Cyanopyridine and cyanopyrimidine BCL6 degraders

Abstract

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

Description

[Technical field]

[0001] Related Applications This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 228,303, filed August 2, 2021, and U.S. Provisional Patent Application No. 63 / 352,063, filed June 14, 2022, each of which is incorporated by reference in its entirety. [Background technology]

[0002] Small molecule-induced protein degradation has emerged as a powerful therapeutic strategy, as demonstrated by the clinical efficacy of thalidomide analogues for the treatment of hematological malignancies. Thalidomide analogues, including lenalidomide and pomalidomide, inhibit Cullin Really Interesting New gene (RING) ligase 4-cereblon (CRBN) (CRL4 CRBN ) regulate the activity of E3 ubiquitin ligases to recruit and ubiquitinate nascent substrates, including Ikaros family zinc finger 1 (IKZF1), IKZF3, and casein kinase 1-alpha (CK1α), leading to their proteasomal degradation (Kronke et al., Science 343:301-305 (2014); Lu et al., Science 343:305-309 (2014); Kronke et al., Nature 523:183-188 (2015)). Other small molecules that induce protein degradation include CRL4-DNA damage binding protein 1 (DDB1) and CUL4-associated factor 15 (DCAF15) (CRL4 DCAF15 These include aryl sulfonamides that promote the destruction of RNA-binding motif protein 39 (RBM39) in a CHO-dependent manner (Han et al., Science 356:eaal3755 (2017)).

[0003] 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. Chem. Biol. 11:611-617(2015)), and epigenetic enzymes (Winter et al., Science 348:1376-1381(2015)). These small molecule degraders engage both the E3 ligase and the target protein substrate, promoting the formation of a substrate-drug-ligase ternary complex (Nowak et al., Nat. Chem. Biol. 14:706-714 (2018); Petzold et al., Nature 532:127-130 (2016); Sievers et al., Science 362:aat0572 (2018)).

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

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

[0006] BCL6 also represses a number of oncogenes in GC B cells, including MYC, BCL2, BMI1, and CCND1. (Ci et al., Blood 113:5536-5548 (2009)). Through this function, BCL6 may alleviate its own pro-oncogenic checkpoint suppression effect and thus reduce the potential for malignant transformation of GC B cells. This effect is abrogated in the presence of BCL2 or MYC translocations that drive the expression of these oncogenes through aberrant regulatory elements. The presence of both MYC and / or BCL2 together with BCL6 (regardless of translocation) is clearly detrimental as it results in B cells concomitant suppression of BCL6-mediated checkpoints along with the growth promoting and survival effects of MYC and BCL6 (Cardenas et al., Clin. Cancer Res. 23:885-893 (2017)). In normal immune responses, BCL6 function is terminated by the disruption of the BCL6 transcription complex via CD40-induced ERK signaling and downregulation of BCL6 mRNA by IRF4 and PRDM1 (Polo et al., Blood 112:644-651 (2008)). Termination of BCL6 function is required for B cells to exit the GC response.

[0007] BCL6 is a promising drug target for non-Hodgkin's lymphomas such as diffuse large B-cell lymphoma (DLBCL) (Cerchietti et al., Cancer Cell 17:400-411 (2010); Cardenas et al., J. Clin. Invest. 126:3351-3362 (2016)) and follicular lymphoma (Bosga-Bouwer et al., Genes Chromosomes Cancer 44:301-304 (2005)). Pathologically increased BCL6 expression, as a result of somatic BCL6 translocations, exonic mutations, promoter mutations, or mutations in regulatory pathways, is a common driver of B-cell malignancies (Hatzi et al., Trends Mol. Med. 20:343-352 (2014)). In genetically engineered mice, overexpression of BCL6 is sufficient to drive lymphoma development (Cattoretti et al., Cancer Cell 7:445-455 (2005)). BCL6 acts as a master transcriptional repressor that allows rapid expression of germinal center (GC) B cells and resistance to genomic instability caused by hypermutation and class switch recombination of immunoglobulin genes (Hatzi et al., Trends Mol. Med. 20:343-352 (2014)). BCL6 is involved in DNA damage response (Ranuncolo et al., Blood Cells Mol. Dis. 41:95-99 (2008)), cell cycle checkpoints (Tunyaplin et al., J. Immunol. 173:1158-1165 (2004)), and differentiation (Phan et al., Nat. Immunol. 6:1054-1060 (2005)). As expected, knockout of BCL6 in lymphoid cells results in tumor stasis (Schlager et al., Oncotarget 11:875-890 (2020)).Several peptide and small molecule inhibitors targeting BCL6 have shown efficacy in vivo, but only at high concentrations, which has limited their translation into clinical therapeutics (Cerchietti et al., Cancer Cell 17:400-411 (2010); Cardenas et al., J. Clin. Invest. 126:3351-3362 (2016)).

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

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

[0010] The first aspect of the present invention is a compound of formula (I): [ka] Of interest is a compound having a structure represented by: In the formula, A, X 1 , X 2 , and R 1 is as defined herein, or a pharma- ceutically acceptable salt or stereoisomer thereof.

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

[0012] A further aspect of the present invention is directed to a method of treating a disease or disorder characterized by or mediated by aberrant BCL6 activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0013] In some embodiments, the disease or disorder is 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 myelogenous leukemia, or B-cell non-Hodgkin's lymphoma.In some embodiments, the disease or disorder is cancer. [Brief description of the drawings]

[0014] [Figure 1A] 1 is a graph showing the antiproliferative effect of tazemetostat (Taz) treatment. [Figure 1B] 1 is a graph showing the antiproliferative effect of Lirametostat (Lira) treatment. [Figure 1C]1 is a heat map showing the calculated Bliss (eob) scores for tazemetostat treatment. [Figure 1D] 1 is a heatmap showing above Bliss (eob) scores calculated for Lirametostat treatment. [Figure 1E] 1 is a plot showing that both Tazemetostat and Lirametostat treatment reduced the dose requirement of BCL6 degrading agents. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of this specification belongs. As used in this specification and the appended claims, unless expressly stated to the contrary, the following terms have the meanings set forth to facilitate understanding of the invention.

[0016] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a composition" includes mixtures of two or more such compositions, reference to "an inhibitor" includes mixtures of two or more such inhibitors, etc.

[0017] Unless otherwise specified, the term "about" means within 10% (eg, within 5%, 2%, or 1%) of the particular value that is modified by the term "about."

[0018] The transitional phrase "comprising," which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional unrecited elements or method steps. In contrast, the transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional phrase "consisting essentially of" limits the claim to certain materials or steps "and that do not materially affect the basic and novel characteristic(s)" of the claimed invention.

[0019] With respect to the compounds of the present invention, to the extent the following terms are used herein to further describe them, the following definitions apply.

[0020] As used herein, the term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon radical. In one embodiment, an alkyl group is a C 1 ~C 18 In another embodiment, the alkyl group is a C 0 ~C 6 , C 0 ~C 5 , C 0 ~C 3 , C 1 ~C 12 , C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 5 , C 1 ~C 4 or C 1 ~C 3 Group (where C 0(Alkyl means a bond). Examples of alkyl groups include methyl, ethyl, 1-propyl, 2-propyl, i-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 1-pentyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. In some embodiments, the alkyl group is C 1 ~C 3 In some embodiments, the alkyl group is C 3 ~C 5 It is a branched chain alkyl group.

[0021] As used herein, the term "alkylene" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing no unsaturation, having 1 to 12 carbon atoms, linking the rest of the molecule to a radical group, e.g., methylene, ethylene, propylene, n-butylene, etc. The alkylene chain may be attached to the rest of the molecule through a single bond and to the radical group through a single bond. In some embodiments, an alkylene group contains 1 to 8 carbon atoms (C 1 ~C 8 In other embodiments, the alkylene group contains 1 to 5 carbon atoms (C 1 ~C 5 In other embodiments, the alkylene group contains 1 to 4 carbon atoms (C 1 ~C 4 In other embodiments, the alkylene contains 1 to 3 carbon atoms (C 1 ~C 3 In other embodiments, the alkylene group contains 1 to 2 carbon atoms (C 1 ~C 2In other embodiments, the alkylene group contains one carbon atom (C 1 alkylene).

[0022] As used herein, the term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical having at least one carbon-carbon double bond. Alkenyl includes radicals having "cis" and "trans" orientations, alternatively "E" and "Z" orientations. In one example, an alkenyl radical is a C 2 ~C 18 In another embodiment, the alkenyl group is a C 2 ~C 12 , C 2 ~C 10 , C 2 ~C 8 , C 2 ~C 6 or C 2 ~C 3 Examples include ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hex-1,3-dienyl.

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

[0024] As used herein, the term "alkoxylenes" refers to compounds having the general formula (-OC n H 2n"alkoxylene" refers to a saturated monovalent aliphatic radical of the formula: (-OC--), where n represents an integer (e.g., 1, 2, 3, 4, 5, 6, or 7), and includes both straight-chain and branched-chain radicals. The alkoxylene chain may be attached to the rest of the molecule through a single bond and to the radical group through a single bond. In some embodiments, the alkoxylene group contains 1 to 3 carbon atoms (-OC 1 ~C 3 In another embodiment, the alkoxylene group contains 1 to 5 carbon atoms (-OC 1 ~C 5 Alkoxylenes).

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

[0026] As used herein, the term "carbocycle" (also referred to as "carbocyclyl"), used alone or as part of a larger moiety, refers to a group (e.g., an alkcarbocyclic group) that contains a saturated, partially unsaturated, or aromatic ring system of 3 to 20 carbon atoms, either alone or as part of a larger moiety. The term carbocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged, and spiro ring systems, and combinations thereof. In one embodiment, a carbocyclyl is a ring system having 3 to 15 carbon atoms (C 3 ~C 15 In one embodiment, carbocyclyl is an alkyl group having 3 to 12 carbon atoms (C 3 ~C 12 In another embodiment, the carbocyclyl is 3 ~C 8 , C 3 ~C 10 or C5 ~C 10 In another embodiment, the carbocyclyl, as a single ring, is 3 ~C 8 , C 3 ~C 6 or C 5 ~C 6 In some embodiments, the carbocyclyl as a bicycle is C 7 ~C 12 In another embodiment, the carbocyclyl, as a spiro system, is 5 ~C 12 Representative examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, perdeuterocyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, phenyl, and cyclododecyl; bicyclic carbocyclyls having 7 to 12 ring atoms include [4,3], [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, naphthalene, and bicyclo[3.2.2]nonane. Representative examples of spirocarbocyclyl include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane. The term carbocyclyl includes aryl ring systems as defined herein. The term carbocyclyl also includes cycloalkyl rings (e.g., saturated or partially unsaturated monocyclic, bicyclic, or spirocyclic carbocycles). The term carbocyclic group also includes carbocyclic rings fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., aryl or heterocyclic rings), where a radical or point of attachment is on the carbocyclic ring.

[0027] As used herein, the term "heterocyclyl" used alone or as part of a larger moiety, refers to a ring system containing a saturated, partially unsaturated or aromatic ring system in which one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by a heteroatom (e.g., O, N, N(O), S, S(O) or S(O)). 2 ) is substituted. The term heterocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged, and spiro ring systems, and combinations thereof. In some embodiments, heterocyclyl refers to a 3-15 membered heterocyclyl ring system. In some embodiments, heterocyclyl refers to a 3-12 membered heterocyclyl ring system. In some embodiments, heterocyclyl refers to a saturated ring system, such as a 3-12 membered saturated heterocyclyl ring system. In some embodiments, heterocyclyl refers to a heteroaryl ring system, such as a 5-14 membered heteroaryl ring system. The term heterocyclyl also includes C-, C-, C-C-, C-D-, C-E-, C-F-, C-G-, C-H-, C-H-, C-I ... 3 ~C 8 Also included are heterocycloalkyls.

[0028] In some embodiments, a heterocyclyl group contains 3-12 ring atoms, including monocyclic, bicyclic, tricyclic, and spirocyclic ring systems, where the ring atoms are carbon and 1-5 ring atoms are heteroatoms such as nitrogen, sulfur, or oxygen. In some embodiments, a heterocyclyl contains a 3-7 membered monocyclic ring having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In some embodiments, a heterocyclyl contains a 4-6 membered monocyclic ring having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In some embodiments, a heterocyclyl contains a 3 membered monocyclic ring. In some embodiments, a heterocyclyl contains a 4 membered monocyclic ring. In some embodiments, a heterocyclyl contains a 5-6 membered monocyclic ring. In some embodiments, a heterocyclyl contains 0-3 double bonds. In any of the foregoing embodiments, a heterocyclyl contains 1, 2, 3, or 4 heteroatoms. Any nitrogen or sulfur heteroatoms may be optionally oxidized (e.g., NO, SO, SO 2 ), any nitrogen heteroatom may be optionally quaternized (e.g., [NR 4 ] + Cl - , [NR 4 ] + OH -Representative examples of heterocyclyl include oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydropyranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, and the like. , thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzo[ d]imidazolyl, 1,6-dihydroimidazole[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, thiophenyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrimidine, pyrimidine Lazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl, piperazedionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.azaspiro[4.5]decan-2-one, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, and 1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclyls containing a sulfur or oxygen atom and 1 to 3 nitrogen atoms are thiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl, such as oxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl and 1,2,4-oxadiazol-5-yl. Examples of 5-membered heterocyclyls containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl, such as 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, such as 1H-tetrazol-5-yl. Representative examples of benzo-fused 5-membered heterocyclyls are benzoxazol-2-yl, benzothiazol-2-yl and benzimidazol-2-yl. Examples of 6-membered heterocyclyls contain 1 to 3 nitrogen atoms and optionally sulfur or oxygen atoms, such as pyridyl, e.g. pyrid-2-yl, pyrid-3-yl and pyrid-4-yl; pyrimidyl, e.g. pyrimid-2-yl and pyrimid-4-yl; triazinyl, e.g. 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl and pyrazinyl.

[0029] Thus, the term "heterocyclic" includes N-heterocyclyl groups, which as used herein refer to heterocyclyl groups containing at least one nitrogen, where the point of attachment of the heterocyclyl group to the remainder of the molecule is through a nitrogen atom in the heterocyclyl group. Representative examples of N-heterocyclyl groups include 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl and imidazolidinyl. The term "heterocyclic" also includes C-heterocyclyl groups, which as used herein refer to heterocyclyl groups containing at least one heteroatom, where the point of attachment of the heterocyclyl group to the remainder of the molecule is through a carbon atom in the heterocyclyl group. Representative examples of C-heterocyclyl groups include 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, and 2- or 3-pyrrolidinyl. The term "heterocyclic" also refers to groups of the formula -R c -heterocyclyl (wherein R c is an alkylene chain). The term "heterocyclic" as used herein also includes heterocyclylalkyl groups, which refer to groups of the formula -OR c -heterocyclyl (wherein R c is an alkylene chain).

[0030] The term "aryl" as used herein alone or as part of a larger moiety (e.g., "aralkyl" where the atom of the terminal carbon on the alkyl is the point of attachment, e.g., a benzyl group), "aralkoxy" where the oxygen is the point of attachment, or "aralkoxyalkyl" where the point of attachment is on the aryl) refers to a group that includes a monocyclic, bicyclic, or tricyclic carbocyclic ring system, including fused rings, in which at least one ring in the system is aromatic. In some embodiments, an aralkoxy group is a benzoxy group. The term "aryl" may be used interchangeably with the term "aryl ring." In one embodiment, aryl includes groups having 6 to 18 carbon atoms. In another embodiment, aryl includes groups having 6 to 10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthracyl, biphenyl, phenanthrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, naphthyridinyl, and the like, which may be substituted or independently substituted by one or more substituents described herein. A particular aryl is phenyl. In some embodiments, an aryl group comprises an aryl ring fused to one or more (e.g., one, two, or three) different cyclic groups (e.g., carbocyclic or heterocyclic rings), where the radical or point of attachment is on the aryl ring.

[0031] Thus, the term aryl includes aralkyl groups (e.g., benzyl), which are of the formula -R, as disclosed above. c -aryl (wherein R c is an alkylene chain such as methylene or ethylene. In some embodiments, the aralkyl group is an optionally substituted benzyl group. The term aryl, as used herein, also refers to a group of the formula -OR c -aryl (wherein R c includes aralkoxy groups, which refer to groups attached through an oxygen atom of an alkylene chain such as methylene or ethylene.

[0032] The term "heteroaryl" (e.g., "heteroarylalkyl" (also "heteroaralkyl") or "heteroarylalkoxy" (also "heteroaralkoxy"), as used herein alone or as part of a larger moiety, refers to a monocyclic, bicyclic, or tricyclic ring system having 5 to 14 ring atoms, in which at least one ring is aromatic and contains at least one heteroatom. In one embodiment, heteroaryl includes a 5-6 membered monocyclic aromatic group in which one or more ring atoms are independently optionally substituted nitrogen, sulfur, or oxygen. Representative examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, Included are imidazopyridyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, purinyl, deazapurinyl, benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indolyl, 1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl, 1,2,3-triazol-5-yl, and pyrid-2-yl N-oxide. The term "heteroaryl" also includes groups in which the heteroaryl is fused to one or more cyclic (e.g., carbocyclyl, or heterocyclyl) rings, where the radical or point of attachment is on the heteroaryl ring.Non-limiting examples include indolyl, indolizinyl, isoindolyl, benzothienyl, benzothiophenyl, methylenedioxyphenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzodioxazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups may be monocyclic, bicyclic, or tricyclic. In some embodiments, a heteroaryl group comprises a heteroaryl ring fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., carbocycles or heterocycles), where the radical or point of attachment is on the heteroaryl ring, and in some embodiments, the point of attachment is a heteroatom contained in the heterocycle.

[0033] The term heteroaryl also encompasses N-heteroaryl groups, which as used herein refer to heteroaryl groups as defined above, containing at least one nitrogen atom, and the point of attachment of the N-heteroaryl group to the remainder of the molecule is through a nitrogen atom in the heteroaryl group. The term heteroaryl further encompasses C-heteroaryl groups, which as used herein refer to heteroaryl groups as defined above, and the point of attachment of the heteroaryl group to the remainder of the molecule is through a carbon atom in the heteroaryl group. The term heteroaryl further encompasses heteroarylalkyl groups, which as disclosed above, have the formula --R c -heteroaryl (wherein R c is an alkylene chain as defined above. The term heteroaryl as used herein further refers to a group of the formula -O-R c -heteroaryl (wherein R c and heteroaralkoxy (or heteroarylalkoxy) groups which refer to groups attached through an oxygen atom of the alkyl group (wherein R is an alkylene group as defined above).

[0034] Unless otherwise stated and unless further defined for any particular group(s), any of the groups described herein may be substituted or unsubstituted. As used herein, the term "substituted" refers broadly to all permissible substituents, with the implicit proviso that such substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, etc., according to the permissible valences of the substituted atom and substituent. Representative substituents include halogens, hydroxyl groups, and any other organic group containing any number of carbon atoms, e.g., 1-14 carbon atoms, which may contain one or more (e.g., 1, 2, 3, or 4) heteroatoms, such as oxygen, sulfur, and nitrogen, categorized in a linear, branched, or cyclic structural format.

[0035] Unless otherwise disclosed for any particular group, representative examples of substituents include alkyl (e.g., C 1 ~C 6 , C 1 ~C 5 , C 1 ~C 4 , C 1 ~C 3 , C 1 ~C 2 , C 1 ), substituted alkyl (e.g., substituted C 1 ~C 6 , C 1 ~C 5 , C 1 ~C 4 , C 1 ~C 3 , C 1 ~C 2 , C 1 ), alkoxy (e.g., C 1 ~C 6 , C 1 ~C 5 , C 1 ~C 4 , C 1 ~C 3 , C 1 ~C 2 , C 1), substituted alkoxy (e.g., substituted C 1 ~C 6 , C 1 ~C 5 , C 1 ~C 4 , C 1 ~C 3 , C 1 ~C 2 , C 1 ), haloalkyl (e.g., CF 3 ), alkenyl (e.g., C 2 ~C 6 , C 2 ~C 5 , C 2 ~C 4 , C 2 ~C 3 , C 2 ), substituted alkenyl (e.g., substituted C 2 ~C 6 , C 2 ~C 5 , C 2 ~C 4 , C 2 ~C 3 , C 2 ), alkynyl (e.g., C 2 ~C 6 , C 2 ~C 5 , C 2 ~C 4 , C 2 ~C 3 , C 2 ), substituted alkynyl (e.g., substituted C 2 ~C 6 , C 2 ~C 5 , C 2 ~C 4 , C 2 ~C 3 , C 2 ), rings (e.g., C 3 ~C 12 , C 5 ~C 6 ), substituted rings (e.g., substituted C 3 ~C 12 , C 5 ~C 6 ), carbocyclic rings (e.g., C 3 ~C 12 , C 5 ~C6 ), substituted carbocyclic rings (e.g., substituted C 3 ~C 12 , C 5 ~C 6 ), heterocycle (e.g., 3-12 membered, 5-6 membered), substituted heterocycle (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 pyrimidyl), substituted heteroaryl (e.g., substituted pyridyl or substituted pyrimidyl), aralkyl (e.g., benzyl), substituted aralkyl (e.g., substituted benzyl), halo, hydroxyl, aryloxy (e.g., C 6 ~C 12 , C 6 ), substituted aryloxy (e.g., substituted C 6 ~C 12 , C 6 ), alkylthio (e.g., C 1 ~C 6 ), substituted alkylthio (e.g., substituted C 1 ~C 6 ), arylthio (e.g., C 6 ~C 12 , C 6 ), substituted arylthio (e.g., substituted C 6 ~C 12 , C 6 ), cyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, thio, substituted thio, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfinamide, substituted sulfinamide, sulfonamide, substituted sulfonamide, urea, substituted urea, carbamate, substituted carbamate, amino acid, and peptide groups.

[0036] In one embodiment, the compound of the present invention has formula (I): [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof, During the ceremony, X 1is N, CH, CCl, CF, or CCN; each X 2 are independently 2 , S, CHF, CHCl, CHOH, or CF 2 and; R 1 are hydrogen, =O, -CN, -C≡CH, -OH, -SH, -NH 2 , -COOH, halo, (C 1 ~C 6 ) alkyl, -O-(C 1 ~C 6 ) alkyl, (C 1 ~C 6 )Haloalkyl, amido, carboxy, carbamoyl, sulfamoyl, phenyl, 5-8 membered heterocyclyl, -NR 7 R 8 , -C(O)R 9 , -C(O)NR 10 R 11 , or L 1 Y 1 wherein said alkyl, phenyl, or heterocyclyl is selected from halo, -COOH, -OH, -NH 2 , (C 1 ~C 6 ) alkyl, -C(O)O-(C 1 ~C 6 ) alkyl, -C(O)N(C 1 ~C 6 Alkyl) 2 , -O-(C 1 ~C 6 ) alkyl, -N(C 1 ~C 3 Alkyl) 2 , phenyl, and halo and (C 1 ~C 6 ) 4- to 6-membered heterocyclyl optionally substituted with one or more groups selected from alkyl; R 7 is hydrogen, (C 1 ~C 4 ) alkyl, or (C 3 ~C 6 ) cycloalkyl; R8 is hydrogen, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) haloalkyl, (C 3 ~C 6 ) cycloalkyl, or 6-membered heterocyclyl; R 9 is -(C 1 ~C 3 )Alkyl-N(C 1 ~C 3 Alkyl) 2 , (C 3 ~C 6 )cycloalkyl, or 5- to 6-membered heterocyclyl, wherein the heterocyclyl is (C 1 ~C 3 ) optionally substituted with alkyl; R 10 is hydrogen, (C 1 ~C 3 ) alkyl, or (C 3 ~C 6 ) cycloalkyl; R 11 is -NH 2 , -O-(C 1 ~C 6 ) alkyl, -O-(C 1 ~C 6 )Alkyl-NH 2 , or -O-(C 1 ~C 6 )Alkyl-O-(C 1 ~C 6 )Alkyl-NH 2 Optionally replaced by (C 3 ~C 6 ) cycloalkyl or (C 1 ~C 6 ) alkyl; L 1 does not exist or (C 1 ~C 6 ) alkylene or (C 3 ~C 7 ) carbocyclyl; wherein said alkylene or carbocyclyl is one or more of the same or different R Amay be optionally further substituted by groups; Each R Aare independently selected from the group consisting of oxo, alkyl, alkenyl, alkynyl, halo, haloalkyl, carbocyclyl, heterocyclyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkylenyloxy, alkynyloxy, amino, alkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, aralkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-aralkylamino, hydroxyalkyl, aminoalkyl, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, N-alkyl-N-arylaminosulfonyl, N- alkyl-N-heteroarylaminosulfonyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, 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; Y 1are -CN, -OH, halo, (C 1 ~C 4 ) alkoxy, (C 1 ~C 4 ) haloalkyl, (C 1 ~C 4 ) haloalkoxy, 4- to 7-membered heterocyclyl, (C 3 ~C 6 ) Carbocyclyl, -NR 7’ R 8’ , -C(O)R 9 , -C(O)NR 10 R 11 wherein said alkyl, carbocyclyl, or heterocyclyl is (C 1 ~C 4 ) alkyl, halo, (C 1 ~C 4 ) Haloalkyl, -CN, -OH, and -NH 2 is optionally further substituted with one or more identical or different groups selected from: R 7’ and R 8’ are each independently hydrogen, (C 1 ~C 6 ) alkyl, (C 3 ~C 7 ) carbocyclyl, 4- to 7-membered heterocyclyl, (C 6 ~C 10 ) aryl, or monocyclic or bicyclic 5-10 membered heteroaryl; wherein the alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is selected from the group consisting of one or more identical or different R A may be optionally further substituted by a group, or R 7’ and R 8’ together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclyl, wherein the heterocyclyl is selected from one or more of the same or different R A group, which may be further optionally substituted, or L 1 is R 7’ to form a 4- to 6-membered heterocyclyl group (C 2 ~C 4) alkylene; R 1 ' is absent or hydrogen, -CN, -C≡CH, -OH, -SH, -NH 2 , -COOH, halo, (C 1 ~C 6 ) alkyl, -O-(C 1 ~C 6 ) alkyl, (C 1 ~C 6 )Haloalkyl, amido, carboxy, carbamoyl, sulfamoyl, phenyl, 5-8 membered heterocyclyl, -NR 7 R 8 , -C(O)R 9 or -C(O)NR 10 R 11 wherein said alkyl, phenyl, or heterocyclyl is selected from one or more of the same or different R A may be further substituted by a group, or R 1’ and L 1 together with the same carbon atom to which they are attached to form spiro (C 3 ~C 7 ) a carbocyclyl group or a 4- to 7-membered heterocyclyl group; wherein the carbocyclyl or heterocyclyl is one or more identical or different R A may be further substituted by groups; [ka] teeth [ka] and; X 3 and X 4 Independently, CR 12 or N; X 5 is CH or N; R 12 is hydrogen, (C 1 ~C 4 ) alkyl, halo, hydroxy, amino, (C 1 ~C 4 ) alkoxy, (C1 ~C 4 ) haloalkyl, (C 1 ~C 4 ) haloalkoxy, (C 2 ~C 4 ) alkenyl, (C 2 ~C 4 ) alkynyl, nitro, cyano, NH(C 1 ~C 4 ) alkyl, or N(C 1 ~C 4 Alkyl) 2 and; R 2 is hydrogen, (C 1 ~C 6 ) alkyl, (C 3 ~C 6 ) carbocyclyl, 4- to 7-membered heterocyclyl, (C 3 ~C 7 ) Carbocyclyl (C 1 ~C 6 ) alkyl, or 4- to 7-membered heterocyclyl (C 1 ~C 6 ) alkyl; wherein said alkyl, carbocyclyl, or heterocyclyl is selected from one or more of the same or different R 13 may be further substituted by groups, where R 13 is (C 1 ~C 6 ) alkyl, (C 1 ~C 6 )alkoxy, halo, amino, hydroxyl, haloalkyl, NH(C 1 ~C 6 ) alkyl, or N((C 1 ~C 6 )Alkyl) 2 , (C 3 ~C 6 ) carbocyclyl, or 4- to 7-membered heterocyclyl; or R 2 -L 2 -Y 2 -Z; L 2 does not exist or (C 1 ~C 2) optionally substituted with one or more substituents selected from alkyl and oxo (C 1 ~C 5 ) alkylene; Y 2 is not present, O, S, S(O), S(O) 2 , NR', C(O), C(O)O, OC(O), C(O)N(R'), N(R')C(O), N(R')C(O)N(R'), N(R')C(O)O, OC(O)N(R'), S(O) 2 N(R'), or N(R')S(O) 2 and; Each R' is independently hydrogen or (C 1 ~C 4 ) alkyl; Z is hydrogen, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 3 ~C 10 ) carbocyclyl, or 3- to 10-membered heterocyclyl; 1 ~C 4 ) alkyl, halo, (C 1 ~C 4 ) haloalkyl, (C 1 ~C 4 ) haloalkoxy, amino, (C 1 ~C 4 ) Aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, mercapto, ureido, NR r R s ,OR r ,C(O)R r ,C(O)OR r ,OC(O)R r ,C(O)NR r R s ,N(R r )C(O)R r ,S(O) 0-2 R r ,S(O) 2 NR r R s ,N(Rr )SO 2 R r ,Si(R r )(R s )R t and (CH 2 ) 1-3 NR r R s wherein R is optionally substituted with one or more substituents independently selected from r , R s and R t are each independently hydrogen, (C 1 ~C 6 ) alkyl or (C 3 ~C 6 ) cycloalkyl; or R r and R s together with the nitrogen atom to which they are attached, (C 1 ~C 4 ) alkyl, halo, (C 1 ~C 4 ) haloalkyl, (C 1 ~C 4 ) haloalkoxy, (C 1 ~C 4 ) alkoxy, (C 1 ~C 4 ) forming a 4- to 9-membered heterocyclyl optionally substituted by one or more substituents selected from alkylamino, amino, cyano, and hydroxy; R 3 -L 3 CR 14 R 15 R 16 , or -CH=CH-R 16 and; L 3 does not exist or O,S,(C 1 ~C 4 ) alkylene, -O-(C 1 ~C 4 ) alkylene, or -S-(C 1 ~C 4 ) alkylene; R 14 is hydrogen or (C 1 ~C 4 ) alkyl; R 15 is hydrogen or (C 1 ~C 4 ) alkyl, or R 14 and R 15 together with the carbon atoms to which they are attached, (C 3 ~C 5 ) forming a carbocyclyl, 4- to 7-membered heterocyclyl or C=O; R 16 is (C 1 ~C 6 ) alkyl, -NR 17 R 18 , -OR 17 , -C(O)R 17 , -C(O)OR 17 , -N(R 18 )C(O)R 17 , -C(O)NR 17 R 18 , -S(O)-(C 1 ~C 6 ) alkyl, -S(O) 2 -(C 1 ~C6) alkyl, -P(O)-(C 1 ~C 6 Alkyl) 2 , -C(NH)NH 2 , -(C 1 ~C 4 )Alkyl-NR 18 C(O)R 17 or 4- to 7-membered heterocyclyl; R 17 is hydrogen, 3- to 6-membered heterocyclyl, or OH, Cl, F, CF 3 , N(C 1 ~C 4 Alkyl) 2 , (C 3 ~C 6 ) carbocyclyl, 3-6 membered heterocyclyl, (C 2 ~C 4 ) alkenyl, and (C 2 ~C 4 ) alkynyl, optionally substituted by one or more identical or different groups selected from 1 ~C 4) alkyl R 18 is hydrogen or (C 1 ~C 4 ) alkyl; R 4 is hydrogen, methyl, -(CH 2 ) 1-3 W 1 W 2 ,or [ka] and; W 1 CR 19 R 19’ or C(O); R 19 and R 19’ are independently hydrogen, (C 1 ~C 2 ) alkyl, fluoro, hydroxy, cyano, nitro, (C 1 ~C 2 ) alkoxy, (C 1 ~C 2 ) haloalkyl, (C 1 ~C 2 )Haloalkoxy, amino, NH(C 1 ~C 2 ) alkyl, or N(C 1 ~C 2 Alkyl) 2 or R 19 and R 19’ together with the carbon atom to which they are attached, form C(O), (C 3 ~C 6 ) carbocyclyl or 3- to 6-membered heterocyclyl, which is represented by (C 1 ~C 2 ) alkyl, halo, (C 1 ~C 2 ) haloalkyl, (C 1 ~C 2 ) haloalkoxy, (C 1 ~C 2 ) alkoxy, (C 1 ~C 2) optionally substituted by one or more substituents independently selected from alkylamino, amino, cyano and hydroxy; W 2 is cyano, hydroxy, 5- or 6-membered heteroaryl, phenyl, C(O)-(C 1 ~C 2 ) alkyl, S(O) 2 -(C 1 ~C 2 ) alkyl, C(O)OCH 3 , C(O)NHCH 3 , C.R. 20 R 21 R 22 , amino, NH(C 1 ~C 2 ) alkyl, or N(C 1 ~C 2 Alkyl) 2 and; R 20 is hydrogen, (C 1 ~C 2 ) alkyl, fluoro, chloro, bromo, hydroxy, amino, cyano, nitro, (C 1 ~C 2 ) alkoxy, (C 1 ~C 2 ) haloalkyl, or (C 1 ~C 2 ) haloalkoxy; R 21 is hydrogen, (C 1 ~C 2 ) Alkyl, fluoro, chloro, bromo, hydroxy, cyano, nitro, (C 1 ~C 2 ) alkoxy, (C 1 ~C 2 ) haloalkyl, (C 1 ~C 2 ) haloalkoxy, or -Y 3 -L 4 -Z 2 and; Y 3 is not present, 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')SO 2 and; L 4 does not exist or (C 1 ~C 2 ) alkylene; Z 2 is hydrogen, (C 1 ~C 6 ) alkyl, (C 2 ~C 4 ) alkenyl, (C 2 ~C 4 ) alkynyl, phenyl, (C 3 ~C 6 ) carbocyclyl, or 4- to 6-membered heterocyclyl, where Z 2 is (C 1 ~C 4 ) alkyl, halo, (C 1 ~C 4 ) haloalkyl, (C 1 ~C 4 ) haloalkoxy, (C 1 ~C 4 ) alkoxy, (C 1 ~C 4 ) alkylamino, amino, cyano, hydroxy, C(O)R', C(O)OR', OC(O)R', C(O)NR'R', and N(R')C(O)R', where each R' is independently hydrogen or (C 1 ~C 4 ) alkyl; or R 20 and R 21 together with the carbon atoms to which they are attached, (C 1 ~C 2 ) alkyl, halo, (C 1 ~C 2 ) haloalkyl, (C 1 ~C 2 ) haloalkoxy, (C 1 ~C 2 ) alkoxy, (C 1 ~C 2 ) optionally substituted with one or more substituents selected from alkylamino, amino, cyano and hydroxy (C3 ~C 6 ) forming a carbocyclyl or 3- to 6-membered heterocyclyl R 22 is (C 1 ~C 2 )alkyl, -C(O)OR'', OR'', -C(O)NR'', NR''R'', phenyl, or 5-membered heteroaryl, where each R'' is independently hydrogen or (C 1 ~C 2 ) alkyl; A'' is (C 1 ~C 2 ) alkyl, halo, hydroxy, oxo, cyano, and (C 1 ~C 2 ) alkoxy, (C 4 ~C 6 ) carbocyclyl or 4- to 6-membered heterocyclyl; W 3 is NR 23 or CR 24 R 24’ and; R 23 is hydrogen, (C 1 ~C 2 ) alkyl, (C 1 ~C 4 ) haloalkyl, (C 1 ~C 4 ) Hydroxyalkyl, -C(O)CH 3 , or -C(O)O-(C 1 ~C 4 ) alkyl; R 24 and R 24’ are independently hydrogen, (C 1 ~C 2 ) alkyl, cyclopropyl, fluoro, chloro, bromo, hydroxy, amino, cyano, nitro, (C 1 ~C 2 ) haloalkyl, (C 1 ~C 2 ) haloalkoxy, (C 1 ~C 2) alkoxy, -C(O)OR'', NR''R'', phenyl, or 5-membered heteroaryl; R 5 is hydrogen, (C 1 ~C 4 ) alkyl, (C 3 ~C 6 ) cycloalkyl, (C 1 ~C 4 ) haloalkyl, or cyano, wherein said alkyl or cycloalkyl is (C 1 ~C 4 ) alkyl, (C 3 ~C 6 ) cycloalkyl, hydroxy, (C 1 ~C 2 )Alkoxy, amino, NH(C 1 ~C 2 ) alkyl, N((C 1 ~C 2 )Alkyl) 2 , (C 1 ~C 2 ) optionally substituted with one or more substituents selected from aminoalkyl, and halo; R 5’ is hydrogen, (C 1 ~C 4 ) alkyl, cyano, (C 1 ~C 4 ) haloalkyl, or -Y 4 -L 5 -Z 3 and; Y 4 is absent, C(O)O or C(O)N(R''); L 5 does not exist or (C 1 ~C 2 ) alkylene; Z 3 is hydrogen, (C 1 ~C 6 ) alkyl, phenyl, (C 3 ~C 6 cycloalkyl, or 4- to 6-membered heterocyclyl, where Z 3 is (C 1 ~C 2 ) alkyl, halo, (C1 ~C 2 ) haloalkyl, (C 1 ~C 2 ) haloalkoxy, (C 1 ~C 2 ) optionally substituted with one or more substituents independently selected from alkoxy, amino, nitro, cyano, and hydroxy; or R 5 and R 5’ together with the carbon atoms to which they are attached, (C 4 ~C 6 ) forming a carbocyclyl or a 4- to 6-membered heterocyclyl; A' is a 6- or 7-membered heterocyclyl, which is R 5 and R 5’ In addition to oxo, (C 1 ~C 2 ) alkyl, cyclopropyl, spiro-cyclopropyl, halo, (C 1 ~C 2 ) haloalkyl, (C 1 ~C 2 ) haloalkoxy, (C 1 ~C 2 ) may be further substituted by one or more substituents independently selected from alkoxy, amino, cyano, and hydroxy; X 6 CR 25 or N; R 25 is hydrogen, fluorine, chloro, or methyl; R 6 is hydrogen, (C 1 ~C 2 ) alkyl, (C 3 ~C 4 ) cycloalkyl, (C 1 ~C 2 ) haloalkyl, cyano, (C 2 ~C 4 ) alkenyl, or (C 2 ~C 4 ) alkynyl; R 6 ' is (C 1 ~C 4) alkyl, cyano, (C 1 ~C 4 ) haloalkyl, or -Y 5 -L 6 -Z 4 and; Y 5 is absent or is C(O), C(O)O, OC(O), C(O)N(R''), or S(O) 2 N(R''); L 6 does not exist or (C 1 ~C 2 ) optionally substituted with one or more substituents selected from alkyl and oxo (C 1 ~C 2 ) alkylene; Z 4 is hydrogen, (C 1 ~C 6 ) alkyl, (C 2 ~C 4 ) alkenyl, (C 2 ~C 4 ) alkynyl, phenyl, (C 3 ~C 6 ) carbocyclyl, (C 3 ~C 6 cycloalkenyl, or 4- to 6-membered heterocyclyl, where Z 4 is oxo, (C 1 ~C 4 ) alkyl, (C 3 ~C 6 ) cycloalkyl, halo, (C 1 ~C 4 ) haloalkyl, (C 1 ~C 4 ) haloalkoxy, (C 1 ~C 4 ) alkoxy, (C 1 ~C 4 ) Alkylamino, amino, nitro, cyano, hydroxy, C(O)R u , C(O)OR u , O.C.(O)R u , C(O)NR u R u , and N(R u )C(O)R uand each Ru is independently selected from hydrogen, (C 1 ~C 4 ) alkyl, or (C 3 ~C 6 ) cycloalkyl; or Z 4 -QL 7 -W 4 and Q is absent, O, NH, or N(C 1 ~C 2 ) alkyl; L 7 is absent or is oxo and (C 1 ~C 2 ) alkyl, optionally substituted with one or more substituents selected from 1 ~C 2 ) alkylene; W 4 is (C 1 ~C 4 ) alkyl, phenyl, (C 3 ~C 6 ) cycloalkyl, (C 3 ~C 6 ) cycloalkenyl, or 5- or 6-membered heterocyclyl, 4 is (C 1 ~C 4 ) alkyl, halo, (C 1 ~C 4 ) haloalkyl, (C 1 ~C 4 ) haloalkoxy, (C 1 ~C 4 ) alkoxy, (C 1 ~C 4 ) optionally substituted by one or more substituents independently selected from alkylamino, amino, nitro, cyano, or hydroxy; or R 6 and R 6’ together with the carbon atom to which they are attached, (C 3 ~C 10 ) carbocyclyl or 4- to 10-membered heterocyclyl, which is oxo, (C 1~C 2 ) alkyl, halo, (C 1 ~C 2 ) haloalkyl, (C 1 ~C 2 ) haloalkoxy, (C 1 ~C 2 ) alkoxy, (C 1 ~C 2 ) optionally substituted by one or more substituents independently selected from alkylamino, amino, nitro, cyano or hydroxy; or 3 ~C 10 ) carbocyclyl or 4- to 10-membered heterocyclyl may be fused to a 5- or 6-membered heteroaryl or phenyl ring, said 5- or 6-membered heteroaryl or phenyl ring being (C 1 ~C 2 ) alkyl, halo, (C 1 ~C 2 ) haloalkyl, (C 1 ~C 2 ) haloalkoxy, (C 1 ~C 2 ) alkoxy, (C 1 ~C 2 ) optionally substituted with alkylamino, amino, nitro, cyano, or hydroxy; R 6 '' is hydrogen, (C 1 ~C 4 ) alkyl, (C 1 ~C 2 ) haloalkyl, (C 1 ~C 2 ) alkoxy, (C 1 ~C 2 ) haloalkoxy, cyano, nitro, acetylenyl, phenyl, or 5- or 6-membered heteroaryl, wherein said alkyl, phenyl, or heteroaryl is optionally substituted with one or more substituents independently selected from halo, hydroxy, and amino.

[0037] In some embodiments, R 1 is methyl, -OH, -NH 2 , -COOH, -CH 2 CH 2OH, -CH 2 CH 2 NH 2 , [ka] In some embodiments, R 1 is methyl. In some embodiments, R 1 is -OH. In some embodiments, R 1 Ha-NH 2 In some embodiments, R 1 is -COOH. In some embodiments, R 1 Ha-CH 2 CH 2 In some embodiments, R 1 Ha-CH 2 CH 2 NH 2 It is.

[0038] In some embodiments, X 1 is N, CH, CCl, or CF. In some embodiments, X 1 is N. In some embodiments, X 1 is CH. In some embodiments, X 1 is CCl. In some embodiments, X 1 is CF.

[0039] In some embodiments, X 2 is CH 2 , CHF, CHCl, or CF 2 In some embodiments, X 2 CH 2 In some embodiments, X 2 is CHF. In some embodiments, X 2 In some embodiments, X is CHCl. 2 CF 2 It is.

[0040] In some embodiments, [ka] teeth [ka] and the compound of formula (I) is represented by the formula I-1 [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0041] In some embodiments of formula I-1, X 3 is N. In some embodiments of formula I-1, X 3 is CR 12 In some embodiments of formula I-1, X 3 In some embodiments of formula I-1, X 3 In some embodiments of formula I-1, X 3 is COMe.

[0042] In some embodiments of formula I-1, X 4 is N. In some embodiments of formula I-1, X 4 is CR 12 In some embodiments of formula I-1, X 4 In some embodiments of formula I-1, X 4 In some embodiments of formula I-1, X 4 is COMe.

[0043] In some embodiments of formula I-1, X 5 is N. In some embodiments of formula I-1, X 5 is CH.

[0044] In some embodiments of Formula I-1, R 2 (C 1 ~C 2 ) alkyl, 4-membered heterocyclyl, (C3 ) Carbocyclyl (C 1 ) alkyl, or 4-membered heterocyclyl (C 1 ) alkyl; wherein the alkyl, carbocyclyl, or heterocyclyl may further comprise one or more identical or different R 13 In some embodiments, R 2 is methyl. In some embodiments, R 2 is a 4-membered heterocyclyl, (C 3 ) Carbocyclyl (C 1 ) alkyl, or 4-membered heterocyclyl (C 1 ) alkyl, where the heterocyclyl contains one heteroatom selected from N and O.

[0045] In some embodiments of Formula I-1, R 3 -L 3 CR 14 R 15 R 16 In some embodiments of formula I-1, L 3 is (C 1 ~C 4 ) alkylene, -O-(C 1 ~C 4 ) alkylene or -S-(C 1 ~C 4 In some embodiments of formula I-1, L 3 is -O-(C 1 ~C 4 In some embodiments of formula I-1, L 3 is -O-(C 1 ) alkylene.

[0046] In some embodiments of Formula I-1, R 14 and R 15 together with the carbon atom to which they are attached, (C 3 ~C 5 ) carbocyclyl, 4- to 7-membered heterocyclyl, or C=O. In some embodiments of formula I-1, R 14 and R15 together with the same carbon atom to which they are attached to form C=O. In some embodiments of Formula I-1, R 14 and R 15 together with the same carbon atom to which they are attached form a 4- to 7-membered heterocyclyl. In some embodiments of Formula I-1, R 14 and R 15 together with the same carbon atom to which they are attached form an oxetane ring.

[0047] In some embodiments of Formula I-1, R 16 (C 1 ~C 6 ) alkyl, -NR 17 R 18 -OR 17 In some embodiments of formula I-1, R 16 is methyl, hydroxyl, amino, or NHMe. In some embodiments, R 16 is methyl. In some embodiments, R 16 is hydroxyl. In some embodiments, R 16 is amino. In some embodiments, R 16 is NHMe.

[0048] In some embodiments, the compound of formula I-1 has formula I-1a, I-1b, I-1c, I-1d, I-1e, I-1f, I-1g, I-1h, I-1i, or I-1j: [ka] [ka] [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0049] In some embodiments, the compound of formula I-1 has formula I-1a', I-1b', I-1c', I-1d', or I-1e': [ka] [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof. In some embodiments of Formulae I-1a', I-1b', I-1c', I-1d', and I-1e', R 2 In some embodiments of formulae I-1a', I-1b', I-1c', I-1d', and I-1e', R 14 and R 15 forms C=O, R 16 -NR 17 R 18 In some embodiments of formulae I-1a', I-1b', I-1c', I-1d', and I-1e', R 16 is NHMe.

[0050] In some embodiments, the compound of formula I-1 has the formula I-1k, I-1l, I-1m, I-1n, I-1o, I-1p, I-1q, I-1r, I-1s, I-1t, I-1u, I-1v, I-1w, I-1x, I-1y, I-1z, I-1aa, I-1bb, I-1cc, or I-1dd: [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0051] In some embodiments [ka] teeth, [ka] and the compound of formula (I) is represented by formula I-2 [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0052] In some embodiments of formula I-2, X 3 is CR 12 In some embodiments of formula I-2, X 3 In some embodiments of formula I-2, X 3 is N.

[0053] In some embodiments of formula I-2, X 4 is CR 12 In some embodiments of formula I-2, X 4 In some embodiments of formula I-2, X 4 is N.

[0054] In some embodiments of Formula I-2, R 2 (C 1 ~C 2 ) alkyl, 4-membered heterocyclyl, (C 3 ) Carbocyclyl (C 1 ) alkyl, or 4-membered heterocyclyl (C 1 ) alkyl; wherein the alkyl, carbocyclyl, or heterocyclyl may further comprise one or more identical or different R 13 In some embodiments, R 2 is methyl. In some embodiments, R 2 is a 4-membered heterocyclyl, (C 3 ) Carbocyclyl (C1 ) alkyl, or 4-membered heterocyclyl (C 1 ) alkyl, where the heterocyclyl contains one heteroatom selected from N and O.

[0055] In some embodiments of Formula I-2, R 4 Ha-(CH 2 ) 1-3 W 1 W 2 In some embodiments of formula I-2, R 4 Ha-(CH 2 ) 2 W 1 W 2 In some embodiments of formula I-2, R 4 teeth [ka] Wherein W 3 is NR 23 and A″ is an optionally substituted 4-6 membered heterocyclyl. In some embodiments of Formula I-2, R 4 teeth [ka] It is.

[0056] In some embodiments of Formula I-2, W 1 is CR 19 R 19’ In some embodiments of formula I-2, R 19 and R 19’ are independently hydrogen or (C 1 ~C 2 In some embodiments of formula I-2, R 19 and R 19’ Both are (C 1 ~C 2 In some embodiments of formula I-2, R 19 and R 19’ are both methyl. In some embodiments of Formula I-2, R 19and R 19’ together with the carbon atom to which they are attached, (C 3 ~C 6 In some embodiments of formula I-2, R 19 and R 19’ together with the carbon atom to which they are attached form a cyclopropyl.

[0057] In some embodiments of Formula I-2, W 2 In some embodiments of formula I-2, W is cyano, hydroxy, or amino. 2 is hydroxy.

[0058] In some embodiments, the compound of formula I-2 has formula I-2a, I-2b, I-2c, I-2d, I-2e, I-2f, I-2g, I-2h, I-2i, or I-2j: [ka] [ka] [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0059] In some embodiments, the compound of formula I-2 has the formula I-2k, I-2l, I-2m, I-2n, I-2o, I-2p, I-2q, I-2r, I-2s, I-2t, I-2u, I-2v, I-2w, I-2x, I-2y, I-2z, I-2aa, I-2bb, I-2cc, or I-2dd: [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0060] In some embodiments, [ka] teeth, [ka] and the compound of formula (I) is represented by formula I-3 [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0061] In some embodiments of formula I-3, X 2 CH 2 In some embodiments of formula I-3, X 2 CF 2 It is.

[0062] In some embodiments of formula I-3, X 3 is CR 12 In some embodiments of formula I-3, X 3 In some embodiments of formula I-3, X 3 is N.

[0063] In some embodiments of formula I-3, X 4 is CR 12 In some embodiments of formula I-3, X 4 In some embodiments of formula I-3, X 4 is N.

[0064] In some embodiments of Formula I-3, R 2 is (C1 ~C 2 ) alkyl, 4-membered heterocyclyl, (C 3 ) Carbocyclyl (C 1 ) alkyl or 4-membered heterocyclyl (C 1 ) alkyl; wherein said alkyl, carbocyclyl or heterocyclyl is selected from one or more of the same or different R 13 In some embodiments, R 2 is methyl. In some embodiments, R 2 is a 4-membered heterocyclyl, (C 3 ) Carbocyclyl (C 1 ) alkyl, or 4-membered heterocyclyl (C 1 ) alkyl, where the heterocyclyl contains one heteroatom selected from N and O.

[0065] In some embodiments of Formula I-3, R 5 (C 3 ~C 6 ) cycloalkyl, R 5’ is H. In some embodiments of Formula I-3, R 5 is cyclopropyl, R 5’ is H.

[0066] In some embodiments of formula I-3, A' is a 7-membered heterocyclyl, where the heterocyclyl contains two heteroatoms selected from N and O, and R 5 and R 5’ In addition to oxo, (C 1 ~C 2 ) alkyl, cyclopropyl, spiro-cyclopropyl, halo, (C 1 ~C 2 ) haloalkyl, (C 1 ~C 2 ) may be further substituted by one or more substituents independently selected from alkoxy, amino, cyano, and hydroxy.

[0067] In some embodiments, the compound of formula I-3 has formula I-3a, I-3b, I-3c, I-3d, I-3e, I-3f, I-3g, I-3h, I-3i, I-3j, I-3k, I-3l, I-3m, I-3n, I-3o, I-3p, I-3q, I-3r, I-3s, or I-3t: [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein each R 25 are independently oxo, (C 1 ~C 2 ) alkyl, cyclopropyl, spiro-cyclopropyl, halo, (C 1 ~C 2 ) haloalkyl, (C 1 ~C 2 ) alkoxy, amino, cyano, and hydroxy; and n is 0 to 3.

[0068] In some embodiments, the compound of formula I-3 has formula I-3u or I-3v: [ka] [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0069] In some embodiments [ka] teeth, [ka] and the compound of formula (I) is represented by formula I-4 [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0070] In some embodiments of formula I-4, X 3 is CR 12 In some embodiments of formula I-4, X 3 In some embodiments of formula I-4, X 3 is N.

[0071] In some embodiments of formula I-4, X 4 is CR 12 In some embodiments of formula I-4, X 4 In some embodiments of formula I-4, X 4 is N.

[0072] In some embodiments of formula I-4, X 6 is N. In some embodiments of formula I-4, X 6 is CH.

[0073] In some embodiments of Formula I-4, R 2 is (C 1 ~C 2 ) alkyl, 4-membered heterocyclyl, (C 3 ) Carbocyclyl (C 1 ) alkyl or 4-membered heterocyclyl (C 1 ) alkyl; wherein said alkyl, carbocyclyl or heterocyclyl is selected from one or more of the same or different R 13 In some embodiments, R 2 is methyl. In some embodiments, R 2 is a 4-membered heterocyclyl, (C 3 ) Carbocyclyl (C 1 ) alkyl, or 4-membered heterocyclyl (C 1) alkyl, where the heterocyclyl contains one heteroatom selected from N and O.

[0074] In some embodiments, the compound of formula I-4 has formula I-4a, I-4b, I-4c, I-4d, I-4e, I-4f, I-4g, I-4h, I-4i, or I-4j: [ka] [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0075] In some embodiments, [ka] teeth [ka] and the compound of formula (I) is represented by formula I-5 [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0076] In some embodiments of formula I-5, X 3 is N. In some embodiments of formula I-5, X 3 is CR 12 In some embodiments of formula I-5, X 3 In some embodiments of formula I-5, X 3 In some embodiments of formula I-5, X is CF. 3 is COMe.

[0077] In some embodiments of formula I-5, X 4 is N. In some embodiments of formula I-5, X 4 is CR12 In some embodiments of formula I-5, X 4 In some embodiments of formula I-5, X 4 In some embodiments of formula I-5, X is CF. 4 is COMe.

[0078] In some embodiments of Formula I-5, R 2 is a 4-membered heterocyclyl or a 4-membered heterocyclyl (C 2 ) alkyl; wherein said alkyl, carbocyclyl or heterocyclyl is selected from one or more of the same or different R 13 In some embodiments, R 2 is a 4-membered heterocyclyl or a 4-membered heterocyclyl (C 2 ) alkyl, where the heterocyclyl contains one heteroatom selected from N and O.

[0079] In some embodiments of Formula I-5, R 2 is (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) alkyl-OH, (C 1 ~C 6 )Alkyl-NH(C 1 ~C 6 ) alkyl, or (C 1 ~C 6 )Alkyl-N((C 1 ~C 6 )Alkyl) 2 It is.

[0080] In some embodiments of Formula I-5, R 3 -L 3 CR 14 R 15 R 16 In some embodiments of formula I-5, L 3 is (C 1 ~C 4 ) alkylene, -O-(C 1 ~C4 ) alkylene or -S-(C 1 ~C 4 In some embodiments of formula I-5, L is alkylene. 3 is -O-(C 1 ~C 4 In some embodiments of formula I-5, L is alkylene. 3 is -O-(C 1 ) alkylene.

[0081] In some embodiments of Formula I-5, R 14 and R 15 together with the carbon atom to which they are attached, (C 3 ~C 5 ) forms a carbocyclyl, a 4- to 7-membered heterocyclyl, or C=O. In some embodiments of formula I-5, R 14 and R 15 together with the same carbon atom to which they are attached to form C=O. In some embodiments of Formula I-5, R 14 and R 15 together with the same carbon atom to which they are attached form a 4- to 7-membered heterocyclyl. In some embodiments of Formula I-5, R 14 and R 15 together with the same carbon atom to which they are attached form an oxetane ring.

[0082] In some embodiments of Formula I-5, R 16 (C 1 ~C 6 ) alkyl, -NR 17 R 18 -OR 17 In some embodiments of formula I-5, R 16 is methyl, hydroxyl, amino, or NHMe. In some embodiments, R 16 is methyl. In some embodiments, R 16 is hydroxyl. In some embodiments, R 16 is amino. In some embodiments, R 16is NHMe.

[0083] In some embodiments, the compound of formula I-5 has formula I-5a, I-5b, I-5c, I-5d, I-5e, I-5f, I-5g, I-5h, I-5i, or I-5j: [ka] [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0084] Representative examples of compounds of the present invention include: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0085] The compounds of the present invention may be in the form of free acid or free base, or pharma- ceutically acceptable salts. As used herein, the term "pharma-ceutically acceptable" in the context of salts refers to salts of compounds that do not abrogate the biological activity or properties of the compounds and are relatively non-toxic, i.e., the salt form of the compound can be administered to a subject without causing undesirable biological effects (such as dizziness or stomach upset) or interacting in a harmful manner with any of the other components of the composition in which it is contained. The term "pharma-ceutically acceptable salts" refers to the products obtained by reacting the compounds of the present invention with a suitable acid or base. Examples of pharma-ceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic bases, such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 4-methylbenzenesulfonate or p-toluenesulfonate. Certain compounds of the present invention can form pharmaceutically acceptable salts with various organic bases, such as lysine, arginine, guanidine, diethanolamine or metformin. Suitable base salts include aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc salts.

[0086] The compounds of the present invention may have at least one chiral center and therefore may be in the form of stereoisomers, which as used herein encompass all isomers of individual compounds that differ only in the orientation of their atoms in space. The term stereoisomer includes enantiomers (enantiomers, including the (R-) or (S-) configuration of a compound), mixtures of enantiomers of a compound (physical mixtures of enantiomers, and racemates or racemic mixtures), geometric (cis / trans or E / Z, R / S) isomers of a compound, and isomers of a compound that have two or more chiral centers that are not mirror images of each other (diastereoisomers). The chiral centers of a compound may undergo epimerization in vivo; therefore, for these compounds, administration of a compound in its (R-) form is considered equivalent to administration of a compound in its (S-) form. Thus, the compounds of the present invention may be made and used in the form of individual isomers, substantially free of other isomers, or in the form of mixtures of various isomers, such as racemic mixtures of stereoisomers.

[0087] In some embodiments, the compounds are isotopically derivatives in that they have at least one desired isotopic substitution of an atom at an amount greater than the natural abundance of the isotope, i.e., enriched. In one embodiment, the compounds contain deuterium or multiple deuterium atoms. Deuterium, i.e. 2 Substitution with heavier isotopes, such as H, may confer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore may be advantageous in some circumstances.

[0088] The compounds of formula (I) may also be in the form of N-oxides of the compounds, crystalline forms (also known as polymorphs), active metabolites of the compounds having the same type of activity, prodrugs, tautomers, and unsolvated and solvated (e.g., hydrated) forms with pharma- ceutically acceptable solvents such as water, ethanol, and the like.

[0089] The compounds of the present invention can be prepared by crystallization under different conditions and can exist as one or a combination of polymorphs of the compound. For example, different polymorphs can be identified and / or prepared by performing crystallization at different temperatures, using different solvents or different solvent mixtures for recrystallization, or by using various cooling modes ranging from very fast to very slow cooling during crystallization. Polymorphs can also be obtained by heating or melting the compound, followed by gradual or rapid cooling. The presence of polymorphs can be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffractograms and / or other known techniques.

[0090] In some embodiments, the pharmaceutical composition comprises a co-crystal of the compound of the present invention. As used herein, the term "co-crystal" refers to a stoichiometric multi-component system that includes a compound of the present invention and a co-crystal former, which are bound by non-covalent interactions. As used herein, the term "co-crystal former" refers to a compound that can form an intermolecular interaction with the compound of the present invention and co-crystallize therewith. Representative examples of co-crystal formers include benzoic acid, succinic acid, fumaric acid, glutaric acid, trans-cinnamic acid, 2,5-dihydroxybenzoic acid, glycolic acid, trans-2-hexanoic acid, 2-hydroxycaproic acid, lactic acid, sorbic acid, tartaric acid, ferulic acid, suberic acid, picolinic acid, salicylic acid, maleic acid, saccharin, 4,4'-bipyridine p-aminosalicylic acid, nicotinamide, urea, isonicotinamide, methyl 4-hydroxybenzoate, adipic acid, terephthalic acid, resorcinol, pyrogallol, phloroglucinol, hydroxyquinol, isoniazid, theophylline, adenine, theobromine, phenacetin, phenazone, etophylline, and phenobarbital.

[0091] Synthesis method In another aspect, the present invention relates to a method for preparing a compound of formula (I), or a pharma- ceutically acceptable salt or stereoisomer thereof. Generally, the compounds of the present invention, or a pharma- ceutically acceptable salt or stereoisomer thereof, can be prepared by any process known to be applicable to the preparation of chemically related compounds. The compounds of the present invention will be better understood in connection with the synthetic schemes described in the various examples, which illustrate non-limiting methods by which the compounds of the present invention can be prepared.

[0092] Pharmaceutical Compositions Another aspect of the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof and a pharma- ceutically acceptable carrier. The term "pharma- ceutically acceptable carrier" as known in the art refers to a pharma- ceutically acceptable material, composition or vehicle suitable for administering the compound of the present invention to a mammal. Suitable carriers include, for example, liquids (both aqueous and non-aqueous, and combinations thereof), solids, encapsulating materials, gases, and combinations thereof (e.g., semi-solids), and gases, which function to carry or transport the compound from one organ or part of the body to another organ or part of the body. A carrier is "acceptable" in the sense of being physiologically inert and compatible with the other ingredients of the formulation and not harmful to the subject or patient. Depending on the type of formulation, the composition may also include one or more pharma- ceutically acceptable excipients.

[0093] In general, the compounds of formula (I) and their pharma- ceutically acceptable salts and stereoisomers can be formulated into a given type of composition according to conventional pharmaceutical practices such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping and compression processes (see, for example, Remington: The Science and Practice of Pharmacy (20th ed.), ed. A R Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York). The type of formulation depends on the mode of administration, which may include enteral (e.g., oral, buccal, sublingual and rectal), parenteral (e.g., subcutaneous (sc), intravenous (iv), intramuscular (im) and intrasternal injection or infusion techniques, intraocular, intraarterial, intramedullary, intrathecal, intraventricular, transdermal, intradermal, intravaginal, intraperitoneal, mucosal, intranasal, intratracheal instillation, bronchial instillation and inhalation) and topical (e.g., transdermal). In general, the most appropriate route of administration will depend on a variety of factors, including, for example, the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). For example, parenteral (e.g., intravenous) administration may also be advantageous in that the compound may be administered relatively quickly, such as in the case of single-dose treatments and / or acute conditions.

[0094] In some embodiments, the compounds are formulated for oral or intravenous administration (eg, systemic intravenous injection).

[0095] Thus, the compounds of formula (I) can be formulated into solid compositions (e.g., powders, tablets, dispersible granules, capsules, cachets, and suppositories), liquid compositions (e.g., solutions in which the compound is dissolved, suspensions in which solid particles of the compound are dispersed, emulsions, and solutions containing liposomes, micelles, or nanoparticles, syrups and elixirs); semi-solid compositions (e.g., gels, suspensions, and creams); and gases (e.g., propellants for aerosol compositions). The compounds may also be formulated for immediate, intermediate, or sustained release.

[0096] Oral solid dosage forms include capsules, tablets, pills, powders, and granules.In these solid dosage forms, the active compound is mixed with a carrier such as sodium citrate or dicalcium phosphate, and a) a filler or extender such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) a binder such as methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) a wetting agent such as glycerol, d) a crosslinked polymer (e.g., crosslinked polyvinylpyrrolidone (crospovidone), crosslinked sodium carboxymethylcellulose, (croscarmellose sodium), sodium starch glycolate, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate), e) disintegrating agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include buffering agents. Similar types of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms 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 an opacifying agent.

[0097] In some embodiments, the compound of formula (I) can be formulated in hard or soft gelatin capsules.Representative excipients that can be used include pregelatinized starch, magnesium stearate, mannitol, sodium stearyl fumarate, lactose anhydrous, microcrystalline cellulose and croscarmellose sodium.Gelatin shell can include gelatin, titanium dioxide, iron oxide and coloring agent.

[0098] Liquid dosage forms for oral administration include solutions, suspensions, emulsions, microemulsions, syrups and elixirs.In addition to the compound, liquid dosage forms may contain aqueous or non-aqueous carriers (depending on the solubility of the compound) commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.Oral compositions may also contain excipients such as wetting agents, suspending agents, coloring agents, sweeteners, flavoring agents and aromatic agents.

[0099] Injectable preparations for parenteral administration may include sterile aqueous or oily suspensions. They may be formulated according to standard techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any non-irritating fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in injectable preparations. Injectable preparations may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. The effect of a compound can be prolonged by slowing its absorption, which can be accomplished by the use of a liquid suspension of poor water solubility or of crystalline or amorphous material. Prolonged absorption of a compound from a parenterally administered formulation can also be accomplished by suspending the compound in an oil vehicle.

[0100] In certain embodiments, the compound of formula (I) can be administered locally rather than systemically, for example, by direct injection of the conjugate into an organ, often in a depot preparation or sustained release formulation. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers, such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). The release rate of the compound can be controlled by varying the ratio of compound to polymer and the nature of the particular polymer used. Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. Furthermore, in other embodiments, the compound is delivered in a targeted drug delivery system, for example, liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are targeted to and taken up selectively by the organ.

[0101] The compositions may be formulated for buccal or sublingual administration and include, for example, tablets, lozenges and gels.

[0102] The compound of formula (I) can be formulated for administration by inhalation. Various forms suitable for administration by inhalation include aerosol, mist or powder. The pharmaceutical composition can be delivered in the form of aerosol spray presentation from pressurized pack or nebulizer using suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In some embodiments, the dosage unit of the pressurized aerosol can be determined by providing a valve to deliver a metered amount. In some embodiments, capsules and cartridges containing, for example, gelatin for use in inhaler or insufflator can be formulated to contain a powder mixture of the compound and suitable powder base such as lactose or starch.

[0103] The compounds of formula (I) can be formulated for topical administration, which as used herein refers to intradermal administration of the formulations according to the invention to the epidermis. These types of compositions are typically in the form of ointments, pastes, creams, lotions, gels, solutions and sprays.

[0104] Representative examples of carriers useful for formulating compounds for topical application include solvents (e.g., alcohol, polyalcohol, water), creams, lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffer solutions (e.g., hypotonic or buffered saline).Creams can be formulated with saturated or unsaturated fatty acids, such as, for example, stearic acid, palmitic acid, oleic acid, palmito-oleic acid, cetyl, or oleyl alcohol.Creams can also contain non-ionic surfactants, such as polyoxy-40-stearate.

[0105] In some embodiments, topical formulations may also include excipients, examples of which are penetration enhancers. These agents can preferably transport pharmacologically active compounds through the stratum corneum to the epidermis or dermis with little or no systemic absorption. A wide variety of compounds have been evaluated for their effectiveness in enhancing the penetration rate of drugs through the skin. For example, see Percutaneous Penetration Enhancers, Maibach HI and Smith HE (eds.), CRC Press, Inc., Boca Raton, Fla. (1995), which reviews the use and testing of various skin penetration enhancers, and Buyuktimkin et al., Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal and Topical Drug Delivery Systems, Gosh TK, Pfister WR, Yum SI (Eds.), Interpharm Press Inc., Buffalo Grove, Ill. (1997). Representative examples of penetration enhancers include triglycerides (e.g., soybean oil), aloe compositions (e.g., aloe vera gel), ethyl alcohol, isopropyl alcohol, octylphenyl polyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decylmethyl sulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate), and N-methylpyrrolidone.

[0106] Representative examples of further excipients that may be included in topical formulations and other types of formulations (to the extent that they are compatible) include preservatives, antioxidants, moisturizers, emollients, buffers, solubilizers, skin protectants, and surfactants. Suitable preservatives include alcohols, quaternary amines, organic acids, parabens, and phenols. Suitable antioxidants include ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol, and chelating agents such as EDTA and citric acid. Suitable moisturizers include glycerin, sorbitol, polyethylene glycol, urea, and propylene glycol. Suitable buffers include citric acid, hydrochloric acid, and lactic acid buffers. Suitable solubilizers include quaternary ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates. Suitable skin protectants include vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, and zinc oxide.

[0107] Transdermal formulations typically use transdermal delivery devices and transdermal delivery patches, where the compound is formulated in a lipophilic emulsion or buffered aqueous solution dissolved and / or dispersed in a polymer or adhesive. Patches can be constructed for continuous, pulsatile, or on-demand delivery of pharmaceuticals. Transdermal delivery of compounds can be achieved by iontophoretic patches. Transdermal patches can provide controlled delivery of compounds, where the absorption rate is slowed by using a rate-controlling membrane or by trapping the compound within a polymer matrix or gel. Absorption enhancers can be used to increase absorption, examples of which include absorbable pharma- ceutically acceptable solvents that aid passage through the skin.

[0108] Ophthalmic preparations include eye drops.

[0109] Formulations for rectal administration include enemas, rectal gels, rectal foams, rectal aerosols, and retention enemas, which may contain conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, etc. Compositions for rectal or vaginal administration can also be formulated as suppositories, which can be prepared by mixing the compound with suitable non-irritating carriers and excipients, such as cocoa butter, mixtures of fatty acid glycerides, polyethylene glycol, suppository waxes, and combinations thereof, all of which are solid at ambient temperature but liquid at body temperature, and thus melt in the rectum or vaginal cavity and release the compound.

[0110] Dosage As used herein, the term "therapeutically effective amount" refers to the amount of the compound of formula (I) or its pharmaceutically acceptable salt or stereoisomer that is effective to produce desired therapeutic response in a particular patient suffering from a disease or disorder mediated by abnormal BCL6 activity.Thus, the term "therapeutically effective amount" includes the amount of the compound or its pharmaceutically acceptable salt or stereoisomer that is sufficient when administered to induce positive modification in the disease or disorder being treated, or prevent the onset or progression of the disease or disorder, or to alleviate to some extent one or more symptoms of the disease or disorder being treated in the subject, or simply kill or inhibit the growth of diseased (e.g., cancer) cells, or reduce the amount of BCL6 in diseased cells.

[0111] The total daily dosage of compound and its use can be determined according to standard medical practice, for example by attending physician using sound medical judgment.The specific therapeutically effective dose for any specific subject can depend on various factors, including the disease or disorder to be treated and its severity (e.g., its current condition); the subject's age, weight, general health, sex and diet; administration time, administration route and excretion rate of the specific compound used; duration of treatment; the drug used in combination with or simultaneously with the compound; and similar factors well known in the medical field (for example, see Goodman and Gilman's, The Pharmacological Basis of Therapeutics, 10th Edition, A.gilman, J. Hardman and L. Limbird, eds.,McGraw-Hill Press, 155-173, 2001).

[0112] The compounds of formula (I) and their pharma- ceutically acceptable salts and stereoisomers may be effective over a wide dosage range. In some embodiments, the total daily dose (e.g., for adult humans) may range from about 0.001 to about 1600 mg, 0.01 to about 1600 mg, 0.01 to about 500 mg, about 0.01 to about 100 mg, about 0.5 to about 100 mg, 1 to about 100 to 400 mg per day, about 1 to about 50 mg per day, and about 5 to about 40 mg per day, or in still other embodiments, about 10 to about 30 mg per day. In some embodiments, the total daily dose may range from 400 mg to 600 mg. Individual doses may be formulated to contain the desired dosage, depending on the number of times the compound is administered per day. By way of example, capsules may be formulated with about 1 to about 200 mg of compound (e.g., 1, 2, 2.5, 3, 4, 5, 10, 15, 20, 25, 50, 100, 150, and 200 mg). In some embodiments, the compound may be administered at a dose ranging from about 0.001 mg / kg to about 200 mg / kg body weight per day. In some embodiments, it may be effective to administer a dose of 0.1 to 100, e.g., 1 to 30 mg / kg per day, in one or more doses per day. By way of example, a suitable dose for oral administration may range from 1 to 30 mg / kg body weight per day, and a suitable dose for intravenous administration may range from 1 to 10 mg / kg body weight per day.

[0113] In some embodiments, the compounds of formula (I) and their pharma- ceutically acceptable salts and stereoisomers can be administered at dosage levels of from about 0.001 mg to about 50 mg, from about 0.01 mg to about 25 mg, or from about 0.1 mg to about 10 mg per kg of subject body weight per day, either once or multiple times per day, to obtain the desired therapeutic effect.

[0114] How to use In some embodiments, the present invention is directed to treating disease or disorder characterized by or mediated by abnormal BCL6 activity (e.g., elevated levels of BCL6, or otherwise functionally abnormal, e.g., dysfunctional BCL6 levels) compared to non-pathological conditions. The method involves administering a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof to a subject in need thereof. A "disease" is generally considered to be a health condition of a subject in which the subject is unable to maintain homeostasis and in which the subject's health continues to deteriorate if the disease is not improved. In contrast, a "disorder" in a subject is a health condition in which the subject is able to maintain homeostasis, but the subject's health is less favorable than in the absence of the disorder. If left untreated, the disorder does not necessarily cause further deterioration of the subject's health.

[0115] The term "subject" (or "patient") as used herein includes all members of the animal kingdom susceptible to or afflicted with the indicated disease or disorder. In some embodiments, the subject is a mammal, e.g., a human or non-human mammal. The method is also applicable to companion animals such as dogs and cats, as well as livestock such as cows, horses, sheep, goats, pigs, and other domesticated and wild animals. A subject "in need" of treatment according to the present invention may be one "suffering or suspected of suffering from" a particular disease or disorder, may have been positively diagnosed, or may otherwise exhibit a sufficient number of risk factors or a sufficient number or combination of signs or symptoms to allow a medical professional to diagnose or suspect that the subject suffers from a disease or disorder. Thus, subjects suffering from a particular disease or disorder and subjects suspected of suffering from a particular disease or disorder are not necessarily two distinct groups.

[0116] In some embodiments, the compounds of the invention may be useful in the treatment of cell proliferative diseases and disorders (e.g., cancer or benign neoplasms). As used herein, the term "cell proliferative disease or disorder" refers to conditions characterized by abnormal cell proliferation or both, including neoplasms, precancerous conditions, benign tumors, and noncancerous conditions such as cancer.

[0117] In some embodiments, the method is intended to treat subjects with cancer.Includes both adult tumors / cancers and pediatric tumors / cancers.Cancer can be vascularized or not yet substantially vascularized or non-vascularized tumors.

[0118] In some embodiments, the methods of the invention involve treatment of a subject having a cell proliferative disease or disorder of the hematological system.

[0119] As used herein, "cell proliferative diseases or disorders of the blood system" includes lymphoma, leukemia, myeloid neoplasm, mast cell neoplasm, myelodysplasia, benign monoclonal gammopathy, lymphomatoid papulosis, polycythemia vera, chronic myeloid leukemia, myeloid metaplasia of unknown etiology, and essential thrombocythemia. Thus, representative examples of hematological cancers include multiple myeloma, lymphomas (including T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma (diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and ALK+ anaplastic large cell lymphoma (e.g., B-cell non-Hodgkin's lymphoma selected from diffuse large B-cell lymphoma (e.g., germinal center B-cell-like diffuse large B-cell lymphoma or activated B-cell-like diffuse large B-cell lymphoma))), Burkitt's lymphoma / leukemia, mantle cell lymphoma , mediastinal (thymic) large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia, metastatic pancreatic adenocarcinoma, refractory B-cell non-Hodgkin's lymphoma, and relapsed B-cell non-Hodgkin's lymphoma, childhood lymphomas, and lymphomas of lymphocytic and cutaneous origin, such as small lymphocytic lymphoma, leukemias (including childhood leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myeloid leukemia (e.g., acute monocytic leukemia), chronic lymphocytic leukemia, small lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, and mast cell leukemia), myeloid neoplasms, and mast cell neoplasms.

[0120] In some embodiments, the methods are directed to treating a subject with a lymphoid malignancy.

[0121] 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.

[0122] In some embodiments, the cancer is melanoma, breast cancer, or non-small cell lung cancer.

[0123] The compound of formula (I) can be administered to patients, such as cancer patients, as a monotherapy or in combination therapy. The treatment can be a "front / first line" treatment, i.e., as an initial treatment in patients who have not received a previous anticancer treatment regimen, alone or in combination with other treatments; or a "second line" treatment, alone or in combination with other treatments, in patients who have received a previous anticancer treatment regimen; or a "third line," "fourth line," etc. treatment, alone or in combination with other treatments. The treatment can also be given to patients who have previously received unsuccessful or partially successful treatments, but who have become non-responsive or intolerant to a particular treatment. The treatment can also be given as an adjuvant treatment, i.e., to prevent recurrence of cancer in patients who currently have no detectable disease, or after surgical removal of a tumor. Thus, in some embodiments, the compound can be administered to patients who have received another therapy, such as chemotherapy, radioimmunotherapy, surgical therapy, immunotherapy, radiation therapy, targeted therapy, or any combination thereof.

[0124] The method of the present invention may require administering a compound of formula (I) or a pharmaceutical composition thereof to a patient in a single dose or multiple doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 20 or more doses). For example, the dosing frequency may range from once a day to about once every 8 weeks. In some embodiments, the dosing frequency ranges from about once a day to 1, 2, 3, 4, 5, or 6 weeks, with at least one 28-day cycle including daily dosing for 3 weeks (21 days) followed by a 7-day "off" period. In other embodiments, the compound may be administered twice a day (BID) for 2 1 / 2 days (a total of 5 doses), or once a day (QD) for 2 days (a total of 2 doses). In other embodiments, the compound may be administered once a day (QD) for 5 days.

[0125] Combination therapy The compounds of formula (I) and their pharma- ceutically acceptable salts and stereoisomers can be used in combination or simultaneously with at least one other active agent, such as an anti-cancer agent or regimen, in the treatment of diseases and disorders. The terms "in combination" and "simultaneously" in this context mean that the agents are administered simultaneously, including substantially contemporaneous administration, either by the same or separate dosage forms and by the same or different modes of administration, or sequentially, e.g., as part of the same treatment regimen or by sequential treatment regimens. Thus, when given sequentially, at the start of administration of the second compound, the first of the two compounds is in some cases still detectable at effective concentrations at the site of treatment. The order and time intervals can be determined so that they can act together (e.g., synergistically) to provide a greater benefit than if they were administered otherwise. For example, the therapeutic agents can be administered simultaneously or at different times in any order sequentially, but if not administered simultaneously, they can be administered close enough in time to provide the desired therapeutic effect, which can be in a synergistic manner. Thus, these terms are not limited to administering the active agents at exactly the same time.

[0126] In some embodiments, the treatment regimen may include administration of a compound of formula (I) in combination with one or more additional therapeutic agents known for use in treating a disease or condition (e.g., cancer). The dosage of the additional therapeutic agent may be the same as or lower than known or recommended doses. See Hardman et al., eds., Goodman & Gilman's the Pharmacological Basis of Basis of Therapeutics, 10th ed., McGraw-Hill, New York, 2001; Physician's Desk Reference 60th ed., 2006. For example, anti-cancer agents that may be suitable for use in combination with the compounds of the present invention 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., antimitotic agents, angiogenesis inhibitors, antihormones, autophagy inhibitors, alkylating agents, intercalating antibiotics, growth factor inhibitors, antiandrogens, signal transduction pathway inhibitors, anti-microtubule agents, platinum coordination complexes, HDAC inhibitors, proteasome inhibitors, and topoisomerase inhibitors), immunomodulatory agents, therapeutic antibodies (e.g., monospecific and bispecific antibodies), and CAR-T therapy.

[0127] In some embodiments, the compound of Formula (I) and the additional (e.g., anti-cancer) therapeutic agent can be administered less than 5 minutes apart, less than 30 minutes apart, less than 1 hour apart, about 1 hour apart, about 1 to about 2 hours apart, about 2 to about 3 hours apart, about 3 to about 4 hours apart, about 4 to about 5 hours apart, about 5 to about 6 hours apart, about 6 to about 7 hours apart, about 7 to about 8 hours apart, about 8 to about 9 hours apart, about 9 to about 10 hours apart, about 10 to about 11 hours apart, about 11 to about 12 hours apart, about 12 to 18 hours apart, 18 to 24 hours apart, 24 to 36 hours apart, 36 to 48 hours apart, 48 to 52 hours apart, 52 to 60 hours apart, 60 to 72 hours apart, 72 to 84 hours apart, 84 to 96 hours apart, or 96 to 120 hours apart. Two or more (eg, anti-cancer) therapeutic agents may be administered within the same patient visit.

[0128] It is understood that when the active ingredients of the combination are not administered in the same pharmaceutical composition, they can be administered to the subject in need in any order.For example, the compound of the present invention can be administered to the 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), at the same time, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks after) the administration of additional therapeutic agent. In various embodiments, the therapeutic agents are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1-2 hours apart, 2-3 hours apart, 3-4 hours apart, 4-5 hours apart, 5-6 hours apart, 6-7 hours apart, 7-8 hours apart, 8-9 hours apart, 9-10 hours apart, 10-11 hours apart, 11-12 hours apart, 24 hours or less apart, or 48 hours or less apart. In one example, the (e.g., anti-cancer) therapeutic agents are administered within the same outpatient clinic. In another example, the combined anti-cancer therapeutic agents may be administered 1 minute to 24 hours apart.

[0129] In some embodiments, including cancer treatment, the compound of formula (I) and the additional anti-cancer or therapeutic agent are administered periodically. Cycling therapy includes administering one anti-cancer therapeutic agent for a period of time, followed by administering a second anti-cancer therapeutic agent for a period of time, and repeating this sequential administration (i.e., cycle), thereby reducing the occurrence of resistance to one or both of the anti-cancer therapeutic agents, avoiding or reducing the side effects of one or both of the anti-cancer therapeutic agents, and / or improving the efficacy of the treatment. In one example, cycling therapy includes administering a first anti-cancer therapeutic agent for a period of time, followed by administering a second anti-cancer therapeutic agent for a period of time, optionally followed by administering a third anti-cancer therapeutic agent for a period of time, etc., and repeating this sequential administration, i.e., cycle, to reduce the occurrence of resistance to one of the anti-cancer therapeutic agents, avoiding or reducing the side effects of one of the anti-cancer therapeutic agents, and / or improving the efficacy of the anti-cancer therapeutic agents.

[0130] In some embodiments, the compounds of the present invention can be used in combination with other anti-cancer agents, examples of which include etoposide (e.g., lymphomas and non-lymphocytic leukemias), vincristine (e.g., leukemias), daunorubicin (e.g., acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), and Kaposi's sarcoma), rituximab (e.g., non-Hodgkin's lymphoma), alemtuzumab (e.g., chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL), and T-cell lymphoma), bortezomib (e.g., multiple myeloma and mantle cell lymphoma), pegaspargase (e.g., acute lymphoblastic leukemia), Keytruda (e.g., Hodgkin's lymphoma), and dexamethasone (e.g., acute multiple myeloma).

[0131] In some embodiments, the additional anticancer agent is an enhancer of zeste homolog 2 (EZH2) inhibitor, examples of which include tazemetostat, GSK126, liramettostat (CPI-1205), CPI-0209, PF-06821497, SHR2554, HH2853, valemetostat (DS3201), MAK-683, and FTX-6058.

[0132] Medicine Kit The composition can be assembled into a kit or pharmaceutical system.The kit or pharmaceutical system according to this aspect of the present invention comprises a carrier or package such as a box, carton, tube, etc., with one or more containers, such as vials, tubes, ampoules or bottles, sealed therein, containing the compound of the present invention or the pharmaceutical composition containing the compound and pharma- ceutical acceptable carrier, and the compound and the carrier can be placed in the same or separate containers.The kit or pharmaceutical system of the present invention can also comprise printed instructions for using the compound and the composition.

[0133] These and other aspects of the present invention will be further understood by consideration of the following examples, which are intended to illustrate certain embodiments of the invention, but are not intended to limit the scope of the invention as defined by the claims. EXAMPLES

[0134] Example 1: Synthesis of 2-((6-((5-cyano-4-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (1) [ka]

[0135] Dimethyl 2,4-dimethyl-3-oxopentanedioate

[0136] K 2 CO 3 (39.68 g, 287.11 mmol) was added to a solution of dimethyl 3-oxopentanedioate (20 g, 114.84 mmol) in THF (240 mL) at 20° C., and the resulting mixture was stirred at 45° C. for 20 min. Then, CH 3 I (32.60 g, 229.69 mmol) was added and the reaction mixture was heated to 60° C. and stirred for 100 min. The reaction mixture was cooled to 20° C., filtered, and the filter cake was washed with THF (400 mL). The filtrate was dried in vacuum to give the title compound as a crude yellow oil (40 g). 1 H NMR (400 MHz, CDCl 3 ) δ 3.80-3.71 (m, 6H), 1.44-1.34 (m, 6H).

[0137] Dimethyl 1-benzyl-3,5-dimethyl-4-oxopiperidine-3,5-dicarboxylate

[0138] Aqueous HCl (1M, 21.76 mL), phenylmethanamine (11.66 g, 108.80 mmol) and formaldehyde (17.66 g, 217.60 mmol, 37% purity) were added to a solution of dimethyl 2,4-dimethyl-3-oxo-pentanedioate (22 g, 108.80 mmol) in MeOH (400 mL) at 0° C. The reaction mixture was stirred at 15° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=100 / 1 to 20 / 1) to give the title compound as a yellow oil (15 g, 41%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.37-7.27 (m, 5H), 3.67 (s, 6H), 3.65 (s, 2H), 3.53 (d, J = 11.6 Hz, 2H), 1.30 (s, 6H).

[0139] (3S,5R)-1-Benzyl-3,5-dimethylpiperidin-4-one

[0140] 1-Benzyl-3,5-dimethyl-4-oxo-piperidine-3,5-dicarboxylate dimethyl (15 g, 44.99 mmol) in aqueous HCl (150 mL, 4 M) was stirred at 100° C. for 24 h. The reaction mixture was concentrated under reduced pressure and the pH was adjusted to 8 with 2 M NaOH, and then the mixture was extracted with ethyl acetate (200 mL×3). The organic phases were combined and washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=20 / 1 to 5 / 1) to give the title compound as a yellow oil (7.2 g, 74%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.33-7.27 (m, 5H), 3.57 (s, 2H), 3.12 (dd, J = 8.8, 5.2 Hz 2H), 2.69 (dd, J = 10.8, 5.6 Hz 2H), 2.05-1.99 (m, 2H), 0.93 (d, J = 6.8Hz, 6H).

[0141] (3S,5R)-1-Benzyl-4,4-difluoro-3,5-dimethylpiperidine

[0142] DAST (55.63 g, 345.14 mmol) was added to a solution of (3S,5R)-1-benzyl-3,5-dimethyl-piperidin-4-one (5 g, 23.01 mmol) in DCM (50 mL) and the reaction mixture was stirred at 50° C. for 12 h. The pH was adjusted to 0.1 with saturated NaHCO 3 The acid was adjusted to 7-8 with ethyl acetate (500 mL x 3) and extracted with ethyl acetate. The organic phases were combined and diluted with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 0-20 / 1) to give the title compound as a yellow oil (2.5 g, 45%). 1 H NMR (400 MHz, CDCl 3) δ 7.28-7.21 (m, 5H), 3.46 (s, 2H), 2.71 (d, J = 10.8 Hz, 2H), 2.09-2.03 (m, 2H), 1.96-1.90 (m, 2H), 0.93 (d, J = 6.8 Hz, 6H).

[0143] (3S,5R)-4,4-Difluoro-3,5-dimethylpiperidine

[0144] TFA (4.76 g, 41.79 mmol) and Pd / C (0.8 g, 10% purity) were dissolved in N 2 A solution of (3S,5R)-1-benzyl-4,4-difluoro-3,5-dimethyl-piperidine (2.5 g, 10.45 mmol) in MeOH (25 mL) was added under atmospheric pressure and the reaction mixture was heated to 100° C. for 2 hours. 2 (15 Psi) for 12 h at 60° C. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound as a white solid (2.3 g, 84%, TFA salt). 1 H NMR (400 MHz, CDCl 3 ) δ 9.64-9.51 (m, 2H), 3.34 (d, J = 12.4 Hz, 2H), 2.88-2.80 (m, 2H), 2.46-2.37 (m, 2H), 1.12 (d, J = 6.8 Hz, 6H).

[0145] 2-Chloro-4-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidine-5-carbonitrile

[0146] A mixture of 2,4-dichloropyrimidine-5-carbonitrile (300 mg, 1.72 mmol), (3R,5S)-4,4-difluoro-3,5-dimethyl-piperidine (453.83 mg, 1.72 mmol, TFA salt), and DIEA (557.11 mg, 4.31 mmol) in DMF (5 mL) was diluted with N 2The mixture was stirred at 100° C. under atmospheric pressure for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by reverse-phase HPLC (neutral conditions: column: 80 g Agela C18; mobile phase: [water-ACN]; B%: 30-60% 15 min; 60% 5 min) to give 4-chloro-2-[(3R,5S)-4,4-difluoro-3,5-dimethyl-1-piperidyl]pyrimidine-5-carbonitrile as a white solid (150 mg, 30%, LCMS: [M+H + ] = 287, retention time = 0.928 min), the title compound was purified as a white solid (60 mg, 12%, LCMS: [M+H + ]=287, retention time=0.885 min).

[0147] 2-((6-((5-cyano-4-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (1)

[0148] A mixture of 2-[(6-amino-1-methyl-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide (30 mg, 114.82 μmol), 2-chloro-4-[(3R,5S)-4,4-difluoro-3,5-dimethyl-1-piperidyl]pyrimidine-5-carbonitrile (36.21 mg, 126.30 μmol), and 4-methylbenzenesulfonic acid hydrate (26.21 mg, 137.79 μmol) in DMF (1 mL) was dissolved in N 2 The mixture was stirred at 130°C for 12 hours under atmospheric conditions. 2 O (15 mL) was added to the reaction mixture and the precipitated solid was filtered and washed with H 2 The solid was washed with 0 (30 mL) and ethyl acetate (30 mL). The solid was dried under reduced pressure. The solid was triturated with ethanol (5 mL) at 15° C. for 30 min to give the title compound as a yellow solid (21.2 mg, 35%). 1 H NMR (400 MHz, DMSO-d 6) δ 10.05 (s, 1H), 8.49 (s, 1H), 7.90-7.89 (m, 2H), 7.68 (dd, J = 8.8, 2.0 Hz, 1H), 7.46 (d, J = 9.2 Hz, 1H), 7.18 (s, 1H), 4.62 (d, J = 13.6 Hz, 2H), 4.56 (s, 2H), 3.66 (s, 3H), 2.93 (t, J = 12.8 Hz, 2H), 2.66 (d, J = 4.8 Hz, 3H), 2.33-2.27 (m, 2H), 1.00 (d, J = 6.8 Hz, 6H).LCMS: [M+H + ] = 512.2.

[0149] Example 2: Synthesis of 2-((6-((3-chloro-5-cyano-6-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (2) [ka]

[0150] 2-((6-((3,6-dichloro-5-cyanopyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0151] DIEA (197.86 mg, 1.53 mmol) was added to a mixture of 2,5,6-trichloropyridine-3-carbonitrile (158.79 mg, 765.47 μmol) and 2-[(6-amino-1-methyl-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide (200 mg, 765.47 μmol) in DMF (3 mL), and the reaction mixture was cooled to 5° C. 2The mixture was stirred at 100° C. for 4 h under reduced pressure. The reaction mixture was cooled to 15° C. and water (approx. 5 mL) was added, resulting in the formation of a precipitate. The reaction mixture was filtered, and the filter cake was washed with EtOAc (approx. 20 mL) and concentrated in vacuo to give the title compound as a yellow solid (250 mg, 76%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.64 (s, 1H), 8.39 (s, 1H), 7.93 (s, 1H), 7.73 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.22 (s, 1H), 4.58 (s, 2H), 3.69 (s, 3H), 2.67 (s, 3H).

[0152] 2-((6-((3-chloro-5-cyano-6-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (2)

[0153] DIPEA (298.99 mg, 2.31 mmol) was added to a solution of 2-[[6-[(3,6-dichloro-5-cyano-2-pyridyl)amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (100 mg, 231.34 μmol) and (3R,5S)-4,4-difluoro-3,5-dimethyl-piperidine (304.45 mg, 1.16 mmol, TFA salt) in DMSO (3 mL) and the reaction mixture was stirred at 130° C. for 3 h. The reaction mixture was then cooled to 15° C. and treated with water (8 mL), which caused the formation of a precipitate. The mixture was filtered and washed with water (10 mL), EtOAc (10 mL) and EtOH (20 mL), respectively. The filter cake was concentrated under reduced pressure to give the title compound as a light brown solid (80.6 mg, 62%). 1 H NMR (400 MHz, DMSO-d 6) δ 9.14 (s, 1H), 7.99 (s, 1H), 7.92 (br s, 1H), 7.78 (s, 1H), 7.63 (br d, J = 8.8 Hz, 1H), 7.47 (br d, J = 9.2 Hz, 1H), 7.23 (s, 1H), 4.54 (s, 2H), 4.13 (br d, J = 13.2 Hz, 2H), 3.68 (s, 3H), 2.78 (br t, J = 12.8 Hz, 2H), 2.66 (br d, J = 4.4 Hz, 3H), 2.15-1.98 (m, 2H), 0.84 (br d, J = 6.8 Hz, 6H).

[0154] Example 3: Synthesis of 2-((6-((5-cyano-4-((3S,5R)-4,4-difluoro-3-(2-hydroxyethyl)-5-methylpiperidin-1-yl)pyrimidin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (3) and 2-((6-((5-cyano-4-((3R,5S)-4,4-difluoro-3-(2-hydroxyethyl)-5-methylpiperidin-1-yl)pyrimidin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (4) [ka]

[0155] Methyl 2-(1-benzyl-5-methyl-4-oxo-3-piperidyl)acetate

[0156] LDA (2M, 73.80 mL) was added dropwise to a solution of 1-benzyl-3-methyl-piperidin-4-one (30 g, 147.58 mmol) in THF (300 mL) at -78°C and the reaction was stirred at -78°C for 30 min. Then, methyl 2-bromoacetate (33.86 g, 221.38 mmol) and HMPA (31.74 g, 177.10 mmol) were added dropwise at -78°C and the reaction mixture was stirred at -78°C for 2.5 h. The reaction mixture was warmed to 20°C and stirred for an additional 9 h. The reaction mixture was diluted with saturated NH 4 Quench with Cl (100 mL) and H 2 The mixture was diluted with 200 mL of 2H2O (500 mL) and then extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (200 mL) and 2 SO 4 The mixture was dried at 40° C. for 24 hours, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 0 to 0 / 1) to give the title compound as a yellow oil (8.3 g, 17%). LCMS: [M+H + ]=276.2

[0157] Methyl 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)acetate

[0158] DAST (77.74 g, 482.31 mmol) was added to a solution of methyl 2-(1-benzyl-5-methyl-4-oxo-3-piperidyl)acetate (8.3 g, 30.14 mmol) in DCM (85 mL) and the reaction mixture was stirred at 50° C. for 12 h. The reaction mixture was diluted with DCM (60 mL) and then saturated NaHCO 3 Aqueous solution (200 mL) was added dropwise. The resulting mixture was stirred at 20° C. for 20 min and then extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (50 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C. for 24 hours, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate=1 / 0-0 / 1) to give the title compound as a yellow oil (3.7 g, 41%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.31-7.21 (m, 5H), 3.64-3.60 (m, 3H), 3.57-3.54 (m, 1H), 3.42 (d, J = 13.2 Hz, 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 = 6.8 Hz, 3H).

[0159] 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)ethanol

[0160] LiAlH 4 (255.29 mg, 6.73 mmol) was slowly added to a solution of methyl 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)acetate (1 g, 3.36 mmol) in THF (10 mL) at 0° C., and then the reaction mixture was stirred at 20° C. for 1 h. The reaction mixture was diluted with saturated NH 4 Quench with aqueous Cl (10 mL) and H 2 The mixture was diluted with 200 mL of 2H2O (10 mL) and then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL) and 2 SO 4 Drying at 40° C., filtration and concentration under reduced pressure afforded the title compound as a yellow oil (700 mg, 77%). LCMS: [M+H + ]=270.1.

[0161] 2-(4,4-Difluoro-5-methylpiperidin-3-yl)ethanol

[0162] TFA (3.39 g, 29.70 mmol) and Pd / C (0.5 g, 10% purity) were added to a solution of 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)ethanol (2 g, 7.43 mmol) in MeOH (20 mL), and the reaction mixture was diluted with H 2 (15 psi) for 6 h at 60° C. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound as a white solid (2 g, 92%, TFA salt). 1 H NMR (400 MHz, methanol-d 4 ) δ 3.66 (d, J = 6.4 Hz, 2H), 3.62-3.60 (m, 1H), 3.45-3.39 (m, 1H), 2.97-2.88 (m, 2H), 2.51-2.26 (m, 2H), 2.11-2.03 (m, 1H), 1.53-1.44 (m, 1H), 1.11 (d, J = 6.8 Hz, 3H).

[0163] 2-Chloro-4-(4,4-difluoro-3-(2-hydroxyethyl)-5-methylpiperidin-1-yl)pyrimidine-5-carbonitrile

[0164] A mixture of 2-(4,4-difluoro-5-methyl-3-piperidyl)ethanol (1 g, 3.41 mmol, TFA salt), 2,4-dichloropyrimidine-5-carbonitrile (593.35 mg, 3.41 mmol), and DIEA (1.10 g, 8.53 mmol) in DMF (10 mL) was diluted with N 2 The mixture was stirred at 50° C. under atmospheric pressure for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by reverse phase HPLC (neutral conditions: column: 80 g Agela C18; mobile phase: [water-ACN]; B%: 35-65% 25 min; 65% 5 min) to give the title compound as a yellow solid (120 mg, 11%). LCMS: [M+H + ]=317.0.

[0165] 2-Chloro-4-((3S,5R)-4,4-difluoro-3-(2-hydroxyethyl)-5-methylpiperidin-1-yl)pyrimidine-5-carbonitrile and 2-chloro-4-((3R,5S)-4,4-difluoro-3-(2-hydroxyethyl)-5-methylpiperidin-1-yl)pyrimidine-5-carbonitrile

[0166] 2-Chloro-4-[4,4-difluoro-3-(2-hydroxyethyl)-5-methyl-1-piperidyl]pyrimidine-5-carbonitrile (170 mg, 536.73 μmol) was purified by SFC (column: DAICEL Separation by CHIRALCEL® OJ (250mm*30mm, 10μm); mobile phase: [Neu-MeOH]; B%: 10%-40%, 15min) gave 2-chloro-4-[(3S,5R)-4,4-difluoro-3-(2-hydroxyethyl)-5-methyl-1-piperidyl]pyrimidine-5-carbonitrile as a yellow solid (70mg, 41%, retention time=1.894min), 2-chloro-4-[(3R,5S)-4,4-difluoro-3-(2-hydroxyethyl)-5-methyl-1-piperidyl]pyrimidine-5-carbonitrile as a yellow solid (70mg, 40%, retention time=2.013min).

[0167] 2-((6-((5-cyano-4-((3S,5R)-4,4-difluoro-3-(2-hydroxyethyl)-5-methylpiperidin-1-yl)pyrimidin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (3)

[0168] A mixture of 2-chloro-4-[(3S,5R)-4,4-difluoro-3-(2-hydroxyethyl)-5-methyl-1-piperidyl]pyrimidine-5-carbonitrile (70 mg, 221.01 μmol), 2-[(6-amino-1-methyl-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide (52.49 mg, 200.91 μmol), and 4-methylbenzenesulfonic acid monohydrate (42.04 mg, 221.01 μmol) in DMF (1 mL) was dissolved in N 2The mixture was stirred under atmospheric pressure at 130° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Waters® Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (10 mM NH 4 HCO 3 )-ACN]; B%: 25% to 55%, 8 min) to give the title compound as a white solid (38 mg, 34%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.06 (s, 1H), 8.49 (s, 1H), 7.93 (d, J = 4.4 Hz, 1H), 7.85 (s, 1H), 7.71 (d, J = 9.2 Hz, 1H), 7.46 (d, J = 9.2 Hz, 1H), 7.20 (s, 1H), 4.83 (d, J = 13.2 Hz, 1H), 4.62 (t, J = 5.2 Hz, 2H), 4.56 (s, 2H), 3.66 (s, 3H), 3.52 -3.47 (m, 2H), 2.96-2.87 (m, 2H), 2.66 (d, J = 4.8 Hz, 3H), 2.21-2.14 (m, 2H), 1.91-1.83 (m, 1H), 1.42-1.33 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H). LCMS: [M+H + ] = 542.2.

[0169] 2-((6-((5-cyano-4-((3R,5S)-4,4-difluoro-3-(2-hydroxyethyl)-5-methylpiperidin-1-yl)pyrimidin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (4) A mixture of 2-chloro-4-[(3R,5S)-4,4-difluoro-3-(2-hydroxyethyl)-5-methyl-1-piperidyl]pyrimidine-5-carbonitrile (70 mg, 221.01 μmol), 2-[(6-amino-1-methyl-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide (52.49 mg, 200.91 μmol), and 4-methylbenzenesulfonic acid monohydrate (45.86 mg, 241.10 μmol) in DMF (2 mL) was dissolved in N 2 The mixture was stirred under atmospheric pressure at 130° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Waters® Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (10 mM NH 4 HCO 3 )-ACN]; B%: 25% to 55%, 8 min) to afford the title compound as a white solid (16 mg, 14%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.07 (s, 1H), 8.49 (s, 1H), 7.94-7.86 (m, 2H), 7.71 (d, J = 9.2 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.20 (s, 1H), 4.83 (d, J = 11.6 Hz, 1H), 4.62 (t, J = 5.2 Hz, 2H), 4.56 (s, 2H), 3.67 (s, 3H), 3.50-3.49 (m, 2H), 2.96-2.87 (m, 2H), 2.66 (d, J = 4.4 Hz, 3H), 2.20 (s, 2H), 1.86 (s, 1H), 1.37 (s, 1H), 1.00 (d, J = 6.8 Hz, 3H). LCMS: [M+H + ] = 542.2.

[0170] Example 4: Synthesis of 2-((6-((4-(3-(2-aminoethyl)-4,4-difluoro-5-methylpiperidin-1-yl)-5-cyanopyrimidin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (mixture of 14 and 15) [ka]

[0171] 2-[2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)ethyl]isoindoline-1,3-dione

[0172] PPh 3 (886.20 mg, 3.38 mmol) was added to a solution of 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)ethanol (700 mg, 2.60 mmol) and isoindoline-1,3-dione (458.88 mg, 3.12 mmol) in DCM (7 mL) at 0° C. Then, a solution of DEAD (588.43 mg, 3.38 mmol) in DCM (1 mL) was added dropwise at 0° C. The reaction mixture was then stirred at 20° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 0 to 0 / 1) to give the title compound as a colorless oil (600 mg, 58%). LCMS: [M+H + ] = 399.1.

[0173] 2-Chloro-4-(3-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-4,4-difluoro-5-methylpiperidin-1-yl)pyrimidine-5-carbonitrile

[0174] A mixture of 2-[2-(4,4-difluoro-5-methyl-3-piperidyl)ethyl]isoindoline-1,3-dione (1 g, 2.37 mmol, TFA salt), 2,4-dichloropyrimidine-5-carbonitrile (494.35 mg, 2.84 mmol), and DIEA (612.03 mg, 4.74 mmol) in DMF (10 mL) was diluted with N 2 The mixture was stirred at 100° C. under atmospheric pressure for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by reverse phase HPLC (neutral conditions: column: 120 g Agela C18; mobile phase: [water-ACN]; gradient B%: 30-60% 20 min; 60% 10 min) to give the title compound as a yellow solid (200 mg, 19%). LCMS: [M+H + ] = 446.1.

[0175] 2-((6-((5-cyano-4-(3-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-4,4-difluoro-5-methylpiperidin-1-yl)pyrimidin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0176] A mixture of 2-chloro-4-[3-[2-(1,3-dioxoisoindolin-2-yl)ethyl]-4,4-difluoro-5-methyl-1-piperidyl]pyrimidine-5-carbonitrile (200 mg, 448.58 μmol), 2-[(6-amino-1-methyl-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide (106.55 mg, 407.80 μmol), and DIEA (105.41 mg, 815.60 μmol) in NMP (3 mL) was dissolved in N 2 The mixture was stirred at 130°C for 2 hours under atmospheric conditions. 2 O (5 mL) was added to the reaction mixture and the precipitated solid was filtered and washed with H 2 0 (5 mL) and EtOAc (5 mL). The solid was dried under reduced pressure to give the title compound as a brown solid (200 mg, 64%). 1 H NMR (400 MHz, DMSO-d 6) δ 10.06 (s, 1H), 8.50 (s, 1H), 7.87-7.82 (m, 5H), 7.75-7.66 (m, 2H), 7.46 (d, J = 9.2 Hz, 1H), 7.17 (s, 1H), 4.83 (d, J = 12.8 Hz, 1H), 4.6 (d, J = 12.4 Hz, 1H), 4.52 (s, 2H), 3.60 (s, 3H), 3.30-3.28 (m, 2H), 2.69 (s, 3H), 2.65 (d, J = 4.4 Hz, 2H), 2.00-1.86 (m, 3H), 1.57-1.48 (m, 1H), 0.98 (d, J = 6.4 Hz, 3H).

[0177] 2-((6-((4-(3-(2-aminoethyl)-4,4-difluoro-5-methylpiperidin-1-yl)-5-cyanopyrimidin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (mixture of 14 and 15)

[0178] NH 2 NH 2 . H 2 O (279.91 mg, 5.59 mmol) was added to a mixture of 2-[[6-[[5-cyano-4-[3-[2-(1,3-dioxoisoindolin-2-yl)ethyl]-4,4-difluoro-5-methyl-1-piperidyl]pyrimidin-2-yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (250 mg, 372.76 μmol) in NMP (0.5 mL) and the reaction was heated to 100° C. and stirred for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Phenomenex Luna® 80*30 mm*3 μm; mobile phase: [water (TFA)-ACN]; B%: 10%-40%, 8 min) to give the title compound as a yellow solid (25 mg, 12%). 1 H NMR (400 MHz, DMSO-d 6) δ 10.12 (s, 1H), 8.52 (s, 1H), 7.95 (d, J = 4.8 Hz, 1H), 7.88 (s, 1H), 7.74-7.69 (m, 3H), 7.47 (d, J = 9.2 Hz, 1H), 7.18 (s, 1H), 4.72-4.64 (m, 2H), 4.57 (s, 2H), 3.67 (s, 3H), 3.02 (d, J = 12.8 Hz, 1H), 2.91-2.84 (m, 3H), 2.66 (d, J = 4.4 Hz, 3H), 2.25-2.15 (m, 2H), 2.03-1.94 (m, 1H), 1.59-1.49 (m, 1H), 1.01 (d, J = 6.8 Hz, 3H).

[0179] Example 5: Synthesis of 5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-6-((1-methyl-3-((3-methyloxetan-3-yl)methoxy)-2-oxo-1,2-dihydroquinolin-6-yl)amino)nicotinonitrile (9) [ka]

[0180] 3-Hydroxy-1-methyl-6-nitroquinolin-2(1H)-one

[0181] Diazomethyl(trimethyl)silane (2M, 29.10 mL) was added dropwise to a mixture of 1-methyl-5-nitro-indoline-2,3-dione (10 g, 48.51 mmol) and TEA (9.82 g, 97.01 mmol) in EtOH (300 mL) and the reaction mixture was stirred at 20° C. for 12 h. The reaction mixture was concentrated under reduced pressure, 1N HCl (100 mL) was added and the mixture was stirred at 20° C. for 2 h. The mixture was filtered, washed with DMF / ethyl acetate (1 / 10, 50 mL) and the filter cake was dried under reduced pressure to give the title compound as a yellow solid (2 g, 19%). 1 H NMR (400 MHz, DMSO-d 6) δ 10.09 (s, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.19 (dd, J = 9.2, 2.4 Hz, 1H), 7.65 (d, J = 9.2 Hz, 1H), 7.34 (s, 1H), 3.74 (s, 3H).

[0182] 1-Methyl-3-((3-methyloxetan-3-yl)methoxy)-6-nitroquinolin-2(1H)-one

[0183] 3-Hydroxy-1-methyl-6-nitro-quinolin-2-one (500 mg, 2.27 mmol), 3-(iodomethyl)-3-methyl-oxetane (577.78 mg, 2.73 mmol) and Cs 2 CO 3 A mixture of (1.48 g, 4.54 mmol) in DMF (5 mL) was diluted with N 2 The mixture was stirred at 60°C for 12 hours under atmospheric conditions. 2 2H2O (5 mL) was added and the precipitated solid was filtered and 2 0 (10 mL) and EtOAc (5 mL). The solid was dried under reduced pressure to give the title compound as a brown solid (350 mg, 51%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.57 (d, J = 2.4 Hz, 1H), 8.24 (dd, J = 9.2, 2.4 Hz, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.65 (s, 1H), 4.50 (d, J = 6.0 Hz, 2H), 4.34 (d, J = 6.0 Hz, 2H), 4.13 (s, 2H), 3.70 (s, 3H), 1.40 (s, 3H).

[0184] 6-Amino-1-methyl-3-((3-methyloxetan-3-yl)methoxy)quinolin-2(1H)-one

[0185] Pd / C (10 mg, 10% purity) was dissolved in N 2The reaction mixture was added under atmospheric pressure to a solution of 1-methyl-3-[(3-methyloxetan-3-yl)methoxy]-6-nitro-quinolin-2-one (350 mg, 1.15 mmol) in DMF (0.5 mL). 2 (15 Psi) for 12 h at 20° C. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound as a brown solid (250 mg, 79%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.18 (d, J = 9.2 Hz, 1H), 7.10 (s, 1H), 6.78 (dd, J = 8.8, 2.4 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 5.03 (s, 2H), 4.49 (d, J = 5.6 Hz, 2H), 4.31 (d, J =6.0 Hz, 2H), 4.06 (s, 2H), 3.56 (s, 3H), 1.38 (s, 3H).

[0186] 2,5-Dichloro-6-((1-methyl-3-((3-methyloxetan-3-yl)methoxy)-2-oxo-1,2-dihydroquinolin-6-yl)amino)nicotinonitrile

[0187] A mixture of 6-amino-1-methyl-3-[(3-methyloxetan-3-yl)methoxy]quinolin-2-one (250 mg, 911.36 μmol), 2,5,6-trichloropyridine-3-carbonitrile (207.96 mg, 1.00 mmol), and DIEA (235.57 mg, 1.82 mmol) in DMF (3 mL) was diluted with N 2 The mixture was stirred at 100°C for 4 hours under atmospheric conditions. 2 Add 2 mL of HO (3 mL) and filter the precipitated solid. 2 0 (3 mL) and EtOAc (5 mL). The solid was dried under reduced pressure to give the title compound as a brown solid (300 mg, 74%). 1 H NMR (400 MHz, DMSO-d 6) δ 9.42 (s, 1H), 8.29 (s, 1H), 7.78 (s, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 9.2 Hz, 1H), 7.27 (s, 1H), 4.55 (d, J = 5.6 Hz, 2H), 4.33 (d, J = 6.0 Hz, 2H), 4.16 (s, 2H), 3.68 (s, 3H), 1.42 (s, 3H).

[0188] 5-Chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-6-((1-methyl-3-((3-methyloxetan-3-yl)methoxy)-2-oxo-1,2-dihydroquinolin-6-yl)amino)nicotinonitrile (9)

[0189] A mixture of 2,5-dichloro-6-[[1-methyl-3-[(3-methyloxetan-3-yl)methoxy]-2-oxo-6-quinolyl]amino]pyridine-3-carbonitrile (100 mg, 224.57 μmol), (3S,5R)-4,4-difluoro-3,5-dimethyl-piperidine (76.84 mg, 291.94 μmol, TFA salt), and DIEA (72.56 mg, 561.42 μmol) in DMSO (1 mL) was diluted with N 2 The mixture was stirred at 130° C. under atmospheric pressure for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Phenomenex C18 80*40 mm*3 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 35% to 65%, 8 min) to give the title compound as a yellow solid (40 mg). 1 H NMR (400 MHz, DMSO-d 6) δ 9.16 (s, 1H), 8.0 (s, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.59 (dd, J = 9.2, 2.4 Hz, 1H), 7.46 (d, J = 9.2 Hz, 1H), 7.29 (s, 1H), 4.48 (d, J = 6.0 Hz, 2H), 4.33 (d, J = 6.0 Hz, 2H), 4.13 (d, J = 12.8 Hz, 2H), 4.09 (s, 2H), 3.66 (s, 3H), 2.78 (t, J = 12.8 Hz, 2H), 2.11-2.04 (m, 2H), 1.39 (s, 3H), 0.85 (t, J = 6.8 Hz, 6H).

[0190] Example 6: Synthesis of 2-((3S,5R)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloro-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (48) and 2-((3R,5S)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloro-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (49) [ka]

[0191] tert-Butyl 3-(1,3-dioxoisoindolin-2-yl)-4-oxopiperidine-1-carboxylate

[0192] A mixture of tert-butyl 3-bromo-4-oxo-piperidine-1-carboxylate (100 g, 359.53 mmol) and (1,3-dioxoisoindolin-2-yl)potassium (73.25 g, 395.48 mmol) in DMF (800 mL) was stirred for 2 h at 20° C. The mixture was slowly added to water (2.5 L) forming a precipitate which was filtered, the filter cake was washed with water (500 mL) and dried in vacuum to give the title compound as a white solid (80 g, 59% yield, 91% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ = 7.97 - 7.82 (m, 4H), 4.88 (dd, J = 7.2, 11.6 Hz, 1H), 4.41 - 4.11 (m, 2H), 3.76 - 3.51 (m, 1H), 3.29 - 3.16 (m, 1H), 2.85 - 2.71 (m, 1H), 2.47 (t, J = 3.0 Hz, 1H), 1.47 - 1.43 (s, 9H).

[0193] tert-Butyl 3-(1,3-dioxoisoindolin-2-yl)-5-methyl-4-oxopiperidine-1-carboxylate

[0194] To a solution of tert-butyl 3-(1,3-dioxoisoindolin-2-yl)-4-oxo-piperidine-1-carboxylate (25 g, 72.60 mmol) in THF (250 mL) was added LDA (2M, 43.56 mL) dropwise at -70°C, the mixture was stirred at -70°C for 45 min, then HMPA (15.61 g, 87.12 mmol, 15.31 mL) was added dropwise and stirred for another 30 min. Finally, iodomethane (15.46 g, 108.90 mmol, 6.78 mL) was added dropwise at -70°C, and the resulting mixture was stirred at 20°C for 11 h. The reaction mixture was diluted with saturated NH 4 The mixture was quenched with aqueous Cl (400 mL), and then it was extracted with DCM (500 mL×3). The combined organic layers were washed with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (silica flash column, eluent of 25-50% ethyl acetate / petroleum ether gradient) to give the title compound as a pink solid (4.3 g, 7% yield, 87% purity). 1 H NMR (400 MHz, CDCl 3 ) δ = 7.90 - 7.83 (m, 2H), 7.77 - 7.74 (m, 2H), 4.86 (dd, J = 7.2, 11.2 Hz, 1H), 4.65 - 4.29 (m, 2H), 3.97 - 3.81 (m, 1H), 2.90 (s, 1H), 2.67 (s, 1H), 1.52 (s, 9H), 1.13 (d, J = 6.8 Hz, 3H).

[0195] 2-(5-Methyl-4-oxopiperidin-3-yl)isoindoline-1,3-dione

[0196] A mixture of tert-butyl 3-(1,3-dioxoisoindolin-2-yl)-5-methyl-4-oxo-piperidine-1-carboxylate (4.3 g, 12.00 mmol) in HCl / EtOAc (4 M, 21.50 mL) was stirred for 1 h at 20° C. The reaction mixture was concentrated under reduced pressure to give the title compound as a white solid (3.5 g, crude, HCl).

[0197] 2-(1-benzyl-5-methyl-4-oxopiperidin-3-yl)isoindoline-1,3-dione

[0198] A mixture of 2-(5-methyl-4-oxo-3-piperidyl)isoindoline-1,3-dione (3.5 g, 9.50 mmol, 80% purity, HCl), benzaldehyde (1.21 g, 11.40 mmol, 1.15 mL) and AcOH (285.25 mg, 4.75 mmol, 271.67 μL) in DMF (35 mL) was stirred at 20° C. for 2 h, then sodium triacetoxyborohydride (4.03 g, 19.00 mmol, 2 equiv.) was added to the mixture and the reaction mixture was stirred at 20° C. for 10 h. The reaction mixture was treated with water (50 mL) to form a precipitate which was filtered and the solid was collected and dried under vacuum. The crude product was triturated with (PE:EtOAc=15:1, 60 mL) at 20° C. for 30 min to give the title compound as a white solid (3 g, 75% yield, 83% purity). 1 H NMR (400 MHz, CDCl 3 ) δ = 7.76 - 7.70 (m, 2H), 7.65 - 7.59 (m, 2H), 7.29 - 7.16 (m, 5H), 5.01 - 4.92 (m, 1H), 3.69 - 3.54 (m, 2H), 3.21 - 3.04 (m, 3H), 2.76 - 2.64 (m, 1H), 2.34 - 2.26 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H).

[0199] 2-(1-benzyl-4,4-difluoro-5-methylpiperidin-3-yl)isoindoline-1,3-dione

[0200] To a solution of 2-(1-benzyl-5-methyl-4-oxo-3-piperidyl)isoindoline-1,3-dione (3 g, 8.61 mmol) in DCM (30 mL) was added DAST (20.82 g, 129.16 mmol, 17.07 mL) in one portion and the reaction mixture was stirred at 50° C. for 12 h. The reaction mixture was diluted with DCM (50 mL) and then saturated NaHCO 3 Aqueous solution (200 mL) was added to the stirred mixture. The organic phase was separated and the aqueous phase was extracted with EtOAc (100 mL×3). The combined organic phase was washed with brine (150 mL) and anhydrous Na 2 SO 4It was dried at rt, filtered, and the filtrate was concentrated in vacuo and purified by flash silica gel chromatography (silica flash column, eluent of 5-30% ethyl acetate / petroleum ether gradient) to give the title compound as a white solid (2 g, 3.78 mmol, 44% yield, 70% purity). 1 H NMR (400 MHz, CDCl 3 ) δ = 7.81 - 7.74 (m, 2H), 7.69 - 7.62 (m, 2H), 7.27 - 7.15 (m, 5H), 4.71 - 4.55 (m, 1H), 3.67 - 3.59 (m, 1H), 3.55 - 3.46 (m, 2H), 2.85 - 2.76 (m, 2H), 2.35 - 2.15 (m, 2H), 0.97 (d, J = 6.4 Hz, 3H).

[0201] 2-(4,4-Difluoro-5-methylpiperidin-3-yl)isoindoline-1,3-dione

[0202] 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)isoindoline-1,3-dione (2 g, 5.40 mmol) 2 To the mixture in 20 O (20 mL) and ACN (80 mL) was added CAN (29.60 g, 54.00 mmol, 26.91 mL) and the reaction mixture was stirred at 40° C. for 12 h. The reaction mixture was diluted with saturated K 2 CO 3 Upon treatment with aqueous solution (50 mL), a precipitate formed which was filtered and the filter cake was washed with EtOAc (80 mL). The filtrate was extracted with EtOAc (100 mL×3) and the combined organic phase was washed with brine (150 mL) and anhydrous Na 2 SO 4 The mixture was dried over 100° C., filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (silica flash column, eluent of 80-100% ethyl acetate / petroleum ether gradient). It was then purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [water (NH 3 H 2O+NH 4 HCO 3 )-ACN]; B%: 20% to 50%, 8 min) to give the title compound as a yellow solid (550 mg, 1.95 mmol, 36% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ = 7.94 - 7.83 (m, 4H), 4.50 - 4.34 (m, 1H), 3.72 (t, J = 12.4 Hz, 1H), 3.15 - 3.03 (m, 1H), 2.98 - 2.88 (m, 1H), 2.54 (s, 1H), 2.41 - 2.31 (m, 1H), 2.22 - 2.01 (m, 1H), 0.90 (d, J = 6.4 Hz, 3H).

[0203] 2-((3S,5R)-4,4-difluoro-5-methylpiperidin-3-yl)isoindoline-1,3-dione and 2-((3R,5S)-4,4-difluoro-5-methylpiperidin-3-yl)isoindoline-1,3-dione

[0204] 2-(4,4-Difluoro-5-methyl-3-piperidyl)isoindoline-1,3-dione (550 mg) was subjected to SFC (column: DAICEL CHIRALPAK IG (250 mm*50 mm, 10 μm); mobile phase: [0.1%NH 3 H 2 O ETOH]; B%: 40%-40%, 3.8 min) to give 2-[(3S,5R)-4,4-difluoro-5-methyl-3-piperidyl]isoindoline-1,3-dione as a white solid (200 mg, 520.93 μmol, 27% yield) and 2-[(3R,5S)-4,4-difluoro-5-methyl-3-piperidyl]isoindoline-1,3-dione as a white solid (190 mg, 460.99 μmol, 23% yield).

[0205] Intermediate 1: 1 H NMR (400MHz, DMSO-d 6)δ=7.95-7.81(m,4H),4.52-4.32(m,1H),3.73(t,J=12.4Hz,1H),3.14-3.03(m,1H)2.96-2 .90(m,1H),2.58(s,1H),2.36(t,J=12.6Hz,1H),2.20-2.03(m,1H),0.90(d,J=6.8Hz,3H).

[0206] Intermediate 2: 1 H NMR (400MHz, DMSO-d 6 )δ=7.93-7.82(m,4H),4.55-4.30(m,1H),3.73(t,J=12.4Hz,1H),3.14-3.04(m,1H),2.96-2.91(m,1H),2.70 (s,1H),2.36(t,J =12.0Hz,1H),2.21-2.02(m, 1H),0.91(d,J=6.8Hz,3H).

[0207] 3-Hydroxy-3-methylbutyl 4-methylbenzenesulfonate

[0208] To a mixture of 3-methylbutane-1,3-diol (50 g, 480.09 mmol, 51.23 mL) in DCM (1 L) was added DMAP (5.87 g, 48.01 mmol) and TEA (97.16 g, 960.18 mmol, 133.64 mL) under nitrogen atmosphere at 15° C. 4-Methylbenzenesulfonyl chloride (91.53 g, 480.09 mmol) was added slowly at 0° C. The reaction was stirred at 15° C. for 12 h and then saturated NaHCO 3 The biphasic layers were separated and the aqueous layer was extracted with DCM (2000 mL). The combined organic layers were washed with brine (1500 mL) and diluted with anhydrous Na 2 SO 4 The residue was purified by column chromatography (silica gel, eluted with petroleum ether / ethyl acetate=10 / 1 to 2 / 1) to give the title compound as a colorless oil (250 g, 953.23 mmol, 99% yield, 98% purity), which was used without further purification. 1 H NMR (400 MHz, CDCl3 ) δ ppm 7.75 - 7.80 (m, 2 H), 7.34 (d, J = 7.99 Hz, 2 H), 4.19 (t, J = 6.91 Hz, 2 H), 2.44 (s, 3 H), 1.84 (t, J = 6.85 Hz, 2 H), 1.68 (s, 1 H), 1.20 (s, 6 H).

[0209] 1-Methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one

[0210] A mixture of N-1-methyl-4-nitrobenzene-1,2-diamine (50 g, 299.11 mmol) and di(imidazol-1-yl)methanone (48.50 g, 299.11 mmol) in DMF (500 mL) was stirred for 12 h at 15° C. The resulting suspension was filtered, and the filter cake was washed with EtOAc (100 mL) and concentrated under reduced pressure to afford the crude title compound as a red solid (92 g, 468.15 mmol, 78% yield, 98% purity), which was used without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.38 (br s, 1 H), 7.99 (dd, J = 8.70, 2.15 Hz, 1 H), 7.71 (d, J = 2.03 Hz, 1 H), 7.26 (d, J = 8.70 Hz, 1 H), 3.34 (s, 3 H).

[0211] 3-(3-hydroxy-3-methylbutyl)-1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one

[0212] A mixture of 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (24.07 g, 93.19 mmol) and 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one (15 g, 77.66 mmol) in DMSO (400 mL) was cooled to 100° C. under a nitrogen atmosphere and cooled to 100° C. 2 CO 3(50.60 g, 155.31 mmol) was added in one portion. The mixture was stirred at 100° C. for 12 h. (3-Hydroxy-3-methyl-butyl) 4-methylbenzenesulfonate (6.02 g, 23.30 mmol) was added. The mixture was stirred at 100° C. for 12 h. Water (600 mL) was then added and the biphasic mixture was extracted with ethyl acetate (500 mL×2). The combined organic phase was washed with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration afforded the crude title compound as a black oil (46 g, 154.92 mmol, 99% yield, 94% purity) which was used without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.02 (dd, J = 8.70, 2.15 Hz, 1 H), 7.96 (d, J = 2.15 Hz, 1 H), 7.32 (d, J = 8.70 Hz, 1 H), 4.52 (s, 1 H), 3.91 - 4.00 (m, 2 H), 3.38 (s, 3 H), 1.67 - 1.75 (m, 2 H), 1.16 (s, 6 H). M+H + = 280.0.

[0213] 5-Amino-3-(3-hydroxy-3-methylbutyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one

[0214] To a solution of 3-(3-hydroxy-3-methylbutyl)-1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one (15 g, 53.71 mmol) in DMF (200 mL) was added Pd / C (10 g, 10%) under an argon atmosphere. The suspension was degassed under vacuum and diluted with H 2 The mixture was purged with H several times. 2 The mixture was stirred at 50° C. under (50 psi) for 96 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with DCM:MeOH=20:1 to 5:1) to give the title compound as a pink solid (13 g, 51.44 mmol, yield 96%, purity 99%). 1H NMR (400 MHz, DMSO-d 6 ) δ 6.78 (d, J = 8.31 Hz, 1 H), 6.37 (d, J = 1.83 Hz, 1 H), 6.30 (dd, J = 8.25, 1.90 Hz, 1 H), 4.79 (s, 2 H), 4.45 (s, 1 H), 3.73 - 3.83 (m, 2 H), 3.21 (s, 3 H), 1.59 - 1.72 (m, 2 H), 1.16 (s, 6 H). M+H + = 250.1.

[0215] 2,5-Dichloro-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile

[0216] To a mixture of 5-amino-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (3 g, 12.03 mmol) and 2,5,6-trichloropyridine-3-carbonitrile (2.50 g, 12.03 mmol) in DMSO (30 mL) was added DIEA (3.11 g, 24.07 mmol, 4.19 mL) in N 2 The mixture was stirred at 100° C. for 12 h. Water (20 mL) was added to the mixture, and the precipitated solid was filtered and diluted with H 2 O (30 mL) and ethyl acetate (20 mL), then the solid was dried under reduced pressure to give the title compound as a black solid (4 g, 6.53 mmol, 54% yield, 69% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.50 (s, 1 H), 8.28 (s, 1 H), 7.35 (m, 1 H), 7.20 (dd, J = 8.44, 1.59 Hz, 1 H), 7.11 (m, 1 H), 4.44 (s, 1 H), 3.87 (m, 2 H), 2.54 (s, 3 H), 1.72 (m, 2 H), 1.17 (s, 6 H).

[0217] 5-Chloro-2-(3-(1,3-dioxoisoindolin-2-yl)-4,4-difluoro-5-methylpiperidin-1-yl)-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile

[0218] A mixture of 2,5-dichloro-6-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyridine-3-carbonitrile (1.5 g, 3.57 mmol) and 2-(4,4-difluoro-5-methyl-3-piperidyl)isoindoline-1,3-dione (1.10 g, 3.93 mmol) in DMSO (15 mL) was added to the flask. 2 DIEA (922.52 mg, 7.14 mmol, 1.24 mL) was added in one portion. The mixture was stirred at 100° C. for 12 h. The mixture was cooled to 15° C., poured into water (30 mL), and the aqueous phase was extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with brine (50 mL) and diluted with anhydrous Na 2 SO 4 Drying at rt, filtration and concentration in vacuo afforded the title compound as a yellow solid (2.25 g, 2.35 mmol, 66% yield, 69% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.13 (s, 1 H), 8.01 (s, 1 H), 7.45 - 7.95 (m, 4 H), 7.11 - 7.20 (m, 1 H), 7.00 - 7.08 (m, 1 H), 6.81 (d, J = 8.34 Hz, 1 H), 4.12 - 4.54 (m, 4 H), 3.83 - 3.93 (m, 1 H), 3.58 - 3.77 (m, 1 H), 3.07 - 3.25 (m, 1 H), 2.82 (s, 2 H), 2.54 (s, 3 H), 2.08 - 2.28 (m, 1 H), 1.67 - 1.76 (m, 1 H), 1.05 - 1.21 (m, 6 H), 0.80 - 1.02 (m, 3 H).

[0219] 2-(3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloro-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile

[0220] To a mixture of 5-chloro-2-[3-(1,3-dioxoisoindolin-2-yl)-4,4-difluoro-5-methyl-1-piperidyl]-6-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyridine-3-carbonitrile (2.25 g, 3.39 mmol) in EtOH (25 mL) was added N 2 bottom, N 2 H 4 H 2 0 (2.99 g, 50.82 mmol, 2.91 mL, 85% purity) was added in one portion. The mixture was stirred at 60° C. for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral condition; column: Welch Xtimate C18 250*70 mm#10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 25%-60%, 20 min) to give the title compound as a yellow solid (1.5 g, 83% yield, 88% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.13 (s, 1 H), 8.01 (s, 1 H), 7.45 - 7.95 (m, 4 H), 7.11 - 7.20 (m, 1 H), 7.00 - 7.08 (m, 1 H), 6.81 (d, J = 8.34 Hz, 1 H), 4.12 - 4.54 (m, 4 H), 3.83 - 3.93 (m, 1 H), 3.58 - 3.77 (m, 1 H), 3.07 - 3.25 (m, 1 H), 2.82 (s, 2 H), 2.54 (s, 3 H), 2.08 - 2.28 (m, 1 H), 1.67 - 1.76 (m, 1 H), 1.05 - 1.21 (m, 6 H), 0.80 - 1.02 (m, 3 H).

[0221] 2-((3R,5S)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloro-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile and 2-((3S,5R)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloro-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile

[0222] A mixture of 2-(3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloro-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile was subjected to SFC (Conditions: Column: DAICEL CHIRALCEL OJ (250mm*50mm, 10μm); Mobile phase: [0.1%NH 3 H 2 O MEOH]; B%: 20%-20%, 5.3 min) to give 2-((3R,5S)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloro-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile as a white solid and 2-((3S,5R)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloro-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile as a white solid.

[0223] 2-((3S,5R)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloro-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (48): 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.00 (s, 1 H), 7.95 (s, 1 H), 7.29 (d, J = 1.63 Hz, 1 H), 7.22 (dd, J = 8.32, 1.81 Hz, 1 H), 7.11 (d, J = 8.38 Hz, 1 H), 4.47 (s, 1 H), 4.10 - 4.25 (m, 1 H), 3.93 - 4.02 (m, 1 H), 3.84 - 3.93 (m, 2 H), 2.58 - 2.94 (m, 3 H), 1.92 - 2.12 (m, 1 H), 1.61 - 1.76 (m, 4 H), 1.15 (s, 6 H), 0.78 (d, J = 6.75 Hz, 3 H).

[0224] 2-((3R,5S)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloro-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (49): 1 H NMR (400 MHz, DMSO-d 6) δ 9.00 (s, 1 H), 7.95 (s, 1 H), 7.29 (d, J = 1.75 Hz, 1 H), 7.22 (dd, J = 8.38, 1.75 Hz, 1 H), 7.11 (d, J = 8.38 Hz, 1 H), 4.47 (s, 1 H), 4.11 - 4.25 (m, 1 H), 3.78 - 4.04 (m, 3 H), 2.75 - 2.95 (m, 2 H), 2.68 (br t, J = 12.69 Hz, 1 H), 1.88 - 2.13 (m, 1 H), 1.50 - 1.80 (m, 4 H), 1.15 (s, 6 H), 0.78 (d, J = 6.75 Hz, 3H).

[0225] The absolute configurations of compounds 48 and 49 were randomly assigned based on the cis conformation of the amino and methyl groups.

[0226] Example 7: Synthesis of 5-chloro-2-[(3S,4R,5R)-4-fluoro-3-hydroxy-5-methyl-1-piperidyl]-6-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyridine-3-carbonitrile (50) and 5-chloro-2-[(3R,4S,5S)-4-fluoro-3-hydroxy-5-methyl-1-piperidyl]-6-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyridine-3-carbonitrile (51) [ka]

[0227] 1-Benzyl-3-methyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate

[0228] To a solution of 1-benzyl-3-methyl-piperidin-4-one (50 g, 245.97 mmol) in THF (500 mL) was added LiHMDS (1 M, 295.16 mL) (1 M in THF) dropwise at -65°C. After addition, the mixture was stirred at -65°C for 1 h, then 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (96.66 g, 270.56 mmol) in THF (400 mL) was added dropwise at -65°C. The resulting mixture was stirred at 15°C for 3 h. The mixture (combined with another batch of the same scale) was diluted with saturated NH 4 The mixture was slowly quenched with Cl (800 mL) and water (800 mL) was added. The mixture was extracted with ethyl acetate (800 mL x 3). The combined organic phase was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (silica gel, petroleum ether / ethyl acetate=1 / 0, 20 / 1) to give 180 g of crude product. The crude product was dissolved in ethyl acetate (1 L), then water (1 L) was added to the mixture, followed by 1N HCl until pH=3. A white precipitate was formed, and the mixture was filtered to give a filter cake. Water (1 L) was added to the filter cake, followed by saturated Na 2 CO 3 was added until pH=8. The mixture was extracted with ethyl acetate (1 L×3). The combined organic phase was washed with anhydrous Na 2 SO 4 Drying at 40° C., filtering and concentrating afforded the title compound as a yellow oil (140 g, 93% purity). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.33 - 7.36 (m, 4 H), 7.27 - 7.32 (m, 1 H), 5.69 - 5.74 (m, 1 H), 3.57 - 3.67 (m, 2 H), 3.06 - 3.18 (m, 2 H), 2.79 (dd, J= 11.31, 4.95 Hz, 1 H), 2.62 - 2.72 (m, 1 H), 2.37 (dd, J = 11.37, 5.87 Hz, 1 H), 1.16 (d, J = 6.85 Hz, 3 H).

[0229] 1-Benzyl-3-methyl-1,2,3,6-tetrahydropyridine

[0230] 1-Benzyl-3-methyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (30 g, 89.46 mmol), Pd(OAc)2 (401.69 mg, 1.79 mmol), PPh 3 A mixture of (938.58 mg, 3.58 mmol) and TEA (27.16 g, 268.38 mmol, 37.36 mL) in DMF (300 mL) was diluted with N 2 The mixture was stirred at 60° C. for 10 min, and then formic acid (4.12 g, 89.46 mmol, 3.37 mL) was added to the mixture in one portion. 2 The mixture was stirred at 60° C. under atmospheric pressure for 50 min. Water (2 L) was added to the mixture (combined with three other batches of the same scale), followed by extraction with ethyl acetate (3×800 mL). The combined organic phase was washed with brine (1 L) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuum. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=1 / 0-20 / 1) to give the title compound as a yellow oil (32 g, 148.65 mmol, yield 42%, purity 87%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.30 - 7.39 (m, 4 H), 7.27 (s, 2 H), 7.23 - 7.26 (m, 1 H), 5.59 - 5.68 (m, 2 H), 3.52 - 3.66 (m, 2 H), 3.02 - 3.14 (m, 1 H), 2.74 - 2.88 (m, 2 H), 2.37 - 2.48 (m, 1 H), 1.98 (dd, J = 10.94, 8.13 Hz, 1 H), 0.96 (d, J = 7.09 Hz, 3 H).

[0231] 3-Benzyl-5-methyl-7-oxa-3-azabicyclo[4.1.0]heptane

[0232] H 2 O 2 To a solution of (15.14 g, 133.49 mmol, 12.83 mL, 30% purity) in DCM (150 mL) was added dropwise a solution of trifluoroacetic anhydride (TFAA) (84.11 g, 400.47 mmol, 55.70 mL) in DCM (50 mL) at 0° C. and the resulting suspension was stirred at 0° C. for 2 h. Meanwhile, TFA (3.04 g, 26.70 mmol, 1.98 mL) was added dropwise to a solution of 1-benzyl-3-methyl-1,2,3,6-tetrahydropyridine (5 g, 26.70 mmol) in DCM (100 mL) at 0° C. and stirred for 2 h. The cold TFA / piperidine solution was added dropwise to H 2 O 2 The mixture was slowly washed with saturated sodium sulfite solution (300 mL) at 0° C. under N2, then the system was adjusted to pH=8 with saturated NaHCO3. The mixture was extracted with DCM (3×200 mL). Peroxides were detected using moist potassium iodide starch paper, and the combined organic phase was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (silica gel, petroleum ether / ethyl acetate=1 / 0, 10 / 1) to give the title compound as a yellow oil (2.9 g, 13.12 mmol, yield 49%, purity 92%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.30 - 7.33 (m, 4 H), 7.22 - 7.27 (m, 1 H), 3.47 (s, 2 H), 3.22 (t, J = 3.70 Hz, 1 H), 2.97 (d, J = 3.93 Hz, 1 H), 2.84 - 2.92 (m, 1 H), 2.76 - 2.83 (m, 1 H), 2.46 (dd, J = 11.50, 4.71 Hz, 1 H), 2.20 (t, J = 6.44 Hz, 1 H), 1.88 (dd, J = 11.44, 6.08 Hz, 1 H), 1.10 (d, J = 7.15Hz, 3H).

[0233] (3R,4R,5R)-1-Benzyl-4-fluoro-5-methylpiperidin-3-ol

[0234] To a solution of 3-benzyl-5-methyl-7-oxa-3-azabicyclo[4.1.0]heptane (2.9 g, 14.27 mmol) in DCM (45 mL), ethoxyethane; trifluoroborane; hydrofluoride (9.24 g, 28.53 mmol, 7.83 mL, 50% purity) were added with N 2 The mixture was stirred at 15° C. for 10 min. Saturated NaHCO 3 (20 mL) was added to the mixture. The mixture was extracted with DCM (3×15 mL). The combined organic phase was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give a residue, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=1 / 0 to 5 / 1) to give the title compound as a yellow solid (2 g, 8.51 mmol, yield 60%, purity 95%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.27 - 7.38 (m, 5 H), 4.35 - 4.52 (m, 1 H), 3.87 (br s, 1 H), 3.54 (s, 2 H), 2.81 - 3.01 (m, 1 H), 2.74 (br d, J = 10.37 Hz, 1 H), 2.48 - 2.59 (m, 2 H), 1.99 - 2.25 (m, 2 H), 0.99 (d, J = 6.79 Hz, 3 H).

[0235] (4R,5R)-1-Benzyl-4-fluoro-5-methylpiperidin-3-one

[0236] (COCl) 2To a solution of (1.71 g, 13.44 mmol, 1.18 mL) in DCM (50 mL) was added dropwise DMSO (2.10 g, 26.87 mmol, 2.10 mL) in DCM (5 mL) at -65 °C. After stirring for 15 min at -65 °C, a solution of (3R,4R,5R)-1-benzyl-4-fluoro-5-methyl-piperidin-3-ol (2 g, 8.96 mmol, 1 equiv) in DCM (20 mL) was added dropwise slowly at -65 °C. The mixture was stirred for another 15 min at -65 °C and TEA (4.53 g, 44.79 mmol, 6.23 mL) was added to the mixture. After addition, the mixture was stirred at 15 °C for 0.5 h. Water (150 mL) was added slowly at 0 °C and the mixture was extracted with DCM (3 x 100 mL). The combined organic phase was washed with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration afforded the title compound as a yellow oil (2 g, 5.69 mmol, 64% yield, 63% purity) in 20 mL of THF.

[0237] (3S,4R,5R)-1-Benzyl-4-fluoro-5-methylpiperidin-3-ol

[0238] To a solution of (4R,5R)-1-benzyl-4-fluoro-5-methylpiperidin-3-one (1 g, 4.52 mmol) in EtOH (10 mL) and THF (10 mL), 2 NaBH at 0 °C 4 (205.17 mg, 5.42 mmol) was added. The mixture was stirred at 0° C. for 1 h. The reaction was quenched with cold water (50 mL) and extracted with ethyl acetate (50 mL×3). The organic layer was collected, washed with water, brine, and added Na 2 SO 4 The mixture was dried at 40° C. and concentrated under vacuum. The residue was purified by flash silica gel column chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent of 0-25% ethyl acetate / petroleum ether gradient @ 120 mL / min) to give 500 mg of crude product. The crude product was purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (NH 4 HCO 3)-ACN]; B%: 25% to 45%, 8 min) to afford the title compound as a white solid (400 mg, 1.68 mmol, 37% yield, 94% purity). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.24 - 7.36 (m, 5 H), 4.50 - 4.71 (m, 1 H), 3.70 - 3.84 (m, 1 H), 3.55 (d, J = 1.71 Hz, 2 H), 2.90 (br dd, J = 10.39, 5.01 Hz, 1 H), 2.49 - 2.59 (m, 1 H), 2.07 - 2.18 (m, 1 H), 1.81 - 2.03 (m, 3 H), 1.02 (d, J = 6.72 Hz, 3 H).

[0239] (3S,4R,5R)-4-Fluoro-5-methylpiperidin-3-ol

[0240] To a mixture of Pd / C (0.2 g, 10% purity) in THF (20 mL) was added (3S,4R,5R)-1-benzyl-4-fluoro-5-methylpiperidin-3-ol (400 mg, 1.79 mmol) and TFA (612.79 mg, 5.37 mmol, 397.92 μL) under Ar. The mixture was cooled to 37° C. for 1 h. 2 (15 psi) for 10 h at 15° C. The mixture was filtered and the filtrate was concentrated in vacuo without further purification to give the title compound as a white solid (450 mg, crude, TFA). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 4.52 - 4.76 (m, 1 H), 3.70 - 3.91 (m, 1 H), 3.02 - 3.21 (m, 2 H), 2.70 - 2.86 (m, 1 H), 2.59 (q, J = 12.15 Hz, 1 H), 1.94 - 2.11 (m, 1 H), 0.95 - 1.01 (m, 3 H).

[0241] 5-Chloro-2-((3S,4R,5R)-4-fluoro-3-hydroxy-5-methylpiperidin-1-yl)-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile

[0242] To a solution of 2,5-dichloro-6-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyridine-3-carbonitrile (100 mg, 237.93 μmol) in DMSO (1 mL) was added DIEA (153.75 mg, 1.19 mmol, 207.22 μL) and 4-fluoro-5-methyl-piperidin-3-ol (60.54 mg, 356.89 μmol, HCl). The mixture was stirred at 100° C. for 12 h. The solution was filtered and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 25% to 55%, 8 min) to give the title compound as a white solid (80 mg, 154.59 μmol, 65% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.94 (s, 1H), 7.92 (s, 1H), 7.32 (d, J = 1.7 Hz, 1H), 7.27 - 7.22 (m, 1H), 7.10 (d, J = 8.4 Hz, 1H), 5.26 (d, J = 6.0 Hz, 1H), 4.65 - 4.58 (m, 1H), 4.51 - 4.40 (m, 2H), 4.10 (br dd, J = 4.3, 12.9 Hz, 1H), 3.96 - 3.75 (m, 4H), 3.59 - 3.43 (m, 1H), 2.94 (t, J = 11.9Hz, 1H), 2.74 - 2.60 (m, 2H), 1.94 - 1.76 (m, 1H), 1.74 - 1.66 (m, 2H), 1.18 - 1.14 (m, 6H), 0.84 - 0.78 (m, 3H).

[0243] 5-Chloro-2-((3S,4R,5R)-4-fluoro-3-hydroxy-5-methylpiperidin-1-yl)-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (50) and 5-chloro-2-((3R,4S,5S)-4-fluoro-3-hydroxy-5-methylpiperidin-1-yl)-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (51).

[0244] Racemic 5-chloro-2-((3S,4R,5R)-4-fluoro-3-hydroxy-5-methylpiperidin-1-yl)-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (80 mg, 154.59 μmol) was purified by SFC (ChiralPak column). The resulting solution was purified by IH, 250*30mm, 10μm; mobile phase: [Neu-IPA]; B%: 45%~45%, 10min) to give 5-chloro-2-((3S,4R,5R)-4-fluoro-3-hydroxy-5-methylpiperidin-1-yl)-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile as a white solid (30mg, 5 as 7.45 μmol, 30% yield, 99% purity) and 5-chloro-2-((3R,4S,5S)-4-fluoro-3-hydroxy-5-methylpiperidin-1-yl)-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile as a white solid (30 mg, 56.00 μmol, 29% yield, 96% purity).

[0245] 50: 1 H NMR (400MHz, DMSO-d 6)δ=8.94(s,1H),7.92(s,1H),7.32(d,J=1.5Hz,1H),7.28-7.21(m,1H),7.10(d,J=8.3Hz,1H),5.76(s,1H),5.27( d,J=5.9Hz,1H),4.64-4.48(m,1H),4.47(s,1H),4.17-4.05(m,1H),3.95-3.80(m,3H),3.59-3.42(m,1H),3.30(br s,1H),2.95(t,J=12.0Hz,1H),2.74-2.65(m,1H),2.34(s,1H),1.96-1.76(m,1H),1.74-1.61(m,2H),1.17(s,6H),0.82(d,J=6.9Hz,3H).

[0246] 51: 1 H NMR (400MHz, DMSO-d 6 )δ=8.93(s,1H),7.92(s,1H),7.32(d,J=1.6Hz,1H),7.24(dd,J=1.7, 8.3Hz,1H),7.09(d,J=8.4Hz,1H),5.26(d,J=6.0Hz,1H),4.65-4.47(m,1H ),4.46(s,1H),4.15-4.06(m,1H),3.94-3.79(m,3H),3.60-3.42(m,1H),3 .29(s,1H),2.94(t,J=11.9Hz,1H),2.76-2.62(m,2H),2.36-2.29(m,1H), 1.98-1.76(m,1H),1.75-1.64(m,2H),1.16(s,6H),0.81(d,J=6.9Hz,3H).

[0247] The absolute configurations of compounds 50 and 51 were randomly assigned on the basis that all substituents on the piperidine ring were in the cis-conformation.

[0248] Example 8: Synthesis of 5-fluoro-2-[(3S,4R,5S)-4-fluoro-3-hydroxy-5-methyl-1-piperidyl]-6-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyridine-3-carbonitrile (52) and 5-fluoro-2-[(3R,4S,5S)-4-fluoro-3-hydroxy-5-methyl-1-piperidyl]-6-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyridine-3-carbonitrile (53) [ka]

[0249] 2-Chloro-5-fluoro-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile

[0250] A mixture of 5-amino-3-(3-hydroxy-3-methylbutyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one (10 g, 40.11 mmol) and 2,6-dichloro-5-fluoro-pyridine-3-carbonitrile (7.66 g, 40.11 mmol) in DMSO (100 mL) was diluted with N 2 Under reduced pressure, DIEA (10.37 g, 80.22 mmol, 13.97 mL) was added in one portion. The mixture was stirred at 100° C. for 1.3 h. Water (150 mL) was added to the mixture, the resulting suspension was filtered, and the filter cake was dried under reduced pressure to afford the crude title compound as a white solid (16 g, crude), which was used without further purification. 1 H NMR (400 MHz, DMSO-d 6) δ ppm 9.95 (s, 1H), 8.02 - 8.24 (m, 1H), 7.51 (d, J = 3.00 Hz, 1H), 7.25 - 7.35 (m, 1H), 7.13 (dd, J = 8.38, 5.13 Hz, 1H), 4.44 (d, J M+H + = 404.1.

[0251] 5-Fluoro-2-((3S,4R,5R)-4-fluoro-3-hydroxy-5-methylpiperidin-1-yl)-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile

[0252] 2-Chloro-5-fluoro-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (300 mg, 742.87 μmol), 4-fluoro-5-methyl-piperidin-3-ol (367.26 mg, 1.49 mmol, TFA) and Cs 2 CO 3 To a suspension of (2.42 g, 7.43 mmol) in dioxane (6 mL) was added rac-BINAP-Pd-G3 (73.72 mg, 74.29 μmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h. The mixture was filtered and the filtrate was concentrated and then purified by preparative HPLC to give the title compound as a white solid (60 mg, 114.01 μmol, 15% yield, 95% purity). 1 H NMR (400 MHz, DMSO-d 6) δ ppm 9.41 (s, 1H), 7.77 (d, J = 10.88 Hz, 1H), 7.44 (s, 1H), 7.38 (d, J = 8.31 Hz, 1H), 7.08 (d, J = 8.44 Hz, 1H), 5.27 (d, J = 5.87 Hz, 1H), 4.50 - 4.66 (m, 1H), 4.47 (s, 1H), 4.02 (dd, J = 12.41, 4.71 Hz, 1H), 3.85 - 3.91 (m, 2H), 3.80 (br dd, J = 12.72, 3.30 Hz, 1H), 3.50 - 3.66 (m, 1H), 2.96 (t, J = 11.80 Hz, 1H), 2.74 (t, J = 12.47 Hz, 1H), 1.85 - 2.02 (m, 1H), 1.66 - 1.73 (m, 2H), 1.16 (s, 6H), 0.91 (d, J = 6.85 Hz, 3H).

[0253] 5-Fluoro-2-((3S,4R,5R)-4-fluoro-3-hydroxy-5-methylpiperidin-1-yl)-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (52)

[0254] 5-Fluoro-2-((3S,4R,5R)-4-fluoro-3-hydroxy-5-methylpiperidin-1-yl)-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (70 mg, 139.85 μmol) was separated by SFC to give the title compound as a yellow solid (25.7 mg, 50.83 μmol, 36% yield, 99% purity). 1 H NMR (400 MHz, MeCN-d 3) δ ppm 7.76 (s, 1H), 7.55 (d, J = 1.83 Hz, 1H), 7.44 (d, J = 10.64 Hz, 1H), 7.20 (dd, J = 8.44, 1.96 Hz, 1H), 7.00 (d, J = 8.44 Hz, 1H), 4.55 - 4.72 (m, 1H), 4.10 (dd, J = 12.10, 3.18 Hz, 1H), 3.90 - 4.02 (m, 2H), 3.82 - 3.90 (m, 1H), 3.61 - 3.77 (m, 2H), 3.33 (s, 3H), 2.97 - 3.06 (m, 2H), 2.84 (t, J = 12.53 Hz, 1H), 1.98 - 2.11 (m, 1H), 1.80 (t, J = 7.95 Hz, 2H), 1.22 (d, J = 2.81 Hz, 6H), 0.99 (d, J = 6.97 Hz, 3H). M+H + = 501.3.

[0255] 5-Fluoro-2-((3R,4S,5S)-4-fluoro-3-hydroxy-5-methylpiperidin-1-yl)-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (53)

[0256] 5-Fluoro-2-((3S,4R,5R)-4-fluoro-3-hydroxy-5-methylpiperidin-1-yl)-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (70 mg, 139.85 μmol) was separated by SFC to give the title compound as a yellow solid (24.8 mg, 49.05 μmol, 35% yield, 99% purity). 1 H NMR (400 MHz, MeCN-d 3) δ ppm 7.76 (s, 1H), 7.55 (d, J = 1.83 Hz, 1H), 7.45 (d, J = 10.76 Hz, 1H), 7.20 (dd, J = 8.38, 1.90 Hz, 1H), 7.00 (d, J = 8.31 Hz, 1H), 4.54 - 4.72 (m, 1H), 4.06 - 4.15 (m, 1H), 3.90 - 4.02 (m, 2H), 3.86 (dd, J = 13.20, 3.18 Hz, 1H), 3.59 - 3.78 (m, 2H), 3.33 (s, 3H), 2.99 - 3.06 (m, 1H), 2.98 (s, 1H), 2.84 (t, J = 12.53 Hz, 1H), 1.98 - 2.12 (m, 1H), 1.77 - 1.84 (m, 2H), 1.22 (d, J = 2.69 Hz, 6H), 0.99 (d, J = 6.97 Hz, 3H).M+H + = 501.3.

[0257] The absolute configurations of compounds 52 and 53 were randomly assigned based on the fact that all substituents on the piperidine ring are in the cis conformation.

[0258] Example 9: Synthesis of 5-fluoro-2-((3S,4R,5R)-4-fluoro-3,5-dimethylpiperidin-1-yl)-6-((3-((S)-3-hydroxybutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (54) and 5-fluoro-2-((3S,4S,5R)-4-fluoro-3,5-dimethylpiperidin-1-yl)-6-((3-((R)-3-hydroxybutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (55) [ka]

[0259] 3-Hydroxybutyl 4-methylbenzenesulfonate

[0260] To a mixture of butane-1,3-diol (25 g, 277.41 mmol, 51.23 mL) in DCM (500 mL), 2 Under the conditions below, DMAP (3.39 g, 27.74 mmol) and TEA (56.14 g, 554.81 mmol, 77.22 mL) were added in one portion. Then, 4-methylbenzenesulfonyl chloride (52.89 g, 277.41 mmol) was added slowly at 0° C. The mixture was stirred at 20° C. for 12 h. The mixture was poured into saturated NaHCO3 (500 mL) and extracted with DCM (500 mL×3). The combined organic layer was washed with brine (1.2 L) and diluted with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=10 / 1 to 2 / 1) to give the title compound as a purple oil (58 g, 227.71 mmol, 41% yield, 96% purity). 1 H NMR (400 MHz, CDCl 3 ) δ 7.73 (br d, J = 7.83 Hz, 2H), 7.30 (br d, J = 7.82 Hz, 2H), 4.11 - 4.25 (m, 1H), 4.00 - 4.11 (m, 1H), 3.78 - 3.93 (m, 1H), 2.39 (s, 3H), 1.58 - 2.06 (m, 3H), 1.11 (br d, J = 6.11 Hz, 3H).

[0261] 3-Hydroxybutyl 4-methylbenzenesulfonate

[0262] To a mixture of butane-1,3-diol (25 g, 277.41 mmol, 51.23 mL) in DCM (500 mL), 2Under the conditions below, DMAP (3.39 g, 27.74 mmol) and TEA (56.14 g, 554.81 mmol, 77.22 mL) were added in one portion. Then, 4-methylbenzenesulfonyl chloride (52.89 g, 277.41 mmol) was added slowly at 0° C. The mixture was stirred at 20° C. for 12 h. The mixture was diluted with saturated NaHCO 3 (500 mL) and extracted with DCM (500 mL x 3). The combined organic layers were washed with brine (1.2 L) and anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=10 / 1 to 2 / 1) to give the title compound as a purple oil (58 g, 227.71 mmol, 41% yield, 96% purity). 1 H NMR (400 MHz, CDCl 3 ) δ 7.73 (br d, J = 7.83 Hz, 2H), 7.30 (br d, J = 7.82 Hz, 2H), 4.11 - 4.25 (m, 1H), 4.00 - 4.11 (m, 1H), 3.78 - 3.93 (m, 1H), 2.39 (s, 3H), 1.58 - 2.06 (m, 3H), 1.11 (br d, J = 6.11 Hz, 3H).

[0263] 3-(3-hydroxybutyl)-1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H),-one

[0264] A solution of 3-methyl-6-nitro-1H-benzimidazol-2-one (3 g, 15.53 mmol) and 3-hydroxybutyl 4-methylbenzenesulfonate (7.59 g, 31.06 mmol) in DMSO (30 mL) was added to the reaction mixture. 2 CO 3 (10.12 g, 31.06 mmol) and KI (1.29 g, 7.77 mmol) were added. The flask was degassed and filled with N 2 Purge the mixture three times with N 2The mixture was stirred at 100° C. for 12 hours under atmospheric pressure. Water (50 mL) was added to the mixture. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration gave a residue which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=10:1 to 1:1) and then triturated with petroleum ether / ethyl acetate=3:1 (15 mL) for 15 min to give the title compound as a yellow solid (2 g, 6.26 mmol, 40% yield, 83% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 1.09 (d, J = 6.25 Hz, 3H), 1.61 - 1.77 (m, 2H), 3.40 (s, 3H), 3.57 - 3.67 (m, 1H), 3.93 - 4.03 (m, 2H), 4.63 (d, J = 4.88 Hz, 1H), 7.35 (d, J = 8.63 Hz, 1H), 8.04 - 8.07 (m, 1H), 8.08 (d, J = 2.13 Hz, 1H).

[0265] 5-Amino-3-(3-hydroxybutyl)-1-methyl-1H-benzo[d]imidazol-2(3H),-one

[0266] To a solution of Pd / C (0.5 g, 10% purity) in DMF (20 mL) was added 3-(3-hydroxybutyl)-1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one (2 g, 7.54 mmol) under Ar. The mixture was cooled to 37° C. for 1 h. 2 (15 psi) at 50° C. for 12 h. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a grey solid (1.7 g, 6.86 mmol, 91% yield, 95% purity) which was used without further purification. 1 H NMR (400 MHz, DMSO-d 6) δ ppm 1.09 (d, J = 6.11 Hz, 3H), 1.56 - 1.68 (m, 2H), 3.22 (s, 3H), 3.61 (br s, 1H), 3.68 - 3.85 (m, 2H), 4.64 (br d, J = 3.55 Hz, 1H), 4.78 (br s, 2H), 6.31 (dd, J = 8.31, 1.71 Hz, 1H), 6.41 (d, J = 1.59 Hz, 1H), 6.79 (d, J = 8.19 Hz, 1H).

[0267] 2-Chloro-5-fluoro-6-((3-(3-hydroxybutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile

[0268] To a solution of 5-amino-3-(3-hydroxybutyl)-1-methyl-benzimidazol-2-one (200 mg, 850.05 μmol) and 2,6-dichloro-5-fluoro-pyridine-3-carbonitrile (194.82 mg, 1.02 mmol) in DMSO (2 mL) was added DIPEA (219.72 mg, 1.70 mmol, 296.13 μL). The mixture was stirred at 100° C. for 12 hours. The mixture was poured into water (5 mL) and stirred for 10 minutes. The mixture was filtered and the filter cake was washed with ethyl acetate (3 mL). The filter cake was dried in vacuum to give the title compound as a yellow solid (300 mg, 644.26 μmol, 84% yield, 84% purity). 1 H NMR (400 MHz, DMSO-d 6) δ 9.94 (s, 1H), 8.11 (d, J = 10.63 Hz, 1H), 7.50 (d, J = 1.38 Hz, 1H), 7.29 (dd, J = 8.44, 1.56 Hz, 1H), 7.12 (d, J = 8.38 Hz, 1H), 4.63 (d, J = 4.63 Hz, 1H), 3.74 - 3.96 (m, 2H), 3.57 - 3.71 (m, 1H), 3.32 (s, 3H), 1.59 - 1.80 (m, 2H), 1.10 (d, J = 6.13 Hz, 3H).

[0269] (S)-2-chloro-5-fluoro-6-((3-(3-hydroxybutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile and (R)-2-chloro-5-fluoro-6-((3-(3-hydroxybutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile.

[0270] The residue was purified by preparative HPLC (neutral conditions; column: Phenomenex C18 80*40mm*3μm; mobile phase: [water (NH 4 HCO 3 The residue was purified by SFC (conditions: column: REGIS(S,S)WHELK-O1 (250mm*25Mm, 10μm); mobile phase: [0.1% NH in IPA]. 3 H 2Further separation by HPLC using a HPLC-HPLC system (HPLC-HPLC: ... 1 H NMR (400 MHz, MeOD-d 4 ) δ ppm 7.72 - 7.80 (m, 1H), 7.68 (s, 1H), 7.35 (br d, J = 8.25 Hz, 1H), 7.13 (br d, J = 8.25 Hz, 1H), 4.02 (br t, J = 7.00 Hz, 2H), 3.78 (br d, J = 4.38 Hz, 1H), 3.43 (s, 3H), 1.97 - 2.10 (m, 1H), 1.74 - 1.97 (m, 2H), 1.27 - 1.39 (m, 1H), 1.22 (br d, J = 6.00 Hz, 3H).

[0271] 5-Fluoro-2-((3S,4R,5R)-4-fluoro-3,5-dimethylpiperidin-1-yl)-6-((3-((S)-3-hydroxybutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (54)

[0272] To a mixture of (S)-2-chloro-5-fluoro-6-((3-(3-hydroxybutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (40 mg, 102.61 μmol) and (3S,4S,5R)-4-fluoro-3,5-dimethyl-piperidine (37.74 mg, 153.92 μmol, TFA) in DMSO (0.5 mL), N2 DIEA (26.52 mg, 205.23 μmol, 35.75 μL) was added under the conditions described above. The mixture was stirred at 100° C. for 12 hours. The residue was analyzed by preparative HPLC (neutral conditions; column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 25% to 55%, 8 min) to give the title compound as a white solid (16 mg, 33.02 μmol, yield 32%, purity 100%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.37 (s, 1H), 7.76 (d, J = 11.00 Hz, 1H), 7.50 (d, J = 1.71 Hz, 1H), 7.37 (dd, J = 8.44, 1.83 Hz, 1H), 7.09 (d, J = 8.44 Hz, 1H), 4.54 - 4.64 (m, 2H), 4.45 (s, 1H), 3.76 - 3.98 (m, 4H), 3.55 - 3.68 (m, 1H), 2.80 (t, J = 12.59 Hz, 2H), 1.77 - 1.98 (m, 2H), 1.54 - 1.77 (m, 2H), 1.08 (d, J = 6.11 Hz, 3H), 0.90 (dd, J = 6.85, 2.57 Hz, 6H).

[0273] 5-Fluoro-2-((3S,4S,5R)-4-fluoro-3,5-dimethylpiperidin-1-yl)-6-((3-((R)-3-hydroxybutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (55)

[0274] To a mixture of (R)-2-chloro-5-fluoro-6-((3-(3-hydroxybutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (40 mg, 102.61 μmol) and (3S,4S,5R)-4-fluoro-3,5-dimethyl-piperidine (37.74 mg, 153.92 μmol, TFA) in DMSO (0.5 mL), N 2 DIEA (26.52 mg, 205.22 umol, 35.75 μL) was added under the above conditions. The mixture was stirred at 100° C. for 12 hours. The residue was analyzed by preparative HPLC (neutral conditions; column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 25% to 55%, 8 min) to give the title compound as a white solid (9.5 mg, 19.61 μmol, 19% yield, 100% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.38 (s, 1H), 7.76 (d, J = 11.00 Hz, 1H), 7.50 (d, J = 1.83 Hz, 1H), 7.37 (dd, J = 8.44, 1.83 Hz, 1H), 7.09 (d, J = 8.44 Hz, 1H), 4.55 - 4.68 (m, 2H), 4.45 (s, 1H), 3.76 - 3.99 (m, 4H), 3.55 - 3.70 (m, 1H), 2.80 (br t, J = 12.59 Hz, 2H), 1.55 - 2.03 (m, 4H), 1.05 - 1.11 (m, 3H), 0.90 (dd, J = 6.91, 2.51 Hz, 6H).

[0275] The absolute configurations of compounds 54 and 55 were randomly assigned on the basis that all substituents on the piperidine ring were in the cis-conformation.

[0276] Example 10: Synthesis of 5-fluoro-2-[(3R,4R,5S)-4-fluoro-3-(2-hydroxyethyl)-5-methyl-1-piperidyl]-6-[[3-(3-hydroxybutyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyridine-3-carbonitrile (56) and 5-fluoro-2-[(3S,4S,5R)-4-fluoro-3-(2-hydroxyethyl)-5-methyl-1-piperidyl]-6-[[3-(3-hydroxybutyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyridine-3-carbonitrile (57) [ka]

[0277] Methyl 2-(1-benzyl-5-methyl-4-oxopiperidin-3-yl)acetate

[0278] To a mixture of 1-benzyl-3-methyl-piperidin-4-one (25 g, 122.98 mmol) in THF (250 mL) was added LDA (2M, 79.94 mL) dropwise at -65°C, the mixture was stirred at -65°C for 30 min, then HMPA (28.65 g, 159.88 mmol, 28.09 mL) was added dropwise, the mixture was stirred at -65°C for 30 min. Then 2-bromoacetate methyl (24.46 g, 159.88 mmol, 15.10 mL) was added dropwise. The mixture was warmed to 15°C and stirred for 12 h. Water (600 mL) was then added to the mixture (combined with another batch of the same scale) and extracted with EtOAc (800 mL x 3). The combined organic layers were washed with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give the title compound as a yellow solid (40 g, 116.22 mmol, yield 47%, purity 80%). 1 H NMR (400 MHz, DMSO-d 6) δ 7.37 - 7.27 (m, 5H), 3.66 - 3.62 (m, 2H), 3.59 - 3.54 (m, 3H), 3.20 - 3.01 (m, 3H), 2.78 (td, J = 6.1, 11.8 Hz, 1H), 2.56 (d, J = 7.6 Hz, 1H), 2.24 - 1.99 (m, 3H), 0.83 (d, J = 6.6 Hz, 3H)

[0279] 1-Benzyl-3-(2-hydroxyethyl)-5-methylpiperidin-4-ol

[0280] To a solution of methyl 2-(1-benzyl-5-methyl-4-oxo-3-piperidyl)acetate (10 g, 36.32 mmol) in THF (100 mL) was added LAH (2.76 g, 72.64 mmol) at 0° C. The mixture was stirred at 20° C. for 1 h. To the mixture was added water (3 mL) and 2M NaOH (3 mL) at 0° C. The mixture was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and stirred for 20 min at 15° C. The mixture was then filtered and the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (9 g, crude). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.35 - 7.20 (m, 7H), 4.62 (d, J = 6.5 Hz, 1H), 4.44 (t, J = 5.0 Hz, 1H), 3.52 - 3.42 (m, 2H), 2.85 (br d, J = 10.3 Hz, 1H), 2.70 - 2.64 (m, 1H), 1.87 - 1.77 (m, 1H), 1.69 - 1.41 (m, 5H), 1.14 - 1.07 (m, 1H), 0.83 (d, J = 6.4 Hz, 3H).

[0281] 1-Benzyl-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-methyl-piperidin-4-ol

[0282] To a solution of 1-benzyl-3-(2-hydroxyethyl)-5-methyl-piperidin-4-ol (5.00 g, 20.05 mmol) in DCM (60 mL) was added TBDPSCl (6.06 g, 22.06 mmol, 5.66 mL), DMAP (734.93 mg, 6.02 mmol) and TEA (10.15 g, 100.26 mmol, 13.96 mL). The mixture was stirred at 15° C. for 4 h. After adding water (100 mL), the solution was extracted with EtOAc (100 mL×3). The combined organic phase was washed with brine (100 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo to give a residue which was purified by flash silica gel column chromatography (silica flash column, eluent of 0-30% ethyl acetate / petroleum ether gradient) to give the title compound as a yellow oil (7.5 g, 14.11 mmol, 70% yield, 92% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.71 - 7.54 (m, 4H), 7.46 - 7.36 (m, 6H), 7.33 - 7.18 (m, 4H), 4.50 (d, J = 6.7 Hz, 1H), 4.03 (q, J = 7.1 Hz, 1H), 3.70 - 3.55 (m, 2H), 3.41 - 3.29 (m, 3H), 2.90 - 2.63 (m, 2H), 2.06 - 1.95 (m, 1H), 1.68 - 1.48 (m, 3H), 1.29 - 1.12 (m, 1H), 1.01 - 0.91 (m, 9H), 0.83 (d, J = 6.4 Hz, 3H).

[0283] 1-benzyl-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-fluoro-5-methylpiperidine

[0284] To a solution of 1-benzyl-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-methyl-piperidin-4-ol (5.00 g, 10.25 mmol) in DCM (50 mL) was added DAST (3.30 g, 20.50 mmol, 2.71 mL) at -65°C. The mixture was stirred at -70°C for 0.5 h and at 15°C for 11.5 h. Saturated NaHCO 3 (50 mL) was added to the mixture and extracted with DCM (50 mL x 3). The combined organic phase was washed with anhydrous Na 2 SO 4 The residue was purified by flash silica gel column chromatography (silica flash column, eluent of 0-30% ethyl acetate / petroleum ether gradient) to give the title compound as a yellow oil (3.3 g, 6.71 mmol, 65% yield, 99% purity). 1 H NMR (400 MHz, CDCl 3 ) δ 7.69 - 7.62 (m, 4H), 7.44 - 7.36 (m, 5H), 7.33 - 7.27 (m, 5H), 3.81 - 3.59 (m, 3H), 3.56 - 3.39 (m, 2H), 3.06 - 2.76 (m, 2H), 2.08 - 1.88 (m, 3H), 1.80 - 1.62 (m, 2H), 1.44 - 1.31 (m, 1H), 1.04 (s, 9H), 0.96 (d, J = 6.5 Hz, 3H).

[0285] 2-[(3R,4R,5S)-1-benzyl-4-fluoro-5-methyl-3-piperidyl]ethoxy-tert-butyl-diphenyl-silane (Intermediate 3) and 2-[(3S,4S,5R)-1-benzyl-4-fluoro-5-methyl-3-piperidyl]ethoxy-tert-butyl-diphenyl-silane (Intermediate 4)

[0286] Racemic 1-benzyl-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-fluoro-5-methylpiperidine was purified by SFC (column: DAICEL CHIRALCEL OD (250mm*50mm, 10μm); mobile phase: [0.1%NH 3 H 2 Purification by ethyl acetate (O, IPA); B%: 25% to 25%, 5 min) gave 2-[(3R,4R,5S)-1-benzyl-4-fluoro-5-methyl-3-piperidyl]ethoxy-tert-butyl-diphenyl-silane as a white solid (1.5 g, 3.03 mmol, 45% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.60 - 7.54 (m, 4H), 7.48 - 7.37 (m, 6H), 7.33 - 7.21 (m, 5H), 3.89 - 3.68 (m, 1H), 3.64 (t, J = 6.3 Hz, 2H), 3.48 - 3.38 (m, 2H), 2.96 - 2.85 (m, 1H), 2.80 - 2.70 (m, 1H), 1.98 - 1.75 (m, 3H), 1.74 - 1.64 (m, 2H), 1.40 - 1.29 (m, 1H), 0.95 (s, 9H), 0.88 (d, J = 6.2 Hz, 3H) and 2-[(3S,4S,5R)-1-benzyl-4-fluoro-5-methyl-3-piperidyl]ethoxy-tert-butyl-diphenyl-silane were obtained as a white solid (1.5 g, 3.03 mmol, 45% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d 6) δ 7.60 - 7.53 (m, 4H), 7.48 - 7.37 (m, 6H), 7.33 - 7.20 (m, 5H), 3.88 - 3.69 (m, 1H), 3.64 (t, J = 6.3 Hz, 2H), 3.43 (d, J = 0.7 Hz, 2H), 2.96 - 2.70 (m, 2H), 2.00 - 1.75 (m, 3H), 1.74 - 1.66 (m, 2H), 1.41 - 1.28 (m, 1H), 0.95 (s, 9H), 0.88 (d, J = 6.3 Hz, 3H).

[0287] 2-[(3R,4R,5S)-1-Benzyl-4-fluoro-5-methyl-3-piperidyl]ethanol

[0288] A solution of 2-[(3R,4R,5S)-1-benzyl-4-fluoro-5-methyl-3-piperidyl]ethoxy-tert-butyl-diphenyl-silane (1.5 g, 3.06 mmol) in HCl / MeOH (50 mL) was stirred at 15° C. for 8 h. Saturated NaHCO 3 After adding aqueous solution (30 mL), the solution was extracted with EtOAc (30 mL×3). The combined organic phase was washed with brine (30 mL) and anhydrous Na 2 SO 4 Drying at rt, filtering and concentrating in vacuo afforded the title compound as a yellow oil (600 mg, 2.39 mmol, 78% yield, 100% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.35 - 7.21 (m, 5H), 4.40 (t, J = 5.1 Hz, 1H), 3.88 - 3.63 (m, 1H), 3.55 - 3.46 (m, 1H), 3.44 - 3.31 (m, 4H), 2.99 - 2.85 (m, 1H), 2.78 - 2.65 (m, 1H), 1.81 - 1.61 (m, 4H), 1.30 - 1.13 (m, 1H), 0.88 (d, J = 6.4 Hz, 3H).

[0289] 2-[(3R,4R,5S)-4-Fluoro-5-methyl-3-piperidyl]ethanol

[0290] To a solution of 2-[(3R,4R,5S)-1-benzyl-4-fluoro-5-methyl-3-piperidyl]ethanol (600 mg, 2.39 mmol) in EtOH (40 mL) was added Pd / C (300 mg, 10% purity) under an Ar atmosphere. The flask was degassed and diluted with H 2 The mixture was purged with H 2 The mixture was stirred under (15 Psi) at 60° C. for 12 h. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to give the title compound as a grey oil (200 mg, 372.17 μmol, 16% yield, 30% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 4.43 (br dd, J = 6.5, 11.8 Hz, 1H), 3.54 - 3.35 (m, 3H), 3.34 - 3.21 (m, 1H), 2.82 - 2.61 (m, 2H), 2.13 - 1.88 (m, 2H), 1.81 (dtd, J = 4.2, 6.7, 13.8 Hz, 1H), 1.39 - 1.29 (m, 1H), 1.22 (t, J = 7.3 Hz, 1H), 1.05 (t, J = 7.0 Hz, 1H), 1.01 - 0.95 (m, 3H).

[0291] 5-Fluoro-2-[(3R,4R,5S)-4-fluoro-3-(2-hydroxyethyl)-5-methyl-1-piperidyl]-6-[[3-(3-hydroxybutyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyridine-3-carbonitrile (50)

[0292] To a solution of 2-chloro-5-fluoro-6-[[3-(3-hydroxybutyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyridine-3-carbonitrile (20 mg, 51.31 μmol) in DMSO (1 mL) was added 2-[(3R,4R,5S)-4-fluoro-5-methyl-3-piperidyl]ethanol (8.27 mg, 51.31 μmol) and DIEA (26.52 mg, 205.24 μmol, 35.75 μL). The mixture was stirred at 100° C. for 2 h. The solution was filtered and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 10% to 40%, 8 min) to give the title compound as a yellow solid (3 mg, 5.36 μmol, 10% yield, 92% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.39 (br s, 1H), 7.78 (br d, J = 10.9 Hz, 1H), 7.52 - 7.31 (m, 2H), 7.14 - 7.00 (m, 1H), 4.62 (br d, J = 4.0 Hz, 1H), 4.49 - 4.37 (m, 1H), 4.29 - 4.14 (m, 1H), 4.08 - 4.00 (m, 1H), 3.98 - 3.90 (m, 1H), 3.89 - 3.78 (m, 2H), 3.62 (br d, J = 1.5 Hz, 1H), 3.47 - 3.36 (m, 3H), 2.78 - 2.69 (m, 1H), 2.67 - 2.60 (m, 1H), 1.82 - 1.62 (m, 6H), 1.37 - 1.25 (m, 2H), 1.09 (br d, J = 5.5 Hz, 3H), 0.92 (br s, 3H).

[0293] 2-[(3S,4S,5R)-1-Benzyl-4-fluoro-5-methyl-3-piperidyl]ethanol

[0294] A solution of 2-[(3S,4S,5R)-1-benzyl-4-fluoro-5-methyl-3-piperidyl]ethoxy-tert-butyl-diphenyl-silane (1.5 g, 3.06 mmol) in HCl / MeOH (1.25 M, 50 mL) was stirred at 15° C. for 8 h. Saturated NaHCO 3 After adding aqueous solution (30 mL), the solution was extracted with EtOAC (30 mL×3). The combined organic phase was washed with brine (30 mL) and anhydrous Na 2 SO 4 Drying at rt, filtration and concentration in vacuo afforded the crude title compound as a yellow oil (400 mg, 1.59 mmol, 52% yield, 100% purity) which was used without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.39 - 7.20 (m, 5H), 4.40 (t, J = 5.1 Hz, 1H), 3.90 - 3.65 (m, 1H), 3.56 - 3.47 (m, 1H), 3.42 - 3.31 (m, 4H), 2.98 - 2.67 (m, 2H), 1.81 - 1.61 (m, 4H), 1.30 - 1.14 (m, 1H), 0.89 (d, J = 6.4 Hz, 3H). M+H + = 252.1.

[0295] 2-[(3S,4S,5R)-4-Fluoro-5-methyl-3-piperidyl]ethanol

[0296] To a solution of 2-[(3S,4S,5R)-1-benzyl-4-fluoro-5-methyl-3-piperidyl]ethanol (400 mg, 1.59 mmol) in EtOH (5 mL) was added Pd / C (50 mg, 10% purity) under an argon atmosphere. The suspension was degassed and diluted with H 2 The mixture was purged with H 2 The mixture was stirred under (15 Psi) at 60° C. for 12 h. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated under reduced pressure to give the crude title compound as a grey oil (200 mg, crude), which was used without further purification. 1 H NMR (400 MHz, DMSO-d6 ) δ 4.48 - 4.38 (m, 1H), 4.23 - 4.02 (m, 1H), 3.53 - 3.38 (m, 3H), 3.33 - 3.22 (m, 1H), 2.85 - 2.60 (m, 2H), 2.12 - 1.90 (m, 2H), 1.81 (dtd, J = 4.2, 6.8, 13.8 Hz, 1H), 1.41 - 1.29 (m, 1H), 1.26 - 1.19 (m, 1H), 1.06 (t, J = 7.0 Hz, 1H), 1.02 - 0.96 (m, 3H).

[0297] 5-Fluoro-2-[(3S,4S,5R)-4-fluoro-3-(2-hydroxyethyl)-5-methyl-1-piperidyl]-6-[[3-(3-hydroxybutyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyridine-3-carbonitrile (56)

[0298] To a solution of 2-chloro-5-fluoro-6-[[3-(3-hydroxybutyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyridine-3-carbonitrile (20 mg, 51.31 μmol) in DMSO (1 mL) was added 2-[(3S,4S,5R)-4-fluoro-5-methyl-3-piperidyl]ethanol (14.12 mg, 87.60 μmol) and DIEA (26.52 mg, 205.24 μmol, 35.75 μL). The mixture was stirred at 100° C. for 2 h. The solution was filtered and the filtrate was concentrated under vacuum to give a residue which was purified by preparative HPLC to give the title compound as a yellow solid (5 mg, 8.94 μmol, 17% yield, 92% purity). 1 H NMR (400 MHz, DMSO-d 6) δ 9.39 (s, 1H), 7.77 (d, J = 10.9 Hz, 1H), 7.49 (dd, J = 1.9, 2.9 Hz, 1H), 7.39 (br d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 4.62 (d, J = 4.6 Hz, 1H), 4.48 - 4.40 (m, 1H), 4.28 - 4.18 (m, 1H), 4.08 - 4.01 (m, 1H), 3.98 - 3.91 (m, 1H), 3.90 - 3.78 (m, 2H), 3.62 (br s, 1H), 3.46 - 3.37 (m, 3H), 2.73 (br t, J = 12.3 Hz, 1H), 2.68 - 2.60 (m, 1H), 1.84 - 1.62 (m, 6H), 1.37 - 1.22 (m, 2H), 1.09 (d, J = 6.1 Hz, 3H), 0.93 (dd, J = 2.4, 6.4 Hz, 3H). M+H + = 515.3.

[0299] The absolute configurations of compounds 56 and 57 were randomly assigned based on the cis conformation of the amino and methyl groups.

[0300] Example 11: Synthesis of 2-((6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-1-(2-(dimethylamino)ethyl)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (11) [ka]

[0301] 3-Hydroxy-6-nitroquinolin-2(1H)-one

[0302] To a mixture of 5-nitroindoline-2,3-dione (20 g, 104.10 mmol) and TEA (21.07 g, 208.19 mmol, 28.98 mL) in EtOH (600 mL) was added TMSCHN 2 (2M, 62.46 mL) was added dropwise at 20° C. The reaction mixture was stirred at 20° C. for 12 h and concentrated under vacuum. 1N HCl (600 mL) was then added to the concentrated reaction mixture and stirred for 3 h. The resulting suspension was filtered and the filter cake was collected and dried under vacuum to give the title compound as an orange-red solid (40 g, crude). 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.54 (s, 1H), 10.38 - 9.71 (m, 1H), 8.51 (d, J = 2.4 Hz, 1H), 8.13 (dd, J = 2.4, 9.2 Hz, 1H), 7.39 (d, J = 9.2 Hz, 1H), 7.31 (s, 1H).

[0303] Methyl 2-((6-nitro-2-oxo-1,2-dihydroquinolin-3-yl)oxy)acetate

[0304] To a solution of 3-hydroxy-6-nitro-1H-quinolin-2-one (20 g, 97.01 mmol) in DMSO (200 mL) was added DBU (17.72 g, 116.42 mmol, 17.55 mL) followed by methyl 2-bromoacetate (17.81 g, 116.42 mmol, 10.99 mL) and the resulting mixture was stirred at 100° C. for 3 h. The reaction mixture was treated with water (600 mL), which caused a precipitate to form. The suspension was filtered, the filter cake was washed with EtOAc (800 mL) and the solid was dried in vacuum to give the title compound as an orange-red solid (26 g, crude). 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.51 (s, 1H), 8.54 (d, J = 2.4 Hz, 1H), 8.20 - 8.17 (m, 1H), 7.49 (s, 1H), 7.39 (d, J = 9.2 Hz, 1H), 4.89 (s, 2H), 3.77 - 3.71 (s, 3H).

[0305] Methyl 2-((6-amino-2-oxo-1,2-dihydroquinolin-3-yl)oxy)acetate

[0306] To a solution of methyl 2-[(6-nitro-2-oxo-1H-quinolin-3-yl)oxy]acetate (16 g, 57.51 mmol) in DMF (200 mL) was added Pd / C (5 g, 10% purity) under Ar atmosphere. The flask was degassed and quenched with H 2 The mixture was purged with H 2 (50 psi) for 12 h at 50° C. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as an off-white solid (12 g, crude). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.60 (s, 1H), 7.95 (s, 1H), 7.03 - 6.98 (m, 2H), 6.72 (dd, J = 2.4, 8.8 Hz, 1H), 6.68 (d, J = 2.0 Hz, 1H), 6.05 - 5.39 (m, 2H), 4.83 (s, 2H), 3.71 (s, 3H).

[0307] Methyl 2-((6-((3,6-dichloro-5-cyanopyridin-2-yl)amino)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)acetate

[0308] To a mixture of methyl 2-[(6-amino-2-oxo-1H-quinolin-3-yl)oxy]acetate (3 g, 12.09 mmol) and 2,5,6-trichloropyridine-3-carbonitrile (2.51 g, 12.09 mmol) in DMF (30 mL) was added DIPEA (3.12 g, 24.17 mmol, 4.21 mL) and the reaction mixture was stirred at 100° C. for 4 h. The mixture was cooled to 15° C. and water (ca. 50 mL) was added, forming a precipitate. The mixture was filtered and the filter cake was washed with EtOAc (ca. 80 mL) and dried under vacuum to give the title compound as a brown solid (15 g, crude). 1 H NMR (400 MHz, DMSO-d6 ) δ 12.02 (s, 1H), 9.58 (s, 1H), 8.35 (s, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.48 (dd, J = 2.0, 8.8 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 7.21 (s, 1H), 4.88 (s, 2H), 3.72 (s, 3H).

[0309] Methyl 2-((6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)acetate

[0310] To a solution of methyl 2-[[6-[(3,6-dichloro-5-cyano-2-pyridyl)amino]-2-oxo-1H-quinolin-3-yl]oxy]acetate (5 g, 11.93 mmol) and (3S,5R)-4,4-difluoro-3,5-dimethyl-piperidine (4.08 g, 15.51 mmol, TFA) in DMSO (50 mL) was added DIPEA (7.71 g, 59.63 mmol, 10.39 mL) and the reaction mixture was stirred at 100° C. for 12 h. The mixture was cooled to 15° C. and water (approx. 50 mL) was added, forming a precipitate. The mixture was filtered and the filter cake was washed with EtOAc (approx. 80 mL) and dried under vacuum. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 1 to 0 / 1) to give a residue, which was then triturated with a mixture of solvents (PE:EtOAc=1:1, 40 mL) at 20° C. for 30 min to give the title compound as a light brown solid (2.3 g, 3.98 mmol, yield 33%, purity 92%). 1 H NMR (400 MHz, DMSO-d 6) δ 11.96 (s, 1H), 9.08 (s, 1H), 7.97 (s, 1H), 7.66 (s, 1H), 7.49 (dd, J = 2.0, 8.8 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.20 (s, 1H), 4.85 (s, 2H), 4.10 (d, J = 13.2 Hz, 2H), 3.72 (s, 3H), 2.77 (t, J = 12.4 Hz, 2H), 2.14 - 1.93 (m, 2H), 0.82 (br d, J = 6.4 Hz, 6H).

[0311] 2-((6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0312] To a mixture of methyl 2-[[6-[[3-chloro-5-cyano-6-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-2-pyridyl]amino]-2-oxo-1H-quinolin-3-yl]oxy]acetate (10 g, 23.85 mmol) in EtOH (90 mL) and NMP (10 mL) was added MeNH 2 (14.82 g, 190.83 mmol, 40% purity) was added and the reaction mixture was stirred at 70° C. for 12 h. The mixture was cooled to 20° C., then the reaction mixture was filtered and the filter cake was collected and dried under reduced pressure to give the title compound as a light brown solid (9.2 g, 21.12 mmol, 89% yield, 96% purity).

[0313] Methyl 2-((6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-1-(2-(dimethylamino)ethyl)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)acetate

[0314] Methyl 2-[[6-[[3-chloro-5-cyano-6-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-2-pyridyl]amino]-2-oxo-1H-quinolin-3-yl]oxy]acetate (350 mg, 657.97 μmol), 2-chloro-N,N-dimethyl-ethanamine (123.21 mg, 855.36 μmol, HCl), Cs 2 CO 3 A mixture of KI (643.14 mg, 1.97 mmol), KI (54.61 mg, 328.99 μmol) in DMSO (5 mL) was diluted with N 2 The mixture was stirred at 60° C. for 2 hours under atmospheric pressure. Water (5 mL) was added to the mixture, and the precipitated solid was filtered and diluted with H 2 HO (20 mL) and petroleum ether / ethyl acetate (1 / 1, 5 mL), then purified by preparative HPLC (column: Phenomenex C18 80*40 mm*3 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 50% to 70%, 8 min) to give the title compound as a yellow solid (50 mg, 78.36 μmol, 12% yield, 95% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.14 (s, 1H), 7.99 (s, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.63 (dd, J = 2.4, 9.2 Hz, 1H), 7.46 (d, J = 9.2 Hz, 1H), 7.22 (s, 1H), 4.86 (s, 2H), 4.38 (t, J = 6.8 Hz, 2H), 4.12 (br d, J = 12.4 Hz, 2H), 3.72 (s, 3H), 2.78 (br t, J = 12.4 Hz, 2H), 2.52 (d, J = 1.6 Hz, 2H), 2.23 (s, 6H), 2.10 - 1.99 (m, 2H), 0.84 (d, J = 6.8 Hz, 6H).

[0315] 2-((6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-1-(2-(dimethylamino)ethyl)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (11)

[0316] To a mixture of methyl 2-[[6-[[3-chloro-5-cyano-6-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-2-pyridyl]amino]-1-[2-(dimethylamino)ethyl]-2-oxo-3-quinolyl]oxy]acetate (50 mg, 82.91 μmol) in EtOH (5 mL) was added methenamine (5 mL, H 2 40% purity in 200) was added. The mixture was stirred at 70° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 35% to 65%, 10 min) to give the title compound as a white solid (6 mg, 9.25 μmol, 11% yield, 93% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.14 (s, 1H), 7.99 (s, 1H), 7.74 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.22 (s, 2H), 4.53 (s, 2H), 4.39 (t, J = 6.8 Hz, 2H), 4.13 (d, J = 12.4 Hz, 2H), 2.78 (t, J = 12.8 Hz, 2H), 2.67 (d, J = 4.4 Hz, 3H), 2.63 - 2.58 (m, 1H), 2.23 (s, 6H), 2.09 - 2.03 (m, 3H), 0.84 (d, J = 6.8 Hz, 6H).

[0317] Example 12: Synthesis of 2-((6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-1-(oxetan-3-ylmethyl)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (7) and 2-((6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-2-(oxetan-3-ylmethoxy)quinolin-3-yl)oxy)-N-methylacetamide (58) [ka]

[0318] Methyl 2-[[6-[[3-chloro-5-cyano-6-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-2-pyridyl]amino]-1-(oxetan-3-ylmethyl)-2-oxo-3-quinolyl]oxy]acetate and methyl 2-((6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-2-(oxetan-3-ylmethoxy)quinolin-3-yl)oxy)acetate

[0319] Methyl 2-((6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)acetate (500 mg, 939.96 μmol) and K 2 CO 3To a solution of (259.82 mg, 1.88 mmol) in DMSO (6 mL) was added 3-(iodomethyl)oxetane (223.34 mg, 1.13 mmol) and the reaction mixture was stirred at 80° C. for 12 h. The reaction mixture was treated with water (9 mL), then a precipitate formed and the suspension was filtered, the filter cake was collected and dried under vacuum to give a mixture of methyl 2-[[6-[[3-chloro-5-cyano-6-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-2-pyridyl]amino]-1-(oxetan-3-ylmethyl)-2-oxo-3-quinolyl]oxy]acetate and methyl 2-((6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-2-(oxetan-3-ylmethoxy)quinolin-3-yl)oxy)acetate as a brown solid (500 mg, crude).

[0320] 2-((6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-1-(oxetan-3-ylmethyl)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide and 2-((6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-2-(oxetan-3-ylmethoxy)quinolin-3-yl)oxy)-N-methylacetamide

[0321] Methyl 2-[[6-[[3-chloro-5-cyano-6-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-2-pyridyl]amino]-1-(oxetan-3-ylmethyl)-2-oxo-3-quinolyl]oxy]acetate and methyl 2-((6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-2-(oxetan-3-ylmethoxy)quinolin-3-yl)oxy)acetate (200 mg, 332.21 μmol) and MeNH 2(25.79mg, 332.21μmol, 10mL, H 2 The mixture of 40% purity in EtOH (10 mL) was stirred at 70° C. for 12 h. The reaction mixture was concentrated in vacuum, then dissolved in DMSO (1.5 mL) and purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 35%-65%, 8 min) to give the two title compounds.

[0322] 2-((6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-1-(oxetan-3-ylmethyl)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (7)

[0323] The title compound was isolated as a white solid (45 mg, 74.79 μmol, 23% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.13 (s, 1H), 7.99 (s, 1H), 7.98 - 7.92 (d, J = 4.4 Hz, 1H), 7.80 - 7.74 (d, J = 2.4 Hz, 1H), 7.64 - 7.58 (m, 1H), 7.57 - 7.51 (m, 1H), 7.22 (m, 1H), 4.66 (d, J = 7.0 Hz, 2H), 4.62 - 4.56 (m, 2H), 4.55 - 4.49 (m, 4H), 4.17 - 4.08 (m, 2H), 3.43 (m, 1H), 2.86 - 2.72 (m, 2H), 2.67 (d, J = 4.8 Hz, 3H), 2.15 - 1.97 (m, 2H), 0.84 (d, J = 6.4 Hz, 6H).

[0324] 2-((6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-2-(oxetan-3-ylmethoxy)quinolin-3-yl)oxy)-N-methylacetamide (58)

[0325] The title compound was isolated as a white solid (45 mg, 74.79 μmol, 23% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.16 (m, 1H), 8.01 (m, 1H), 7.91 - 7.85 (m, 2H), 7.74 - 7.64 (m, 2H), 7.49 (s, 1H), 4.78 - 4.72 (m, 2H), 4.67 (d, J = 6.8 Hz, 2H), 4.63 (s, 2H), 4.51 (t, J = 6.0 Hz, 2H), 4.20 - 4.12 (d, J = 12.4 Hz, 2H), 3.51 - 3.42 (m, 1H), 2.80 (t, J = 12.4 Hz, 2H), 2.66 (d, J = 4.8 Hz, 3H), 2.15 - 1.99 (m, 2H), 0.84 (d, J = 6.8 Hz, 6H).

[0326] Example 13: Synthesis of 2-((3S,5R)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloro-6-((3-(2-(1-hydroxycyclopropyl)ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (59) [ka]

[0327] 2,5-Dichloro-6-((1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile

[0328] A flask containing a mixture of 5-amino-1-methyl-1H-benzo[d]imidazol-2(3H)-one (2 g, 12.26 mmol), 2,5,6-trichloropyridine-3-carbonitrile (2.54 g, 12.26 mmol) and DIEA (3.17 g, 24.51 mmol, 4.27 mL) in DMSO (20 mL) was degassed and flushed with N 2 Purge the mixture three times with N 2 The mixture was stirred under atmosphere for 2 hours at 80° C. Water (50 mL) was added to the mixture to form a precipitate which was filtered and the filter cake was dried under reduced pressure to give the title compound as a brown solid (4 g, 88% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.28 (s, 3H), 7.06 - 7.09 (m, 1H), 7.13 - 7.17 (m, 1H), 7.20 (d, J = 1.71 Hz, 1H), 8.32 (s, 1H), 9.43 (s, 1H), 10.90 (s, 1H).

[0329] 1-(2-Bromoethyl)cyclopropanol

[0330] To a solution of methyl 3-bromopropanoate (10 g, 59.88 mmol, 6.54 mL) and tetraisopropoxytitanium (17.02 g, 59.88 mmol, 17.67 mL) in THF (400 mL) was added EtmgBr (3 M, 43.91 mL) (3 M solution in diethyl ether) 2 The mixture was added dropwise at 0° C. The mixture was stirred at 20° C. for 3 h. The reaction mixture was quenched with saturated ammonium chloride solution (600 mL). The mixture was then added to Celite® and filtered to obtain the filtrate. The filtrate was extracted with EtOAc (3×500 mL). The combined organic phase was washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=0 / 1-10 / 1) to give the title compound as a yellow oil (7 g, 42.42 mmol, 35% yield). 1H NMR (400 MHz, DMSO-d 6 ) δ 5.15 (s, 1H), 3.61 (t, J = 7.6 Hz, 2H), 1.99 (t, J = 7.6 Hz, 2H), 0.56 (dd, J = 6.8, 4.8 Hz, 1H), 0.43 (dd, J = 6.4, 4.4 Hz, 1H).

[0331] 2,5-Dichloro-6-((3-(2-(1-hydroxycyclopropyl)ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile

[0332] 2,5-Dichloro-6-((1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (1.5 g, 4.49 mmol), 1-(2-bromoethyl)cyclopropanol (1.48 g, 8.98 mmol), K 2 CO 3 A flask containing a solution of (1.24 g, 8.98 mmol) and KI (372.58 mg, 2.24 mmol) in DMSO (15 mL) was degassed and filled with N 2 Purge the mixture three times with N 2 The mixture was stirred at 100° C. under atmospheric pressure for 12 hours. The mixture was concentrated under vacuum without further workup. The residue was purified by preparative HPLC (column: Xtimate C18 10 μm 250 mm*80 mm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 35% to 65%, 20 min) to afford the title compound as a yellow solid (600 mg, 1.42 mmol, 32% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d 6) δ 0.27 - 0.33 (m, 2H), 0.51 - 0.57 (m, 2H), 1.76 - 1.82 (m, 2H), 3.34 (s, 3H), 3.95 - 4.03 (m, 2H), 5.22 (s, 1H), 7.14 - 7.17 (m, 1H), 7.18 - 7.21 (m, 1H), 7.36 (d, J = 1.63 Hz, 1H), 8.35 (s, 1H), 9.53 (s, 1H).

[0333] 5-Chloro-2-((3S,5R)-3-(1,3-dioxoisoindolin-2-yl)-4,4-difluoro-5-methylpiperidin-1-yl)-6-((3-(2-(1-hydroxycyclopropyl)ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile

[0334] A flask containing a solution of 2,5-dichloro-6-((3-(2-(1-hydroxycyclopropyl)ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (150 mg, 358.61 μmol), 2-[(3R,5S)-4,4-difluoro-5-methyl-3-piperidyl]isoindoline-1,3-dione (150.76 mg, 537.92 μmol) and DIEA (231.74 mg, 1.79 mmol, 312.31 μL) in DMSO (1.5 mL) was degassed and diluted with N 2 Purge the mixture three times with N 2 The mixture was stirred at 80° C. under atmospheric pressure for 6 hours. The mixture was concentrated under vacuum without further workup. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 40% to 70%, 8 min) to give the title compound as a yellow solid (90 mg, 28% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d 6) δ 0.21 - 0.29 (m, 2H), 0.49 (br d, J = 5.13 Hz, 2H), 0.84 - 0.89 (m, 3H), 1.17 (t, J = 7.09 Hz, 2H), 1.62 - 1.76 (m, 2H), 2.13 - 2.28 (m, 1H), 2.80 - 2.86 (m, 3H), 3.11 - 3.20 (m, 1H), 3.77 - 3.84 (m, 2H), 4.14 - 4.38 (m, 4H), 5.19 (s, 1H), 6.82 (d, J = 8.34 Hz, 1H), 7.05 (dd, J = 8.34, 1.55 Hz, 1H), 7.19 (d, J = 1.79 Hz, 1H), 7.70 - 7.83 (m, 2H), 7.85 - 7.91 (m, 2H), 8.02 (s, 1H), 9.11 (s, 1H).

[0335] 2-((3S,5R)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloro-6-((3-(2-(1-hydroxycyclopropyl)ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (59)

[0336] To a solution of 5-chloro-2-((3R,5S)-3-(1,3-dioxoisoindolin-2-yl)-4,4-difluoro-5-methylpiperidin-1-yl)-6-((3-(2-(1-hydroxycyclopropyl)ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (90 mg, 135.93 μmol) in EtOH (4 mL), MeNH 2 / H 2 HO (4 mL, 40% in water) was added. The mixture was stirred at 70° C. for 1 h. The mixture was concentrated under vacuum without further workup. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH 4 HCO 3)-ACN]; B%: 30% to 60%, 8 min) to give the title compound as a white solid (25 mg, 46.52 μmol, yield 34%, purity 99%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.22 - 0.31 (m, 2H), 0.46 - 0.56 (m, 2H), 0.79 (d, J = 6.72 Hz, 3H), 1.60 - 1.71 (m, 2H), 1.73 - 1.80 (m, 2H), 1.94 - 2.13 (m, 1H), 2.76 - 2.92 (m, 2H), 3.33 (s, 3H), 4.00 (br t, J = 7.64 Hz, 2H), 4.14 - 4.24 (m, 1H), 5.27 (s, 1H), 7.13 (d, J = 8.44 Hz, 1H), 7.23 (dd, J = 8.44, 1.83 Hz, 1H), 7.35 (d, J = 1.83 Hz, 1H), 7.96 (s, 1H), 8.97 (s, 1H).

[0337] The absolute configuration of compound 59 was randomly assigned based on the cis conformation of the amino and methyl groups.

[0338] Example 14: Synthesis of 2-[(3R,5S)-3-amino-4,4-difluoro-5-methyl-1-piperidyl]-5-fluoro-6-[[1-methyl-2-oxo-3-[[(R)-2-oxooxazolidin-4-yl]methyl]benzimidazol-5-yl]amino]pyridine-3-carbonitrile (60) and 2-((3R,5S)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-fluoro-6-((1-methyl-2-oxo-3-(((S)-2-oxooxazolidin-4-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (61) [ka]

[0339] (2-Oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate

[0340] To a solution of 4-(hydroxymethyl)oxazolidin-2-one (12.5 g, 106.74 mmol) and DMAP (26.08 g, 213.49 mmol) in DCM (500 mL) was added 4-methylbenzenesulfonyl chloride (24.42 g, 128.09 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h and then warmed to 15° C. for 1 h. The reaction mixture was diluted with 1N HCl (1 L), H 2 O(1L), saturated NaHCO 3 (1 L), washed with saturated NaCl (1 L), and then with anhydrous Na 2 SO 4 and concentrated in vacuo to give a residue which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=5 / 1 to 0 / 1) to give the title compound as a white solid (45 g, 159.24 mmol, 75% yield, 96% purity). 1 H NMR (400 MHz, MeCN-d 3 ) δ 7.79 (d, J = 8 Hz, 2H), 7.45 (d, J = 8 Hz, 2H), 5.99 (br s, 1H), 4.32 - 4.40 (m, 1H), 3.93 - 4.07 (m, 4H), 2.45 (s, 3H).

[0341] (S)-(2-Oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate and (R)-(2-Oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate

[0342] Racemic (2-oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate (10 g, 36.86 mmol) was analyzed by SFC (column: Phenomenex-Cellulose-2 (250 mm*50 mm, 10 μm); mobile phase: [0.1% NH 3 H 2O / EtOH; B%: 60%–60%, 7.7 min) to give two enantiopure compounds. (S)-(2-oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate (4.9 g, 17.70 mmol, 48% yield, 98% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, MeCN-d 3 ) δ 7.80 (d, J = 8 Hz, 2H), 7.46 (d, J = 8 Hz, 2H), 5.95 (br s, 1H), 4.32 - 4.40 (m, 1H), 3.93 - 4.07 (m, 4H), 2.45 (s, 3H). (R)-(2-Oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate (4.9 g, 17.70 mmol, 48% yield, 98% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, MeCN-d 3 ) δ 7.79 (d, J = 8.34 Hz, 2H), 7.45 (d, J = 8.11 Hz, 2H), 5.98 (br s, 1H), 4.31 - 4.41 (m, 1H), 3.92 - 4.08 (m, 4H), 2.45 (s, 3H).

[0343] (R)-4-[(3-methyl-6-nitro-2-oxo-benzimidazol-1-yl)methyl]oxazolidin-2-one

[0344] 3-Methyl-6-nitro-1H-benzimidazol-2-one (500 mg, 2.59 mmol), [(S)-2-oxooxazolidin-4-yl]methyl 4-methylbenzenesulfonate (842.69 mg, 3.11 mmol), K 2 CO 3 Degas the flask containing a mixture of (715.52 mg, 5.18 mmol) and KI (214.85 mg, 1.29 mmol) in DMSO (10 mL) and add N 2 Purge the mixture three times with N 2The mixture was stirred under atmosphere at 80° C. for 3 h. The reaction mixture was treated with water (20 mL) to form a precipitate which was filtered, and the filter cake was washed with EtOAc (10 mL) and dried under reduced pressure to give the title compound as a black solid (600 mg, 2.03 mmol, 79% yield, 99% purity).

[0345] (R)-4-[(6-amino-3-methyl-2-oxo-benzimidazol-1-yl)methyl]oxazolidin-2-one

[0346] To a solution of (R)-4-[(3-methyl-6-nitro-2-oxo-benzimidazol-1-yl)methyl]oxazolidin-2-one (600 mg, 2.05 mmol) in DMF (2 mL) was added Pd / C (200 mg, 10% purity) under Ar. The suspension was degassed under vacuum and diluted with H 2 The mixture was purged with H 2 (50 psi) at 60° C. for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO 2 , ethyl acetate / ethanol=1 / 0 to 0 / 1) to give the title compound as a yellow solid (500 mg, 1.91 mmol, 93% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.84 (s, 1 H), 6.89 (d, J = 8 Hz, 1H), 6.61 (d, J = 1.8 Hz, 1H), 6.48 (dd, J = 8, 2 Hz, 1H), 6.15 (br s, 2H), 4.31 - 4.40 (m, 1H), 4.09 - 4.19 (m, 2H), 3.77 - 3.85 (m, 2H), 3.25 (s, 3H).

[0347] 2-Chloro-5-fluoro-6-[[1-methyl-2-oxo-3-[[(R)-2-oxooxazolidin-4-yl]methyl]benzimidazol-5-yl]amino]pyridine-3-carbonitrile

[0348] To a solution of (R)-4-[(6-amino-3-methyl-2-oxo-benzimidazol-1-yl)methyl]oxazolidin-2-one (500 mg, 1.91 mmol) and 2,6-dichloro-5-fluoro-pyridine-3-carbonitrile (364.12 mg, 1.91 mmol) in DMSO (10 mL) was added DIPEA (492.79 mg, 3.81 mmol, 664.13 μL). The mixture was stirred at 100° C. for 2 hours. The mixture was treated with water (20 mL) to form a precipitate which was filtered and dried under reduced pressure to give the title compound as a brown solid (550 mg, 1.17 mmol, 62% yield, 89% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.99 (s, 1H), 8.14 (d, J = 10.4 Hz, 1H), 7.83 (s, 1H), 7.49 (d, J = 1.2 Hz, 1H), 7.25 (br dd, J = 8, 1.6 Hz, 1H), 7.15 (d, J = 8 Hz, 1H), 4.32 - 4.44 (m, 1H), 4.14 - 4.24 (m, 2H), 3.80 - 3.97 (m, 2H), 3.33 (br s, 3H).

[0349] 2-((3R,5S)-3-(1,3-dioxoisoindolin-2-yl)-4,4-difluoro-5-methylpiperidin-1-yl)-5-fluoro-6-((1-methyl-2-oxo-3-(((R)-2-oxooxazolidin-4-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile

[0350] 2-Chloro-5-fluoro-6-[[1-methyl-2-oxo-3-[[(R)-2-oxooxazolidin-4-yl]methyl]benzimidazol-5-yl]amino]pyridine-3-carbonitrile (500 mg, 1.20 mmol), 2-[(3R,5S)-4,4-difluoro-5-methyl-3-piperidyl]isoindoline-1,3-dione (336.22 mg, 1.20 mmol) and Cs 2 CO 3To a solution of (781.73 mg, 2.40 mmol) in dioxane (5 mL) was added rac-BINAP-Pd-G3 (119.05 mg, 119.96 μmol). The mixture was stirred at 90° C. for 4 h. The reaction mixture was filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 30% to 60%, 8 min) to give the title compound (150 mg, yield 19%, purity 98%). 1 H NMR (400 MHz, MeCN-d 3 ) δ 7.87 (br s, 1H), 7.83 (dd, J = 5.46, 3.07 Hz, 2H), 7.67 - 7.76 (m, 2H), 7.51 (d, J = 10.54 Hz, 1H), 7.09 - 7.22 (m, 2H), 6.75 (d, J = 8.28 Hz, 1H), 6.08 (s, 1H), 4.48 - 4.57 (m, 1H), 4.33 - 4.47 (m, 2H), 4.24 - 4.32 (m, 3H), 4.17 - 4.23 (m, 2H), 3.69 - 3.87 (m, 2H), 3.21 (dd, J = 14.12, 12.11 Hz, 1H), 2.84 (s, 3H), 0.97 (d, J = 6.78 Hz, 3H).

[0351] 2-[(3R,5S)-3-Amino-4,4-difluoro-5-methyl-1-piperidyl]-5-fluoro-6-[[1-methyl-2-oxo-3-[[(R)-2-oxooxazolidin-4-yl]methyl]benzimidazol-5-yl]amino]pyridine-3-carbonitrile (60).

[0352] To a solution of 2-[(3R,5S)-3-(1,3-dioxoisoindolin-2-yl)-4,4-difluoro-5-methyl-1-piperidyl]-5-fluoro-6-[[1-methyl-2-oxo-3-[[(R)-2-oxooxazolidin-4-yl]methyl]benzimidazol-5-yl]amino]pyridine-3-carbonitrile (100 mg, 151.38 μmol) in EtOH (3.5 mL), MeNH 2 (3.5mL, purity 40%) was added. The mixture was stirred at 70°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 25% to 45%, 8 min) to give the title compound as a white solid (10 mg, 18.66 μmol, 12% yield, 99% purity). 1 H NMR (400 MHz, MeCN-d 3 ) δ 7.81 (br d, J = 1.13 Hz, 1H), 7.55 (d, J = 1.88 Hz, 1H), 7.46 - 7.50 (m, 1H), 7.22 (dd, J = 8.44, 1.94 Hz, 1H), 7.04 (d, J = 8.50 Hz, 1H), 6.36 (br s, 1H), 4.36 - 4.46 (m, 1H), 4.22 - 4.32 (m, 2H), 4.14 - 4.21 (m, 1H), 4.01 - 4.08 (m, 1H), 3.94 - 4.00 (m, 2H), 3.36 (s, 3H), 3.00 - 3.16 (m, 1H), 2.78 - 2.90 (m, 2H), 2.18 - 2.25 (m, 1H), 0.98 (d, J = 6.88 Hz, 3H). [ka]

[0353] (S)-4-((3-methyl-6-nitro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)oxazolidin-2-one

[0354] 3-Methyl-6-nitro-1H-benzimidazol-2-one (500 mg, 2.59 mmol), [(4R)-2-oxooxazolidin-4-yl]methyl 4-methylbenzenesulfonate (842.69 mg, 3.11 mmol), K 2 CO 3 Degas the flask containing a mixture of (715.52 mg, 5.18 mmol) and KI (214.85 mg, 1.29 mmol) in DMSO (10 mL) and add N 2 Purge the mixture three times with N 2 The mixture was stirred under atmosphere for 3 h at 80° C. The reaction mixture was treated with water (20 mL) to form a precipitate which was filtered, and the filter cake was washed with EtOAc (10 mL) and then dried under reduced pressure to give the title compound as a black solid (600 mg, 2.03 mmol, 79% yield, 99% purity).

[0355] (S)-4-((6-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)oxazolidin-2-one

[0356] To a solution of (4R)-4-[(3-methyl-6-nitro-2-oxo-benzimidazol-1-yl)methyl]oxazolidin-2-one (600 mg, 2.05 mmol) in DMF (2 mL) was added Pd / C (200 mg, 10% purity) under Ar. The flask was degassed and H 2 The mixture was purged with H 2 (50 psi) at 60° C. for 10 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO 2 , ethyl acetate / ethanol=1 / 0 to 0 / 1) to give the title compound as a yellow solid (500 mg, 1.70 mmol, yield 83%, purity 89%). 1 H NMR (400 MHz, DMSO-d6 ) δ 7.85 (s, 1H), 6.80 (d, J = 8.23 ​​Hz, 1H), 6.47 (d, J = 1.67 Hz, 1H), 6.34 (dd, J = 8.23, 1.79 Hz, 1H), 4.76 (br s, 2H), 4.30 - 4.39 (m, 1H), 4.07 - 4.20 (m, 2H), 3.78 (br d, J = 5.72 Hz, 2H), 3.23 (s, 3H).

[0357] (S)-2-Chloro-5-fluoro-6-((1-methyl-2-oxo-3-((2-oxooxazolidin-4-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile

[0358] To a solution of (4S)-4-[(6-amino-3-methyl-2-oxo-benzimidazol-1-yl)methyl]oxazolidin-2-one (500 mg, 1.91 mmol) and 2,6-dichloro-5-fluoro-pyridine-3-carbonitrile (364.12 mg, 1.91 mmol) in DMSO (10 mL) was added DIEA (492.79 mg, 3.81 mmol, 664.13 μL). The mixture was stirred at 100° C. for 2 hours. The mixture was treated with water (20 mL) to form a precipitate which was filtered and dried under reduced pressure to give the title compound as a brown solid (560 mg, 1.25 mmol, 66% yield, 93% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.98 (br s, 1H), 8.13 (d, J = 10.61 Hz, 1H), 7.83 (s, 1H), 7.49 (s, 1H), 7.10 - 7.33 (m, 2H), 4.31 - 4.46 (m, 1H), 4.19 (br d, J = 5.25 Hz, 2H), 3.88 (br dd, J = 12.22, 5.30 Hz, 2H), 3.33 (s, 3H).

[0359] 2-((3R,5S)-3-(1,3-dioxoisoindolin-2-yl)-4,4-difluoro-5-methylpiperidin-1-yl)-5-fluoro-6-((1-methyl-2-oxo-3-(((S)-2-oxooxazolidin-4-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile

[0360] 2-Chloro-5-fluoro-6-[[1-methyl-2-oxo-3-[[(4S)-2-oxooxazolidin-4-yl]methyl]benzimidazol-5-yl]amino]pyridine-3-carbonitrile (500 mg, 1.20 mmol), 2-[(3R,5S)-4,4-difluoro-5-methyl-3-piperidyl]isoindoline-1,3-dione (336.22 mg, 1.20 mmol) and Cs 2 CO 3 To a solution of (781.73 mg, 2.40 mmol) in dioxane (5 mL) was added rac-BINAP-Pd-G3 (119.05 mg, 119.96 μmol). The mixture was stirred at 90° C. for 4 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 30% to 60%, 8 min) to give the title compound as a yellow solid (120 mg, 174.39 μmol, 15% yield, 96% purity). 1 H NMR (400 MHz, MeCN-d 3) δ 7.90 (br d, J = 1.00 Hz, 1H), 7.83 (dd, J = 5.46, 3.07 Hz, 2H), 7.74 (br s, 2H), 7.51 (d, J = 10.54 Hz, 1H), 7.21 (d, J = 1.88 Hz, 1H), 7.10 (dd, J = 8.28, 1.76 Hz, 1H), 6.81 (d, J = 8.41 Hz, 1H), 5.94 (s, 1H), 4.45 - 4.57 (m, 1H), 4.32 - 4.44 (m, 2H), 4.22 - 4.32 (m, 3H), 4.11 - 4.22 (m, 2H), 3.75 (dd, J = 14.56, 6.15 Hz, 1H), 3.60 - 3.68 (m, 1H), 3.15 - 3.25 (m, 1H), 2.98 (s, 3H), 0.97 (d, J = 6.78 Hz, 3H).

[0361] 2-((3R,5S)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-fluoro-6-((1-methyl-2-oxo-3-(((S)-2-oxooxazolidin-4-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (61)

[0362] To a solution of 2-[(3R,5S)-3-(1,3-dioxoisoindolin-2-yl)-4,4-difluoro-5-methyl-1-piperidyl]-5-fluoro-6-[[1-methyl-2-oxo-3-[[(4S)-2-oxooxazolidin-4-yl]methyl]benzimidazol-5-yl]amino]pyridine-3-carbonitrile (100.00 mg, 151.38 μmol) in EtOH (5 mL), MeNH 2 (5mL, purity 40%) was added. The mixture was stirred at 70°C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3μm; mobile phase: [water (NH 4 HCO 3)-ACN]; B%: 25% to 45%, 8 min) to give the title compound as a white solid (10 mg, 18.66 μmol, 12% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.45 (br s, 1H), 7.78 - 7.90 (m, 2H), 7.55 (s, 1H), 7.26 - 7.33 (m, 1H), 7.12 (d, J = 8.34 Hz, 1H), 4.33 - 4.41 (m, 1H), 4.16 - 4.25 (m, 2H), 4.06 - 4.15 (m, 1H), 3.94 - 3.99 (m, 1H), 3.91 (br s, 2H), 3.33 (br s, 3H), 2.89 - 3.04 (m, 1H), 2.70 - 2.84 (m, 2H), 2.08 - 2.20 (m, 1H), 1.65 - 1.79 (m, 2H), 0.88 (br d, J = 6.68 Hz, 3H).

[0363] The absolute configurations of compounds 60 and 61 were randomly assigned based on the cis conformation of the amino and methyl groups.

[0364] Example 15: Synthesis of 5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-6-((1-methyl-3-((3-methyloxetan-3-yl)methoxy)-2-oxo-1,2-dihydroquinolin-6-yl)amino)nicotinonitrile (6) [ka]

[0365] Oxetan-2-ylmethyl 4-methylbenzenesulfonate

[0366] To a solution of oxetan-2-ylmethanol (200 mg, 2.27 mmol) and 4-methylbenzenesulfonyl chloride (519.33 mg, 2.72 mmol) in DCM (3 mL) was added DMAP (27.73 mg, 227.00 μmol) and TEA (459.40 mg, 4.54 mmol, 631.92 μL). The mixture was stirred at 20° C. for 12 h. The mixture was concentrated under reduced pressure to give a residue which was analyzed by preparative TLC (SiO 2 , petroleum ether:ethyl acetate=2:1) ​​to afford the title compound as a white solid (440 mg, 1.82 mmol, 80% yield). 1 H NMR (400MHz, CDCl 3 ) δ 7.83 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.96-4.90 (m, 1H), 4.64-4.58 (m, 1H), 4.54-4.89 (m, 1H), 4.16 (d, J = 4.0 Hz, 2H), 2.76-2.67 (m, 1H), 2.62-2.53 (m, 1H), 2.46 (s, 3H).

[0367] Methyl 2-((6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-1-(oxetan-2-ylmethyl)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)acetate

[0368] Methyl 2-[[6-[[3-chloro-5-cyano-6-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-2-pyridyl]amino]-2-oxo-1H-quinolin-3-yl]oxy]acetate (100 mg, 187.99 μmol), oxetan-2-ylmethyl 4-methylbenzenesulfonate (136.65 mg, 563.98 μmol), K 2 CO 3 A mixture of KI (77.94 mg, 563.98 μmol), KI (15.60 mg, 94.00 μmol) in DMSO (1 mL) was diluted with N 2The mixture was stirred at 80° C. for 12 hours under atmospheric pressure. Water (3 mL) was added to form a precipitate, which was filtered and diluted with H 2 O (3 mL) and ethyl acetate (5 mL), and the solid was dried under reduced pressure to give the title compound as a brown solid (100 mg, crude).

[0369] 2-((6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-1-(oxetan-2-ylmethyl)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (6)

[0370] To a mixture of methyl 2-[[6-[[3-chloro-5-cyano-6-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-2-pyridyl]amino]-1-(oxetan-2-ylmethyl)-2-oxo-3-quinolyl]oxy]acetate (100 mg, 166.11 μmol) in EtOH (5 mL) was added methenamine (5 mL, H 2 40% purity in 200 was added. The mixture was stirred at 70° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*25Mm*5μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 45% to 75%, 10 min) to give the title compound as a white solid (5 mg, 7.51 μmol, yield 5%, purity 90%). 1 H NMR (400MHz, DMSO-d 6) δ 9.12 (S, 1H), 7.99 (S, 1H), 7.94 (d, J = 4.4 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.69 (d, J = 9.2 Hz, 1H), 7.61 (dd, J = 2.4, 9.2 Hz, 1H), 7.24 (s, 1H), 5.05 - 5.01 (m, 1H), 4.68 - 4.50 (m, 2H), 4.54 (s, 2H), 4.50 - 4.40 (m, 2H), 4.14 (d, J = 12.8 Hz, 2H), 2.82 - 2.74 (m, 2H), 2.67 - 2.66 (m, 4H), 2.12 - 2.00 (m, 2H), 1.23 (s, 1H), 0.84 (d, J = 6.8 Hz, 6H).

[0371] Example 16: Synthesis of 2-((6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-1-(3-hydroxypropyl)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (18) [ka]

[0372] Methyl 2-((1-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)acetate

[0373] Methyl 2-[[6-[[3-chloro-5-cyano-6-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-2-pyridyl]amino]-2-oxo-1H-quinolin-3-yl]oxy]acetate (100 mg, 187.99 μmol), tert-butyl-(3-iodopropoxy)-dimethyl-silane (56.44 mg, 187.99 μmol, 5.41 μL), K 2 CO 3 A mixture of (51.96 mg, 375.98 μmol) in DMSO (2 mL) was stirred at 80° C. for 12 h. The mixture was cooled to 20° C. and water (1 mL) was added, forming a precipitate which was filtered and the filter cake was diluted with H 2 O (10 mL×2), EtOAc (10 mL×2), and then the filter cake was concentrated to give the title compound as a yellow solid (150 mg, crude), which was used without purification.

[0374] 2-((1-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0375] Methyl 2-[[1-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-6-[[3-chloro-5-cyano-6-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-2-pyridyl]amino]-2-oxo-3-quinolyl]oxy]acetate (150 mg, 85.19 μmol, purity 40%), MeNH 2 (370.59 μmol, 9 mL, H 2 A mixture of 1,2-dichloromethane (40% purity in 200) in EtOH (10 mL) was stirred for 12 h at 70° C. The mixture was concentrated to give the title compound (100 mg, 56.88 μmol, 67% yield, 40% purity) as a yellow solid, which was used without purification.

[0376] 2-((6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-1-(3-hydroxypropyl)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (18)

[0377] To a solution of 2-[[1-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-6-[[3-chloro-5-cyano-6-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-2-pyridyl]amino]-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (100 mg, 142.19 μmol) in THF (2 mL) was added TBAF (1 M, 213.28 μL) and the mixture was then stirred at 20° C. for 12 h. The mixture was concentrated, and the residue was directly purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water (HCl)-ACN]; B%: 30%~60%, 8min) to give the title compound as a white solid (6mg, 9.50μmol, yield 7%, purity 99%, HCl). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.08 - 9.18 (m, 1H), 7.95 - 8.04 (m, 2H), 7.78 (d, J = 2.38 Hz, 1 H), 7.61 - 7.68 (m, 1 H), 7.50 - 7.57 (m, 1H), 7.22 - 7.28 (m, 1H), 4.63 - 4.78 (m, 1H), 4.50 - 4.60 (m, 2H), 4.27 - 4.40 (m, 2H), 4.13 (br d, J = 12.51 Hz, 2H), 3.54 (br t, J = 5.69 Hz, 2H), 2.79 (br t, J = 12.76 Hz, 2H), 2.67 (d, J = 4.50 Hz, 3H), 1.96 - 2.15 (m, 2H), 1.75 - 1.86 (m, 2H), 0.82 - 0.86 (m, 6H).

[0378] Example 17: Synthesis of 2-((6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3-(2-hydroxyethyl)-5-methylpiperidin-1-yl)pyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (62) and 2-((6-((3-chloro-5-cyano-6-((3S,5R)-4,4-difluoro-3-(2-hydroxyethyl)-5-methylpiperidin-1-yl)pyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (63) [ka]

[0379] 2-((3R,5S)-1-benzyl-4,4-difluoro-5-methylpiperidin-3-yl)ethanol and 2-((3S,5R)-1-benzyl-4,4-difluoro-5-methylpiperidin-3-yl)ethanol

[0380] 2-(1-benzyl-4,4-difluoro-5-methyl-3-piperidyl)ethanol (1.2g, 4.46mmol) was separated by SFC (column: Phenomenex-cellulose-2 (250mm*30mm, 5μm); mobile phase: [n-heptane-IPA (0.1%NH3.H2O)]; B%: 10%-10%, 12min) to give 2-[(3R,5S)-1-benzyl-4,4-difluoro-5-methyl-3-piperidyl]ethanol as a colorless oil (540mg, 1.98mmol, yield 44%, purity 99%); 1 H NMR (400 MHz, DMSO-d 6) δ = 7.33 - 7.25 (m, 5H), 4.50 (t, J = 5.2 Hz, 1H), 3.58 - 3.50 (m, 1H), 3.47 - 3.33 (m, 3H), 2.95 (d, J = 10 Hz, 2H), 2.72 (d, J = 10 Hz, 2H), 2.20 - 2.04 (m, 2H), 1.91 - 1.81 (m, 3H), 1.25 - 1.19 (m, 1H), 0.87 (d, J = 6.8 Hz, 3H); and 2-[(3S,5R)-1-benzyl-4,4-difluoro-5-methyl-3-piperidyl]ethanol as a colorless oil (510 mg, 1.79 mmol, 40% yield, 94% purity); 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.35 - 7.25 (m, 5H), 4.50 (t, J = 5.2 Hz, 1H), 3.58 - 3.50 (m, 1H), 3.47 - 3.33 (m, 3H), 2.95 (d, J = 10 Hz, 2H), 2.72 (d, J = 10 Hz, 2H), 2.20 - 2.04 (m, 2H), 1.91 - 1.81 (m, 3H), 1.25 - 1.19 (m, 1H), 0.87 (d, J = 6.8 Hz, 3H).

[0381] 2-((3R,5S)-4,4-Difluoro-5-methylpiperidin-3-yl)ethanol

[0382] To a solution of 2-[(3R,5S)-1-benzyl-4,4-difluoro-5-methyl-3-piperidyl]ethanol (200 mg, 742.59 μmol) in MeOH (2 mL) was added TFA (338.69 mg, 2.97 mmol, 219.93 μL) and Pd / C (10%, 50 mg) under Ar. The mixture was purified by H 2 (15 psi) for 12 h at 60° C. The reaction mixture was filtered and the filtrate was concentrated to give the title compound as a yellow oil (140 mg, crude, TFA). 1 H NMR (400 MHz, MeOD-d 4) δ 3.66 - 3.63 (m, 2H), 3.62 - 3.60 (m, 1H), 3.41 (d, J = 12 Hz, 1H), 2.99 - 2.86 (m, 2H), 2.50 - 2.33 (m, 2H), 2.09 - 2.00 (m, 1H), 1.52 - 1.43 (m, 1H), 1.09 (d, J = 6.8 Hz, 3H).

[0383] 2-((6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3-(2-hydroxyethyl)-5-methylpiperidin-1-yl)pyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (62)

[0384] To a solution of 2-[[6-[(3,6-dichloro-5-cyano-2-pyridyl)amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (40 mg, 92.54 μmol) and 2-[(3R,5S)-4,4-difluoro-5-methyl-3-piperidyl]ethanol (54.27 mg, 185.07 μmol, TFA) in DMSO (0.5 mL) was added DIPEA (47.84 mg, 370.15 μmol, 64.47 μL). The mixture was stirred at 100° C. for 3 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18 80*40 mm*3 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 30% to 60%, 8 min) to give the title compound as a white solid (8 mg, 13.63 μmol, 15% yield, 98% purity). 1 H NMR (400 MHz, DMSO-d 6) δ 9.19 (s, 1H), 8.06 (s, 1H), 8.00 (d, J = 4.4 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.71 (dd, J = 2.4, 8.8 Hz, 1H), 7.39 (d, J = 9.2 Hz, 1H), 7.30 (s, 1H), 4.61 (s, 2H), 4.60 - 4.57 (m, 1H), 4.42 (d, J = 13.2 Hz, 1H), 4.17 (d, J = 12.4 Hz, 1H), 3.74 (s, 3H), 2.90 - 2.76 (m, 2H), 2.73 (d, J = 4.8 Hz, 3H), 2.23 - 2.01 (m, 3H), 1.89 - 1.80 (m, 1H), 1.36 - 1.27 (m, 2H), 0.89 (d, J = 6.4 Hz, 3H).

[0385] 2-((3S,5R)-4,4-Difluoro-5-methylpiperidin-3-yl)ethanol

[0386] To a solution of 2-[(3S,5R)-1-benzyl-4,4-difluoro-5-methyl-3-piperidyl]ethanol (200 mg, 742.59 μmol) in MeOH (2 mL) was added TFA (338.69 mg, 2.97 mmol, 219.93 μL) and Pd / C (10%, 50 mg) under Ar. The mixture was purified by H 2 (15 psi) for 12 h at 60° C. The reaction mixture was filtered and the filtrate was concentrated to give the title compound as a yellow oil (120 mg, crude, TFA). 1 H NMR (400 MHz, MeOD-d 4 ) δ 4.43 - 4.34 (m, 2H), 3.71-3.68 (m, 1H), 3.45 - 3.42 (m, 1H), 3.08 - 2.93 (m, 2H), 2.57-2.43 (m, 2H), 2.08 - 2.00 (m, 1H), 1.51 - 1.42 (m, 1H), 1.07 (d, J = 6.8 Hz, 3H).

[0387] 2-((6-((3-chloro-5-cyano-6-((3S,5R)-4,4-difluoro-3-(2-hydroxyethyl)-5-methylpiperidin-1-yl)pyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (63)

[0388] To a solution of 2-[[6-[(3,6-dichloro-5-cyano-2-pyridyl)amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (40 mg, 92.54 μmol) and 2-[(3S,5R)-4,4-difluoro-5-methyl-3-piperidyl]ethanol (54.27 mg, 185.07 μmol, TFA) in DMSO (0.5 mL) was added DIPEA (35.88 mg, 277.61 μmol, 48.35 μL). The mixture was stirred at 100° C. for 3 hours. The mixture was analyzed by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 25% to 55%, 8 min) to give the title compound as a white solid (11 mg, 18.78 μmol, 20% yield, 98% purity). 1 H NMR (400 MHz, DMSO-d 6) δ 9.13 (s, 1H), 8.00 (s, 1H), 7.92 (d, J = 4.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.64 (dd, J = 2.4, 9.2 Hz, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.24 (s, 1H), 4.55 (s, 2H), 4.52 (t, J = 5.2 Hz, 1H), 4.36 (d, J = 14 Hz, 1H), 4.11 (d, J = 11.2 Hz, 1H), 3.68 (s, 3H), 2.83 - 2.72 (m, 2H), 2.66 (d, J = 4.8 Hz, 3H), 2.16 - 1.94 (m, 3H), 1.82-1.74 (m, 1H), 1.28 - 1.23 (m, 2H), 0.82 (d, J = 6.8 Hz, 3H).

[0389] The absolute configurations of compounds 62 and 63 were randomly assigned based on the cis conformation of the aliphatic alcohol and methyl groups.

[0390] Example 18: Synthesis of 2-((6-((3-chloro-5-cyano-6-((3R,4r,5S)-4-fluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (64) [ka]

[0391] N-Methyl-2-((1-methyl-6-nitro-2-oxo-1,2-dihydroquinolin-3-yl)oxy)acetamide

[0392] 3-Hydroxy-1-methyl-6-nitroquinolin-2(1H)-one (5 g, 22.71 mmol), 2-Bromo-N-methyl-acetamide (4.14 g, 27.25 mmol), Cs 2 CO 3A mixture of (14.80 g, 45.42 mmol) in DMF (100 mL) was stirred at 20° C. for 12 h. The mixture was then poured into water (150 mL) and the precipitated solid was filtered and diluted with H 2 O (200 mL) and MTBE (200 mL), then the solid was dried under reduced pressure to give the title compound as a yellow solid (3.3 g, 10.51 mmol, 46% yield, 93% purity).

[0393] 2-((6-amino-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0394] To a solution of N-methyl-2-((1-methyl-6-nitro-2-oxo-1,2-dihydroquinolin-3-yl)oxy)acetamide (3.3 g, 11.33 mmol) in DMF (60 mL) was added Pd / C (1 g, 11.33 mmol, 10% purity) under an argon atmosphere. The mixture was cooled to 10° C. for 2 h. 2 (50 Psi) for 12 h at 50° C. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (1.8 g, 6.13 mmol, 54% yield, 89% purity).

[0395] 2-((6-((3,6-dichloro-5-cyanopyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0396] A mixture of 2-((6-amino-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (1 g, 3.83 mmol), 2,5,6-trichloropyridine-3-carbonitrile (793.97 mg, 3.83 mmol), DIEA (989.32 mg, 7.65 mmol, 1.33 mL) in DMF (20 mL) was degassed and purified with N 2 Purge the mixture three times with N 2The mixture was stirred under atmosphere at 100° C. for 12 hours. The mixture was cooled to 20° C. Water (10 mL) was added, forming a precipitate which was filtered, and the filter cake was washed with EtOAc (20 mL) and dried in vacuum to give the title compound as a white solid (1.1 g, 1.35 mmol, 35% yield, 53% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.64 (s, 1H), 8.38 (s, 1H), 7.94 (dd, J = 6.60, 1.59 Hz, 1H), 7.74 (s, 1H), 7.66 (d, J = 8.93 Hz, 1H), 7.53 (d, J = 9.29 Hz, 1H), 7.22 (s, 1H), 4.58 (s, 2H), 3.69 (s, 3H), 2.66 (s, 3H).

[0397] 2-((6-((3-chloro-5-cyano-6-((3R,4r,5S)-4-fluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (64)

[0398] A solution of 2-((6-((3,6-dichloro-5-cyanopyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (50 mg, 115.67 μmol) and (3S,4R,5R)-4-fluoro-3,5-dimethyl-piperidine (38.78 mg, 231.34 μmol, HCl) in DMSO (1 mL) was added to the flask. 2 DIEA (74.75 mg, 578.36 μmol, 100.74 μL) was added under the conditions below. The mixture was stirred at 100° C. for 12 hours. The mixture was analyzed by preparative HPLC (column: Phenomenex C18 80*40 mm*3 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 35% to 65%, 8 min) to give the title compound as a white solid (12 mg, 22.07 μmol, 19% yield, 97% purity). 1H NMR (400 MHz, DMSO-d 6 ) δ 9.09 (s, 1H), 7.92 - 7.97 (m, 2H), 7.81 (d, J = 2.20 Hz, 1H), 7.64 (dd, J = 8.99, 2.38 Hz, 1H), 7.46 (d, J = 9.05 Hz, 1H), 7.23 (s, 1H), 4.53 (s, 2H), 4.09 - 4.18 (m, 2H), 3.80 - 3.99 (m, 1H), 3.67 (s, 3H), 2.64 - 2.71 (m, 5H), 1.73 (dd, J = 9.29, 4.65 Hz, 2H), 0.87 (d, J = 6.48 Hz, 6H).

[0399] Example 19: Synthesis of 2-((6-((3-chloro-5-cyano-6-((3R,4r,5S)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (47) and 2-((6-((3-chloro-5-cyano-6-((3R,4s,5S)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (46) [ka]

[0400] (3R,5S)-Benzyl 3,5-dimethyl-4-oxopiperidine-1-carboxylate

[0401] To a solution of (3S,5R)-1-benzyl-3,5-dimethyl-piperidin-4-one (400 mg, 1.84 mmol) in toluene (4 mL) was added benzyl carbonochloridate (480.44 mg, 2.82 mmol, 400.37 μL). The mixture was stirred at 110° C. for 12 h. The residue was purified by flash silica gel chromatography (silica flash column, eluent of 0-30% ethyl acetate / petroleum) to give the title compound as a white solid (300 mg, 1.04 mmol, 57% yield, 91% purity). 1 H NMR (400 MHz, CDCl 3 ) δ 7.41 - 7.32 (m, 5H), 5.20 (d, J = 4.4 Hz, 2H), 4.50 - 4.41 (m, 2H), 2.73 - 2.58 (m, 4H), 1.03 (d, J = 6.4 Hz, 6H).

[0402] (3S,4R,5R)-4-Hydroxy-3,5-dimethyl-piperidine-1-carboxylate benzyl

[0403] To a solution of benzyl (3S,5R)-3,5-dimethyl-4-oxo-piperidine-1-carboxylate (4.1 g, 15.69 mmol) in MeOH (45 mL) was added NaBH 4 (712.30 mg, 18.83 mmol) was added at 0° C. The mixture was stirred at 20° C. for 12 h. The reaction mixture was quenched by adding 1N HCl (10 mL) at 0° C., and then the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL), washed with water (10 mL×3), and the combined organic phase was washed with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Agela DuraShell C18 250*80mm*10μm; mobile phase: [water (NH 4 HCO 3)-ACN]; B%: 25%-50%, 20 min) to give benzyl (3S,4S,5R)-4-hydroxy-3,5-dimethyl-piperidine-1-carboxylate as a colorless oil (1.4 g, 5.26 mmol, 34% yield, 99% purity); 1 H NMR (400 MHz, MeOD-d 4 ) δ 7.36 - 7.31 (m, 5H), 5.11 (s, 2H), 4.09-4.04 (m, 2H), 2.74 (t, J = 9.6 Hz, 1H), 2.52 - 2.46 (m, 2H), 1.50 - 1.39 (m, 2H), 0.99 (d, J = 6.0 Hz, 6H); and benzyl (3S,4R,5R)-4-hydroxy-3,5-dimethyl-piperidine-1-carboxylate was obtained as a colorless oil (0.9 g, 3.35 mmol, 21% yield, 98% purity); 1 H NMR (400 MHz, MeOD-d 4 ) δ = 7.36 - 7.29 (m, 5H), 5.10 (s, 2H), 3.77 (dd, J = 4.4, 13.2 Hz, 2H), 3.54 (s, 1H), 2.77 - 2.72 (m, 2H), 1.70 - 1.60 (m, 2H), 0.94 (d, J = 6.0 Hz, 6H).

[0404] (3R,4R,5S)-3,5-Dimethylpiperidin-4-ol

[0405] To a solution of benzyl (3S,5R)-4-hydroxy-3,5-dimethyl-piperidine-1-carboxylate (200 mg, 759.50 μmol) in MeOH (2 mL) was added TFA (346.39 mg, 3.04 mmol, 224.93 μL) and Pd / C (50 mg, 10% purity) under an Ar atmosphere. The mixture was diluted with H 2 (15 Psi) for 12 h at 20° C. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (150 mg, crude, TFA). 1 H NMR (400 MHz, DMSO-d 6) δ 4.33 (s, 2H), 3.18 - 3.16 (m, 2H), 2.76 - 2.71 (m, 1H), 2.62 - 2.53 (m, 2H), 1.68 - 1.57 (m, 2H), 0.92 (d, J = 6.8 Hz, 6H).

[0406] 2-((6-((3-chloro-5-cyano-6-((3R,4r,5S)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (47)

[0407] To a solution of 2-[[6-[(3,6-dichloro-5-cyano-2-pyridyl)amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (50 mg, 115.67 μmol) and (3S,4R,5R)-3,5-dimethylpiperidin-4-ol (45.00 mg, 185.02 μmol, TFA) in DMSO (1 mL) was added DIPEA (74.75 mg, 578.36 μmol, 100.74 μL). The mixture was stirred at 100° C. for 3 h. Water (2 mL) was added to the reaction mixture to form a precipitate which was filtered, the filter cake was washed with water (5 mL×2), EtOAc (5 mL×2), and the filter cake was dried under reduced pressure to give the title compound as a white solid (30 mg, 56.21 μmol, 49% yield, 98% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.04 (s, 1H), 7.95-7.92 (m, 2H), 7.83 (s, 1H), 7.66 - 7.64 (m, 1H), 7.46- 7.44 (m, 1H), 7.21 (s, 1H), 4.61 (d, J = 4.8 Hz, 1H), 4.53 (s, 2H), 4.14 (d, J = 11.2 Hz, 2H), 3.67 (s, 3H), 2.66 - 2.61 (m, 6H), 1.42 (s, 2H), 0.83 (s, 6H). [ka]

[0408] (3R,4S,5S)-3,5-Dimethylpiperidin-4-ol

[0409] To a solution of benzyl (3S,4S,5R)-4-hydroxy-3,5-dimethyl-piperidine-1-carboxylate (200 mg, 759.50 μmol) in MeOH (2 mL) was added TFA (346.39 mg, 3.04 mmol, 224.93 μL) and Pd / C (50 mg, 10% purity) under an Ar atmosphere. The mixture was diluted with H 2 (15 Psi) for 12 h at 20° C. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (150 mg, crude, TFA). 1 H NMR (400 MHz, MeOD-d 4 ) δ 3.05(s, 1H), 2.74 - 2.70 (m, 2H), 2.61 - 2.55 (m, 2H), 1.69 - 1.65 (m, 2H), 0.74 (d, J = 6.8 Hz, 6H).

[0410] 2-((6-((3-chloro-5-cyano-6-((3R,4s,5S)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (46)

[0411] To a solution of 2-[[6-[(3,6-dichloro-5-cyano-2-pyridyl)amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (25 mg, 57.84 μmol) and (3S,4S,5R)-3,5-dimethylpiperidin-4-ol (21.10 mg, 86.75 μmol, TFA) in DMSO (0.5 mL) was added DIPEA (37.37 mg, 289.18 μmol, 50.37 μL). The mixture was stirred at 100° C. for 3 h. Water (2 mL) was added to the reaction mixture to form a precipitate, which was filtered, the filter cake was washed with water (5 mL×2), EtOAc (5 mL×2), and the filter cake was dried under reduced pressure to give the title compound as a white solid (9.4 mg, 17.52 μmol, 30% yield, 98% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.00 (s, 1H), 7.95 (s, 1H), 7.89 (s, 1H), 7.83 (s, 1H), 7.67- 7.64 (m, 1H), 7.46-7.44 (m, 1H), 7.20 (s, 1H), 4.57 - 4.53 (m, 3H), 3.87 (d, J = 11.2 Hz, 2H), 3.67 (s, 3H), 3.43 (s, 1H), 2.83 (t, J = 12.3 Hz, 2H), 2.67 (m, 3H), 1.66(s, 2H), 0.78 (d, J = 6.4Hz, 6H).

[0412] Example 20: Synthesis of 2-((6-((3-chloro-5-cyano-6-((3R,4S,5S)-4-fluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (45) [ka]

[0413] (3R,4S,5S)-Benzyl 4-fluoro-3,5-dimethylpiperidine-1-carboxylate

[0414] To a solution of (3S,4R,5R)-4-hydroxy-3,5-dimethyl-piperidine-1-carboxylate benzyl (300.00 mg, 1.14 mmol) in DCM (3 mL) was added DAST (367.27 mg, 2.28 mmol, 301.04 μL) at −65° C. The mixture was then stirred at 20° C. for 12 h. Saturated NaHCO 3 was added to the mixture until it reached pH 8-9, and then extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (silica flash column, eluent of 0-10% ethyl acetate / petroleum) to give the semi-purified product. The product was further purified by p-TLC (eluent of 25% ethyl acetate / petroleum) to give the title compound as a yellow oil (50 mg, 150.76 μmol, 13% yield, 80% purity). 1 H NMR (400 MHz, MeOD-d 4 ) δ 7.40 - 7.28 (m, 5H), 5.11 (s, 2H), 4.44 (d, J = 10 Hz, 1H), 4.10 - 4.06 (m, 1H), 3.90 (dd, J = 4.4, 13.2 Hz, 1H), 2.71 - 2.53 (m, 2H), 1.82 - 1.68 (m, 2H), 1.00-0.98 (m, 6H).

[0415] (3R,4S,5S)-4-Fluoro-3,5-dimethylpiperidine

[0416] To a solution of benzyl (3S,4S,5R)-4-fluoro-3,5-dimethyl-piperidine-1-carboxylate (40 mg, 150.76 μmol) in EtOH (1 mL) was added Pd / C (10%, 8 mg) under Ar. The mixture was cooled to 37° C. for 1 h. 2The mixture was stirred under (15 psi) at 20° C. for 12 h. The reaction mixture was filtered, and HCl / dioxane (2 mL) was added to the filtrate and stirred at 20° C. for 0.5 h. The solution was concentrated under reduced pressure to give the title compound as a white oil (20 mg, 57.26 μmol, 38% yield, 48% purity, HCl). 1 H NMR (400 MHz, MeOD-d 4 ) δ 4.61-4.49 (m, 1H), 3.37 - 3.33 (m, 2H), 3.24 - 3.16 (m, 2H), 2.32 - 2.13 (m, 2H), 1.11 - 1.10 (m, 6H).

[0417] 2-((6-((3-chloro-5-cyano-6-((3R,4S,5S)-4-fluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (45)

[0418] To a solution of 2-[[6-[(3,6-dichloro-5-cyano-2-pyridyl)amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (30 mg, 69.40 μmol) and (3S,4S,5R)-4-fluoro-3,5-dimethyl-piperidine (18.62 mg, 111.04 μmol, HCl) in DMF (0.5 mL) was added DIPEA (26.91 mg, 208.20 μmol, 36.27 μL). The mixture was stirred at 100° C. for 3 hours. The mixture was analyzed by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 35% to 65%, 8 min) to give the title compound as a white solid (4.5 mg, 8.38 μmol, 12% yield, 98% purity). 1 H NMR (400 MHz, DMSO-d 6) δ 9.07 (s, 1H), 7.95 (s, 2H), 7.82 (d, J = 2.0 Hz, 1H), 7.64 (dd, J = 2.0, 9.2 Hz, 1H), 7.46 (d, J = 9.2 Hz, 1H), 7.22 (s, 1H), 4.56 - 4.43 (m, 3H), 3.98 (br dd, J = 3.6, 13.2 Hz, 2H), 3.67 (s, 3H), 2.78 (t, J = 12.4 Hz, 2H), 2.66 (d, J = 4.4 Hz, 3H), 1.89 - 1.76 (m, 2H), 0.84 (d, J = 6.8 Hz, 6H).

[0419] Example 21: Synthesis of 2-((6-((6-((3S,5R)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-3-chloro-5-cyanopyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (43) and 2-((6-((6-((3R,5S)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-3-chloro-5-cyanopyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (44) [ka]

[0420] 2-((6-((3-chloro-5-cyano-6-(3-(1,3-dioxoisoindolin-2-yl)-4,4-difluoro-5-methylpiperidin-1-yl)pyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0421] To a solution of 2-(4,4-difluoro-5-methyl-3-piperidyl)isoindoline-1,3-dione (250.00 mg, 892.00 μmol) and 2-[[6-[(3,6-dichloro-5-cyano-2-pyridyl)amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (296.60 mg, 686.15 μmol) in DMSO (3 mL), DIPEA (177.36 mg, 1.37 mmol, 239.03 μL) was added and the reaction mixture was stirred for 3 h at 100° C. The reaction mixture was treated with water (10 mL) to form a precipitate which was filtered, the filter cake was washed, collected and dried under vacuum to give the title compound as a yellow solid (450 mg, crude).

[0422] 2-((6-((6-(3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-3-chloro-5-cyanopyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0423] To a solution of 2-[[6-[[3-chloro-5-cyano-6-[3-(1,3-dioxoisoindolin-2-yl)-4,4-difluoro-5-methyl-1-piperidyl]-2-pyridyl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (400 mg, 591.66 μmol) in EtOH (20 mL), MeNH 2 (86.13mg, 1.11mmol, 20mL, H 2 40% purity in O) was added and the reaction mixture was stirred at 70° C. for 12 h. The reaction mixture (combined with another batch on a 50 mg scale) was concentrated under vacuum and purified by preparative HPLC (column: Phenomenex C18 80*40 mm*3 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 25%-45%, 8 min) to give the title compound as a white solid (68 mg, purity 98.90%).

[0424] 2-((6-((6-((3S,5R)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-3-chloro-5-cyanopyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (43) and 2-((6-((6-((3R,5S)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-3-chloro-5-cyanopyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (44).

[0425] The racemate (68 mg) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O ​​ETOH]; B%: 50%-50%, 15 min) and then purified by preparative HPLC (column: C18-1 150*30mm*5μm; mobile phase: [water(NH4HCO3)-ACN]; B%: 20%-60%, 20min) to give 2-[[6-[[6-[(3R,5S)-3-amino-4,4-difluoro-5-methyl-1-piperidyl]-3-chloro-5-cyano-2-pyridyl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide as a white solid (8.5mg, 15.38μmol, yield 12%, purity 99%); 1 H NMR (400 MHz, DMSO-d 6) δ 9.08 (s, 1H), 8.00 (s, 1H), 7.94 (m, 2H), 7.65 (dd, J = 2.4, 9.2 Hz, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.36 (s, 1H), 4.55 (s, 2H), 4.31 - 4.22 (d, J = 9.2 Hz, 1H), 4.16 - 4.06 (d, J = 11.6 Hz, 1H), 3.67 (s, 3H), 3.05 - 2.91 (m, 1H), 2.87 - 2.74 (m, 2H), 2.66 (d, J = 4.4Hz, 3H), 2.16 - 2.01 (m, 1H), 1.94 - 1.61 (m, 2H), 0.85 (d, J = 6.4 Hz, 3H); and 2-[[6-[[6-[(3S,5R)-3-amino-4,4-difluoro-5-methyl-1-piperidyl]-3-chloro-5-cyano-2-pyridyl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide was obtained as a white solid (13 mg, 23.25 μmol, 19% yield, 98% purity; 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.08 (s, 1H), 8.00 (s, 1H), 7.94 (m, 2H), 7.65 (dd, J = 2.4, 9.2 Hz, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.36 (s, 1H), 4.55 (s, 2H), 4.26 (d, J = 12.8 Hz, 1H), 4.11 (dd, J = 2.4, 14.0 Hz, 1H), 3.67 (s, 3H), 3.05 - 2.91 (m, 1H), 2.86 - 2.74 (m, 2H), 2.66 (d, J = 4.4 Hz, 3H), 2.16 - 2.00 (m, 1H), 1.76 (s, 2H), 0.85 (d, J = 6.8 Hz, 3H).

[0426] The absolute configurations of compounds 43 and 44 were randomly assigned based on the cis conformation of the amino and methyl groups.

[0427] Example 22: Synthesis of 2-((1-(azetidin-3-ylmethyl)-6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (65) [ka]

[0428] tert-Butyl 3-((6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-3-(2-methoxy-2-oxoethoxy)-2-oxoquinolin-1(2H)-yl)methyl)azetidine-1-carboxylate

[0429] Methyl 2-[[6-[[3-chloro-5-cyano-6-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-2-pyridyl]amino]-2-oxo-1H-quinolin-3-yl]oxy]acetate (100 mg, 187.99 μmol), tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (55.86 mg, 187.99 μmol, 5.41 μL), K 2 CO 3 A mixture of (51.96 mg, 375.98 μmol) in DMSO (1.5 mL) was stirred at 80° C. for 12 h. The mixture (combined with another batch of the same scale) was cooled to 20° C. and water (2 mL) was added, forming a precipitate which was filtered and diluted with H 2 O (50 mL) and ethyl acetate (20 mL), then the solid was dried under reduced pressure to give the title compound as a brown solid (200 mg, crude). LCMS: [M+H] + =701.3.

[0430] tert-Butyl 3-((6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-3-(2-(methylamino)-2-oxoethoxy)-2-oxoquinolin-1(2H)-yl)methyl)azetidine-1-carboxylate

[0431] tert-Butyl 3-[[6-[[3-chloro-5-cyano-6-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-2-pyridyl]amino]-3-(2-methoxy-2-oxo-ethoxy)-2-oxo-1-quinolyl]methyl]azetidine-1-carboxylate (200 mg, 285.24 μmol), MeNH 2 / H 2 A mixture of 2H2O (10 mL, 40% purity) in EtOH (10 mL) was stirred at 70° C. for 12 h. The mixture was concentrated to give the title compound as a yellow solid (250 mg, crude), which was used without further purification. LCMS: [M+H] + =700.2.

[0432] 2-((1-(azetidin-3-ylmethyl)-6-((3-chloro-5-cyano-6-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (65)

[0433] A mixture of tert-butyl 3-[[6-[[3-chloro-5-cyano-6-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-2-pyridyl]amino]-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-1-quinolyl]methyl]azetidine-1-carboxylate (250 mg, 357.05 μmol) in DCM (2 mL) and TFA (1 mL) was stirred at 20° C. for 1 h. The mixture was concentrated under vacuum and purified by p-HPLC (column: Waters Xbridge BEH C18 100*25Mm*5 μm; mobile phase: [water (NH 4 HCO 3)-ACN]; B%: 30% to 60%, 10 min) to give the title compound as a white solid (25 mg, 37.34 μmol, 10% yield, 90% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.01 - 9.21 (m, 1H), 8.00 (s, 1H), 7.95 (br d, J = 4.63 Hz, 1H), 7.75 (d, J = 2.13 Hz, 1H), 7.61 (dd, J = 8.94, 1.81 Hz, 1H), 7.51 (br d, J = 9.01 Hz, 1H), 7.22 (s, 1H), 4.49 - 4.61 (m, 4H), 4.12 (br d, J = 12.51 Hz, 2H), 3.41 (br d, J = 5.00 Hz, 4H), 2.99 - 3.10 (m, 1H), 2.78 (br t, J = 13.01 Hz, 2H), 2.67 (d, J = 4.50 Hz, 4H), 1.96 - 2.17 (m, 2H), 0.83 (d, J = 6.63 Hz, 6H).

[0434] Example 23: Synthesis of 2-((3R,5S)-3-amino-5-methylpiperidin-1-yl)-5-chloro-6-(((S)-2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinolin-10-yl)amino)nicotinonitrile (24) and 2-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-5-chloro-6-(((S)-2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinolin-10-yl)amino)nicotinonitrile (25) [ka]

[0435] Ethyl 4-hydroxy-6-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate

[0436] To a solution of 6-nitro-1H-benzo[d][1,3]oxazine-2,4-dione (20 g, 96.09 mmol) and diethyl malonate (23.09 g, 144.14 mmol, 21.78 mL) in DMF (500 mL) was added NaH (7.69 g, 192.19 mmol, 60% purity) at 0° C. The reaction mixture was warmed to 20° C. and stirred for 12 h. The reaction mixture was cooled to 0° C. and water (1000 mL) was added. The aqueous mixture was neutralized to pH=7 with 1N aqueous HCl and the resulting mixture was stirred at 20° C. for 30 min. The resulting yellow precipitate was filtered and washed with water (1 L). The yellow precipitate was dried under reduced pressure to give the title compound as a yellow solid (46 g, 160.49 mmol, 84% yield, 97% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.08 (s, 1H), 8.73 (d, J = 1.9 Hz, 1H), 8.47 - 8.36 (m, 1H), 7.95 (s, 1H), 7.41 (d, J = 9.0 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 2.89 (s, 2H), 2.73 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H).

[0437] Ethyl 2,4-dichloro-6-nitroquinoline-3-carboxylate

[0438] Ethyl 4-hydroxy-6-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate (46 g, 165.34 mmol) POCl 3 (450 mL) and then the mixture was diluted with N 2 The mixture was stirred under atmosphere for 4 hours at 80° C. The reaction mixture was concentrated under reduced pressure to give a residue which was triturated with MTBE (100 mL) at 25° C. for 30 minutes to give the title compound as a yellow solid (37 g, 114.07 mmol, 69% yield, 97% purity). 1 H NMR (400 MHz, DMSO-d 6) δ 8.99 (d, J = 2.5 Hz, 1H), 8.67 (dd, J = 2.5, 9.2 Hz, 1H), 8.31 (d, J = 9.2 Hz, 1H), 4.53 (q, J = 7.0 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H).

[0439] Ethyl 4-chloro-6-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate

[0440] A mixture of ethyl 2,4-dichloro-6-nitroquinoline-3-carboxylate (35 g, 111.07 mmol), NaOAc (10.02 g, 122.18 mmol) in AcOH (350 mL) was then added to the mixture under N 2 The mixture was stirred at 120° C. under atmospheric pressure for 12 hours. Water (500 mL) was added to the reaction mixture (combined with another batch on a 2 g scale) to form a precipitate, which was filtered and diluted with H 2 O (1 L) and then the solid was dried under reduced pressure to give the title compound as a yellow solid (25 g, 92% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.99 (s, 1H), 8.66 (d, J = 2.5 Hz, 1H), 8.49 (dd, J = 2.5, 9.0 Hz, 1H), 7.55 (d, J = 9.0 Hz, 1H), 4.38 (q, J = 7.0 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H).

[0441] Ethyl 4-chloro-1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate

[0442] To a mixture of ethyl 4-chloro-6-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate (15 g, 50.56 mmol) in DMF (150 mL), NaH (2.83 g, 70.79 mmol, 60% purity) was added at 0° C. and the mixture was stirred at 0° C. for 0.5 h, then iodomethane (35.88 g, 252.81 mmol, 15.74 mL) was added to the mixture and the mixture was stirred at 20° C. for 6 h. Water (50 mL) was added to the mixture to form a precipitate which was filtered and purified by H 2 The solid was washed with O (100 mL) and then dried under reduced pressure. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 30 / 1-2 / 1) to give a semi-purified product, which was further purified by reversed-phase MPLC (neutral conditions: column: 330 g Agela C18; mobile phase: [water-ACN]; gradient B%: 25-50% 20 min; 50-50% 20 min) to give the title compound as a yellow solid (9.3 g, 29.68 mmol, 59% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.71 (d, J = 2.6 Hz, 1H), 8.54 (dd, J = 2.6, 9.3 Hz, 1H), 7.87 (d, J = 9.4 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.69 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H).

[0443] (S)-Ethyl 4-((1-cyclopropyl-2,2-difluoro-3-hydroxypropyl)amino)-1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate

[0444] To a solution of ethyl 4-chloro-1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate (500 mg, 1.61 mmol) and (S)-3-amino-3-cyclopropyl-2,2-difluoropropan-1-ol hydrochloride (413.65 mg, 2.20 mmol) in MeCN (5 mL) was added 2DIEA (519.40 mg, 4.02 mmol, 700.00 μL) was added under reduced pressure. The mixture was stirred at 160° C. in a microwave for 32 h. The mixture was concentrated in vacuo to give the title compound as a brown solid (680 mg, 799.28 μmol, 50% yield, 50% purity). LCMS: [M+H] + =426.1.

[0445] (S)-4-((1-cyclopropyl-2,2-difluoro-3-hydroxypropyl)amino)-1-methyl-6-nitroquinolin-2(1H)-one

[0446] To a solution of (S)-ethyl 4-((1-cyclopropyl-2,2-difluoro-3-hydroxypropyl)amino)-1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate (680 mg, 1.60 mmol) in MeCN (5 mL) was added NaOH (2M, 25.00 mL). The mixture was stirred at 85° C. for 2 h. Then water (20 mL) was added, followed by 3N HCl until pH=6. The formed precipitate was filtered and the filter cake was dried under reduced pressure to give the title compound as a yellow solid (400 mg, 520.77 μmol, 33% yield, 46% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.30 (d, J = 2.50 Hz, 1H), 8.39 (dd, J = 9.36, 2.44 Hz, 1H), 7.62 (d, J = 9.42 Hz, 1H), 7.47 (d, J = 8.70 Hz, 1H), 5.72 (s, 1H), 5.59 (t, J = 6.14 Hz, 1H), 3.72 - 3.89 (m, 2H), 3.55 (s, 3H), 3.46 - 3.53 (m, 1H), 1.29 - 1.38 (m, 1H), 0.64 - 0.72 (m, 1H), 0.60 (dq, J = 9.40, 4.77 Hz, 1H), 0.46 - 0.54 (m, 1H), 0.24 (dq, J = 9.55, 4.84 Hz, 1H).

[0447] (S)-3-Bromo-4-((1-cyclopropyl-2,2-difluoro-3-hydroxypropyl)amino)-1-methyl-6-nitroquinolin-2(1H)-one

[0448] To a solution of (S)-4-((1-cyclopropyl-2,2-difluoro-3-hydroxypropyl)amino)-1-methyl-6-nitroquinolin-2(1H)-one (400 mg, 1.13 mmol) and NBS (201.49 mg, 1.13 mmol) in DCM (8 mL), TFA (645.42 mg, 5.66 mmol, 419.10 μL) was added. 2 The mixture was stirred at 0° C. for 0.5 h. Saturated NaHCO 3 (50 mL) was added to the mixture and extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL) and anhydrous Na 2 SO 4 The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent of 0-30% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give the title compound as a white solid (400 mg, 832.92 μmol, 74% yield, 90% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.95 (d, J = 2.45 Hz, 1H), 8.43 (dd, J = 9.35, 2.51 Hz, 1H), 7.75 (d, J = 9.41 Hz, 1H), 5.85 (d, J = 11.13 Hz, 1H), 5.62 (t, J = 5.14 Hz, 1H), 3.96 - 4.06 (m, 1H), 3.77 - 3.90 (m, 2H), 3.71 (s, 3H), 1.20 - 1.33 (m, 1H), 0.52 - 0.70 (m, 3H), 0.41 - 0.51 (m, 1H).

[0449] (S)-2-Cyclopropyl-3,3-difluoro-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one

[0450] To a solution of (S)-3-bromo-4-((1-cyclopropyl-2,2-difluoro-3-hydroxypropyl)amino)-1-methyl-6-nitroquinolin-2(1H)-one (400 mg, 925.46 μmol) in THF (10 mL), 2 t-BuLi (1.3 M, 1.14 mL) (1.3 M in pentane) was added at 20° C. The mixture was stirred at 60° C. for 0.25 h. Water (40 mL) was added and the aqueous mixture was diluted with CH 2 Cl 2 (20 mL x 2). The organic extracts were combined, washed with brine (50 mL), and 2 SO 4 The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent of 0-30% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give the title compound as a yellow solid (250 mg, 711.63 μmol, 77% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.11 (d, J = 2.41 Hz, 1H), 8.34 (dd, J = 9.32, 2.52 Hz, 1H), 7.65 (d, J = 9.43 Hz, 1H), 7.01 (d, J = 3.73 Hz, 1H), 4.34 - 4.56 (m, 2H), 3.61 (s, 3H), 3.22 - 3.30 (m, 1H), 1.29 - 1.40 (m, 1H), 0.68 - 0.77 (m, 1H), 0.49 - 0.59 (m, 2H), 0.30 - 0.38 (m, 1H).

[0451] (S)-10-Amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one

[0452] To a mixture of Pd / C (0.05 g, 768.56 μmol, 10% purity) in THF (10 mL) was added (S)-2-cyclopropyl-3,3-difluoro-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one (250 mg, 711.63 μmol) under Ar. The suspension was degassed under vacuum and diluted with H 2 The mixture was purged with H several times. 2 (15 psi) at 60° C. for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow solid (150 mg, 261.42 μmol, 37% yield, 56% purity). LCMS: [M+H] + =322.1.

[0453] (S)-2,5-Dichloro-6-((2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinolin-10-yl)amino)nicotinonitrile

[0454] To a solution of (S)-10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one (150 mg, 466.82 μmol) and 2,5,6-trichloropyridine-3-carbonitrile (96.84 mg, 466.82 μmol) in DMF (5 mL) was added DIEA (120.67 mg, 933.65 μmol, 162.62 μL). The mixture was stirred at 100° C. for 12 hours. The mixture was cooled to 20° C., water (10 mL) was added, and a precipitate formed which was filtered and the filter cake was concentrated in vacuo to give the title compound as a yellow solid (150 mg, 152.34 μmol, 33% yield, 50% purity). LCMS: [M+H]+=492.0.

[0455] tert-Butyl (1-(5-chloro-3-cyano-6-(((S)-2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinolin-10-yl)amino)pyridin-2-yl)-5-methylpiperidin-3-yl)carbamate

[0456] To a solution of (S)-2,5-dichloro-6-((2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinolin-10-yl)amino)nicotinonitrile (150 mg, 304.69 μmol) and tert-butyl N-(5-methyl-3-piperidyl)carbamate (78.36 mg, 365.63 μmol) in DMSO (2 mL) was added DIEA (78.76 mg, 609.38 μmol, 106.14 μL). The mixture was stirred at 100° C. for 1 h. The mixture was cooled to 20° C. and water (5 mL) was added, forming a precipitate which was filtered and the filter cake was concentrated in vacuo to give the title compound as a yellow solid (150 mg, 111.92 μmol, 37% yield, 50% purity). LCMS: [M+H] + =670.2.

[0457] 2-(3-amino-5-methylpiperidin-1-yl)-5-chloro-6-(((S)-2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinolin-10-yl)amino)nicotinonitrile

[0458] A solution of tert-butyl (1-(5-chloro-3-cyano-6-(((S)-2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinolin-10-yl)amino)pyridin-2-yl)-5-methylpiperidin-3-yl)carbamate (150 mg, 223.83 μmol) in HCl / EtOAc (4M, 7.50 mL). The mixture was stirred at 20° C. for 1 h. The mixture was concentrated under vacuum and used without further workup. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 30% to 60%, 10 min) to give the title compound as a yellow solid (40 mg, 70.07 μmol, yield 31%, purity 99%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.02 (s, 1H), 8.09 - 8.13 (m, 1H), 7.90 (s, 1H), 7.64 (dd, J = 8.99, 1.65 Hz, 1H), 7.44 (dd, J = 9.05, 1.10 Hz, 1H), 6.26 - 6.33 (m, 1H), 4.26 - 4.51 (m, 3H), 4.14 (d, J = 11.74 Hz, 1H), 3.98 - 4.06 (m, 1H), 3.56 (s, 3H), 2.37 - 2.45 (m, 2H), 2.23 - 2.35 (m, 2H), 1.76 - 1.85 (m, 2H), 1.52 (s, 1H), 1.28 - 1.37 (m, 1H), 0.72 - 0.82 (m, 2H), 0.68 (d, J = 7.09 Hz, 3H), 0.52 (d, J = 5.14 Hz, 2H), 0.28 - 0.36 (m, 1H).

[0459] 2-((3R,5S)-3-amino-5-methylpiperidin-1-yl)-5-chloro-6-(((S)-2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinolin-10-yl)amino)nicotinonitrile (24)

[0460] 2-(3-amino-5-methylpiperidin-1-yl)-5-chloro-6-(((S)-2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinolin-10-yl)amino)nicotinonitrile (70.00 mg, 122.80 μmol) was purified by SFC (column: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: [ACN / IPA (0.1% NH 3 H 2 O)]; B%: 65%-65%, 30 min) to give the title compound as a yellow solid (8 mg, 13.31 μmol, 11% yield, 95% purity). 1 H NMR (400 MHz, DMSO-d 6) δ 9.16 (s, 1H), 8.09 (d, J = 1.67 Hz, 1H), 8.02 (s, 1H), 7.92 (s, 2H), 7.68 (dd, J = 8.94, 1.79 Hz, 1H), 7.45 (d, J = 9.06 Hz, 1H), 6.29 (s, 1H), 4.24 - 4.48 (m, 3H), 3.94 (d, J = 12.64 Hz, 1H), 3.57 (s, 3H), 3.18 - 3.26 (m, 1H), 3.06 (t, J = 11.32 Hz, 1H), 2.82 (t, J = 11.98 Hz, 1H), 2.28 - 2.36 (m, 1H), 1.95 (d, J = 12.16 Hz, 1H), 1.59 - 1.71 (m, 1H), 1.30 - 1.37 (m, 1H), 1.23 (s, 1H), 1.05 (q, J = 11.96 Hz, 1H), 0.68 (d, J = 6.44 Hz, 3H), 0.53 (t, J = 5.66 Hz, 2H), 0.28 - 0.35 (m, 1H).

[0461] 2-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-5-chloro-6-(((S)-2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinolin-10-yl)amino)nicotinonitrile (25)

[0462] 2-(3-amino-5-methylpiperidin-1-yl)-5-chloro-6-(((S)-2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinolin-10-yl)amino)nicotinonitrile (70.00 mg, 122.80 μmol) was purified by SFC (column: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: [ACN / IPA (0.1% NH 3 H 2O)]; B%: 65%-65%, 30 min) to give the title compound as a yellow solid (8.2 mg, 14.18 μmol, 12% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.22 (s, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 7.94 (d, J = 2.38 Hz, 2H), 7.73 - 7.78 (m, 1H), 7.51 (d, J = 9.06 Hz, 1H), 6.33 (s, 1H), 4.29 - 4.53 (m, 3H), 3.99 (d, J = 12.52 Hz, 1H), 3.63 (s, 3H), 3.24 - 3.32 (m, 1H), 3.07 - 3.16 (m, 1H), 2.86 (t, J = 11.86 Hz, 1H), 2.39 (t, J = 12.16 Hz, 1H), 2.02 (d, J = 11.21 Hz, 1H), 1.70 (dt, J = 5.27, 2.67 Hz, 1H), 1.35 - 1.42 (m, 1H), 1.29 (s, 1H), 1.12 (q, J = 12.20 Hz, 1H), 0.76 (d, J = 6.44 Hz, 3H), 0.59 (d, J = 5.01 Hz, 2H), 0.38 (d, J = 4.41 Hz, 1H).

[0463] The absolute configurations of compounds 24 and 25 were randomly assigned based on the cis conformation of the amino and methyl groups.

[0464] Example 24: Synthesis of 2-((6-((6-((3R,5S)-3-amino-5-methylpiperidin-1-yl)-3-chloro-5-cyanopyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (39) and 2-((6-((6-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-3-chloro-5-cyanopyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (40) [ka]

[0465] tert-Butyl (1-(5-chloro-3-cyano-6-((1-methyl-3-(2-(methylamino)-2-oxoethoxy)-2-oxo-1,2-dihydroquinolin-6-yl)amino)pyridin-2-yl)-5-methylpiperidin-3-yl)carbamate

[0466] A flask containing a mixture of 2-((6-((3,6-dichloro-5-cyanopyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (300 mg, 694.03 μmol), tert-butyl N-(5-methyl-3-piperidyl)carbamate (178.48 mg, 832.83 μmol) and DIEA (179.40 mg, 1.39 mmol, 241.77 μL) in DMSO (6 mL) was degassed and diluted with N 2 Purge the mixture three times with N 2 The mixture was stirred under atmosphere at 100° C. for 12 hours. The mixture was cooled to 20° C., water (10 mL) was added, a precipitate formed which was filtered, the filter cake was washed with EtOAc (20 mL) and concentrated in vacuo to give the title compound as a grey solid (300 mg, 418.95 μmol, 60% yield, 85% purity). LCMS: [M+H] + =610.2.

[0467] 2-((6-((6-(3-amino-5-methylpiperidin-1-yl)-3-chloro-5-cyanopyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0468] A mixture of tert-butyl (1-(5-chloro-3-cyano-6-((1-methyl-3-(2-(methylamino)-2-oxoethoxy)-2-oxo-1,2-dihydroquinolin-6-yl)amino)pyridin-2-yl)-5-methylpiperidin-3-yl)carbamate (300 mg, 491.72 μmol) and HCl / EtOAc (4N HCl in EtOAc, 20 mL) was stirred at 20° C. for 1 h. The mixture was concentrated in vacuum without further workup, and the residue was purified by preparative HPLC (column: Phenomenex Luna C18 80*40 mm*3 μm; mobile phase: [water (HCl)-ACN]; B%: 20%-50%, 7 min) to give the title compound as a yellow solid (150 mg, HCl, purity 99%). 1 H NMR (400 MHz, DMSO-d 6 , 26℃) δ 9.12 (s, 1H), 8.26 (s, 2H), 8.00 - 8.08 (m, 2H), 7.86 (d, J = 2.20 Hz, 1H), 7.71 (dd, J = 9.05, 2.20 Hz, 1H), 7.54 (d, J = 9.17 Hz, 1H), 7.31 (s, 1H), 4.56 - 4.62 (m, 2H), 4.32 (d, J = 9.17 Hz, 1H), 4.01 (d, J = 11.49 Hz, 1H), 3.69 (s, 3H), 3.10 - 3.21 (m, 1H), 2.84 (t, J = 11.74 Hz, 1H), 2.68 (d, J = 4.52 Hz, 3H), 2.39 - 2.46 (m, 1H), 2.03 - 2.11 (m, 1H), 1.72 - 1.86 (m, 1H), 1.16 (q, J = 11.86 Hz, 1H), 0.84 (d, J = 6.48 Hz, 3H).

[0469] 2-((6-((6-((3R,5S)-3-amino-5-methylpiperidin-1-yl)-3-chloro-5-cyanopyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (39)

[0470] 2-((6-((6-(3-amino-5-methylpiperidin-1-yl)-3-chloro-5-cyanopyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (150 mg, 274.50 μmol, HCl) was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: 0.1% NH 3 H 2 O EtOH; B%: 47%-47%, 7 min) to give the title compound as a white solid (10 mg, 18.50 μmol, 7% yield, 94% purity). 1 H NMR (400 MHz, DMSO-d 6 , 24℃) δ 8.98 (s, 1H), 7.98 (s, 2H), 7.92 (s, 1H), 7.67 (dd, J = 8.80, 1.83 Hz, 1H), 7.47 (d, J = 8.93 Hz, 1H), 7.29 (s, 1H), 4.54 (s, 2H), 4.24 (d, J = 11.62 Hz, 1H), 4.13 (d, J = 12.72 Hz, 1H), 3.67 (s, 3H), 2.66 (d, J = 4.52 Hz, 4H), 2.32 - 2.45 (m, 1H), 1.88 (d, J = 12.23 Hz, 1H), 1.68 - 1.75 (m, 1H), 1.64 (d, J = 9.29 Hz, 1H), 1.18 - 1.30 (m, 1H), 0.79 (d, J = 6.48 Hz, 3H).

[0471] 2-((6-((6-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-3-chloro-5-cyanopyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (40)

[0472] 2-((6-((6-(3-amino-5-methylpiperidin-1-yl)-3-chloro-5-cyanopyridin-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (150 mg, 274.50 μmol, HCl) was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: 0.1% NH 3 H 2 O EtOH; B%: 47%-47%, 7 min) to give the title compound as a white solid (10 mg, 18.50 μmol, 7% yield, 94% purity). 1 H NMR (400 MHz, DMSO-d 6 , 24℃) δ 9.13 (s, 1H), 8.25 (s, 2H), 8.01 - 8.11 (m, 2H), 7.86 (s, 1H), 7.70 (d, J = 8.93 Hz, 1H), 7.54 (d, J = 9.17 Hz, 1H), 7.31 (s, 1H), 4.59 (s, 2H), 4.31 (d, J = 10.88 Hz, 1H), 4.00 (d, J = 11.25 Hz, 1H), 3.68 (s, 3H), 3.15 (t, J = 10.58 Hz, 1H), 2.83 (t, J = 11.80 Hz, 1H), 2.67 (d, J = 4.40 Hz, 3H), 2.37 - 2.45 (m, 1H), 2.02 - 2.10 (m, 1H), 1.78 (d, J = 3.55 Hz, 1H), 1.09 - 1.29 (m, 2H), 0.83 (d, J = 6.48 Hz, 3H).

[0473] The absolute configurations of compounds 39 and 40 were randomly assigned based on the cis conformation of the amino and methyl groups.

[0474] Example 25: Synthesis of 2-((3R,5S)-3-amino-5-methylpiperidin-1-yl)-5-chloro-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (35) and 2-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-5-chloro-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (36) [ka]

[0475] tert-Butyl (1-(5-chloro-3-cyano-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)pyridin-2-yl)-5-methylpiperidin-3-yl)carbamate

[0476] A flask containing a mixture of 2,5-dichloro-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (100 mg, 237.93 μmol), tert-butyl(5-methylpiperidin-3-yl)carbamate (61.19 mg, 285.52 μmol) and DIEA (61.50 mg, 475.86 μmol, 82.89 μL) in DMSO (1 mL) was degassed and diluted with N 2 Purge the mixture three times with N 2Stirred at 100° C. under atmospheric pressure for 1 hour. Water (5 mL) was added to form a precipitate, which was filtered and the filter cake was dried under reduced pressure to give the title compound as a yellow solid (150 mg, 213.51 μmol, 90% yield, 85% purity). LCMS: [M-Boc+H] + =498.2.

[0477] 2-(3-amino-5-methylpiperidin-1-yl)-5-chloro-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile

[0478] A mixture of tert-butyl (1-(5-chloro-3-cyano-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)pyridin-2-yl)-5-methylpiperidin-3-yl)carbamate (130 mg, 217.34 μmol) and HCl / EtOAc (4 M, 13 mL) was diluted with N 2 The mixture was stirred under atmosphere for 1 hour at 20° C. The mixture was concentrated in vacuo to give the title compound as a yellow solid (25 mg, 46.43 μmol, 21% yield, 99% purity, HCl). 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.78 (d, J = 6.60 Hz, 3H), 1.17 (s, 7H), 1.67 - 1.75 (m, 3H), 2.02 (br d, J = 11.98 Hz, 1H), 2.34 - 2.42 (m, 1H), 2.83 (t, J = 11.92 Hz, 1H), 3.07 - 3.17 (m, 1H), 3.32 (s, 2H), 3.85 - 3.90 (m, 2H), 3.93 - 3.99 (m, 1H), 4.26 - 4.32 (m, 1H), 7.12 (d, J = 8.31 Hz, 1H), 7.25 - 7.33 (m, 2H), 7.98 (s, 1H), 8.09 (br s, 3H), 8.99 (s, 1H).

[0479] 2-((3R,5S)-3-amino-5-methylpiperidin-1-yl)-5-chloro-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (35) and 2-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-5-chloro-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (36)

[0480] Racemic 2-(3-amino-5-methylpiperidin-1-yl)-5-chloro-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (50 mg, HCl) was analyzed by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH 3 H 2 O IPA]; B%: 30%-30%, 10 min) to give 2-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-5-chloro-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile as a white solid (11.6 mg, 22.90 μmol, 24% yield, 98% purity); 1 H NMR (400 MHz, DMSO-d 6) δ 0.78 (d, J = 6.60 Hz, 3H), 1.08 - 1.16 (m, 2H), 1.17 (s, 6H), 1.67 - 1.74 (m, 3H), 2.04 (br d, J = 11.49 Hz, 1H), 2.40 (br d, J = 11.86 Hz, 1H), 2.85 (br t, J = 11.86 Hz, 1H), 3.10 (br t, J = 10.82 Hz, 1H), 3.32 (br s, 2H), 3.84 - 3.91 (m, 2H), 3.96 (br d, J = 11.49 Hz, 1H), 4.28 (br d, J = 9.66 Hz, 1H), 7.14 (d, J = 8.44 Hz, 1H), 7.28 - 7.31 (m, 1H), 7.32 (s, 1H), 7.98 (s, 1H), 8.22 (br s, 3H), 8.99 (s, 1H); and 2-((3R,5S)-3-amino-5-methylpiperidin-1-yl)-5-chloro-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile as a white solid (12.2 mg, 24.27 μmol, 26% yield, 99% purity). 1 H NMR (400 MHz, DMSO-d 6) δ 0.76 (d, J = 6.60 Hz, 3H), 0.79 - 0.87 (m, 1H), 1.16 (s, 6H), 1.57 - 1.65 (m, 1H), 1.67 - 1.73 (m, 1H), 1.86 (br d, J = 12.23 Hz, 1H), 2.33 (br t, J = 12.10 Hz, 2H), 2.60 - 2.69 (m, 2H), 3.32 (br s, 2H), 3.86 - 3.92 (m, 2H), 4.04 (br d, J = 11.74 Hz, 1H), 4.16 - 4.22 (m, 1H), 7.10 (d, J = 8.44 Hz, 1H), 7.25 (dd, J = 8.44, 1.59 Hz, 1H), 7.38 (d, J = 1.47 Hz, 1H), 7.89 (s, 1H), 8.87 (s, 1H).

[0481] The absolute configurations of compounds 35 and 36 were randomly assigned based on the cis conformation of the amino and methyl groups.

[0482] Example 26: Synthesis of chloro-5-cyanopyridin-2-yl)amino)-1-(oxetan-3-ylmethyl)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (41) and 2-((6-((6-((3R,5S)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-3-chloro-5-cyanopyridin-2-yl)amino)-1-(oxetan-3-ylmethyl)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (42) [ka]

[0483] Methyl 2-((6-((3,6-dichloro-5-cyanopyridin-2-yl)amino)-1-(oxetan-3-ylmethyl)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)acetate

[0484] To a solution of methyl 2-[[6-[(3,6-dichloro-5-cyano-2-pyridyl)amino]-2-oxo-1H-quinolin-3-yl]oxy]acetate (3.5 g, 8.35 mmol) in DMSO (35 mL), 2 CO 3 (2.31 g, 16.70 mmol) and 3-(iodomethyl)oxetane (1.65 g, 8.35 mmol) were added. The mixture was stirred at 80° C. for 12 h. The reaction mixture was cooled to 15° C. and water (20 mL) was added, forming a precipitate which was filtered and the filter cake was dried in vacuum to give the title compound as a yellow solid (4 g, crude). LCMS: [M+H] + =489.0.

[0485] 2-((6-((3,6-dichloro-5-cyanopyridin-2-yl)amino)-1-(oxetan-3-ylmethyl)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)acetic acid

[0486] Methyl 2-[[6-[(3,6-dichloro-5-cyano-2-pyridyl)amino]-1-(oxetan-3-ylmethyl)-2-oxo-3-quinolyl]oxy]acetate (4 g, 8.17 mmol) in EtOH (40 mL) and H 2 To a solution of LiOH H 2 0 (1.72 g, 40.87 mmol) was added. The mixture was stirred at 25° C. for 1 h. The mixture was concentrated in vacuo to give the title compound as a yellow solid (4 g, crude). LCMS: [M+H] + =474.9.

[0487] 2-((6-((3,6-dichloro-5-cyanopyridin-2-yl)amino)-1-(oxetan-3-ylmethyl)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0488] 2-[[6-[(3,6-dichloro-5-cyano-2-pyridyl)amino]-1-(oxetan-3-ylmethyl)-2-oxo-3-quinolyl]oxy]acetic acid (4 g, 8.42 mmol) and MeNH2 To a solution of (1.14 g, 16.83 mmol, HCl) in DMF (30 mL) was added HATU (6.40 g, 16.83 mmol) and DIPEA (4.35 g, 33.66 mmol, 5.86 mL). The mixture was stirred at 25° C. for 12 h. Water (60 mL) was added and then the mixture was extracted with ethyl acetate (50 mL×2). The combined organic phase was washed with brine (100 mL) and anhydrous Na 2 SO 4 The crude product was triturated with EtOAc (20 mL) at 25° C. for 10 min to give the title compound as a yellow solid (1.2 g, 1.72 mmol, 20% yield, 70% purity). LCMS: [M+H] + =488.2.

[0489] 2-((6-((3-chloro-5-cyano-6-(3-(1,3-dioxoisoindolin-2-yl)-4,4-difluoro-5-methylpiperidin-1-yl)pyridin-2-yl)amino)-1-(oxetan-3-ylmethyl)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0490] To a solution of 2-[[6-[(3,6-dichloro-5-cyano-2-pyridyl)amino]-1-(oxetan-3-ylmethyl)-2-oxo-3-quinolyl]oxy]-N-methylacetamide (200 mg, 409.57 μmol) and 2-(4,4-difluoro-5-methyl-3-piperidyl)isoindoline-1,3-dione (114.79 mg, 409.57 μmol) in DMSO (2 mL) was added DIPEA (105.87 mg, 819.13 μmol, 142.68 μL). The mixture was stirred at 100° C. for 12 hours. The mixture was cooled to 20° C. and water (3 mL) was added. The mixture was filtered and the filter cake was concentrated under vacuum to give a residue, which was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (NH 4 HCO 3)-ACN]; B%: 40% to 65%, 8 min) to give the title compound as a yellow solid (100 mg, 136.59 μmol, 25% yield).

[0491] 2-((6-((6-(3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-3-chloro-5-cyanopyridin-2-yl)amino)-1-(oxetan-3-ylmethyl)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (41)

[0492] To a solution of 2-[[6-[[3-chloro-5-cyano-6-[3-(1,3-dioxoisoindolin-2-yl)-4,4-difluoro-5-methyl-1-piperidyl]-2-pyridyl]amino]-1-(oxetan-3-ylmethyl)-2-oxo-3 quinolyl]oxy]-N-methyl-acetamide (100 mg, 136.59 μmol) in EtOH (4 mL), was added NH 2 NH 2 H 2 2H2O (102.56 mg, 2.05 mmol, 99.58 μL) was added. The mixture was stirred at 60° C. for 1 h. The mixture was cooled to 20° C. and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex C18 80*40 mm*3 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 15% to 45%, 8 min) to give the title compound as a white solid (40 mg, 61.58 μmol, yield 45%, purity 93%). 1 H NMR (400 MHz, DMSO-d 6) δ 9.08 (s, 1H), 8.00 (s, 1H), 7.91 - 7.97 (m, 2H), 7.60 - 7.66 (m, 1H), 7.52 - 7.57 (m, 1H), 7.36 (s, 1H), 4.66 (br d, J = 7.00 Hz, 2H), 4.57 - 4.63 (m, 2H), 4.48 - 4.56 (m, 4H), 4.21 - 4.31 (m, 1H), 4.11 (br d, J = 12.01 Hz, 1H), 3.43 (dt, J = 14.07, 7.10 Hz, 1H), 2.89 - 3.06 (m, 1H), 2.74 - 2.87 (m, 2H), 2.67 (d, J = 4.63 Hz, 3H), 1.98 - 2.18 (m, 1H), 1.77 (br d, J = 1.63 Hz, 2H), 0.86 (d, J = 6.63 Hz, 3H).

[0493] 2-((6-((6-((3S,5R)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-3-chloro-5-cyanopyridin-2-yl)amino)-1-(oxetan-3-ylmethyl)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (41) and 2-((6-((6-((3R,5S)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-3-chloro-5-cyanopyridin-2-yl)amino)-1-(oxetan-3-ylmethyl)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (42).

[0494] 2-[[6-[[6-(3-amino-4,4-difluoro-5-methyl-1-piperidyl)-3-chloro-5-cyano-2-pyridyl]amino]-1-(oxetan-3-ylmethyl)-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (40 mg, 66.44 μmol) was subjected to SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH 3 H 2O EtOH]; B%: 55%-55%, 10 min) to give 2-[[6-[[6-[(3S,5R)-3-amino-4,4-difluoro-5-methyl-1-piperidyl]-3-chloro-5-cyano-2-pyridyl]amino]-1-(oxetan-3-ylmethyl)-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide as a white solid (12 mg, 19.73 μmol, 30% yield, 99% purity); 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.07 (s, 1H), 8.00 (s, 1H), 7.93 (br d, J = 1.79 Hz, 2H), 7.61 - 7.65 (m, 1H), 7.52 - 7.56 (m, 1H), 7.36 (s, 1H), 4.66 (br d, J = 6.91 Hz, 2H), 4.57 - 4.62 (m, 2H), 4.47 - 4.56 (m, 4H), 4.08 - 4.30 (m, 2H), 3.43 (dt, J = 14.04, 6.99 Hz, 1H), 3.30 (br s, 1H), 2.92 - 3.05 (m, 1H), 2.80 (td, J = 12.58, 7.27 Hz, 2H), 2.67 (d, J = 4.53 Hz, 3H), 1.99 - 2.17 (m, 1H), 1.77 (br s, 1H), 0.86 (d, J = 6.68 Hz, 3H); and 2-[[6-[[6-[(3R,5S)-3-amino-4,4-difluoro-5-methyl-1-piperidyl]-3-chloro-5-cyano-2-pyridyl]amino]-1-(oxetan-3-ylmethyl)-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide as a white solid; 1 H NMR (400 MHz, DMSO-d 6) δ 9.07 (s, 1H), 8.00 (s, 1H), 7.91 - 7.97 (m, 2H), 7.60 - 7.66 (m, 1H), 7.52 - 7.57 (m, 1H), 7.36 (s, 1H), 4.66 (br d, J = 7.03 Hz, 2H), 4.57 - 4.63 (m, 2H), 4.49 - 4.56 (m, 4H), 4.07 - 4.30 (m, 2H), 3.39 - 3.48 (m, 1H), 3.30 (br s, 1H), 2.92 - 3.05 (m, 1H), 2.80 (td, J = 12.55, 7.21 Hz, 2H), 2.67 (d, J = 4.53 Hz, 3H), 1.99 - 2.15 (m, 1H), 1.72 - 1.90 (m, 1H), 0.86 (d, J = 6.68 Hz, 3H).

[0495] The absolute configurations of compounds 41 and 42 were randomly assigned based on the cis conformation of the amino and methyl groups.

[0496] Example 27: Synthesis of 2-((3S,5R)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloro-6-((3-(3-hydroxy-3-methylbutyl)-1-(oxetan-3-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (37) and 2-((3R,5S)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloro-6-((3-(3-hydroxy-3-methylbutyl)-1-(oxetan-3-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (38) [ka]

[0497] 4-Nitro-N1-(oxetan-3-ylmethyl)benzene-1,2-diamine

[0498] A solution of 2-fluoro-5-nitro-aniline (2 g, 12.81 mmol) and oxetan-3-ylmethanamine (1.34 g, 15.37 mmol) in DMSO (20 mL) was added with K 2 CO 3 (2.66 g, 19.22 mmol) was added. The mixture was stirred at 100° C. for 12 h. Water (200 mL) was added, and then the mixture was extracted with DCM (300 mL×4). The combined organic phase was washed with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration gave a residue which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=5 / 1 to 0 / 1) to give the title compound as a white solid (2.5 g, 10.53 mmol, yield 82%, purity 94%). 1 H NMR (400 MHz, DMSO-d 6 , 25℃) δ 7.51 (dd, J = 8.82, 2.62 Hz, 1H), 7.40 (d, J = 2.62 Hz, 1H), 6.52 (d, J = 8.82 Hz, 1H), 5.93 (t, J = 5.01 Hz, 1H), 5.15 (s, 2H), 4.69 (dd, J = 7.51, 6.08 Hz, 2H), 4.31 (t, J = 5.90 Hz, 2H), 3.50 (dd, J = 7.27, 5.36 Hz, 2H), 3.20 - 3.28 (m, 1H).

[0499] 6-nitro-3-(oxetan-3-ylmethyl)-1H-benzimidazol-2-one

[0500] A flask containing a mixture of 4-nitro-N1-(oxetan-3-ylmethyl)benzene-1,2-diamine (1 g, 4.48 mmol) and CDI (1.09 g, 6.72 mmol) in DMF (10 mL) was degassed and flushed with N 2 Purge the mixture three times with N 2 The mixture was stirred at 15° C. for 12 hours under atmospheric pressure. Then, water (80 mL) was added, and the mixture was extracted with ethyl acetate (45 mL×3). The combined organic phase was washed with anhydrous Na 2 SO4 Drying at 40° C., filtration and concentration gave a residue which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=4 / 1 to 0 / 1) to give the title compound as a yellow solid (1.1 g, 4.10 mmol, yield 92%, purity 93%). 1 H NMR (400 MHz, DMSO-d 6 , 25℃) δ 8.00 (dd, J = 8.70, 2.26 Hz, 1H), 7.74 (d, J = 2.15 Hz, 1H), 7.41 (d, J = 8.70 Hz, 1H), 4.61 (dd, J = 7.63, 6.20 Hz, 2H), 4.41 (t, J = 6.08 Hz, 2H), 4.18 (d, J = 7.15 Hz, 2H), 3.33 - 3.44 (m, 1H).

[0501] 3-(3-hydroxy-3-methyl-butyl)-5-nitro-1-(oxetan-3-ylmethyl)benzimidazol-2-one

[0502] 6-nitro-3-(oxetan-3-ylmethyl)-1H-benzimidazol-2-one (1.3 g, 5.22 mmol), 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (2.02 g, 7.83 mmol) and Cs 2 CO 3 Degas the flask containing the mixture of (5.10 g, 15.66 mmol) in DMF (10 mL) and flush with N 2 Purge the mixture three times with N 2 The mixture was stirred at 100° C. for 2 hours under atmospheric pressure. Then, water (60 mL) was added, and the mixture was extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration gave a residue which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=3 / 1 to 0 / 1) to give the title compound as a yellow solid (1 g, purity 92%). 1 H NMR (400 MHz, DMSO-d 6, 25℃) δ 8.05 (dd, J = 8.69, 2.06 Hz, 1H), 8.00 (d, J = 2.00 Hz, 1H), 7.48 (d, J = 8.63 Hz, 1H), 4.61 (dd, J = 7.63, 6.25 Hz, 2H), 4.51 (s, 1H), 4.40 (t, J = 6.07 Hz, 2H), 4.23 (d, J = 7.13 Hz, 2H), 3.96 - 4.02 (m, 2H), 3.39 (dt, J = 13.91, 6.86 Hz, 1H), 1.70 - 1.76 (m, 2H), 1.16 (s, 6H).

[0503] 5-Amino-3-(3-hydroxy-3-methyl-butyl)-1-(oxetan-3-ylmethyl)benzimidazol-2-one

[0504] To a mixture of Pd / C (200 mg, 10% purity) in DMF (10 mL) was added 3-(3-hydroxy-3-methyl-butyl)-5-nitro-1-(oxetan-3-ylmethyl)benzimidazol-2-one (1 g, 2.98 mmol). The mixture was diluted with H 2 (15 psi) for 12 hours at 15° C. The mixture was added Celite® and filtered to give a filtrate which was concentrated in vacuo to give the title compound as a red solid (900 mg, 2.71 mmol, 91% yield, 92% purity). 1 H NMR (400 MHz, DMSO-d 6 , 25℃) δ 6.85 (d, J = 8.25 Hz, 1H), 6.38 (d, J = 1.88 Hz, 1H), 6.30 (dd, J = 8.25, 2.00 Hz, 1H), 4.81 (br s, 2H), 4.58 (dd, J = 7.75, 6.13 Hz, 2H), 4.47 (s, 1H), 4.38 (t, J = 6.07 Hz, 2H), 4.01 (d, J = 7.00 Hz, 2H), 3.74 - 3.86 (m, 2H), 3.27 - 3.35 (m, 1H), 1.58 - 1.73 (m, 2H), 1.16 (s, 6H).

[0505] 2,5-Dichloro-6-[[3-(3-hydroxy-3-methyl-butyl)-1-(oxetan-3-ylmethyl)-2-oxo-benzimidazol-5-yl]amino]pyridine-3-carbonitrile

[0506] Degas a flask containing a mixture of 5-amino-3-(3-hydroxy-3-methyl-butyl)-1-(oxetan-3-ylmethyl)benzimidazol-2-one (800 mg, 2.62 mmol), 2,5,6-trichloropyridine-3-carbonitrile (543.46 mg, 2.62 mmol) and DIEA (677.17 mg, 5.24 mmol, 912.63 µL) in DMF (9 mL) and flush with N. 2 Purge the mixture three times with N 2 The mixture was stirred at 100° C. under atmospheric pressure for 1 hour. The mixture was concentrated under vacuum without further workup. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250*70mm#10μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 30% to 60%, 20 min) to give the title compound as a white solid (700 mg, 1.40 mmol, 53% yield, 95% purity). 1 H NMR (400 MHz, DMSO-d 6 , 25℃) δ 9.54 (s, 1H), 8.35 (s, 1H), 7.35 (d, J = 1.67 Hz, 1H), 7.22 - 7.26 (m, 1H), 7.16 - 7.19 (m, 1H), 4.62 (dd, J = 7.69, 6.14 Hz, 2H), 4.42 - 4.44 (m, 2H), 4.40 (s, 1H), 4.14 (d, J = 7.03 Hz, 2H), 3.85 - 3.92 (m, 2H), 3.35 - 3.45 (m, 1H), 1.65 - 1.77 (m, 2H), 1.17 (s, 6H).

[0507] 5-Chloro-2-((3S,5R)-3-(1,3-dioxoisoindolin-2-yl)-4,4-difluoro-5-methylpiperidin-1-yl)-6-((3-(3-hydroxy-3-methylbutyl)-1-(oxetan-3-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile

[0508] A flask containing a mixture of 2,5-dichloro-6-[[3-(3-hydroxy-3-methyl-butyl)-1-(oxetan-3-ylmethyl)-2-oxo-benzimidazol-5-yl]amino]pyridine-3-carbonitrile (150 mg, 314.89 μmol), 2-((3S,5R)-4,4-difluoro-5-methylpiperidin-3-yl)isoindoline-1,3-dione (88.25 mg, 314.89 μmol) and DIEA (203.49 mg, 1.57 mmol, 274.24 μL) in DMSO (1.5 mL) was degassed and diluted with N 2 Purge the mixture three times with N 2 The mixture was stirred at 100° C. for 12 hours. The mixture was concentrated under vacuum without further workup. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 40% to 60%, 8 min) to give the title compound as a yellow solid (170 mg, 228.98 μmol, 73% yield, 97% purity). LCMS: [M+H] + =720.0.

[0509] 2-((3S,5R)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloro-6-((3-(3-hydroxy-3-methylbutyl)-1-(oxetan-3-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (37)

[0510] To a solution of 5-chloro-2-((3S,5R)-3-(1,3-dioxoisoindolin-2-yl)-4,4-difluoro-5-methylpiperidin-1-yl)-6-((3-(3-hydroxy-3-methylbutyl)-1-(oxetan-3-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (170 mg, 236.06 μmol) in EtOH (10 mL), MeNH 2 / H 2 2H2O (10 mL, 40% purity) was added. The mixture was stirred at 70° C. for 1 h. The mixture was concentrated under vacuum and purified by preparative HPLC (column: Phenomenex C18 80*40 mm*3 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 20% to 50%, 8 min) to give the title compound as a white solid (35 mg, 55.76 μmol, 24% yield, 94% purity). 1 H NMR (400 MHz, DMSO-d 6 , 22℃) δ 7.97 (s, 1H), 7.29 (s, 1H), 7.23 (s, 2H), 4.61 (s, 2H), 4.50 (s, 1H), 4.42 (s, 2H), 4.15 (s, 3H), 3.97 (br s, 1H), 3.89 (br s, 2H), 3.36 - 3.46 (m, 2H), 2.77 - 2.91 (m, 2H), 2.64 - 2.71 (m, 1H), 1.92 - 2.09 (m, 1H), 1.68 - 1.73 (m, 2H), 1.66 (br s, 1H), 1.16 (d, J = 0.73 Hz, 6H), 0.76 (d, J = 6.72 Hz, 3H).

[0511] 5-Chloro-2-((3R,5S)-3-(1,3-dioxoisoindolin-2-yl)-4,4-difluoro-5-methylpiperidin-1-yl)-6-((3-(3-hydroxy-3-methylbutyl)-1-(oxetan-3-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile

[0512] A flask containing a mixture of 2,5-dichloro-6-[[3-(3-hydroxy-3-methyl-butyl)-1-(oxetan-3-ylmethyl)-2-oxo-benzimidazol-5-yl]amino]pyridine-3-carbonitrile (150 mg, 314.89 μmol), 2-((3R,5S)-4,4-difluoro-5-methylpiperidin-3-yl)isoindoline-1,3-dione (88.25 mg, 314.89 μmol) and DIEA (203.49 mg, 1.57 mmol, 274.24 μL) in DMSO (1.5 mL) was degassed and diluted with N 2 Purge the mixture three times with N 2 The mixture was stirred at 100° C. under atmospheric pressure for 12 hours. The mixture was concentrated under vacuum without further workup. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 40% to 60%, 8 min) to give the title compound as a white solid (150 mg, 202.04 μmol, 64% yield, 97% purity). LCMS: [M+H] + =720.0.

[0513] 2-((3R,5S)-3-amino-4,4-difluoro-5-methylpiperidin-1-yl)-5-chloro-6-((3-(3-hydroxy-3-methylbutyl)-1-(oxetan-3-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (38)

[0514] To a solution of 5-chloro-2-((3R,5S)-3-(1,3-dioxoisoindolin-2-yl)-4,4-difluoro-5-methylpiperidin-1-yl)-6-((3-(3-hydroxy-3-methylbutyl)-1-(oxetan-3-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile (150 mg, 208.29 μmol) in EtOH (10 mL), MeNH 2 / H 22H2O (10 mL, 40% purity) was added. The mixture was stirred at 70° C. for 1 h. The mixture was concentrated under vacuum and purified by preparative HPLC (column: Phenomenex C18 80*40 mm*3 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 20% to 50%, 8 min) to give the title compound as a white solid (30 mg, 50.33 μmol, yield 24%, purity 99%). 1 H NMR (400 MHz, DMSO-d 6 , 22℃) δ 9.02 (s, 1H), 7.96 (s, 1H), 7.28 (s, 1H), 7.22 (s, 2H), 4.60 (dd, J = 7.76, 6.05 Hz, 2H), 4.49 (s, 1H), 4.41 (t, J = 6.05 Hz, 2H), 4.11 - 4.19 (m, 3H), 3.94 (br dd, J = 13.51, 2.14 Hz, 1H), 3.85 - 3.91 (m, 2H), 3.35 - 3.43 (m, 2H), 2.78 - 2.91 (m, 2H), 2.63 - 2.70 (m, 1H), 1.94 - 2.09 (m, 1H), 1.67 - 1.72 (m, 2H), 1.65 (br s, 1H), 1.15 (s, 6H), 0.75 (d, J = 6.72 Hz, 3H).

[0515] The absolute configurations of compounds 37 and 38 were randomly assigned based on the cis conformation of the amino and methyl groups.

[0516] Example 28: Synthesis of 2-((1-(2-aminoethyl)-6-((3-chloro-5-cyano-6-((3S,4S,5R)-4-fluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (66) [ka]

[0517] Methyl 2-((1-(2-((tert-butoxycarbonyl)amino)ethyl)-6-nitro-2-oxo-1,2-dihydroquinolin-3-yl)oxy)acetate

[0518] Methyl 2-[(6-nitro-2-oxo-1H-quinolin-3-yl)oxy]acetate (500 mg, 1.80 mmol), tert-butyl N-(2-bromoethyl)carbamate (2.01 g, 8.99 mmol), K 2 CO 3 The flask containing a mixture of (496.77 mg, 3.59 mmol) and KI (149.16 mg, 898.58 μmol, 0.5 equiv.) in DMSO (10 mL) was degassed and filled with N 2 Purge the mixture three times with N 2 The mixture was stirred at 80° C. for 2 hours under atmospheric pressure. Then, water (60 mL) was added, and the mixture was extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration afforded the title compound as a brown oil (1 g, crude). LCMS: [M+H] + =422.2.

[0519] 2-((1-(2-((tert-butoxycarbonyl)amino)ethyl)-6-nitro-2-oxo-1,2-dihydroquinolin-3-yl)oxy)acetic acid

[0520] Methyl 2-((1-(2-((tert-butoxycarbonyl)amino)ethyl)-6-nitro-2-oxo-1,2-dihydroquinolin-3-yl)oxy)acetate (800 mg, 1.90 mmol) in EtOH (4 mL) and H 2 To a solution of LiOH H 2 O (159.33 mg, 3.80 mmol) was added and the mixture was then stirred at 20° C. for 1 h. The mixture was concentrated in vacuo to give the title compound as a yellow solid (800 mg, crude). LCMS: [M+H] + =408.0.

[0521] tert-Butyl (2-(3-(2-(methylamino)-2-oxoethoxy)-6-nitro-2-oxoquinolin-1(2H)-yl)ethyl)carbamate

[0522] To a solution of 2-((1-(2-((tert-butoxycarbonyl)amino)ethyl)-6-nitro-2-oxo-1,2-dihydroquinolin-3-yl)oxy)acetic acid (800 mg, 1.96 mmol), methenamine (530.37 mg, 7.86 mmol, HCl), HATU (1.49 g, 3.93 mmol) and DIEA (1.02 g, 7.86 mmol, 1.37 mL) in DMF (6 mL) was added and the mixture was stirred at 20° C. for 1 h. Then, water (40 mL) was added and the mixture was extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration afforded the title compound as a yellow oil (800 mg, 1.09 mmol, 56% yield, 57% purity). LCMS: [M+H] + =421.2.

[0523] tert-Butyl (2-(6-amino-3-(2-(methylamino)-2-oxoethoxy)-2-oxoquinolin-1(2H)-yl)ethyl)carbamate

[0524] To a solution of Pd / C (0.1 g, 10% purity) in DMF (15 mL) under Ar was added tert-butyl (2-(3-(2-(methylamino)-2-oxoethoxy)-6-nitro-2-oxoquinolin-1(2H)-yl)ethyl)carbamate (600 mg, 1.43 mmol). The mixture was cooled to 37° C. for 1 h. 2 (50 psi) at 50° C. for 12 h. The mixture was filtered and the filtrate was concentrated under vacuum without further workup. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 250*50 mm*10 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 15% to 45%, 10 min) to give the title compound as a white solid (90 mg, 187.91 μmol, 13% yield, 82% purity).1 H NMR (400 MHz, DMSO-d 6 ) δ 1.37 (s, 9H), 2.67 - 2.72 (m, 3H), 3.37 (br d, J = 5.87 Hz, 2H), 4.31 (br t, J = 5.44 Hz, 2H), 4.56 (s, 2H), 5.22 (br s, 2H), 6.70 (d, J = 2.45 Hz, 1H), 6.88 (dd, J = 8.80, 2.45 Hz, 1H), 7.01 (br t, J = 5.44 Hz, 1H), 7.25 (s, 1H), 7.38 (d, J = 8.80 Hz, 1H), 7.84 (br d, J = 4.03 Hz, 1H).

[0525] tert-Butyl (2-(6-amino-3-(2-(methylamino)-2-oxoethoxy)-2-oxoquinolin-1(2H)-yl)ethyl)carbamate

[0526] A flask containing a mixture of tert-butyl (2-(6-amino-3-(2-(methylamino)-2-oxoethoxy)-2-oxoquinolin-1(2H)-yl)ethyl)carbamate (60 mg, 153.68 μmol), 2,5,6-trichloropyridine-3-carbonitrile (31.88 mg, 153.68 μmol) and DIEA (39.72 mg, 307.35 μmol, 53.54 μL) in DMF (1 mL) was degassed and flushed with N 2 Purge the mixture three times with N 2 The mixture was stirred at 100° C. under atmospheric pressure for 12 hours. Water (15 mL) was then added and the mixture was filtered to obtain a filter cake which was dried under vacuum to give the title compound as a grey solid (60 mg, 56.98 μmol, 37% yield, 53% purity). LCMS: [M+H] + =561.2.

[0527] tert-Butyl (2-(6-((3-chloro-5-cyano-6-((3S,4S,5R)-4-fluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-3-(2-(methylamino)-2-oxoethoxy)-2-oxoquinolin-1(2H)-yl)ethyl)carbamate

[0528] A flask containing a mixture of tert-butyl (2-(6-amino-3-(2-(methylamino)-2-oxoethoxy)-2-oxoquinolin-1(2H)-yl)ethyl)carbamate (60.00 mg, 106.87 μmol), (3S,4S,5R)-4-fluoro-3,5-dimethyl-piperidine (53.75 mg, 320.62 μmol, HCl) and DIEA (138.13 mg, 1.07 mmol, 186.15 μL) in DMSO (1 mL) was degassed and flushed with N 2 Purge the mixture three times with N 2 The mixture was stirred at 100° C. under atmospheric pressure for 2 hours. Water (20 mL) was then added and the mixture was filtered to obtain a filter cake which was dried under vacuum to give the title compound as a grey solid (60 mg, 62.78 μmol, 59% yield, 69% purity). LCMS: [M-56] + =600.2, [M-100] + =556.3.

[0529] 2-((1-(2-aminoethyl)-6-((3-chloro-5-cyano-6-((3S,4S,5R)-4-fluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (66)

[0530] A solution of tert-butyl (2-(6-((3-chloro-5-cyano-6-((3S,4S,5R)-4-fluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-3-(2-(methylamino)-2-oxoethoxy)-2-oxoquinolin-1(2H)-yl)ethyl)carbamate (60 mg, 91.44 μmol) in HCl / EtOAc (4M, 6 mL) was stirred at 20° C. for 1 h. The mixture was concentrated under vacuum without further workup. The residue was purified by preparative HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (HCl)-ACN]; B%: 20%-50%, 8 min) to give the title compound as a yellow solid (45 mg, 74.12 μmol, yield 11%, purity 98%, HCl). 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.86 (d, J = 6.85 Hz, 6H), 1.74 - 1.95 (m, 2H), 2.67 (d, J = 4.65 Hz, 3H), 2.79 (t, J = 12.65 Hz, 2H), 3.08 (d, J = 5.87 Hz, 2H), 3.99 (dd, J = 12.59, 3.79 Hz, 2H), 4.53 - 4.58 (m, 4H), 7.25 - 7.27 (m, 1H), 7.63 - 7.66 (m, 2H), 7.85 - 7.88 (m, 1H), 7.95 - 8.01 (m, 2H), 8.12 (s, 3H), 9.07 - 9.12 (m, 1H).

[0531] Example 29: Synthesis of 2-((6-((3-chloro-5-cyano-6-((3S,4S,5R)-4-fluoro-3,5-dimethylpiperidin-1yl)pyridin-2-yl)amino)-1-(2-hydroxy-3-(methylamino)propyl)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (67) [ka]

[0532] tert-Butyl 2-((6-((3,6-dichloro-5-cyanopyridin-2-yl)amino)-3-(2-methoxy-2-oxoethoxy)-2-oxoquinolin-1(2H)-yl)methyl)morpholine-4-carboxylate

[0533] To a solution of methyl 2-[[6-[(3,6-dichloro-5-cyano-2-pyridyl)amino]-2-oxo-1H-quinolin-3-yl]oxy]acetate (2 g, 4.77 mmol) and tert-butyl 2-(bromomethyl)morpholine-4-carboxylate (1.47 g, 5.25 mmol) in DMSO (25 mL) was added K 2 CO 3 (1.32 g, 9.54 mmol) and KI (395.98 mg, 2.39 mmol) were added. The mixture was stirred at 80° C. for 4 h. Water (50 mL) was added to the mixture, which was then extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration under reduced pressure afforded the title compound as a white solid (2.9 g, crude). LCMS: [M+H] + =618.1.

[0534] 2-((1-((4-(tert-butoxycarbonyl)morpholin-2-yl)methyl)-6-((3,6-dichloro-5-cyanopyridin-2-yl)amino)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)acetic acid

[0535] Dissolve tert-butyl 2-[[6-[(3,6-dichloro-5-cyano-2-pyridyl)amino]-3-(2-methoxy-2-oxo-ethoxy)-2-oxo-1-quinolyl]methyl]morpholine-4-carboxylate (2.9 g, 4.69 mmol) in EtOH (20 mL) and H 2 To a solution of LiOH H 2 255.80 mg, 6.10 mmol) was added. The mixture was stirred at 20° C. for 12 h. The mixture was purified by preparative HPLC (column: Agela DuraShell C 18 250*80mm*10μm; Mobile phase: [Water (NH4 HCO 3 )-ACN]; B%: 30%-60%, 20 min) to afford the title compound as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) = 9.67 (s, 1H), 8.38 (s, 1H), 7.73 (s, 1H), 7.63 (s, 2H), 7.16 (s, 1H), 4.52 - 4.14 (m, 4H), 3.84 - 3.56 (m, 4H), 3.17- 2.67 (m, 4H), 1.38 (s, 9H).

[0536] tert-Butyl 2-((6-((3,6-dichloro-5-cyanopyridin-2-yl)amino)-3-(2-(methylamino)-2-oxoethoxy)-2-oxoquinolin-1(2H)-yl)methyl)morpholine-4-carboxylate

[0537] To a solution of 2-[[1-[(4-tert-butoxycarbonylmorpholin-2-yl)methyl]-6-[(3,6-dichloro-5-cyano-2-pyridyl)amino]-2-oxo-3-quinolyl]oxy]acetic acid (1 g, 1.65 mmol) and methenamine (223.41 mg, 3.31 mmol, HCl) in DMF (10 mL) was added HATU (1.26 g, 3.31 mmol) and DIPEA (855.29 mg, 6.62 mmol, 1.15 mL). The mixture was stirred at 25° C. for 12 h. Water (10 mL) was added to the mixture to form a precipitate, which was filtered, the filter cake was washed with water (20 mL×2), PE (20 mL×2), and the filter cake was dried under reduced pressure to give the title compound as a white solid. LCMS: [M+H] + =617.2.

[0538] tert-Butyl (3-(6-((3-chloro-5-cyano-6-((3S,4S,5R)-4-fluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-3-(2-(methylamino)-2-oxoethoxy)-2-oxoquinolin-1(2H)-yl)-2-methylpropyl)carbamate

[0539] To a solution of tert-butyl 2-[[6-[(3,6-dichloro-5-cyano-2-pyridyl)amino]-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-1-quinolyl]methyl]morpholine-4-carboxylate (100 mg, 161.95 μmol) and (3S,4S,5R)-4-fluoro-3,5-dimethyl-piperidine (32.58 mg, 194.34 μmol, HCl) in DMSO (1 mL) was added DIPEA (62.79 mg, 485.85 μmol, 84.63 μL). The mixture was stirred at 100° C. for 2 h. Water (5 mL) was added to the mixture, forming a precipitate which was filtered and the filter cake was washed with water (10 mL×2) and EA (10 mL×2). The filter cake was dried under reduced pressure to give the title compound as a white solid (90 mg, 126.37 μmol, 78% yield). LCMS: [M+H] + =712.3.

[0540] 2-((6-((3-chloro-5-cyano-6-((3S,4S,5R)-4-fluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-1-(2-hydroxy-3-(methylamino)propyl)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (67)

[0541] A solution of tert-butyl 2-[[6-[[3-chloro-5-cyano-6-[(3S,4S,5R)-4-fluoro-3,5-dimethyl-1-piperidyl]-2-pyridyl]amino]-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-1-quinolyl]methyl]morpholine-4-carboxylate (330 mg, 463.35 μmol) in HCl / EtOAc (4 mL, 4M) was stirred for 1 h at 25° C. 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 (HCl)-ACN]; B%: 20%-50%, 8 min) to give the title compound as a white solid (30 mg, 45.74 μmol, yield 10%, purity 99%, HCl).1 H NMR (400 MHz, DMSO-d 6 ) δ 9.61-9.59 (m, 1H), 9.52-9.50 (m, 1H), 9.08 - 9.05 (m, 1H), 8.03 (d, J = 4.4 Hz, 1H), 7.95 - 7.94 (m, 1H), 7.82 - 7.81 (m, 1H), 7.65 - 7.62 (m, 1H), 7.58 - 7.56 (m, 1H), 7.25 - 7.24 (m, 1H), 4.55 (s, 2H), 4.43 - 4.41 (m, 1H), 4.18 - 4.15 (m, 2H), 3.99 (d, J = 13.2 Hz, 2H), 3.88 (d, J = 12.8 Hz, 1H), 3.68-3.65 (m, 1H), 3.34 (d, J = 12.4 Hz, 1H), 3.13 (br d, J = 12.0 Hz, 1H), 3.03 - 2.93 (m, 2H), 2.83 - 2.72 (m, 2H), 2.67 (d, J = 4.8 Hz, 3H), 1.90 - 1.73 (m, 2H), 0.89 - 0.85 (m, 6H).

[0542] Example 30: Synthesis of 2-((6-((3-chloro-5-cyano-6-((3S,4S,5R)-4-fluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (68) [ka]

[0543] 2-(4,4-difluoro-3-hydroxy-5-methylpiperidin-1-yl)-5-fluoro-6-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nicotinonitrile

[0544] To a solution of methyl 2-[[6-[(3,6-dichloro-5-cyano-2-pyridyl)amino]-2-oxo-1H-quinolin-3-yl]oxy]acetate (3 g, 7.16 mmol) in NMP (3 mL) and EtOH (27 mL), MeNH 2 (4.44 g, 57.25 mmol, 40% purity) was added. The mixture was stirred at 70° C. for 12 h. The reaction mixture was cooled to 20° C. and EtOH (90 mL) was added. The suspension was filtered and the filter cake was dried under reduced pressure to give the title compound as a yellow solid (2.6 g, 5.41 mmol, 76% yield, 87% purity). LCMS: [M+H] + =418.0.

[0545] 2-((6-((3-chloro-5-cyano-6-(4-fluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0546] To a solution of 2-[[6-[(3,6-dichloro-5-cyano-2-pyridyl)amino]-2-oxo-1H-quinolin-3-yl]oxy]-N-methyl-acetamide (500 mg, 1.20 mmol) and (3R,5S)-4-fluoro-3,5-dimethyl-piperidine (300.64 mg, 1.79 mmol, HCl) in DMSO (1 mL) was added DIEA (618.04 mg, 4.78 mmol, 832.94 μL). The mixture was stirred at 100° C. for 2 h. The reaction mixture was treated with water (20 mL) to form a precipitate, which was filtered. The filter cake was washed with EtOAc (30 mL), and then the filter cake was dried under reduced pressure to give the title compound as a brown solid (600 mg, 818.77 μmol, 68% yield, 70% purity). LCMS: [M+H] + =513.3.

[0547] 2-[[6-[[3-chloro-5-cyano-6-[(3R,5S)-4-fluoro-3,5-dimethyl-1-piperidyl]-2-pyridyl]amino]-1-(2-morpholinoethyl)-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (68).

[0548] A solution of 2-[[6-[[3-chloro-5-cyano-6-[(3R,5S)-4-fluoro-3,5-dimethyl-1-piperidyl]-2-pyridyl]amino]-2-oxo-1H-quinolin-3-yl]oxy]-N-methyl-acetamide (200 mg, 389.89 μmol) and 4-(2-bromoethyl)morpholine (189.17 mg, 974.73 μmol) in DMSO (2 mL) was added with Cs 2 CO 3 (254.07mg, 779.78μmol) and KI (32.36mg, 194.95μmol) were added. The mixture was stirred at 80°C for 5h. The reaction mixture was treated with water (30mL) to form a precipitate which was filtered. The filter cake was washed with EtOAc (30mL), collected and dried under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water(HCl)-ACN]; B%: 25%~55%, 8min) and purified by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm, 10μm); mobile phase: [0.1%NH 3 H 2 Further separation by elution with 30 mL of 3H2O (O:EtOH); B%:50% to 50%, 10 min) afforded the title compound as a white solid (18 mg, 23.29 μmol, yield 29%, purity 81%). 1 H NMR (400 MHz, DMSO-d 6) δ 9.07 (s, 1H), 7.88 - 8.01 (m, 2H), 7.78 (br s, 1H), 7.66 (dd, J = 9.13, 2.38 Hz, 1H), 7.49 (br d, J = 9.13 Hz, 1H), 7.22 (s, 1H), 4.52 - 4.58 (m, 2H), 4.43 (br s, 2H), 3.98 (br dd, J = 12.94, 3.69 Hz, 2H), 3.58 (br s, 4H), 3.30 (br s, 1H), 2.79 (br t, J = 12.69 Hz, 2H), 2.67 (d, J = 4.63 Hz, 3H), 2.52 - 2.53 (m, 4H), 1.75 - 1.93 (m, 2H), 1.23 (s, 2H), 0.85 (d, J = 6.88 Hz, 6H).

[0549] Example 31: Synthesis of 2-((1-(3-aminopropyl)-6-((3-chloro-5-cyano-6-((3S,4S,5R)-4-fluoro-3,5-dimethylpiperidin-1-yl)pyridin-2-yl)amino)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (69) [ka]

[0550] Methyl 2-((1-(3-((tert-butoxycarbonyl)amino)propyl)-6-((3,6-dichloro-5-cyanopyridin-2-yl)amino)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)acetate

[0551] To a solution of methyl 2-[[6-[(3,6-dichloro-5-cyano-2-pyridyl)amino]-2-oxo-1H-quinolin-3-yl]oxy]acetate (1 g, 2.39 mmol) and tert-butyl N-(3-bromopropyl)carbamate (852.02 mg, 3.58 mmol) in DMSO (10 mL) was added K 2 CO 3(659.35 mg, 4.77 mmol, 359.55 μL) was added. The mixture was stirred at 80° C. for 12 h. Another batch of tert-butyl N-(3-bromopropyl)carbamate (568.01 mg, 2.39 mmol) was added and stirred at 80° C. for 12 h. The mixture was treated with water (10 mL) to form a precipitate which was filtered and the filter cake was collected and dried in vacuum to give the title compound as a yellow solid (1.4 g, crude). LCMS: [M+H] + =576.0.

[0552] 2-((1-(3-((tert-butoxycarbonyl)amino)propyl)-6-((3,6-dichloro-5-cyanopyridin-2-yl)amino)-2-oxo-1,2-dihydroquinolin-3-yl)oxy)acetic acid

[0553] Methyl 2-[[1-[3-(tert-butoxycarbonylamino)propyl]-6-[(3,6-dichloro-5-cyano-2-pyridyl)amino]-2-oxo-3-quinolyl]oxy]acetate (1.4 g, 2.43 mmol) in EtOH (16 mL) and H 2 To a solution of LiOH H 2 0 (203.84 mg, 4.86 mmol) was added. The mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow solid (1.5 g, crude). LCMS: [M+H] + =562.1.

[0554] tert-Butyl (3-(6-((3,6-dichloro-5-cyanopyridin-2-yl)amino)-3-(2-(methylamino)-2-oxoethoxy)-2-oxoquinolin-1(2H)-yl)propyl)carbamate

[0555] To a solution of 2-[[1-[3-(tert-butoxycarbonylamino)propyl]-6-[(3,6-dichloro-5-cyano-2-pyridyl)amino]-2-oxo-3-quinolyl]oxy]acetic acid (2.2 g, 3.91 mmol) and methenamine (396.17 mg, 5.87 mmol, HCl) in DMF (22 mL) was added HATU (2.97 g, 7.82 mmol) and DIPEA (2.02 g, 15.65 mmol, 2.73 mL). The mixture was stirred at 25° C. for 12 h. The reaction mixture was treated with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layer was washed with brine and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel column chromatography (silica flash column, eluent of 0-100% DMF / ...

Claims

1. Formula I: 【Chemical 1】 or a pharmaceutically acceptable salt or stereoisomer thereof. (In the formula, X １ is N, CH, CCl, CF, or CCN; X 2 is CH ２ , S, CHF, CHCl, CHOH, or CF ２ and R １ represents hydrogen, ═O, —CN, —C≡CH, —OH, —SH, —NH ２ , -COOH, halo, (C １ ~C ６ ) alkyl, —O—(C １ ~C ６ ) alkyl, (C １ ~C ６ ) haloalkyl, amido, carboxy, carbamoyl, sulfamoyl, phenyl, 5- to 8-membered heterocyclyl, —NR ７ R ８ , -C(O)R ９ , —C(O)NR １０ R １１ , or L １ Y １ wherein said alkyl, phenyl, or heterocyclyl is selected from halo, —COOH, —OH, —NH ２ , (C １ ~C ６ ) alkyl, —C(O)O—(C １ ~C ６ ) alkyl, —C(O)N(C １ ~C ６ alkyl) ２ , —O—(C １ ~C ６ ) alkyl, —N(C １ ~C ３ alkyl) ２ , phenyl, and halo and (C １ ~C ６ ) 4- to 6-membered heterocyclyl optionally substituted with one or more groups selected from alkyl; R ７ is hydrogen, (C １ ~C ４ ) alkyl, or (C ３ ~C ６ ) cycloalkyl; R ８ is hydrogen, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) haloalkyl, (C ３ ~C ６ ) cycloalkyl, or 6-membered heterocyclyl; R ９ is -(C １ ~C ３ ) alkyl-N(C １ ~C ３ alkyl) ２ , (C ３ ~C ６ ) cycloalkyl, or 5- to 6-membered heterocyclyl, wherein said heterocyclyl is (C １ ~C ３ ) optionally substituted with alkyl; R １０ is hydrogen, (C １ ~C ３ ) alkyl, or (C ３ ~C ６ ) cycloalkyl; R １１ is -NH ２ , —O—(C １ ~C ６ ) alkyl, —O—(C １ ~C ６ ) alkyl-NH ２ , or —O—(C １ ~C ６ ) alkyl-O—(C １ ~C ６ ) alkyl-NH ２ (C ３ ~C ６ ) cycloalkyl or (C １ ~C ６ ) alkyl; L １ does not exist or (C １ ~C ６ ) alkylene or (C ３ ~C ７ ) carbocyclyl; wherein said alkylene or carbocyclyl is one or more of the same or different R Ａ may be further optionally substituted by groups; Each R Ａ are independently oxo, alkyl, alkenyl, alkynyl, halo, haloalkyl, carbocyclyl, heterocyclyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkylenyloxy, alkynyloxy, amino, alkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, aralkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-aralkylamino, hydroxyalkyl, aminoalkyl, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, N-alkyl-N-arylaminosulfonyl, N- alkyl-N-heteroarylaminosulfonyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, heterocycloalkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, N-alkyl-N-heteroarylaminocarbonyl, cyano, nitro, azido, or phosphinyl; Y １ is -CN, -OH, halo, (C １ ~C ４ ) alkoxy, (C １ ~C ４ ) haloalkyl, (C １ ~C ４ ) haloalkoxy, 4- to 7-membered heterocyclyl, (C ３ ~C ６ ) carbocyclyl, —NR ７’ R ８’ , -C(O)R ９ , —C(O)NR １０ R １１ wherein said alkyl, carbocyclyl, or heterocyclyl is (C １ ~C ４ ) alkyl, halo, (C １ ~C ４ ) haloalkyl, —CN, —OH, and —NH ２ is optionally further substituted with one or more identical or different groups selected from R ７’ and R ８’ are each independently hydrogen, (C １ ~C ６ ) alkyl, (C ３ ~C ７ ) carbocyclyl, 4- to 7-membered heterocyclyl, (C ６ ~C １０ ) aryl, or monocyclic or bicyclic 5-10 membered heteroaryl; wherein said alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is selected from the group consisting of one or more of the same or different R Ａ may be further optionally substituted by a group, or R ７’ and R ８’ together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclyl, wherein the heterocyclyl is selected from one or more of the same or different R Ａ may be further substituted by a group, or L １ is (C ２ ~C ４ ) alkylene, which is R ７’ to form a 4- to 6-membered heterocyclyl group; R １’ is absent or is hydrogen, —CN, —C≡CH, —OH, —SH, —NH ２ , -COOH, halo, (C １ ~C ６ ) alkyl, —O—(C １ ~C ６ ) alkyl, (C １ ~C ６ ) haloalkyl, amido, carboxy, carbamoyl, sulfamoyl, phenyl, 5- to 8-membered heterocyclyl, —NR ７ R ８ , -C(O)R ９ or —C(O)NR １０ R １１ wherein said alkyl, phenyl, or heterocyclyl is selected from one or more of the same or different R Ａ may be further substituted by a group, or R １’ and L １ together with the same carbon atom to which they are attached to form spiro (C ３ ~C ７ ) form a carbocyclyl group or a 4- to 7-membered heterocyclyl group; wherein said carbocyclyl or heterocyclyl is one or more of the same or different R Ａ may be further substituted by groups; 【Chemistry 2】 teeth 【Chemistry 3】 and X ３ and X ４ is independent, CR １２ or N; X ５ is CH or N; R １２ is hydrogen, (C １ ~C ４ ) alkyl, halo, hydroxy, amino, (C １ ~C ４ ) alkoxy, (C １ ~C ４ ) haloalkyl, (C １ ~C ４ ) haloalkoxy, (C ２ ~C ４ ) alkenyl, (C ２ ~C ４ ) alkynyl, nitro, cyano, NH(C １ ~C ４ ) alkyl, or N(C １ ~C ４ alkyl) ２ and R ２ is hydrogen, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) carbocyclyl, 4- to 7-membered heterocyclyl, (C ３ ~C ７ ) carbocyclyl (C １ ~C ６ ) alkyl, or 4- to 7-membered heterocyclyl (C １ ~C ６ ) alkyl; wherein said alkyl, carbocyclyl, or heterocyclyl is selected from one or more of the same or different R １３ may be further substituted by groups, where R １３ is (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo, amino, hydroxyl, haloalkyl, NH(C １ ~C ６ ) alkyl, or N((C １ ~C ６ ) alkyl) ２ , (C ３ ~C ６ ) carbocyclyl, or 4- to 7-membered heterocyclyl; or R ２ Is, -L ２ -Y ２ -Z; L ２ does not exist or (C １ ~C ２ ) optionally substituted by one or more substituents selected from alkyl and oxo (C １ ~C ５ ) alkylene; Y ２ does not exist, or is O, S, S(O), S(O) ２ , NR', C(O), C(O)O, OC(O), C(O)N(R'), N(R')C(O), N(R')C(O)N(R'), N(R')C(O)O, OC(O)N(R'), S(O) ２ N(R'), or N(R')S(O) ２ and Each R' is independently hydrogen or (C １ ~C ４ ) alkyl; Z is hydrogen, (C １ ~C ６ ) alkyl, (C ２ ~C ６ ) alkenyl, (C ２ ~C ６ ) alkynyl, (C ３ ~C １０ ) carbocyclyl, or 3- to 10-membered heterocyclyl; １ ~C ４ ) alkyl, halo, (C １ ~C ４ ) haloalkyl, (C １ ~C ４ ) haloalkoxy, amino, (C １ ~C ４ ) aminoalkyl, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, mercapto, ureido, NR ｒ R ｓ , OR ｒ , C(O)R ｒ , C(O)OR ｒ , OC(O)R ｒ , C(O)NR ｒ R ｓ , N(R ｒ ) C(O)R ｒ , S(O) ０－２ R ｒ , S(O) ２ NR ｒ R ｓ , N(R ｒ ) SO ２ R ｒ , Si(R ｒ ) (R ｓ ) R ｔ and (CH ２ ) １－３ NR ｒ R ｓ and optionally substituted by one or more substituents independently selected from: ｒ , R ｓ and R ｔ are each independently hydrogen, (C １ ~C ６ ) alkyl or (C ３ ~C ６ ) cycloalkyl; or R ｒ and R ｓ together with the nitrogen atom to which they are attached, (C １ ~C ４ ) alkyl, halo, (C １ ~C ４ ) haloalkyl, (C １ ~C ４ ) haloalkoxy, (C １ ~C ４ ) alkoxy, (C １ ~C ４ ) forming a 4- to 9-membered heterocyclyl optionally substituted by one or more substituents selected from alkylamino, amino, cyano, and hydroxy; R ３ Is, -L ３ CR １４ R １５ R １６ or -CH=CH-R １６ and L ３ does not exist or O,S,(C １ ~C ４ ) alkylene, —O—(C １ ~C ４ ) alkylene, or —S—(C １ ~C ４ ) alkylene; R １４ is hydrogen or (C １ ~C ４ ) alkyl; R １５ is hydrogen or (C １ ~C ４ ) alkyl, or R １４ and R １５ together with the carbon atoms to which they are attached, (C ３ ~C ５ ) forming a carbocyclyl, a 4- to 7-membered heterocyclyl, or C═O; R １６ is (C １ ~C ６ ) alkyl, —NR １７ R １８ , -OR １７ , -C(O)R １７ , -C(O)OR １７ , -N(R １８ ) C(O)R １７ , —C(O)NR １７ R １８ , —S(O)—(C １ ~C ６ ) alkyl, —S(O) ２ -(C １ ~C ６ ) alkyl, —P(O)—(C １ ~C ６ alkyl) ２ , —C(NH)NH ２ , -(C １ ~C ４ ) alkyl-NR １８ C(O)R １７ or 4- to 7-membered heterocyclyl; R １７ is hydrogen, 3- to 6-membered heterocyclyl, or OH, Cl, F, CF ３ , N(C １ ~C ４ alkyl) ２ , (C ３ ~C ６ ) carbocyclyl, 3- to 6-membered heterocyclyl, (C ２ ~C ４ ) alkenyl, and (C ２ ~C ４ ) alkynyl (C １ ~C ４ ) alkyl R １８ is hydrogen or (C １ ~C ４ ) alkyl; R ４ is hydrogen, methyl, -(CH ２ ) １－３ W １ W ２ ,or 【Chemistry 4】 and W １ is CR １９ R １９’ or C(O); R １９ and R １９’ are independently hydrogen, (C １ ~C ２ ) alkyl, fluoro, hydroxy, cyano, nitro, (C １ ~C ２ ) alkoxy, (C １ ~C ２ ) haloalkyl, (C １ ~C ２ ) haloalkoxy, amino, NH(C １ ~C ２ ) alkyl, or N(C １ ~C ２ alkyl) ２ or R １９ and R １９’ together with the carbon atoms to which they are attached, form C(O), (C ３ ~C ６ ) carbocyclyl or 3- to 6-membered heterocyclyl, which is (C １ ~C ２ ) alkyl, halo, (C １ ~C ２ ) haloalkyl, (C １ ~C ２ ) haloalkoxy, (C １ ~C ２ ) alkoxy, (C １ ~C ２ ) optionally substituted with one or more substituents independently selected from alkylamino, amino, cyano, and hydroxy; W ２ is cyano, hydroxy, 5- or 6-membered heteroaryl, phenyl, C(O)—(C １ ~C ２ ) alkyl, S(O) ２ -(C １ ~C ２ ) alkyl, C(O)OCH ３ , C(O)NHCH ３ , C.R. ２０ R ２１ R ２２ , amino, NH(C １ ~C ２ ) alkyl, or N(C １ ~C ２ alkyl) ２ and R ２０ is hydrogen, (C １ ~C ２ ) alkyl, fluoro, chloro, bromo, hydroxy, amino, cyano, nitro, (C １ ~C ２ ) alkoxy, (C １ ~C ２ ) haloalkyl, or (C １ ~C ２ ) haloalkoxy; R ２１ is hydrogen, (C １ ~C ２ ) alkyl, fluoro, chloro, bromo, hydroxy, cyano, nitro, (C １ ~C ２ ) alkoxy, (C １ ~C ２ ) haloalkyl, (C １ ~C ２ ) haloalkoxy, or -Y ３ -L ４ -Z ２ and Y ３ does not exist, or is O, S, S(O), S(O) ２ , NR', C(O), C(O)O, OC(O), C(O)N(R'), N(R')C(O), S(O) ２ N(R'), or N(R')SO ２ and L ４ does not exist or (C １ ~C ２ ) alkylene; Z ２ is hydrogen, (C １ ~C ６ ) alkyl, (C ２ ~C ４ ) alkenyl, (C ２ ~C ４ ) alkynyl, phenyl, (C ３ ~C ６ ) carbocyclyl, or 4- to 6-membered heterocyclyl, wherein Z ２ is (C １ ~C ４ ) alkyl, halo, (C １ ~C ４ ) haloalkyl, (C １ ~C ４ ) haloalkoxy, (C １ ~C ４ ) alkoxy, (C １ ~C ４ and N(R')C(O)R', where each R' is independently selected from hydrogen or (C １ ~C ４ ) alkyl; or R ２０ and R ２１ together with the carbon atoms to which they are attached, (C １ ~C ２ ) alkyl, halo, (C １ ~C ２ ) haloalkyl, (C １ ~C ２ ) haloalkoxy, (C １ ~C ２ ) alkoxy, (C １ ~C ２ ) optionally substituted by one or more substituents selected from alkylamino, amino, cyano and hydroxy (C ３ ~C ６ ) forming a carbocyclyl or a 3- to 6-membered heterocyclyl R ２２ is (C １ ~C ２ ) alkyl, —C(O)OR″, OR″, —C(O)NR″, NR″R″, phenyl, or 5-membered heteroaryl, where each R′ ' are independently hydrogen or (C １ ~C ２ ) alkyl; A'' is (C １ ~C ２ ) alkyl, halo, hydroxy, oxo, cyano, and (C １ ~C ２ ) optionally substituted with one or more substituents independently selected from alkoxy; (C ４ ~C ６ ) carbocyclyl or 4- to 6-membered heterocyclyl; W ３ is NR ２３ or CR ２４ R ２４’ and R ２３ is hydrogen, (C １ ~C ２ ) alkyl, (C １ ~C ４ ) haloalkyl, (C １ ~C ４ ) hydroxyalkyl, —C(O)CH ３ , or —C(O)O—(C １ ~C ４ ) alkyl; R ２４ and R ２４’ are independently hydrogen, (C １ ~C ２ ) alkyl, cyclopropyl, fluoro, chloro, bromo, hydroxy, amino, cyano, nitro, (C １ ~C ２ ) haloalkyl, (C １ ~C ２ ) haloalkoxy, (C １ ~C ２ ) alkoxy, —C(O)OR″, NR″R″, phenyl, or 5-membered heteroaryl; R ５ is hydrogen, (C １ ~C ４ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C １ ~C ４ ) haloalkyl, or cyano, wherein said alkyl or cycloalkyl is (C １ ~C ４ ) alkyl, (C ３ ~C ６ ) cycloalkyl, hydroxy, (C １ ~C ２ ) alkoxy, amino, NH(C １ ~C ２ ) alkyl, N((C １ ~C ２ ) alkyl) ２ , (C １ ~C ２ ) optionally substituted with one or more substituents selected from aminoalkyl, and halo; R ５’ is hydrogen, (C １ ~C ４ ) alkyl, cyano, (C １ ~C ４ ) haloalkyl, or -Y ４ -L ５ -Z ３ and Y ４ is absent, C(O)O or C(O)N(R''); L ５ does not exist or (C １ ~C ２ ) alkylene; Z ３ is hydrogen, (C １ ~C ６ ) alkyl, phenyl, (C ３ ~C ６ ) cycloalkyl, or 4- to 6-membered heterocyclyl, where Z ３ is (C １ ~C ２ ) alkyl, halo, (C １ ~C ２ ) haloalkyl, (C １ ~C ２ ) haloalkoxy, (C １ ~C ２ ) optionally substituted with one or more substituents independently selected from alkoxy, amino, nitro, cyano, and hydroxy; or R ５ and R ５’ together with the carbon atoms to which they are attached, (C ４ ~C ６ ) forming a carbocyclyl or a 4- to 6-membered heterocyclyl; A' is a 6- or 7-membered heterocyclyl, which is R ５ and R ５’ In addition to oxo, (C １ ~C ２ ) alkyl, cyclopropyl, spiro-cyclopropyl, halo, (C １ ~C ２ ) haloalkyl, (C １ ~C ２ ) haloalkoxy, (C １ ~C ２ ) may be further substituted with one or more substituents independently selected from alkoxy, amino, cyano, and hydroxy; X ６ is CR ２５ or N; R ２５ is hydrogen, fluorine, chloro, or methyl; R ６ is hydrogen, (C １ ~C ２ ) alkyl, (C ３ ~C ４ ) cycloalkyl, (C １ ~C ２ ) haloalkyl, cyano, (C ２ ~C ４ ) alkenyl, or (C ２ ~C ４ ) alkynyl; R ６’ is (C １ ~C ４ ) alkyl, cyano, (C １ ~C ４ ) haloalkyl, or -Y ５ -L ６ -Z ４ and Y ５ is absent, C(O), C(O)O, OC(O), C(O)N(R″), or S(O) ２ N(R″); L ６ does not exist or (C １ ~C ２ ) optionally substituted by one or more substituents selected from alkyl and oxo (C １ ~C ２ ) alkylene; Z ４ is hydrogen, (C １ ~C ６ ) alkyl, (C ２ ~C ４ ) alkenyl, (C ２ ~C ４ ) alkynyl, phenyl, (C ３ ~C ６ ) carbocyclyl, (C ３ ~C ６ ) cycloalkenyl, or 4- to 6-membered heterocyclyl, where Z ４ is oxo, (C １ ~C ４ ) alkyl, (C ３ ~C ６ ) cycloalkyl, halo, (C １ ~C ４ ) haloalkyl, (C １ ~C ４ ) haloalkoxy, (C １ ~C ４ ) alkoxy, (C １ ~C ４ ) alkylamino, amino, nitro, cyano, hydroxy, C(O)R ｕ , C(O)OR ｕ , O.C.(O.)R ｕ , C(O)NR ｕ R ｕ , and N(R ｕ ) C(O)R ｕ and each R is optionally substituted by one or more substituents independently selected from ｕ are independently hydrogen, (C １ ~C ４ ) alkyl, or (C ３ ~C ６ ) cycloalkyl; or Z ４ Is -Q-L ７ -W ４ and Q is absent, O, NH, or N(C １ ~C ２ ) alkyl; L ７ is absent or is oxo and (C １ ~C ２ ) alkyl (C １ ~C ２ ) alkylene; W ４ is (C １ ~C ４ ) alkyl, phenyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkenyl, or 5- or 6-membered heterocyclyl, where W ４ is (C １ ~C ４ ) alkyl, halo, (C １ ~C ４ ) haloalkyl, (C １ ~C ４ ) haloalkoxy, (C １ ~C ４ ) alkoxy, (C １ ~C ４ ) optionally substituted with one or more substituents independently selected from alkylamino, amino, nitro, cyano, or hydroxy; or R ６ and R ６’ together with the carbon atoms to which they are attached, (C ３ ~C １０ ) carbocyclyl or 4- to 10-membered heterocyclyl, which is oxo, (C １ ~C ２ ) alkyl, halo, (C １ ~C ２ ) haloalkyl, (C １ ~C ２ ) haloalkoxy, (C １ ~C ２ ) alkoxy, (C １ ~C ２ ) optionally substituted by one or more substituents independently selected from alkylamino, amino, nitro, cyano, or hydroxy; or (C ３ ~C １０ ) carbocyclyl or 4- to 10-membered heterocyclyl may be fused to a 5- or 6-membered heteroaryl or phenyl ring, and the 5- or 6-membered heteroaryl or phenyl ring may be fused to a (C １ ~C ２ ) alkyl, halo, (C １ ~C ２ ) haloalkyl, (C １ ~C ２ ) haloalkoxy, (C １ ~C ２ ) alkoxy, (C １ ~C ２ ) optionally substituted with alkylamino, amino, nitro, cyano or hydroxy; R ６ '' is hydrogen, (C １ ~C ４ ) alkyl, (C １ ~C ２ ) haloalkyl, (C １ ~C ２ ) alkoxy, (C １ ~C ２ ) haloalkoxy, cyano, nitro, acetylenyl, fluorine and alkyl, phenyl, or 5- or 6-membered heteroaryl, wherein said alkyl, phenyl, or heteroaryl is optionally substituted with one or more substituents independently selected from halo, hydroxy, and amino.

2. a) R １ Methyl, -OH, -NH ２ , -CH ２ CH ２ OH, -CH ２ CH ２ NH ２ , 【Chemistry 5】 and optionally, R 1 is methyl, —OH, —CH 2 CH 2 OH, —NH 2 or —CH 2 CH 2 NH 2 , and / or b) X 1 is N, CH, CCl, or CF; and / or c) X2 is CH2, CHF, CHCl, or CF2; The compound of claim 1. 【Request 3】 【Chemical 6】 but 【Chemistry 7】 and the compound of formula (I) is represented by formula I-1 【Chemistry 8】 3. The compound of claim 1 or 2, having the structure: or a pharmaceutically acceptable salt or stereoisomer thereof.

4. a) X ３ is CH, N, CF or COMe, and / or b) X 4 is CH, and / or c) R 2 is (C 1 -C 2 )alkyl, 4-membered heterocyclyl, (C 3 )carbocyclyl(C 1 )alkyl, or 4-membered heterocyclyl(C 1 )alkyl; said alkyl, carbocyclyl, or heterocyclyl may be further substituted with one or more identical or different R 13 groups, and optionally R 2 is methyl or said heterocyclyl contains one heteroatom selected from N and O; The compound of claim 3.

5. R ３ Ga-L ３ CR １４ R １５ R １６ and Optionally, a) L 3 is —O—(C 1 )alkylene; b) R 14 and R 15 together with the carbon atom to which they are attached form a (C 3 -C 5 )carbocyclyl, a 4- to 7-membered heterocyclyl, or C═O; further optionally, R 14 and R 15 together with the same carbon atom to which they are attached form a C═O or oxetane ring; or c) R 16 is (C 1 -C 6 )alkyl, —NR 17 R 18 , or —OR 17 ; Further optionally, R 16 is methyl, hydroxyl, amino, or NHMe; 5. The compound of claim 3 or 4.

6. 1. The compound of claim 1, wherein the compound has formula I-1a, I-1b, I-1c, I-1d, I-1e, I-1f, I-1g, I-1h, I-1i, or I-1j: 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 and Optionally, the compound has the formula I-1a', I-1b', I-1c', I-1d', or I-1e': 【Chemistry 12】 【Chemistry 13】 and Further optionally, the compound has formula I-1k, I-1l, I-1m, I-1n, I-1o, I-1p, I-1q, I-1r, I-1s, I-1t, I-1u, I-1v, I-1w, I-1x, I-1y, I-1z, I-1aa, I-1bb, I-1cc, or I-1dd: 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 That is, 4. The compound of claim 3, or a pharmaceutically acceptable salt or stereoisomer thereof.

7. 【Catalog 19】 but 【Chemistry 20】 and the compound of formula (I) is represented by formula I-2 【Chemical 21】 having the structure Optionally, a) X 3 is CH, and / or b) X 4 is CH, and / or c) R 2 is (C 1 -C 2 )alkyl, 4-membered heterocyclyl, (C 3 )carbocyclyl(C 1 )alkyl, or 4-membered heterocyclyl(C 1 )alkyl; said alkyl, carbocyclyl, or heterocyclyl may be further optionally substituted with one or more identical or different R 13 groups; Further optionally, R 2 is methyl or said heterocyclyl contains one heteroatom selected from N and O; and / or d) R 4 is —(CH 2 ) 2 W 1 W 2 ; Further optionally, W 1 is CR 21 R 21′ ; Even more optionally, R 21 and R 21′ are both methyl; and / or W 2 is cyano, hydroxy, or amino; 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof.

8. 10. The compound of formula I-2a, I-2b, I-2c, I-2d, I-2e, I-2f, I-2g, I-2h, I-2i, or I-2j: 【Chemical 22】 【Chemical 23】 【Chemistry 24】 and Optionally, the compound has the formula I-2k, I-2l, I-2m, I-2n, I-2o, I-2p, I-2q, I-2r, I-2s, I- 2t, I-2u, I-2v, I-2w, I-2x, I-2y, I-2z, I-2aa, I-2bb, I-2cc, or I-2dd: 【Chemistry 25】 【Chemical 26】 【Chemical 27】 【Chemical 28】 【Chemical Formula 29】 That is, 8. The compound of claim 7, or a pharmaceutically acceptable salt or stereoisomer thereof.

9. 【Chemical 30】 but 【Chemical 31】 and the compound of formula (I) is represented by formula I-3 【Chemical 32】 having the structure Optionally, a) X 3 is CH, and / or b) X 4 is CH, and / or c) R 2 is (C 1 -C 2 )alkyl, 4-membered heterocyclyl, (C 3 )carbocyclyl(C 1 )alkyl, or 4-membered heterocyclyl(C 1 )alkyl; wherein said alkyl, carbocyclyl, or heterocyclyl is optionally further substituted by one or more identical or different R 13 groups; and / or d) A' is a 7-membered heterocyclyl, wherein the heterocyclyl contains two heteroatoms selected from N and O and is optionally further substituted with one or more substituents independently selected from, in addition to R 5 and R 5' , oxo, (C 1 -C 2 )alkyl, cyclopropyl, spiro-cyclopropyl, halo, (C 1 -C 2 )haloalkyl, (C 1 -C 2 )alkoxy, amino, cyano, and hydroxy; 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof.

10. The compound has the formula I-3a, I-3b, I-3c, I-3d, I-3e, I-3f, I-3g, I-3h, I-3i, I-3j, I-3k, I-3l, I-3m, I-3n, I-3o, I-3p, I-3q, I-3r, I-3s, or I-3t: 【Chemical 33】 【Chemical 34】 【Chemical 35】 【Chemical 36】 wherein each R ２５ are independently oxo, (C １ ~C ２ ) alkyl, cyclopropyl, spiro-cyclopropyl, halo, (C １ ~C ２ ) haloalkyl, (C １ ~C ２ ) alkoxy, amino, cyano, and hydroxy; n is 0 to 3; Optionally, the compound has the formula I-3u or I-3v: 【Chemical 37】 【Chemical Formula 38】 That is, 10. The compound of claim 9, or a pharmaceutically acceptable salt or stereoisomer thereof.

11. 【Catalog 39】 but 【Chemistry 40】 and the compound of formula (I) is represented by formula I-4 【Chemistry 41】 having the structure Optionally, a) X 3 is CH, and / or b) X 4 is CH, and / or c) R 2 is (C 1 -C 2 )alkyl, 4-membered heterocyclyl, (C 3 )carbocyclyl(C 1 )alkyl, or 4-membered heterocyclyl(C 1 )alkyl; wherein said alkyl, carbocyclyl, or heterocyclyl is optionally further substituted with one or more identical or different R 13 groups; or d) The compound has the formula I-4a, I-4b, I-4c, I-4d, I-4e, I-4f, I-4g, I-4h, I-4i, or I-4j: 【Chemistry 42】 【Chemistry 43】 That is, 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof.

12. 【Catalog 44】 but 【Chemistry 45】 and the compound of formula (I) is represented by formula I-5 【Chemistry 46】 having the structure Optionally, a) X 3 is CH, and / or b) X 4 is CH, and / or c) R 2 is a 4-membered heterocyclyl or a 4-membered heterocyclyl(C 2 )alkyl; wherein said alkyl, carbocyclyl, or heterocyclyl is optionally further substituted with one or more identical or different R 13 groups; or d) the compound has formula I-5a, I-5b, I-5c, I-5d, I-5e, I-5f, I-5g, I-5h, I-5i, or I-5j: 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 That is, 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof.

13. 【Catalog 50】 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemical 54】 【Chemistry 55】 【Chemical 56】 【Chemical 57】 【Chemistry 58】 【Chemical Formula 59】 【Chemistry 60】 【Hua 61】 【Hua 62】 【Chemistry 63】 【Hua 64】 【Chemistry 65】 【Hua 66】 【Hua 67】 2. The compound of claim 1, wherein:

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier, Optionally, said pharmaceutical composition is in liquid or solid form.

15. 1. A pharmaceutical composition for use in a method of treating a disease or disorder characterized by aberrant B-cell lymphoma 6 (BCL6) activity, comprising: Optionally, a) the disease or disorder is a lymphoid malignancy; Further optionally, said 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; and / or b) the pharmaceutical composition is for use in a method of administering an additional anticancer agent; Further optionally, the additional anticancer agent is an enhancer of zeste homolog 2 (EZH2) inhibitor. The pharmaceutical composition of claim 14.

Images