15 ° C for 12 hr. Water (50 mL) was added and the precipitated solid was filtered and washed with H2O (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) δ9.65 (s, 1H), 8.38 (s, 1H), 7.94 (s, 1H), 7.75 (s, 1H), 7.66 (d, J=8.4H z, 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).

[0488] 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

[0489] Under N2 atmosphere, 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 eq), 2-[2-(4,4-difluoro-5-methyl-3-piperidinyl)ethyl]isoindoline-1,3-dione (931.10 mg, 2.20 mmol, 1.5 eq, TFA) and DIEA (379.90 mg, 2.94 mmol, 512.00 μL, 2 eq) in DMSO (10 mL) was stirred at 120 ° C. for 6 hr. Water (15 mL) was added and the precipitated solid was filtered and washed with H2O (30 mL) and ethyl acetate (30 mL). The solid was dried under reduced pressure to give the title compound (1 g, crude) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.99 (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).

[0490] 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

[0491] To a mixture of 2-[[6-[[5-chloro-2-[3-[2-(1,3-dioxoisoindolin-2-yl)ethyl]-4,4-difluoro-5-methyl-1-piperidinyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (400 mg, 588.15 μmol, 1 eq) in NMP (5 mL) was added NH2NH2·H2O (480.00 mg, 9.59 mmol, 466.02 μL, 16.30 eq) and the mixture was stirred at 100°C for 2 hr. 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%-35%, 21 min) to give the title compound (250 mg, 77%) as a white solid. 1 H NMR (400MHz, MeOD) δ8.14 (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 = 13.2H z, 1H), 4.38 (d, J=12.8Hz, 1H), 3.83 (s, 3H), 3.06-2.96 (m, 3H), 2.85 (s, 3H) , 2.21-2.06 (m, 3H), 2.03 (s, 1H), 1.68-1.58 (m, 1H), 1.03 (d, J=6.4Hz, 3H).

[0492] 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)

[0493] 2-[[6-[[2-[3-(2-aminoethyl)-4,4-difluoro-5-methyl-1-piperidinyl]-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% NH3H2OIPA]; B%: 30%-30%, 15 min) to give 51a and 51b each as a white solid. 51a: (12 mg, 10% yield, 100% purity); 1 HNMR (400MHz, MeOD) δ7.99 (s, 1H), 7.87 (d, J=2.0Hz, 1H), 7.80 (dd, J=9.2, 2.4H z, 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=6.8 Hz, 3H); LCMS: [M+H+]=550.2.51b: (4 mg, 3% yield, 95% purity); 1 H NMR (400MHz, DMSO-d6) δ8.96 (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 (m, 4H), 3.69 (s, 3H), 2.66-2.57 (m, 7H), 2.07-1.92 (m, 4H), 1.76-1.67 (m, 1H), 1.23 (s, 1H), 0.94 (d, J=4.4Hz, 3H); LCMS: [M+H + ]=550.1.

[0494] The absolute configurations of compounds 51a and 51b were randomly assigned based on the cis-configuration of the alkylamino and methyl groups.

[0495] Example 5: 2-((6-((5-chloro-2-(3-(2-(dimethylamino)ethyl)-4,4-difluoro-5-methylpiperidin-1- Synthesis of (53) become

[0496]

[0497] 2-(1-Benzyl-4,4-difluoro-5-methylpiperidin-3-yl)ethan-1-amine

[0498] To a solution of 2-[2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidinyl)ethyl]isoindoline-1,3-dione (2.6 g, 6.53 mmol, 1 eq) in EtOH (30 mL) was added NH2NH2H2O (3.27 g, 65.25 mmol, 3.17 mL, 10 eq) 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 (1.15 g, 64% yield, 98% purity) as a colorless oil. LCMS: [M+H] + =269.0.

[0499] 2-(1-Benzyl-4,4-difluoro-5-methylpiperidin-3-yl)-NN-dimethylethan-1-amine

[0500] To a solution of 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidinyl)ethylamine (1 g, 3.73 mmol, 1 eq) in MeOH (15 mL) was added HCHO aqueous solution (2.42 g, 29.81 mmol, 2.22 mL, 37% purity, 8 eq) and AcOH (111.89 mg, 1.86 mmol, 106.57 μL, 0.5 eq). The reaction mixture was stirred at 20 ° C for 30 min, then NaBH3CN (1.87 g, 29.81 mmol, 8 eq) 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 Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex LunaC18 (250*70 mm, 15 μm); mobile phase: [water(HCl)-ACN]; B%: 1%-20%, 20 min) to give the title compound (320 mg, 29% yield, 100% purity) as a colorless oil. 1 H NMR (400MHz, MeOD) δ = 7.38-7.27 (m, 5H), 3.65-3.56 (m, 2H), 3.23-3.18 (m, 2 H) 2.86 (s, 7H), 2.22-2.01 (m, 6H) 1.64-1.61 (m, 1H) 0.97 (d, J=6.63Hz, 3H).

[0501] 2-(4,4-difluoro-5-methylpiperidin-3-yl)-N,N-dimethylethan-1-amine

[0502] Under Ar, Pd / C (0.1 g, 67-48 μmol, 10% purity) was added to a solution of 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidinyl)-N,N-dimethyl-ethylamine (160 mg, 539.82 μmol, 1 eq) in DMF (3 mL). The suspension was degassed under vacuum and purged with H2 several times. The reaction mixture was stirred at 60 ° C for 12 hours under H2 (15 psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (100 mg, 90% yield) as a yellow oil. 1 HNMR (400MHz, DMSO-d6) δppm 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).

[0503] 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)

[0504] 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 eq), 2-(4,4-difluoro-5-methyl-3-piperidinyl)-N,N-dimethyl-ethylamine (100 mg, 484.79 μmol, 1.98 eq) and DIPEA (63-32 mg, 489.91 μmol, 85.33 μL, 2 eq) in DMSO (2 mL) was stirred at 100 °C for 12 h. The mixture was directly purified by preparative HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water(HCl)-ACN]; B%: 1%-30%, 8 min) to give the title compound (12 mg, 8% yield, 94% purity, HCl salt) as a white solid. 1H NMR (400MHz, DMSO-d6) δ = 10-43 (br s, 1H), 9.44 (brs, 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.

[0505] Example 6: 2-((6-((2-(3-(1-amino-2-methylpropan-2-yl)-4,4-difluoro-5-methylpiperidin-1- 2-(4-(2-(2-(2-((2-(((((-((-((-(-chloropyrimidin-4-yl-(amino-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl-(oxy)-N-methylacetamide Synthesis of (57)

[0506]

[0507] 2-(1-benzyl-4,4-difluoro-5-methylpiperidin-3-yl)propanoic acid methyl ester and 2-(1-benzyl-4,4-difluoro-5-methylpiperidin-3-yl)-2-methylpropanoic acid methyl ester

[0508] To a solution of methyl 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidinyl)acetate (2.00 g, 6.73 mmol, 1 eq) in THF (30 mL) was added LiHMDS (1 M, 7.40 mL, 1.1 eq) dropwise at -78 °C under N2. After addition, the reaction mixture was stirred at -78 °C for 15 min, and then MeI (1.05 g, 7.40 mmol, 460.53 μL, 1.1 eq) was added dropwise at -78 °C. The resulting mixture was warmed to 20 °C over 1 hr. The reaction mixture was cooled to -78 °C, and LiHMDS (1 M, 7.40 mL, 1.1 eq) was added dropwise at -78 °C under N2. After addition, the reaction mixture was stirred at -78 ° C for 15 min, and then MeI (1.05 g, 7.40 mmol, 460.61 μL, 1.1 eq) was added dropwise at -78 ° C under N2. The resulting mixture was warmed to 20 ° C over 1 h, and then stirred at 20 ° C for 9.5 h. The reaction mixture was cooled to 0 ° C, quenched with saturated NH4C1 aqueous solution (100 mL), and extracted with ethyl acetate (80 mL × 2). The combined organic phases were 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 a mixture of the title compound as a yellow oil (2.2 g). LCMS: [M+H] + =326.1.

[0509] 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

[0510] At 0 ° C, LAH (279.91 mg, 7.38 mmol, 1.2 eq) was added to a mixture of 2 g 2- (1-benzyl-4,4-difluoro-5-methyl-3-piperidinyl) -2-methyl-propionic acid methyl ester (6.15 mmol, 1 eq) and 2- (1-benzyl-4,4-difluoro-5-methyl-3-piperidinyl) propionic acid methyl ester (6.15 mmol, 1 eq) in THF (20 mL). After addition, the reaction mixture was stirred at 20 ° C for 1 hr, and then the reaction mixture was cooled to 0 ° C and quenched with water (2 mL). 10 g of anhydrous Na2SO4 was added and the mixture was stirred for 2 min. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a mixture of the title compound as a yellow oil (1.6 g). LCMS: [M+H] + =298.1.

[0511] 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

[0512] To a solution of 1.1 g 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidinyl)-2-methyl-propan-1-ol (1.68 mmol, 1 eq) and 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidinyl)propan-1-ol (1.68 mmol, 1 eq), isoindoline-1,3-dione (321.59 mg, 2.19 mmol, 1.3 eq) and PPh3 (573.30 mg, 2.19 mmol, 1.3 eq) in THF (20 mL) was added DEAD (380.67 mg, 2.19 mmol, 397.36 μL, 1.3 eq) 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 (merged with another batch on a 0.5g scale) was quenched with water (50mL) and extracted with ethyl acetate (50mL×2). The combined organic phase was washed with brine (50mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase MPLC (neutral conditions) to obtain 2-[2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidinyl)-2-methyl-propyl]isoindoline-1,3-dione (400mg, 73.3% purity, LCMS: [M+H]) as a yellow oil. + =427.1) and 2-[2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidinyl)propyl]isoindoline-1,3-dione as a yellow oil (600 mg, 89.4% purity, LCMS: [M+H] + =413.1.

[0513] 2-(2-(4,4-difluoro-5-methylpiperidin-3-yl)-2-methylpropyl)isoindoline-1,3-dione

[0514] To a solution of 2-[2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidinyl)-2-methyl-propyl]isoindoline-1,3-dione (300 mg, 703.40 μmol, 1 eq) in ACN (12 mL) and H2O (3 mL) was added CAN (3.86 g, 7.03 mmol, 3.51 mL, 10 eq) and stirred at 50 °C for 12 h. Saturated aqueous Na2CO3 (about 10 mL) was added to the reaction mixture (combined with another batch on a 100 mg scale). 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 phases were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica chromatography (silica flash column, 0-30% MeOH / DCM eluent) to give the title compound as a yellow solid (130 mg). LCMS: [M+H] + =337.1.

[0515] 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

[0516] To a solution of 2-[2-(4,4-difluoro-5-methyl-3-piperidinyl)-2-methyl-propyl]isoindoline-1,3-dione (130 mg, 386.47 μmol, 1 eq) and 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide (157.77 mg, 386.47 μmol, 1 eq) in DMSO (2 mL) was added DIPEA (99.90 mg, 772.95 μmol, 134.63 μL, 2 eq) and the reaction mixture was stirred at 100° C. for 1 hr. 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). 1H 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).

[0517] 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)

[0518] 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-piperidinyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide (40 mg, 56.49 μmol, 1 eq) in EtOH (1 mL) was added NH2NH2.H2O (42.41 mg, 847.28 μmol, 41.18 μL, 15 eq) and the reaction mixture was stirred at 60°C for 2 h. The reaction mixture was concentrated under reduced pressure and purified directly by preparative HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water(HCl)-ACN]; B%: 20%-40%, 8 min) to give the title compound (5.8 mg, 14% yield, 99% purity, HCl) as a white solid. 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.

[0519] Example 7: 2-((6-((2-(3-(1-aminopropan-2-yl)-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloropyrimidine Synthesis of 2-(4-pyridin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (56)

[0520]

[0521] 2-(2-(4,4-difluoro-5-methylpiperidin-3-yl)propyl)isoindoline-1,3-dione

[0522] CAN (6.65 g, 12.12 mmol, 6.04 mL, 10 eq) was added to a solution of 2-[2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidinyl)propyl]isoindoline-1,3-dione (500 mg, 1.21 mmol, 1 eq) in MeCN (20 mL) and H2O (5 mL). The reaction mixture was stirred at 50 °C for 12 hr. The pH of the reaction mixture (combined with another batch on a 100 mg scale) was adjusted to 9-10 by adding saturated aqueous Na2CO3 solution, and then the reaction mixture was 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 Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica chromatography (silica flash column, 0-50% ethyl acetate / MeOH eluent) to give the title compound as a yellow solid (250 mg, 73% purity). LCMS: [M+H] + =323.0.

[0523] 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

[0524] To a solution of 2-[2-(4,4-difluoro-5-methyl-3-piperidinyl)propyl]isoindoline-1,3-dione (200 mg, 620.45 μmol, 1 eq) 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 eq) in DMSO (2 mL) was added DIPEA (160.38 mg, 1.24 mmol, 216.14 μL, 2 eq) and the reaction mixture was stirred at 100 ° C for 1 h. Water (5 mL) was added to the reaction mixture and 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 (200 mg, 98% purity) as a white solid. 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.

[0525] 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)

[0526] 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-piperidinyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (150 mg, 216.10 μmol, 1 eq) in EtOH (2 mL) and NMP (2 mL) was added NH2NH2.H2O (162.27 mg, 3.24 mmol, 157.55 μL, 15 eq) and the reaction mixture was stirred at 60°C for 12 h. Water (5 mL) was added to the reaction mixture and 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 HNMR (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.

[0527] Example 8: 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 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 Synthesis of (4-(2-(4-(2-(4-(2-(4-oxy)-N-methylacetamide)))

[0528]

[0529] 2-(1-Benzyl-4,4-difluoro-5-methylpiperidin-3-yl)acetaldehyde

[0530] PCC (4.80 g, 22.28 mmol, 2 eq) was added to a solution of 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidinyl)ethanol (3 g, 11.14 mmol, 1 eq) in DCM (30 mL) 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, 10-50% ethyl acetate / petroleum eluent) to give the title compound (1 g, 34% yield) as a yellow oil. LCMS: [M+H] + =268.0.

[0531] 1-Benzyl-3-(2-(3,3-difluoroazetidin-1-yl)ethyl)-4,4-difluoro-5-methylpiperidine

[0532] To a solution of 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidinyl)acetaldehyde (1g, 3.74mmol, 1eq) and 3,3-difluoroazetidine (969.17mg, 7.48mmol, 2eq, HCl) in MeOH (10mL) was added DIPEA (1.93g, 14.96mmol, 2.61mL, 4eq) and the reaction mixture was stirred at 20°C for 1h. NaBH3CN (470.17mg, 7.48mmol, 2eq) was then added and the reaction mixture was stirred at 40°C for 11h. Saturated NaHCO3 (40mL) was added and the mixture was extracted with ethyl acetate (30mL×3). The combined organic phases were washed with brine (50mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica chromatography (silica flash column, elution gradient 10 to 50% ethyl acetate in petroleum ether) to give the title compound (300 mg, 22% yield, 96% purity) as a yellow oil. 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), 2.65-2.5 3 (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.

[0533] 3-(2-(3,3-difluoroazetidin-1-yl)ethyl)-4,4-difluoro-5-methylpiperidine

[0534] A mixture of 1-benzyl-3-[2-(3,3-difluoroazetidine-1-yl)ethyl]-4,4-difluoro-5-methyl-piperidine (200 mg, 580.74 μmol, 1 eq), CAN (3.18 g, 5.81 mmol, 2.89 mL, 10 eq) in MeCN (8 mL) and H2O (2 mL) was stirred at 40 ° C for 12 h. The pH of the reaction mixture (combined with another batch on a 100 mg scale) was adjusted to 10 by adding saturated Na2CO3 aqueous solution (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 (230 mg, crude) as a yellow oil. LCMS: [M+H] + =255.2.

[0535] 2-(6-((5-chloro-2-(3-(2-(3,3-difluoroaminobutane-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

[0536] 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 eq), 3-[2-(3,3-difluoroazetidin-1-yl)ethyl]-4,4-difluoro-5-methyl-piperidine (152.66 mg, 306.19 μmol, 51% purity, 2.5 eq), DIPEA (31.66 mg, 244.96 μmol, 42.67 μL, 2 eq) in DMSO (1 mL) was stirred at 100° C. for 3 hr. The mixture (combined with another batch on a 20 mg scale) was directly purified by preparative HPLC (column: Phenomenex C 18 80*40 mm*3 μm; mobile phase: [water(NH 4 HCO 3 )-ACN]; B%: 50%-80%, 8 min) to give the title compound (50 mg, 100% purity) as a white solid. 1HNMR (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).

[0537] 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)

[0538] 2-[[6-[[5-chloro-2-[3-[2-(3,3-difluoroazetidin-1-yl)ethyl]-4,4-difluoro-5-methyl-1-piperidinyl]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% NH3H2OETOH]; B%: 50%-50%, 10 min) to give Compound 54a (13.9 mg, 27% yield, 99% purity) as a white solid; 1HNMR (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 (12.2 mg, 24% yield, 99% purity) as a white solid; 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.

[0539] Example 9: 5-[[2-[(3S,5R)-3-amino-4,4-difluoro-5-methyl-1-piperidinyl]-5-chloro-pyrimidine-4- [3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzoimidazol-2-one (1)

[0540]

[0541] 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-piperidinyl]isoindoline-1,3-dione

[0542] 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 eq) in DMSO (1 mL) was added DIEA (65.22 mg, 504.7 μmol, 87.92 μL, 2 eq) and 2-[(3S, 5R)-4,4-difluoro-5-methyl-3-piperidinyl]isoindoline-1,3-dione (70.73 mg, 252.35 μmol, 1 eq). The reaction mixture was stirred at 100 ° C for 12 hr under N2. The reaction mixture was diluted with water (10 mL), filtered and the filter cake was dried under reduced pressure to give the title compound (120 mg, 59% yield, 79% purity) as a yellow solid. LCMS: [M+H] + =640-3.

[0543] 5-[[2-[(3S,5R)-3-amino-4,4-difluoro-5-methyl-1-piperidinyl]-5-chloro-pyrimidin-4-yl]amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (1)

[0544] To a solution of 2-[(3-S,5R)-1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzoimidazol-5-yl]amino]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidinyl]isoindoline-1,3-dione (120 mg, 187.48 μmol, 1 eq) in EtOH (6 mL) was added MeNH2 (6 mL, 40% purity in water) and the reaction mixture was stirred at 70° C. for 1 hr. 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 (35 mg, 33% yield, 98% purity) as a white solid. 1H 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.

[0545] Example 10: Degradation activity in SU-DHL-4 cells

[0546] HiBiT Solution

[0547] The degradation was determined by cellular degradation assay in Su-DHL-4 cells (HiBiT, Promega TM )Determine DC 50 (Concentration to achieve 50% degradation) values ​​(Table 1). Endogenous B cell lymphoma 6 (BCL6) was labeled with 11-amino acid small BiT (SmBiT) by clustered regularly interspaced short palindromic repeat (CRISPR) / CRISPR-associated protein 9 (Cas9) gene editing and single cell clone selection. After 24 hours of compound treatment, the cells were lysed and incubated with large BiT (LgBiT) protein to reconstruct complete nanoluciferase. The substrate was then added and the relative luciferase units were measured. The degradation level of each treatment was considered as a percentage (Prism) compared to the control (100% DMSO).

[0548] Example 11: Kinetic Solubility

[0549] Prepare 50 mM phosphate buffer (PB) at pH 7.4:

[0550] a) Preparation of 50 mM NaH2PO4: Dissolve 3.00 g NaH2PO4 in 500 mL water, and the measured pH is about 4.5;

[0551] b) Preparation of 50 mM Na2HPO4: Dissolve 3.55 g Na2HPO4 in 500 mL water, and the measured pH is about 9.4;

[0552] c) Preparation of 50 mM PB (pH 7.4): Add 15 mL of 50 mM Na2HPO4 to a 50 mL tube, then adjust the pH to 7.4 with 50 mM Na2HPO4.

[0553] plan:

[0554] a) Add 10 μL of 10 mM DMSO in the test compound and control compound to In the lower chamber of the vial;

[0555] b) Add 490 μL of 50 mM PB (pH 7.4) to In the lower chamber of the vial;

[0556] c) vortex the solubility samples for at least 2 minutes;

[0557] d) The vials were shaken at 800 rpm on a Bamstead shaker at room temperature for 24 hours and then centrifuged for 20 minutes (e.g., 4000 rpm);

[0558] e) Compression Vials to prepare filtrate for injection into the UPLC system to calculate concentration using a standard curve.

[0559] Example 12: Metabolic stability in human liver microsomes

[0560] Solution preparation

[0561] a) Phosphate buffer

[0562] Na2HPO4 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.

[0563] b) Quenching solution

[0564] A 1 mg / mL stock solution of terfenadine / tolbutamide was prepared in DMSO and then made into a quenching solution (5 / 10 ng / mL terfenadine / tolbutamide) using cerium ammonium nitrate (can).

[0565] c) Test compound working solution

[0566] Prepare 10 mM stock solutions of test compounds in DMSO and then make 200 μM working solutions in DMSO.

[0567] d) Control compound working solution

[0568] A 10 mM stock solution of control compound was prepared in DMSO and then a 200 μM working solution was made in DMSO.

[0569] e) Liver microsome working solution

[0570] The liver microsomes were thawed in a 37°C water bath and then prepared into a 0.63 mg / mL liver microsome working solution using phosphate buffered saline.

[0571] f) NADPH working solution

[0572] Prepare a 5 mM NADPH working solution in phosphate buffer.

[0573] Sample preparation

[0574] a) 1.5 μL of the test compound / control compound working solution was added to 238.5 μL of liver microsomes (n=1).

[0575] b) Pre-incubate the solution at 37°C for 5 min.

[0576] c) Start the reaction by adding 60 μL of NADPH working solution.

[0577] d) At each time point (0, 5, 15, 30 and 60 min), 30 μL of the reaction mixture was removed and added to 300 μL of the quench solution.

[0578] e) All samples were centrifuged at 4,000 rpm for 15 min at 4°C, and then 100 μL of the supernatant and 100 μL of water were transferred for LC-MS / MS analysis.

[0579] Table 1. Potency and Solubility Data

[0580]

[0581]

[0582] *NT = Not Tested

[0583] Structures of known compounds:

[0584] The results shown in Table 1 demonstrate that polar or charged moieties on the piperidine ring (compounds 1, 50, 51, and 97) lead to degradants of BCL6. These results are surprising and unexpected given reports that polar or charged moieties generally lead to non-degradants (Kerres et al., Cell Rep. 20(12): 2860-2875 (2017)). The introduction of a basic center allows the potency of the compound to be maintained / enhanced and / or the kinetic solubility to be improved.

[0585] All patent publications and non-patent publications are indicative of the level of skill of those skilled in the art to which the invention pertains. All of these publications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

[0586] Although the present invention has been described herein with reference to specific embodiments, it should be understood that these embodiments are only illustrative of the principles and applications of the present invention. Therefore, it should be understood that many modifications may be made to the illustrative embodiments and other arrangements may be designed without departing from the spirit and scope of the present invention as defined in the appended claims.

Claims

1. A compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has a structure represented by Formula I: in: X is CH2, S, CHF, CHCl, CHOH or CF2; R1 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SO2N(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 to 10 membered heteroaryl, (C2-C6)alkenyl or (C2-C6)alkynyl; wherein the alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is further optionally replaced by one or more identical or different R 10 Group substitution; Each R9 is independently hydrogen, (C1-C6) alkyl, (C3-C7) carbocyclyl, 4- to 7-membered heterocyclyl, (C6-C 10 ) aryl or monocyclic or bicyclic 5 to 10 membered heteroaryl; wherein the alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is further optionally replaced by one or more identical or different R 10 Group substitution; Each R 10 and alkyl, alkenyl, alkynyl, halo, haloalkyl, carbocyclyl, heterocyclyl, hydroxy, alkoxy, cycloalkyloxy, heterocycloalkyloxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkenyloxy, 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-aryl alkylaminosulfonyl, N-alkyl-N-heteroarylaminosulfonyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxyl, 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, -SO2N(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 to 10 membered heteroaryl, (C2-C6)alkenyl or (C2-C6)alkynyl; wherein the alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is further optionally replaced by one or more identical or different R 10 Group substitution, or R1 and R2 together with the same carbon atom to which they are attached form a spiro (C3-C7) carbocyclyl or a 4- to 7-membered heterocyclyl; wherein the carbocyclyl or heterocyclyl is further optionally replaced by one or more identical or different R 10 Group substitution; R3 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SO2N(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 to 10 membered heteroaryl, (C2-C6)alkenyl or (C2-C6)alkynyl; wherein the alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is further optionally replaced by one or more identical or different R 10 Group substitution; R4 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SO2N(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 to 10 membered heteroaryl, (C2-C6)alkenyl or (C2-C6)alkynyl; wherein the alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is further optionally replaced by one or more identical or different R 10 Group substitution; R5 is hydrogen, cyano, halo, -OR9, -N(R9)2, -C(O)N(R9)2, -SO2N(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 to 10 membered heteroaryl, (C2-C6)alkenyl or (C2-C6)alkynyl; wherein the alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is further optionally replaced by one or more identical or different R 10 Group substitution; R6 is absent, or is (C1-C6) alkylene or (C3-C7) carbocyclyl; wherein the alkylene or carbocyclyl is further optionally replaced by one or more identical or different R 10 Group substitution, or R5 and R6 together with the same carbon atom to which they are attached form a spiro (C3-C7) carbocyclyl or a 4- to 7-membered heterocyclyl; wherein the carbocyclyl or heterocyclyl is further optionally replaced by one or more identical or different R 10 Group substitution, or R6 is a (C2-C4)alkylene group bonded to R7 to form a 4- to 6-membered heterocyclic 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 to 10 membered heteroaryl; wherein the alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is further optionally replaced by one or more identical or different R 10 Group substitution, or R7 and R8 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic group, wherein the heterocyclic group is further optionally substituted by one or more identical or different R 10 Group substitution; yes X1 and X2 are CR independently 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)2; X3 is CH or N; X4 is CR 17 , or N; R 17 , is hydrogen, fluorine, chlorine or methyl; R 11 is Cl or CN; R 12 is hydrogen, (C1-C6)alkyl, (C3-C6)carbocyclyl, 4 to 7 membered heterocyclyl, (C3-C7)carbocyclyl(C1-C6)alkyl or 4 to 7 membered heterocyclyl(C1-C6)alkyl; wherein the alkyl, carbocyclyl or heterocyclyl is further optionally substituted by one or more identical or different groups selected from (C1-C6)alkyl, (C1-C6)alkoxy, halo, amino, hydroxy, haloalkyl, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl and 4 to 7 membered heterocyclyl, or R 12 is -LYZ or -LYZ; L is absent or is (C1-C5)alkylene optionally substituted with one or more substituents selected from (C1-C2)alkyl and oxo; Y is absent or is O, S, S(O), S(O)2, NR', C(O), C(O)O, OC(O), C(O)N(R'), N(R')C(O), N(R')C(O)N(R'), N(R')C(O)O, OC(O)N(R'), S(O)2N(R') or N(R')S(O)2; Each R' is independently 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; wherein Z is optionally substituted by one or more substituents independently selected from the group consisting of (C1-C4) alkyl, halo, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, amino, (C1-C4) aminoalkyl, cyano, hydroxy, carboxyl, carbamoyl, sulfamoyl, thiol, urea, NR r R s , OR r 、C(O)R r 、C(O)OR r 、OC(O)R r 、C(O)NR r R s 、N(R r )C(O)R r 、S(O) 0-2 R r 、S(O)2NR r R s 、N(R r )SO2R r 、Si(R r )(R s )R t and (CH2) 1-3 NR r R s ; where R r , R s and R t are each independently hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl; or R r and R s Together with the nitrogen atom to which they are attached, they form a 4- to 9-membered heterocyclic group, which is optionally substituted with one or more substituents selected from the group consisting of (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 W1 is CR 18 R 18 , or C(O); R 18 and R 18 , are independently hydrogen, (C1-C2)alkyl, fluorine, hydroxy, cyano, nitro, (C1-C2)alkoxy, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, amino, NH(C1-C2)alkyl or N(C1-C2alkyl)2, 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 with one or more substituents independently selected from the group consisting of (C1-C2)alkyl, halo, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, (C1-C2)alkoxy, (C1-C2)alkylamino, amino, cyano and hydroxy; W2 is cyano, hydroxyl, 5-membered 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-C2alkyl)2: R 19 is hydrogen, (C1-C2)alkyl, fluorine, chlorine, bromine, hydroxy, amino, cyano, nitro, (C1-C2)alkoxy, (C1-C2)haloalkyl or (C1-C2)haloalkoxy; R 20 is hydrogen, (C1-C2)alkyl, fluorine, chlorine, bromine, hydroxy, cyano, nitro, (C1-C2)alkoxy, (C1-C2)haloalkyl, (C1-C2)haloalkoxy or -Y2-L2-Z2; Y2 is absent or is O, S, S(O), S(O)2, NR', C(O), C(O)O, OC(O), C(O)N(R'), N(R')C(O), S(O)2N(R') or N(R')SO2; L2 does not exist or is (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, wherein Z2 is optionally substituted with one or more substituents independently selected from the group consisting of (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', wherein 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, they form a (C3-C6) carbocyclyl or a 3- to 6-membered heterocyclyl, which is optionally substituted with one or more substituents selected from the group consisting of (C1-C2) alkyl, 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, wherein each R" is independently hydrogen or (C1-C2)alkyl; A" is a (C4-C6)carbocyclyl or a 4- to 6-membered heterocyclyl, which is optionally substituted by one or more substituents independently selected from the group consisting of (C1-C2)alkyl, halo, hydroxy, cyano and (C1-C2)alkoxy; W3 is NR 22 or CR 23 R 23 ,; 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, fluorine, chlorine, bromine, hydroxyl, amino, cyano, nitro, (C1-C2)haloalkyl, (C1-C2)haloalkoxy, (C1-C2)alkoxy, -C(O)OR", NR"R", phenyl or 5-membered heteroaryl; R 14 Yes - L3CR 24 R 25 R 26 or -CH=CH-R 26 ; L3 is absent, or is 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, they 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 ; R 27 is hydrogen, 3- to 6-membered heterocyclyl or (C1-C4)alkyl, which is optionally substituted by one or more identical or different groups selected from OH, Cl, F, CF3, N(C1-C4alkyl)2, (C3-C6)carbocyclyl, 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 the alkyl or cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of (C1-C4)alkyl, (C3-C6)cycloalkyl, hydroxy, (C1-C2)alkoxy, amino, NH(C1-C2)alkyl, N((C1-C2)alkyl)2, (C1-C2)aminoalkyl and halo; R 15 ' is hydrogen, (C1-C4) alkyl, cyano, (C1-C4) haloalkyl or -Y3-L4-Z3; Y3 is absent, or is C(O)O or C(O)N(R'); L4 does not exist or is (C1-C2) alkylene; Z3 is hydrogen, (C1-C6)alkyl, phenyl, (C3-C6)cycloalkyl or 4 to 6 membered heterocyclyl, wherein Z3 is optionally substituted by one or more substituents independently selected from the group consisting of (C1-C2)alkyl, 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, they form a (C4-C6) carbocyclyl or a 4- to 6-membered heterocyclyl; A' is a 6-membered or 7-membered heterocyclic group, which, except for R 15 and R 15 ', optionally further substituted by one or more substituents independently selected from the group consisting of 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 or is C(O), C(O)O, OC(O), C(O)N(R') or S(O)2N(R'); L5 is absent or is (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, wherein Z4 is optionally substituted by one or more substituents independently selected from the group consisting of 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 , where each R u are independently hydrogen, (C1-C4)alkyl or (C3-C6)cycloalkyl, or Z4 is -Q-L6-W, where Q is absent, or is O, NH or N(C1-C2)alkyl; L6 is absent or is (C1-C2)alkylene optionally substituted with one or more substituents selected from oxo and (C1-C2)alkyl; W is (C1-C4)alkyl, phenyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or 5-membered or 6-membered heterocyclyl, wherein W is optionally substituted by one or more substituents independently selected from the group consisting of (C1-C4)alkyl, halo, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C1-C4)alkoxy, (C1-C4)alkylamino, amino, nitro, cyano or hydroxy, or R 16 and R 16 'Together with the carbon atoms to which they are attached, they form (C3-C 10 ) carbocyclic group or 4 to 10 membered heterocyclic group, which is optionally substituted by one or more substituents independently selected from the following: oxo, (C1-C2) alkyl, halo, (C1-C2) haloalkyl, (C1-C2) haloalkoxy, (C1-C2) alkoxy, (C1-C2) alkylamino, amino, nitro, cyano or hydroxy; or the (C3-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 optionally substituted with (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, ethynyl, phenyl or 5-membered or 6-membered heteroaryl, wherein said alkyl, phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy and amino; Provided that when R7 is (C1-C3)alkyl and R8 is (C1-C3)alkyl, R6 is not (C1-C6)alkylene, and The premise is that yes R 11 When it is Cl, X is CH2 or CF2, and R6 is absent or is optionally substituted (C1-C2)alkylene, R7 and R8 cannot a) independently be hydrogen or (C1-C2)alkyl optionally substituted with oxo, or b) R7 and R8 together with the nitrogen atom to which they are attached form a 4-membered heterocyclyl optionally substituted with gem-difluoro.

2. The compound according to claim 1, wherein yes And the compound has the structure of formula I-1, 3. The compound according to claim 1, wherein yes And the compound has the structure of formula I-2, 4. The compound according to claim 1, wherein yes And the compound has the structure of formula I-3, 5. The compound according to claim 1, wherein yes And the compound has the structure of formula I-4, 6. The compound according to claim 1, wherein yes And the compound has the structure of formula I-5, 7. The compound according to claim 1, wherein R 11 It is Cl.

8. The compound according to claim 1, wherein R 11 It is CN.

9. The compound of claim 1, wherein R1 is hydrogen, -OR9 or (C1-C6)alkyl.

10. The compound of claim 9, wherein R1 is hydrogen, methyl or -OH.

11. The compound according to claim 10, wherein R1 is hydrogen.

12. The compound according to claim 10, wherein R1 is methyl.

13. The compound of claim 1, wherein R2 is hydrogen, -OR9 or (C1-C6)alkyl.

14. The compound of claim 13, wherein R2 is hydrogen, methyl or -OH.

15. The compound of claim 14, wherein R2 is hydrogen.

16. The compound of claim 14, wherein R2 is methyl.

17. The compound according to claim 1, wherein R1 and R2 together with the same carbon atom to which they are attached form a spiro (C3-C7) carbocyclyl.

18. The compound according to claim 17, wherein R1 and R2 together with the same carbon atom to which they are attached form a spiro (C3) carbocyclyl.

19. The compound of claim 1, wherein R3 is hydrogen.

20. The compound of claim 1, wherein R4 is hydrogen.

21. The compound of claim 1, wherein R5 is hydrogen, -OR9 or (C1-C6)alkyl.

22. The compound of claim 21, wherein R5 is hydrogen, methyl or -OH.

23. The compound of claim 22, wherein R5 is hydrogen.

24. The compound of claim 22, wherein R5 is methyl.

25. The compound of claim 1, wherein R6 is an optionally substituted (C1-C6)alkylene or an optionally substituted (C3-C7)carbocyclyl.

26. The compound of claim 25, wherein R6 is optionally substituted (C1-C2)alkylene or optionally substituted (C3-C4)carbocyclyl.

27. The compound of claim 26, wherein R6 is C1-alkylene.

28. The compound of claim 26, wherein R6 is C2-alkylene.

29. The compound according to claim 26, wherein R6 is replaced by one or more identical or different R 10 C1-alkylene substituted with a radical.

30. The compound according to claim 26, wherein R6 is replaced by one or more identical or different R 10 C2-alkylene substituted with a radical.

31. The compound according to claim 29, wherein each R 10 is methyl, fluoro or cyclopropyl.

32. The compound of claim 26, wherein R6 is a C3-carbocyclyl.

33. The compound of claim 26, wherein R6 is a C4-carbocyclyl.

34. The compound of claim 1, wherein R5 and R6 together with the same carbon atom to which they are attached form a spiro (C3-C7) carbocyclyl.

35. The compound of claim 34, wherein R5 and R6 together with the same carbon atom to which they are attached form a spiro (C3) carbocyclyl.

36. The compound of claim 1, wherein R6 is a (C2-C4)alkylene group bonded to R7 to form a 4- to 6-membered heterocyclic group.

37. The compound of claim 36, wherein R6 is a (C2-C3)alkylene group bonded to R7 to form a 4-membered heterocyclic group.

38. The compound of claim 1, wherein R7 is hydrogen or (C1-C6)alkyl.

39. The compound of claim 38, wherein R7 is hydrogen or methyl.

40. The compound of claim 1, wherein R8 is hydrogen or (C1-C6)alkyl.

41. The compound of claim 40, wherein R8 is hydrogen or methyl.

42. The compound of claim 1, wherein R7 and R8 together with the nitrogen atom to which they are attached form a 3 to 7 membered heterocyclic group.

43. The compound of claim 42, wherein R7 and R8 together with the nitrogen atom to which they are attached form a 3-membered heterocyclic radical.

44. The compound of claim 1, wherein X is CH2.

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

46. ​​The compound of claim 1, wherein X is CF2.

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

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

49. The pharmaceutical composition according to claim 48, which is in liquid or solid form.

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

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

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

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

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