Pyrido five-element aromatic ring compound, preparation method therefor and use thereof

Abstract

The present invention provides a pyrido five-element aromatic ring compound, and a preparation method therefor and a use thereof. The compound provided in the present invention has an inhibitory effect on wild-type and / or mutant EZH2, and is well positioned to become a novel anti-tumor drug or a drug for the treatment of autoimmune diseases.

Description

<DP=1>²CA 03036114 2019-03-07²PYRIDO FIVE-ELEMENT AROMATIC RING COMPOUND,²PREPARATION METHOD THEREFOR AND USE THEREOF²FIELD OF THE INVENTION²The invention belongs to field of medicinal chemistry. In particular, the ²present²invention relates to a pyridino five-membered aromatic ring compound or a ²pharmaceutically acceptable salt thereof, a preparation process thereof and ²use ²thereof. The compound of the present invention can be used for the treatment ²of ²Drosophila enhancer of Zeste homolog 2 (EZH2)-related diseases such as ²malignant² tumors.²BACKGROUND OF THE INVENTION²Epigenetics means that expression of a gene has undergone heritable changes²while the nucleotide sequence of the gene keep unchanged, which play an ²important²role in regulating cell proliferation, differentiation, survival and ²apoptosis. An²important mechanism of epigenetic regulation is histone covalent modification. ²In ²eukaryotic cells, DNA surrounds the histones to form nucleosomes, which is the ²²basic structure of chromatin. In each nucleosome, two molecules of 1-12A, H2B, ²H3 ²and H4 form a histone octamer. A variety of covalent modifications occur at ²the² N-terminal amino acid end of each histone, such as methylation, acetylation,²phosphorylation, ubiquitination, etc., so as to control gene expression. ²Enzymes ²which catalyze the methylation of histones are called histone ²methyltransferases ²(HMTs).²The polycomb protein PRC2 is a multiprotein complex that functions to catalyze²the methylation of lysine (H3K27) at position 27 of histone H3, thus causing²silencing of related genes. The catalytic subunit of PRC2 is EZH1 or EZH2. ²EZH1 or ²EZEI2 alone has no catalytic function and must be combined with EED and SUZ12 ²before it can exert methyltransfertion. EZH2 is highly expressed in cells of ²various ²tumors (such as breast cancer, colorectal cancer, endometrioma, gastric ²cancer, liver²cancer, kidney cancer, lung cancer, melanoma, ovarian cancer, pancreatic ²cancer,²prostate cancer and bladder cancer), and is closely related to a process of ²tumor cells,²1²<DP=2>²CA 03036114 2019-03-07²such as proliferation, invasion, drug resistance and migration.²In recent years, EZH2 has been found to have mutated in 8-24% of ²non-Hodgkin's lymphomas, such as Y641F, Y641N, Y641 S, Y641H, A677G and ²A687V. These mutants have enhanced dimethylation and trimethylation catalytic²functions to histone H3 at position 27 of lysine compared with wild-type EZH2.²Excessive expression or mutation of EZH2 causes an increase in the level of 27 ²²lysine trimethylation products (H3K27me3) of H3, and high levels of H3K27me3 ²plays an important role in tumor cell proliferation and survival. Abnormal ²EZH2 ²activity leads to the development of tumors. The multiple target genes ²regulated by²EZH2 are tumor suppressor genes, and the silencing of tumor suppressor genes ²may²be an important mechanism. Down-regulation of EZH2 by siRNA or shRNA or ²indirect inhibition of EZH2 by SAH hydrolase inhibitor 3-deazaneplanocin A ²(3-DZNep) can significantly reduce the proliferation and invasion of tumor ²cells in ²vitro and the growth of tumors in vivo.² EZH2 also plays an important role in the differentiation of T cells. EZ1-12²reduces the expression of Thl / Th2 cytokines (such as IFN-y, 1L-4, IL-5, ²etc.), ²inhibits Th1 / Th2-dependent T cell migration, and activates regulatory T cells. ²In the ²tumor microenvironment, EZH2 inhibits Thl chemokines such as CXCL9 and ²CXCLIO, which is an important mechanism for tumor immune escape.²In summary, there is an urgent need in the art to develop effective drugs ²capable²of inhibiting wild-type and / or mutant EZH2.²SUMMARY OF THE INVENTION²An object of the present invention is to provide a pyridino five-membered².. aromatic ring compound, a preparation process thereof and the use as an ²EZH2²inhibitor thereof. The compounds of the present invention have a clear ²structure-activity relationship and have an inhibitory effect on wild-type ²and / or ²mutant EZH2, thus being expected to be novel drugs for anti-tumor or ²autoimmune ²diseases.² According to a first aspect of the invention, a compound of formula I, or a ²pharmaceutically acceptable salt, an enantiomer, a diastereomer, a tautomer, a²2²<DP=3>²CA 03036114 2019-03-07²solvate thereof, a polymorph or prodrug thereof is provided,²R2²R3²where XI is CR4 or N;²X' is CR5 or N;² X3 is CR6 or N; and at most one of XI, X', X3 is N;²R4 is selected from H, a halogen, substituted or unsubstituted CI -C6 alkyl;²R5 or R6 is selected from H, a halogen, -COOH, -CN, substituted or ²unsubstituted 5-8 membered aryl, substituted or unsubstituted 5-8 membered ²heteroaryl, substituted or unsubstituted 5-8 membered aryl fused to ²substituted or²unsubstituted 5-8 membered heterocyclic group, substituted or unsubstituted 5-²8²membered heteroaryl fused to substituted or unsubstituted 5-8 membered ²heterocyclic group, substituted or unsubstituted 5-8 membered aryl fused to ²substituted or unsubstituted 5-8 membered carbocyclic group, substituted or ²unsubstituted 5-8 membered heteroaryl fused to substituted or unsubstituted 5-²8²membered carbocyclic group, substituted or unsubstituted 4-8 membered ²saturated or²unsaturated carbocyclic group, substituted or unsubstituted 4-8 membered ²saturated ²or unsaturated heterocyclic group, substituted or unsubstituted Cl -C6 ²alkylcarbonyl ²group, -C(0)0-(substituted or unsubstituted Cl -C6 alkyl), -C(0)(NR3Rb), ²substituted ²or unsubstituted -(CH2)n,NRaftb, substituted or unsubstituted C I -C6 alkyl, ²boronic²acid group, substituted or unsubstituted C2-C8 alkenyl, substituted or ²unsubstituted²C2-C8 alkynyl; wherein the heteroaryl or heterocyclic group contains 1-3 ²hetero ²atoms selected from N, 0, S, P; m is an integer from 0 to 5; and said ²"substituted" ²means having one or more (e.g., I, 2, 3, or 4) substituents selected from ²group A;²Wherein Ra, Rb are each independently selected from H, a halogen, substituted²or unsubstituted C I -C6 alkyl, substituted or unsubstituted 5-8 membered ²carbocyclic²ring, substituted or unsubstituted 5-8 membered heterocyclic ring or Ra and Rb ²are ²bonded to N to form a substituted or unsubstituted 4-8 membered heterocyclic ²ring; ²wherein said heterocyclic ring contains 1-3 hetero atoms selected from N, 0, ²S, or P;²3²<DP=4>²CA 03036114 2019-03-07²0 R8 R9²R10²Y õ--Z=1;z11²IV is selected from R7 Or-iy²R2 is selected from H, a halogen, substituted or unsubstituted Cl-C6 alkyl, ²substituted or unsubstituted aryl;²0 8²H R R9 R19 R8²I 1(²R3 is selected from R7 or ; and when R1 is R7 , ²then R3 is²R10²z,² wherein, R7 is selected from H, a substituted or unsubstituted Cl -C6 alkyl;²R8 and R9 are each independently selected from H, a substituted or ²unsubstituted²Cl-C6 alkyl;²0²0²12 p²R² I '²R" R19 14 RI7 , N 20²R2`²Y is selected from 12'4 , or R2, =²wherein, R12 and R13 are each independently selected from H, a substituted or ²unsubstituted CI-C4 alkyl;²R14 and R15 are each independently selected from H, a halogen, -NH2, -NO2, ²-CF3, substituted or unsubstituted Cl-C4 alkyl, substituted or unsubstituted ²Cl-C4 ²alkoxy, substituted or unsubstituted (CH2)0NRcR1, or R14 and R15 are joined to ²form a²5-6 membered saturated heterocyclic ring, or R14 and R15 are linked to form a ²5-6 ²membered aromatic ring; n is an integer of 0-4;²R16 is 14, a substituted or unsubstituted Cl-C4 alkyl;²R17 and R19 are each independently selected from H, a substituted or ²substituted ²Cl -C4 alkyl, substituted or unsubstituted Cl -C4 alkoxy, -(CH2)nNRcRd; n is ²an² integer from 0-4;²R18 is selected from H, a halogen, -NH2, -NO2, substituted or substituted C I -²C4 ²alkyl, substituted or unsubstituted Cl-C4 alkoxy, substituted or unsubstituted²(CH2)0NRc Rd; where n is an integer from 0-4;²R29 and R21 are each independently selected from H, a substituted or ²substituted² C I -C4 alkyl;²4²<DP=5>²CA 03036114 2019-03-07²ENOR22 is selected from H, a substituted or unsubstituted CI-C4 alkyl;²S-0 ², or substituted or unsubstituted Cl-C4 alkoxy;²wherein R', Rd are each independently selected from H, a substituted or²unsubstituted C I -C4 alkyl;² Z is selected from N or Cu;²RI and Ril are each independently selected from: H, -OH, a substituted or ²unsubstituted Cl-C6 alkyl, -OR', substituted or unsubstituted 4-8 membered ²heterocyclic group, substituted or unsubstituted 4-8 membered carbocyclic ²group, ²substituted or unsubstituted 5-8 membered aryl, -NRfRg; wherein said ²heterocyclic²ring contains 1-3 hetero atoms selected from N, 0, S, or P; and said ²"substituted"²means having one or more (e.g., 1, 2, 3 or 4) substituents selected from group ²B; ²wherein Re is selected from H, a substituted or unsubstituted C -C6 alkyl, ²substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ²²alkynyl, substituted or unsubstituted saturated or unsaturated 4-8 membered²carbocyclic ring, substituted or unsubstituted saturated or unsaturated 4-8 ²membered²heterocyclic ring, substituted or unsubstituted 5-8 membered aryl, substituted ²or ²unsubstituted 5-8 membered heteroaryl, -(CH2)p(substituted or unsubstituted 5-²8 ²membered aryl), -(CH2)p(substituted or unsubstituted 5-8 membered heteroaryl); ²²wherein the heterocyclic or heteroaryl group comprises 1-3 heteroatoms ²selected²from N, 0, S, or P; p is an integer from 0 to 3; and said "substituted" refers ²to one or²more of the following (e.g., 1, 2, 3 or 4) substituent: halogen, a CI-C4 ²alkyl. Cl-C4 ²alkoxy, -NO2, -NRsRt;²wherein Rand Rg are each independently selected from: H, a substituted or ²unsubstituted Cl-C6 alkyl, wherein the substituent is -OH, CI-C4 alkoxy, or -²NRs1V;² group A substituents are selected from the group consisting of H, =0, -CN,²-COOH, -NRIV, a halogen, substituted or unsubstituted Cl -C6 alkoxycarbonyl, ²unsubstituted or substituted Cl -C6 alkyl. substituted or unsubstituted 4-8 ²membered ²heterocyclic group, substituted or unsubstituted Cl-C4 alkoxy; wherein the ²heterocyclic group contains 1-3 hetero atoms selected from N, 0, S or P;²group B substituents are selected from the group consisting of H, -OH, a²5²<DP=6>²CA 03036114 2019-03-07²halogen, unsubstituted or substituted Cl-C6 alkyl, -NRsRt, -NO2. substituted ²or ²unsubstituted Cl-C6 alkoxycarbonyl, substituted or unsubstituted Cl-C6 ²alkylsulfonyl, substituted or unsubstituted CI-C6 alkylcarbonyl, substituted ²or ²unsubstituted Cl-C6 alkoxy, substituted or unsubstituted 4-6 membered ²heterocyclic²ring, unsubstituted or substituted C5-C8 heteroaryl, Boc, benzyl; wherein said²heteroaryl comprises 1-3 heteroatoms selected from N, 0, S or P;²also, in the group A and group B substituents and Ra, Rb, the substitution ²means ²having one or more (e.g. 1, 2, 3 or 4) substitutions selected from group C: H, ²a²halogen, -OH, -CN, Cl-C4 alkyl, Cl-C4 alkoxy, -NRIV, 5-8 membered aryl, 4-8²membered heterocyclic group, Boc, C1-C4 acyl; and said substitution is one or ²more²(e.g., 1, 2, 3 or 4) substituents;²and, in the R7, Rs, R9, R12, R13, RI4, R15, R16, RI8, ²R19, R20, R21, R22, Rc, Rd,²the "substituted" means having one or more (e.g., 1, 2, 3 or 4) substituents ²selected ²from the group D: H, a halogen, CI-C4 alkyl, CI-C4 haloalkyl, nitro, -OH, ²amino;² RS and Rt are each independently selected from the group consisting of: H, a²Cl-C4 alkyl, CI-C4 haloalkyl.²In another preferred embodiment, I21 is a substituted or unsubstituted Cl-C4 ²alkoxy, substituted or unsubstituted Cl-C4 alkyl.² In another preferred embodiment, RI is selected from methyl or ethyl.²In another preferred embodiment, R11 is selected from the group consisting of²RI R1RJ Rrn Rn²0²,N²Q¨Rh ((:) ) ORk (-)²-OH, , -R-NRfg , , , , , -"1"- , "-r" , 'sr ,²?H²0 0²wherein Re is selected from the group consisting of a substituted or² unsubstituted C I -C4 alkyl, allyl, isobutenyl, propargyl, cyclohexane group,²O¨Re2 3COI I L(S²cyclohexenyl, N,²5 5 Re,,²²6²<DP=7>²CA 03036114 2019-03-07²S²I NH² -Re3 Re3,²wherein, Rd is selected from the group consisting of H, a halogen, Cl-C4 ²alkoxy, phenyl; and the number of Rd is 1-3; Re2 is selected from -NO2, -NH2,²-N(CH3)2; Re3 is selected from H, a halogen, -NRItt, substituted or ²unsubstituted² CI-C4 alkyl (preferably methyl);²Rf is H, or a substituted or unsubstituted Cl-C4 alkyl;²Rg is a Cl-C4 alkoxy or -NsIV substituted CI-C4 alkyl, or cyclopentyl;²Rh is selected from H, a halogen;²R' is selected from H, an unsubstituted or substituted Cl -C4 alkyl, ²substituted or² unsubstituted Cl-C4 alkylcarbonyl, substituted or unsubstituted Cl-C4²alkoxycarbonyl, substituted or unsubstituted Cl-C4 alkylsulfonyl, ²trifluoromethyl²I Rh,²C I -C2 alkyl, difluoromethyl CI-C2 alkyl, -NRIV, , and , wherein²Rh' is selected from -OH, -CN, a Cl-C4 alkyl;²Ri is selected from the group consisting of: -OH, a halogen, Cl-C4 alkoxy,²o² N N²-NRIV, ; wherein IV' is selected from a Cl-C4 alkoxy (preferably²dimethylamino, -OH, -NH2, methoxy);²R is selected from H or a halogen;²and when RI is a halogen, then IV' is a halogen;²Rk is selected from the group consisting of H, -OH, a Cl-C4 alkoxy,² RI is selected from the group consisting of H, -NRsIkt, preferably H or²dimethylamino;²Rm is selected from the group consisting of: H, -NRsIV, preferably H or²dimethylamino;²Rn is selected from the group consisting of trifluoromethyl Cl -C4 alkyl,² preferably CF3CH2-.²In another preferred embodiment, R5 or R6 are each independently selected from ²²the group consisting of: H, a substituted or unsubstituted Cl -C4 alkyl, -CN, ²halogen,²7²<DP=8>²CA 03036114 2019-03-07²C 1-C4 alkylcarbonyl, R51(C1-C4 alkoxy)carbonyl, R52C(0)-, -COOH, -²C(0)(NRaRb),²¶s H² 0 7,,,-NH²R55 ii ...s-R55²R55 N--- / ²H²pq R / N², 55 n² .,..r,s.x.__N A,_s²1 ;7_55²I 7 S_ R55 I >--R55²"N -----S - --- / n55 R55 , ----S , -- ----N² / ²:b X,--S² 1,_,---\ ;0-._-s² / Y sr¨ N 1 ,²1 , 1 ,²\ 0²RW, RW 0 ,² 9 9 9 9²rN N--² I , N-²I , Ys'N.-- S² S---b HN / HN / litb__²1.,,,o ?sc=-%-\ ___( \²N N-Rb'² 0 , N-Rb' , 0², R5,², 0², '.----'N / / ² / ²CN²õ.õ...N.,`2,(. --...,,\'' N( 1 '²N 0 D 55 H R55-1¨ R55-'¨²,s ,² Ni ik,N% Nõ---²-----'N / __ / N--,Rb' 1--...õ%i²R55 9 9 9 9 , ,²,----,.²y.. / fl²r) ²\ / ²1 '-' '''N-----N'Rb' "--Nl'IRb' ''-- , R57(C 1 -²C3)alkylalkynyl;²,²--\N1-²wherein R51 is selected from the group consisting of dimethylamino, ------ / ²,²0, Rb.-NJ , and wherein Rb is selected from the group consisting of ²H, a² C I -C4 alkyl, Boc, CI -C4 acyl;²,---N\- ,24.² R52 is selected from , ------j RI,, ,NJ , Rty--",---7 =², ,²Ra is selected from H, a substituted or unsubstituted Cl -C4 alkyl;²Rb' )n)(²Rb is selected from H, a substituted or unsubstituted C 1 -C4 alkyl,²cyclopentyl, Rb"(C 1-C4)alkyl; wherein X is a hetero atom selected from N, 0 ²or S;²R55 is 1-3 substituents selected from the group consisting oft-I, R551C1-C4 ²alkyl,²halogen, -CN, -NH2, (R551C 1 -C4 alkyl) NH-, (R551C 1 -C4 alky1)0-, ²dimethylamino,²,,,,,i² -CH2(Me)2, J , R6,11 , R551(C 1-C6)alkyl OC(0)-, -COOH, -C(0)(NRaRb);²8²<DP=9>²CA 03036114 2019-03-07²wherein R551 is H, -OH, a Cl-C4 alkoxy, amino, dimethylamino, methylamino,²RõjNJ R641²diethylamino, methylethylamino, ethylamino, ,² _______________________ 1µ131 / L'²N ) )²F HO H2N wherein R541 is²selected from a Cl- C4 alkyl;² R57 is selected from a (CI-C4)alkyl, O , dimethylamino;²Rb" is selected from the group consisting of -OH, a CI-C3 alkoxy,²rNk 0:õ²N11¨²dimethylamino, o)², and²Rb-²In another preferred embodiment, the compound of formula I has the structure² of formula la:²122²R1iR3²µ(-R4²R6²b²wherein, the R1, R2, R3, R4, R5, and R6 are as described above.²In another preferred embodiment, R2, R4, R7-R9, R12-R22, Ra, Rb, Re, Rd, Re ²are²substituted by a substituent selected from the group consisting of halogen, a ²C1-4² alkyl, trifluoromethyl, amino, nitro, -OH.²In another preferred embodiment, R7 is H.²In another preferred embodiment, R8=R9=H.²In another preferred embodiment, Z is CH.²In another preferred embodiment, R2 is methyl.² In another preferred embodiment, the compound is selected from the group²consisting of:²9²<DP=10>²CA 03036114 2019-03-07²L²oitL,: HN 1 rett, HIYIN't4 L ''-%²i²0 .."...r, 0 0A / I 0 0²4:frrOIL.1; 0,.....,r²N_Ilra'frIV, Ht,itaY, 0 --'''r-1 Ka.) -3t0-²1:::1²11:1 -.ili²O OH². tw.²a². iti _16²i_o 11v----oc a N 0 H...1., Y`Ni,c(r-kr"-CrF²I H²Or, ft, .?.=\ \²"a' 1 4 --tf ' 14)YritC10 ,..,)õ.,_1 / 411)VD 11:6CNItC Lif²N N N²V 1²N²55i, rd²O _alto)*²Tk 7yttoitc5,11.,²N² / 1 / ²A²I n r) C )²ft1².....iy ft rn=-'4`.- ItN.L.,²YVN 0 ²i iN G, i²Or² (0N) C3)²0 0 N²0 0 N 0 0 N 0 0 ²)k. HtfArN²1,..1tHr j N²FIN.A.V1 j N C0) ' ( )²0 0 N n²0 0 N CC)) 0 0 N²0 0 N² / 1 / ²µ², 0²C D C) C²C ) 0 0 N n² 0 N²0 jOt 0 yti²*=-² / H I²j5C²²11 I .²4 / ²-²N CI CI²a CI') "N,a c)²0 0 N 0 0 N²NA': =====ris=-.1²? 1 N N H²'... N² \ HN...)..klif²1²-²µN-14-- CI²1-1²NI²a C )²N²( )²Oil yit ()²`..&1141"1-ke'N²'fr2 0t F:r..² I / Icilk²Br Br²CI²Br²<DP=11>²CA 03036114 2019-03-07² r ay,² N N N, N²i j A ( ) C J C )²jot. N 0 y ..t..r.cyy, 0 N²0²Hisfrri².2iy-11 1 N² ' N² Br Br Br Bf²*F F²0, ,0 F²---.;² F F OH²N² a c") ( (²0 0 N) ...., N 0 f k 0 ti N²\ / ²0 0 N²\²,,,,,,, 1 ==,,N HI,Apil 1 -",;., / litpli 1 ."-N²\ / ² Br Br²Br²0'²6 ci) 0²N²:.:²0 y y 0² ti.,. / N 0 y 6 0²ithIL, ²Br² Br Br²Br² 0 C) C)²,² N 0 N 0 0 N²a 0 0 N².:,,O2 1 N 7a-Crii 1 N²N² 0 Itri,r / N , ² I / 0²0²\ 0²Or²(0 / ²D²)² () 0 yti 0 0 N 0 0²1 , N²9 0 1,1²,,,,,,,-1,²H h ,, A,,² I / / ²0 ii 0\²0 / ²0-7 0\²i²,²11²<DP=12>²CA 03036114 2019-03-07²0 0 N²0 0 N C )²0 0 N²H)....'W,²0 0 N "Ia'N N².Ari. 1 N²\²tirAizi 1 -s-² / F 4 N²0\²0²0² / / ²a C )²0 0 ²0 ft²0 0 N²HANN 1 N²0 0 N²760 N 1 / ²NPM0 / ²0\²,N²õ0²F²( ) 0 0 N 0 0 N 0 0 N 0 0 N²7 ja---11 1 N²4,,N111 I ,²1,54,aprj(q4 -²\ / 1²--J²1 \ NH N,²N²a²²0 0 c )², N c) cc)²N 0² N f . 0 ²}1)01 I N²HA' Naltj'.., -²oti C,²F i 1² / ²N -²-0²12²<DP=13>²CA 03036114 2019-03-07² C ) C0)²0 o 1 7 _ C)²0 yysc o 0 r=ci²( )²N²0 0 N² la) 1.-',,r ":_ti'l Cr H.Ali 1 ====N²I / ²I / ²-N² / N3² N I²(0) 0 0 C )² N 0 0 (7)² N 0²0 0 N .7A, 1²I / ²-.64H²C) 0 a .² (0 ri ( )²1 y²a 0 N-². 0 N²0 r '111)²I / ²=N²-²=N²= ,N....1²NH NIP .N²L.....AH ²X²( ) a C )²0 N²0 0 N 0 0 14a fr 0² 0 N²HP² a' li 1 N HPA141 1 N² / \² / \ _²1 ) ..²) ( )². ii 1 ir² C) 0 31 a yt1²HP:1,,,a".²1 rir-rr---²N²HN:Y.ti 0 1 N²1 / ²\²-'11..² -N HIAg 1 N²I²N²NH, "All I N²1 t² / µN²OH il_N²-²µ14²Q²13²<DP=14>²CA 03036114 2019-03-07²rie²'N'²N 6²y cA)²c Le J.,. y . . ,.. ,v o o N²0 0 N 0 0 N²71.......1 i ".-N²0² / Al CI / ,²-1²NH²F F ,N, ,FFF²,AF r,,²6 N²a N²( ) 0 0 N ( )²0 0 N ,*fri3Ol*N 0 0 N²':OCI:i I 0²,,²i 1²I \ / ²N' V / N / ²) ²fel N²F 'N' F F²CF²a (kF²N²(C) N C)²²0 0 N 0 0 N²0 0 ²0 3 ( q)²1,1,....X, =cLi'1,4²I 1 / / ²IN1²?²( )²(A) ( ) t²&-N L., ²0 ..10t4 N²oN²1:1 0 0 0² -... N 0 0 y I..q A²1 I H I ,,,, 7.4...y.11 ""--N²H:Lj.-0-N² \ / I 1 / ²4 S² N N.²14²<DP=15>²CA 03036114 2019-03-07²(FF² N n r) n² C N 0 0 N 0 õV²) Nss..²0 0 N 0 0²'INI.,..'N²1 I / ²s / 3 / ²0 0²N²H² N N N²0 0²0 0 y 0 0 coy) . 0 <T>² Br Br Br² C0) E0) ²( ,J²0 0 N 0 0 N 0 yi..,,,,,Ncl²0 LI² / Br N Ti²HnAti 1 ---N²\²t²NH 0²p ,o²A²`Y)²,:_ii...---ti² HNA-11 1 `NN N, =-.. N²0 Br Br²(0.1 0 0²(0,1² H2 0 0²0 0 y 0 0²,:õ.. J.,,-,,1õ4 i ,,,,, NI H1:1,1µ.11 ² 1 =,,,, NI²1 / ² / ²0²0²()²0 0 (T) 0 0 EN)²0 0 ²HA-rd 1 ,-N NI (01²Hi),..., i ....,.²-N -0²0 / -N²0-2²'5²<DP=16>²CA 03036114 2019-03-07²CO)²a²0 0 0,- a . C)²N 0 0 N²F_Irs& F5.....'N' '=== H N,... 1 -IJI 1 ...,N 0 ²N 0²1 11 IN I H I² I H I²\ / ² / ²0 0 N)(7 ²\ / ¨N²\ CN (CF3²0 0²C ) ( ) a N²C ) 0²0 0 N 0 N² 0 yt I, 0 0 N²OCI N²H..... Ht.... / ...'N -²,²11 I N I H I² / NH Br²0 0 (CF3 F (CF,²C) C ) N N²N²0 N 0 0 C) C)²0²I H I²0 0 N 0²0 tyy² H:f.,....'N- '', ''''= \ 0²I H I I H I²0² \ / '' 0 N N²HN,H, / ,\19²N H² H H²16²<DP=17>²CA 03036114 2019-03-07²rCF, rCF 3² rCF, (CF3²N²C ) N²C ) ) N² 0 0 N 0 0 N²0 0 N 0 0 N²HNõ,.. HN i0 ' Id '"....N²I²HN²1² / IN² N" \ N,0 / ² H (CF, (CF, µN-N.'²....,CF3 H211 N (CF3²N i N²C C C ) N ) N ) ( )² 0 0 0 0 N 0 N 0 0 N²0 N²HN 1 rii 1 ,²\ -- 0 N 0² i \²¨..²N \ / \ / ²HA²H N²2N N ----N N²¨IV²0rCF3²H (CF²N 3²r--\²ii,CF 3²Ny, S²N² ( ) ..,i²0 0 C) ( ) 0 0 N 0 0 0²0 0 N²HN 1 Vi I Vi 1 ''.. HN I 11 I N ' ² N HN 1 N 1 -=²0__²\ -- ..N,NH²11 (CF²0 rCF3 \ / ²N rc,, N N rcr,²CF,²N ²N (²0 0 C) ( J N ) 0 0 N 0 0 N )²N²II. o o N² FIN , Iii HN 1 N 1 -.. HN 1 N- I I 1 ....N ,²1 N HN 1 N² N / 1 -...N²-- 0 ²CI CI N² CI 0--²rCF3 (CF (CF²3 ².²N C) N N²C:) C ) ( D 0 0 N² 0 0 0 0 N 0 0 N² HN 1 il 1 , HN 1 N²HN 1 NI 1 N²_²N²0¨ 0-- MC¨. HN_²r,CF 3 r.,3²1,,c,.CF, (CF² 1 rm,²N N²L. )²C ) C ) 0 0 N² 0 0 N ( ) 0 0 N²0 0 N² I H I HN 1 1 1 N N²I I²I² -- __²N / ² / 1\4 / ²N--²HN¨ 1² / N¨²² / N--²1 7²<DP=18>²CA 03036114 2019-03-07²(CF 3 (CF ,CF3²3² I ,CF3²N N 1²N N²( ) ( ) C C )²0 0 N²0 0 N²0 0 N 0 0 N²1-...IN N".=²I H I²F11:&N ''.=² I H I²1 1 / ²- - -²\ / ²N²(CF, (CF 3 (063 (CF,²N N N N²C) ( ) C)²0 0 N²)²0 0 N 0 0 N²0 0 N²HN 1 N 1--,²N²'' 0²-- --- --² N \ 1,;,N \ 4,N²18²<DP=19>²CA 03036114 2019-03-07²..CF, 4,CF3 ,,,(0F, ,,,.CF²ii ,²E ) ( ) ) C )²0 0 0 N 0 0 1 H 0 0²HANcy,² 1 N WAN 1 y=-= "'All I N²¨²---²\ 4.N ),, ;-_,.( )i-N=²rcFs 0F,²ir, 4...cF²N (N) C) ( )²( ) 0 0 N² 0 0 N²0 0 ²N²HAT, 1 N²õ."---N , N²' 0 ' ,²1 , / Hi4,,A=N 1 ",N 7.Y0'11 I ²''N²I \ / ²¨ / \ ¨ = ¨²H,N N HN²(CF, (CF 3 ir,CF,²q²N r0F,²( ) 0 0 0 0 0 0 (rJ 0 0 C.²N "-T.-)²" ²1,4,14&[41 1 ', N.²² 1 I NI²¨ _²_²son²HN- N-. / ²(CF 3 (0F3 4,0F3 ,(CF,²r ,IN²0 a Ly) 0 0 C-1) a 0 0 0 1²HAN I N NIH....l 'iltli , \N² 0 '²N²N' N ²HN-- HN-- / N--²,(CF,cõcF3²(F. (CF² C ) ( ) N²( )²C ) 0²0 0 N 0 0 N² 0 N²0 0 N²iNj'' 11 I '''h, liCI'l I²) \ / :²Hb14i 1 N²F3 \ / ²ii ²1²H²\ , H,N ri 4421.1 N \²N²H211 N H,N²F F²(CF,²F*1²,(.CF,² (N) ?²N²( )²0 (Nj 0 0 N²HN N(`... :²I²NI 9)-.-14, , ---²Eyc.H²-..²N Ni 1²Yj H,N²a²H,N²0²In another preferred embodiment, the compound of formula I is selected from ²compound 1-151.² According to the second aspect of the present invention, a process for the ²preparation of compound of formula I as described in the first aspect of the ²invention ²is provided, wherein the compound of formula I has the structure shown in ²formula ²1-1 and comprises steps:²19²<DP=20>²CA 03036114 2019-03-07²Ra²0 Ft'²CHT² 0 R2 0 112 ICH21¨oT: 0-1C4nT:²0 R2 OH²Rk0V4,..% ILRm Rko RID WOjiti ¨ HO CI, (J-:²dv:t N:x,² x' x'²X24 X2-x2²I-1²9²(1) in the presence of a reducing agent, reducing compound d to form compound ²e, while the reducing agent is selected from the group consisting of sodium ²borohydride, lithium borohydride, potassium borohydride, or combinations ²thereof;² (2) in the presence of a base, reacting compound e with a corresponding²hydrocarbylation reagent to form compound f, wherein,²The base is selected from the group consisting of sodium hydride, potassium ²t-butoxide, sodium hydroxide, potassium hydroxide, n-butyl lithium, lithium²diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide,² potassium hexamethyldisilazide, potassium carbonate, cesium carbonate, sodium²carbonate, or combinations thereof;²The alkylating agent is selected from the group consisting of halogenated²hydrocarbons, methanesulfonate, p-toluenesulfonate, trifluoroacetate, ²triflate, or ²combinations thereof;² (3) hydrolyzing compound f to form compound g;²(4) condensing compound g with an amine compound to form compound 1-1,²wherein R2, R3, R7, R8, R9, Rio, T1, Re, Rf, X1,²X2, X3 and Y are as defined²above, and Rk is a Cl-C4 linear or branched alkyl.² In another preferred embodiment, before the step (I), the method further²comprises a step (1-1): in an inert solvent, reacting the compound a with b in ²the ²presence of a catalyst to form compound d,²0²R,U(0R. R,²0²N,²\²=²In another preferred embodiment, in the step (1-1), the inert solvent is ²selected².. from the group consisting of isopropanol, ethanol, methanol, ²tetrahydrofuran,²chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, ²or combinations thereof.²<DP=21>²CA 03036114 2019-03-07²In another preferred embodiment, in the step (1-1), the catalyst is selected ²from ²the group consisting of alkali such as cesium carbonate, potassium carbonate, ²sodium ²carbonate, potassium phosphate, triethylamine, 1,8-diazabicycloundec-7-ene or ²the ²like, or ammonium acetate, piperidine acetate salt, or combinations thereof.² In another preferred embodiment, before the step (1), the method further²comprises the step (1-1'): in an inert solvent, using compound a and compound ²c to ²conduct Michael addition reaction under basic conditions to form compound d,²0 (3, R,²0 R2 0²121 --1(1 WO² R0I ."- R' c²09M-C3²x'²X -X9 I õ²x'-x9²a d²In another preferred embodiment, in the step (I-I'), the solvent is selected ²from²the group consisting of N,N-dimethylformamide, N.N-dimethylacetamide, dimethyl²sulfoxide, tetrahydrofuran, or combinations thereof.²In another preferred embodiment, in the step (1-1'), the alkali is selected ²from ²the group consisting of cesium carbonate, potassium carbonate, sodium ²carbonate, ²potassium phosphate, or combinations thereof.² According to the third aspect of the present invention, a process for the ²preparation of compound of formula I as described in the first aspect of the ²invention ²is provided, wherein the compound of formula I has the structure shown in ²formula ²1-2 and comprises steps:²RB,REI²0 142 0²0 13213 'N-R' 0 R2ReN-R1 HN ---i²0 R2 WN,Rf²1 Y h²R,0 ,...., wo HNf12.R'²I WO ..", Ric' _... HO 1 ===== le' ²R7²I =i N,²x'-x, 1 =?'' \ X' Y R9 µ ,x'²x'-x2² d 1 1 1-2²(i) in an inert solvent, in the presence of reducing agent, reacting compound ²d ²with compound f to form compound i;²(ii) hydrolyzing compound i to form compound j;²(iii) condensing compound j with amine compound to form compound 1-2;²wherein the R2, R3, R7, R8, R9, RR), Re, Rt, Rk, ),(1, ¨2,²A X3 and Y are as described²above.²21²<DP=22>²CA 03036114 2019-03-07²In another preferred embodiment, in the step (i), the inert solvent is ²selected²from the group consisting of titanium tetraisopropyloxide, tetrahydrofuran, ²acetic ²acid, trifluoroacetic acid, or combinations thereof.²In another preferred embodiment, in the step (i), the reducing agent is ²selected²from the group consisting of sodium borohydride, sodium cyanoborohydride, ²sodium²triacetoxyborohydride, or combinations thereof.²According to the fourth aspect of the present invention, a process for the ²preparation of compound of formula I as described in the first aspect of the ²invention²is provided, wherein the compound of formula I has the structure shown in ²formula²1-3 and comprises steps:²Fe R2 R"²NC NH R2 Ril²NC.,cL-1,,, , NH2²NC², '-- rl'IRIG²N, I²k I X3-x2²m²fe Re²0 R2 121' HN¨V 0 R2 Fel²________________________ .. HOcyIR'' 1 ' R' Y h R7-- 1 il.-1J ²Rto²1 N,²1 ,x'²yAI_Rr 1 N:x,² X3-x2 X3-x²n 1-3²(a) in an inert solvent, in the presence of reducing agent, reducing compound ²k to ²form compound 1;²(b) in the presence of alkylating agent, reacting compound 1 to form compound ²m,²and said alkylating agent is selected from the group consisting of X-R' , HSO4-²le0'², ²HO-R10, R10 ...0-..-=K 10.5²or combinations thereof;²wherein X is halogen; R1 ' is a substituted or unsubstituted Cl -C6 alkyl, ²substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6² alkynyl, substituted or unsubstituted saturated or unsaturated 4-8 membered²heterocyclic group, substituted or unsubstituted saturated or unsaturated 4-8 ²membered carbocyclic group, substituted or unsubstituted 5-8 membered aryl, ²saturated or unsaturated; wherein said heterocyclic ring comprises 1 -3 ²heteroatoms ²selected from N. 0, S, P: and said "substituted- means having one or more ²(e.g., I, 2,²3 or 4) substituents selected from group B as set forth in the first aspect of ²the²present invention;²22²<DP=23>²CA 03036114 2019-03-07²(c) hydrolyzing compound m to form compound n;²(d) condensing compound n with amine compound to form compound 1-3;²wherein the R2, R3, R7, R8, R9, RI , Re, Rf, Rk, XI, X2, X3 and Y are as ²described²above.²According to the fifth aspect of the invention, a pharmaceutical composition ²is²provided, comprising:²(1) a compound of the first aspect of the present invention, or a ²pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate,² polymorph or prodrug thereof; and²(2) pharmaceutically acceptable carriers.²According to a sixth aspect of the invention, use of Formula! compound of the ²first aspect of the present invention, or a pharmaceutically acceptable salt,²enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof is ²provided, wherein the use is selected from the group consisting of:²(a) preparing a medicament for preventing or treating a disease associated ²with ²EZH2 mutation, activity or expression;²(b) non-therapeutic inhibition of the activity of EZH2 and the mutants thereof ²in² vitro; and / or²(c) non-therapeutic inhibition of tumor cell proliferation in vitro.²In another preferred embodiment, the disease associated with EZH2 mutation, ²activity or expression is selected from the group consisting of tumor or ²autoimmune ²disease.² In another preferred embodiment, the disease associated with EZH2 mutation, ²activity or expression is selected from the group consisting of B cell ²lymphoma, ²malignant rhabdomyomas, synovial sarcoma, breast cancer, colorectal cancer, ²endometrioma, gastric cancer, liver cancer, kidney cancer, lung cancer, ²melanoma, ²ovarian cancer, pancreatic cancer, prostate cancer, or bladder cancer.²It should be understood that, in the present invention, each of the technical ²features specifically described above and below (such as those in the ²Examples) can²23²<DP=24>²CA 03036114 2019-03-07²be combined with each other, thereby constituting new or preferred technical ²solutions which need not be specified again herein. .²EMBODIMENTS FOR CARRYING OUT THE INVENTION² Through extensive and intensive research, the present inventors have for the²first time unexpectedly discovered a pyrido-5-membered aromatic ring compound, ²a ²preparation process and use thereof, and the compound of the present invention ²has ²an inhibitory effect on wild-type and / or mutant EZH2. The present invention is ²²completed on this basis.² Terms²Unless otherwise defined, all technical and scientific terms used herein have ²the ²same meaning as commonly understood by one of ordinary skill in the art to ²which ²this invention belongs.²As used herein, when used in reference to a particular recited value, the term²"about" means that the value can vary by no more than 1% from the recited ²value. ²For example, as used herein, the expression "about 100" includes all the ²values ²between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).²As used herein, the terms "containing" or "including (comprising)" may be² opened form, semi-closed form, or closed form. In other words, the terms also²include situations such as "essentially consisting of..." or "consisting ²of..."²Group definitions²The definition of standard chemical terms can be found in references ²(including² Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A²(2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, ²conventional methods within the skill of the art, such as mass spectrometry, ²NMR, ²IR and UV / VIS spectroscopy and pharmacological methods are employed. Unless ²specifically defined, the terms relates to analytical chemistry, organic ²synthetic²chemistry, and pharmaceutical and pharmaceutical chemistry used herein are ²known²in the art. Standard techniques can be used in chemical synthesis, chemical ²analysis, ²pharmaceutical preparation, formulation and delivery, and treatment of ²patients. For²24²<DP=25>²CA 03036114 2019-03-07²example, the reaction can be carried out and purified according to the ²manufacturer's ²instructions for use of the kit, or by methods well known in the art or as ²described in ²the present invention. The above techniques and methods can generally be ²carried out ²according to conventional methods well known in the art, as described in the ²various²summaries and more specific references cited and discussed in this ²specification. In²the present specification, the group and its substituents can be selected by ²those ²skilled in the art to provide stable structural moieties and compounds.²When a substituent is described by a conventional chemical formula written²from left to right, the substituent also includes the chemically equivalent ²substituent²obtained when the structural formula is written from right to left. For ²example,²-CH20- is equivalent to -OCH2-.²The section headings used herein are for the purpose of organizing articles ²only ²and are not to be construed as limiting the subject matter. All documents or ²parts of²the literature cited in this application, including but not limited to ²patents, patent²applications, articles, books, operating manuals and papers, are hereby ²incorporated²by reference in their entirety.²Certain chemical groups defined herein are preceded by a simplified symbol to ²indicate the total number of carbon atoms present in the group. For example, ²Cl-C6 ²alkyl refers to an alkyl as defined below having a total of from 1 to 6 carbon ²atoms.²The total number of carbon atoms in the simplified symbol does not include ²carbon²that may be present in the substituents of the group.²In addition to the foregoing, when used in the specification and claims of the ²²present application, unless otherwise specifically indicated, the following ²terms have ²the meanings indicated below.² In the present application, the term "halogen" means fluoro, chloro, bromo or²iodo.²"Hydroxy" means -OH group.²"Hydroxyalkyl" means alkyl groups as defined below which is substituted by ²hydroxy group (-OH).²"Carbonyl" means -C(=0)- group.²"Nitro" means -NO2.²"Cyano" means -CN.²<DP=26>²CA 03036114 2019-03-07²"Amino" means -NH2.²"Substituted amino" means amino groups substituted by one or two alkyl, ²alkylcarbonyl, arylalkyl, heteroarylalkyl as defined below, for example, ²monoalkylamino, dialkylamino, alkylamido, arylalkylamino, ²heteroarylalkylamino.² "Carboxyl" means -COOH.²In the present application, as a group or part of another group (for example, ²used in a group such as a halogen-substituted alkyl group), the term "alkyl" ²means a ²fully saturated straight or branched hydrocarbon chain group which consists ²only of ²carbon atoms and hydrogen atoms, and has, for example, 1 to 12 (preferably 1 ²to 8,²more preferably 1 to 6) carbon atoms, and is bonded to the rest of a molecule ²by a²single bond, for example, including but not limited to, methyl, ethyl, n-²propyl, ²isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, ²2,2-dimethylpropyl , n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, ²decyl and ²decyl. For the present invention, the term "alkyl" refers to alkyl containing ²from 1 to²6 carbon atoms.²In the present application, as a group or part of another group, the term ²"alkenyl" means a straight or branched hydrocarbon chain group consisting only ²of ²carbon atoms and hydrogen atoms, containing at least one double bond, and ²having ²for example 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms ²and²being attached to the remaining part of a molecule by a single bond, e.g., but ²not²limited to, vinyl, propenyl, allyl, but-l-enyl, but-2-enyl, pent- 1 -enyl, ²pentane-1,4-dienyl, and the like.²In the present application, as a group or part of another group, the term ²"cycloalkyl" means a stable non-aromatic monocyclic or polycyclic hydrocarbon²group consisting of carbon atoms and hydrogen atoms only, which may include ²fused²ring system, bridged ring system or Spiro ring system having from 3 to 15 ²carbon ²atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 ²carbon ²atoms, and which is saturated or unsaturated and may attach to the rest of a ²molecule ²by a single bond via any suitable atoms. Unless otherwise specifically ²indicated in²the specification, carbon atoms in the cyclic hydrocarbon groups may be ²optionally²oxidized. Examples of cycloalkyl groups include, but are not limited to, ²cyclopropyl, ²cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, ²cyclohexadienyl,²26²<DP=27>²CA 03036114 2019-03-07²cycloheptyl, cyclooctyl, 1H-indenyl, 2,3-indanyl, 1,2,3.4-tetrahydro-naphthyl, ²²5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzocycloheptene-6-yl, ²6,7,8,9-tetrahydro-5H-benzocycloheptenyl, ²5,6,7,8,9,10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo [2.2.1] heptyl,²7,7-dimethyl-bicyclo[2.2.11heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2] ²octyl,²bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, ²bicyclo[3.2.1]octenyl, adamantyl, octahydro -4,7-methylene-1H-indenyl and ²octahydro-2,5-methylene-cyclopentadienyl and the like.²In the present application, as a group or part of another group, the term² "heterocycly1" means a stable 3- to 20-membered non-aromatic cyclic group²consisted of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from the ²group ²consisting of nitrogen, phosphorus, oxygen and sulfur. Unless otherwise ²specifically ²indicated in the specification, heterocyclic group may be monocyclic, ²bicyclic, ²tricyclic or ring system with ever more cyclic, which may include fused ring ²system,²bridged ring system or spiro ring system; the nitrogen, carbon or sulfur atom ²may²optionally be oxidized; the nitrogen atom may optionally be quaternized; and ²the ²heterocyclic group may be partially or fully saturated. The heterocyclic group ²may be ²bonded to the remaining part of a molecule via a carbon atom or a hetero atom ²through a single bond. In the heterocyclic group containing a fused ring, one ²or more²of the rings may be aryl or heteroaryl as defined hereinafter, provided that ²the point²of attachment to the rest part of a molecule is a non-aromatic ring atom. For ²the ²purposes of the present invention, the heterocyclic group is preferably a ²stable 4 to ²11 membered non-aromatic monocyclic, bicyclic, bridged or spiro group ²containing ²from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. More ²preferably,²it is a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or ²spiro²group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and ²sulfur. ²Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, ²²morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, ²2,7-diaza-spiro[3.51nonane-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl,²2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza-cyclobutane, pyranyl, ²tetrahydropyranyl,²thiapyranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, ²tetrahydroisoquinolinyl, ²decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinazolidinyl, ²thiazolidinyl,²27²<DP=28>²CA 03036114 2019-03-07²isothiazolidinyl, isoxazolidinyl, dihydroindolyl, octahydroindolyl, ²octahydroisodolyl, ²pyrrolidinyl, pyrazolidinyl , phthalimidoyl and the like.²In the present application, as a group or part of another group, the term ²"aryl"²means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms,²preferably having 6 to 10 carbon atoms. For the purposes of the present ²invention, an²aryl may be a monocyclic, bicyclic, tricyclic ring system or a ring system of ²even ²more rings, and may also be fused to a cycloalkyl or heterocyclic group as ²defined ²above, provided that the aryl group connected to the rest of a molecule by a ²single ²bond via atoms on the aromatic ring. Examples of aryl groups include, but are ²not² limited to, phenyl, naphthyl, anthracenyl, phenanthryl, anthryl,²2,3-dihydro-11-1-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-keto-²7-yl, ²and the like.²In the present application, the term "arylalkyl" refers to an alkyl as defined ²²above substituted by a aryl group as defined above.² In the present application, as a group or part of another group, the term²"heteroaryl" means a conjugated hydrocarbon ring system group having 1 to 15 ²carbon atoms (preferably having 1 to 10 carbon atoms) and 1 to 6 heteroatoms ²selected from nitrogen, oxygen and sulfur. Unlesss otherwise indicated in the ²present ²invention, a heteroaryl may be a monocyclic, bicyclic, tricyclic ring system ²or a ring²system of even more rings, and may also be fused to a cycloalkyl or ²heterocyclic²group as defined above, provided that the aryl group connected to the rest of ²the ²molecule by a single bond via atoms on the aromatic ring. The nitrogen, carbon ²or ²sulfur atom in the heteroaryl group can be optionally oxidized; and the ²nitrogen atom ²can optionally be quaternized. For the purposes of the present invention, the²heterocyclic group is preferably a stable 5 to 12 membered aromatic group²containing from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. ²More²preferably, it is a stable 5-to 10-membered aromatic group containing from Ito ²3 ²heteroatoms selected from nitrogen, oxygen and sulfur, or 5- to 6-membered²aromatic group containing from 1 to 3 heteroatoms selected from nitrogen, ²oxygen²and sulfur Examples of heteroaryl groups include, but are not limited to, ²thienyl,²imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, ²pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, ²furyl,²28²<DP=29>²CA 03036114 2019-03-07²pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, ²indazolyl, isoindazolyl, ²purinyl, quinolyl, isoquinolyl, diazonaphthyl, naphthyridinyl, quinoxalinyl, ²pteridinyl, ²carbazolyl, carboline, phenanthridinyl, phenanthrolinyl, acridinyl, ²phenazinyl, ²isothiazolyl, benzothiazolyl, benzothienyl, oxatriazole, cinnolinyl, ²quinazolinyl,² phenylthio, purrocolinyl, orthophenanthrolenyl, isoxazolyl, phenoxazinyl,²phenothiazine, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridyl, ²[1,2,4]triazolo[4,3-b]pyridazine, [1,2,41triazolo[4,3-a]pyrazine, ²[1,2,4]triazolo[4,3-elpyrimidine, [1,2,4]triazolo[4,3-alpyridine, ²imidazo[1,2-alpyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine, etc.²In the present application, the term "heteroarylalkyl" refers to a alkyl as ²defined²above which is substituted by a heteroaryl as defined above.²In the present application, "optional" or "optionally" means that the²subsequently described event or condition may or may not occur, and that the ²description includes both the occurrence or non-occurrence of the event or ²condition.²For example, "optionally substituted aryl" means that the aryl is substituted ²or²unsubstituted, and the description includes both the substituted aryl and the ²unsubstituted aryl. The "optional" substituents described in the claims and ²the ²specification of the present invention are selected from the group consisting ²of an ²alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, ²nitro,²optionally substituted aryl, optionally substituted heteroaryl, optionally ²substituted²cycloalkyl, optionally substituted heterocyclic hydrocarbon group.²The terms "part", "structural moiety", "chemical moiety", "group", and²"chemical group", as used herein, refer to a particular fragment or functional ²group in ²a molecule. A chemical moiety is generally considered to be a chemical entity ²that is² embedded or attached to a molecule.²"Stereoisomer" refers to a compound composed of same atoms, bonded by the²same bonds, but having a different three-dimensional structure. The invention ²will²cover various stereoisomers and mixtures thereof.²When the compound of the present invention contains olefinic double bonds, the²compounds of the present invention are intended to comprise E- and Z-geometric²isomers unless otherwise stated.²"Tautomer" refers to an isomer formed by the transfer of a proton from one²29²<DP=30>²CA 03036114 2019-03-07²atom of a molecule to another atom of the same molecule. All tautomeric forms ²of²the compounds of the invention will also be embraced within the scope of the²invention.²The compounds of the invention, or pharmaceutically acceptable salts thereof,²may contain one or more chiral carbon atoms and, thus, may give rise to ²enantiomers,²diastereomers, and other stereoisomeric forms. Each chiral carbon atom can be ²defined as (R)- or (S)- based on stereochemistry. The invention is intended to ²include ²all possible isomers, as well as racemic and optically pure forms thereof. ²Racemates, ²diastereomers or enantiomers may employed as starting materials or ²intermediates of²the preparation of the compounds of the invention. Optically active isomers ²can be²prepared by chiral synthons or chiral reagents, or resolved using conventional ²²techniques, such as by crystallization and chiral chromatography.²Conventional techniques for the preparation / isolation of individual isomers²include chiral synthesis from a suitable optically pure precursor, or ²resolution of the²racemate (or racemic form of a salt or derivative) using, for example, chiral ²high²performance liquid chromatography. For example, see Gerald Gtibitz and Martin ²G. ²Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular ²²Biology, Vol. 243, 2004; AM Stalcup, Chiral Separations, Annu. Rev. Anal. ²Chem. ²3 :341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL² ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd.,²Essex, 1991, 809-816; Heller, Acc. Chem Res. 1990, 23, 128.²In the present application, the term "pharmaceutically acceptable salt" ²includes ²pharmaceutically acceptable acid addition salts and pharmaceutically ²acceptable base ²addition salts.² "Pharmaceutically acceptable acid addition salt" means a salt formed with an²inorganic or organic acid which retains the bioavailability of the free base ²without ²bringing other side effects. Inorganic acid salts include, but are not limited ²to, ²hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like; ²organic ²acid salts include, but are not limited to, formate, acetate, 2,2-²dichloroacetate,²trifluoroacetate, propionate, hexanoate, octoate, decanoate, undecylenate, ²glycolate,²gluconate, lactate, sebacate, adipates, glutaric acid salts, malonates, ²oxalates, ²maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, ²oleates ,²<DP=31>²CA 03036114 2019-03-07²cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, ²methanesulfonate, besy late, p-toluenesulfonate, alginate, ascorbate, sal ²icylate, ²4-aminosalicylate, naphthalene disulfonate, and the like. These salts can be ²prepared ²by methods known in the art.² "Pharmaceutically acceptable base addition salt" means a salt formed with an²inorganic or organic base capable of maintaining the bioavailability of the ²free acid ²without bringing other side effects. Salts derived from inorganic bases ²include, but ²are not limited to, sodium salts, potassium salts, lithium salts, ammonium ²salts, ²calcium salts, magnesium salts, iron salts, zinc salts, copper salts, ²manganese salts,²aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium,²potassium, calcium and magnesium salts. Salts derived from organic bases ²include, ²but are not limited to, the following salts: primary amines, secondary amines ²and ²tertiary amines, substituted amines, including naturally substituted amines, ²cyclic ²amines, and basic ion exchange resins. For example, ammonia, isopropylamine,²trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine,²diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, ²²2-diethylaminoethanol, bicyclo hexylamine, lysine, arginine, histidine, ²caffeine, ²procaine, choline, betaine, ethylenediamine, glucosamine, methy lglucosamine, ²theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine ²resin, and²the like. Preferred organic bases include isopropylamine, diethylamine, ²ethanolamine,²trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be ²prepared by methods known in the art.²In the present application, "pharmaceutical composition" refers to a ²formulation ²of a compound of the invention and a medium generally accepted in the art for²delivery of a biologically active compound to a mammal, such as a human. The²medium comprises pharmaceutically acceptable carriers. The purpose of the ²pharmaceutical composition is to promote the administration of the organism, ²thus ²facilitating the absorption of the active ingredients and thereby exerting the ²²biological activity.² The term "pharmaceutically acceptable" as used herein, refers to a substance²(such as a carrier or diluent) that does not affect the biological activity or ²properties ²of the compound of the invention, and is relatively non-toxic, ie, the ²substance can²31²<DP=32>²CA 03036114 2019-03-07²be administered to an individual without causing undesirable organisms, or ²interacts ²with any of the components contained in the composition in an undesirable ²manner. ²In the present application, "pharmaceutically acceptable excipients" include, ²but ²are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, ²diluents,² preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents,²dispersing agents, suspending agents, stabilizers, isotonic agents, solvents ²or ²emulsifiers approved by the relevant government authorities for acceptable use ²in ²humans or domestic animals.²The "tumor" of the present invention includes, but is not limited to, glioma,² sarcoma, melanoma, articular chondrocarcinoma, cholangiocarcinoma, leukemia,²gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung ²cancer, ²small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, lung ²adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, ²epithelial ²cell carcinoma, cervical cancer, ovarian cancer, intestinal cancer, ²nasopharyngeal²cancer, brain cancer, bone cancer, esophageal cancer, melanin tumor, kidney ²cancer,²oral cancer and other diseases.²The terms "prevention", "preventing" and "prevented" as used herein include ²the ²possibility of reducing the occurrence or progression of a disease or ²condition by a ²patient.² The term "treatment" and other similar synonyms as used herein includes the²following meanings:²(i) preventing the occurrence of a disease or condition in a mammal, ²particularly²when such a mammal is susceptible to the disease or condition, but has not ²been ²diagnosed as having the disease or condition;²(ii) inhibiting a disease or condition, i.e., inhibiting its development;²(iii) alleviating the disease or condition, i.e., degrading the condition of ²the ²disease or illness; or²(iv) alleviating the symptoms caused by the disease or condition. ²The term "effective amount," "therapeutically effective amount," or²"pharmaceutically effective amount," as used herein, refers to an amount of at ²least²one agent or compound that, after administration, is sufficient to alleviate ²one or ²more symptoms of the disease or condition being treated to sonic extent. The ²result²32²<DP=33>²CA 03036114 2019-03-07²can be reduction and / or alleviation of signs, symptoms or causes, or any other ²²desired change in the biological system. For example, an "effective amount" ²for ²treatment is an amount of a composition comprising a compound disclosed herein ²²that is required to provide a significant conditional relief effect in clinic. ²An effective²amount suitable for any individual case can be determined using techniques ²such as²dose escalation testing.²The terms "take", "administrate", "apply" and the like, as used herein, refers ²to a ²method of delivering compound or composition to a desired site for biological ²action.²These methods include, but are not limited to, oral, duodenal, parenteral ²injection²(including intravenous, subcutaneous, intraperitoneal, intramuscular, ²intraarterial²injection or infusion), topical administration, and rectal administration. The ²²techniques of administration of the compounds and methods described herein are ²²well known to those skilled in the art, for example, those discussed in ²Goodman and ²Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and² Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co.,²Easton, Pa. In a preferred embodiment, the compounds and compositions ²discussed ²herein are administered orally.²The terms "pharmaceutical combination", "drug combination". "combination",²"administering other treatments", "administering other therapeutic agents" and ²the² like, as used herein, mean a pharmaceutical treatment obtained by mixing or²combining more than one active ingredient which includes both fixed and ²unfixed ²combinations of active ingredients. The term "fixed combination" refers to ²simultaneous administrating at least one compound described herein and at ²least one ²synergistic agent to a patient in the form of a single entity or a single ²dosage form.² The term "unfixed combination" refers to simultaneous administrating,²administrating in combination or sequentially administrating in variable ²interval time ²at least one of the compounds described herein and at least one synergistic ²formulation to the patient in the form of separate entities. These can also be ²applied ²to cocktail therapy, for example, administrating three or more active ²ingredients.² It will also be understood by those skilled in the art that in the methods²described below, functional groups of an intermediate compound may need to be ²protected by suitable protecting groups. Such functional groups include ²hydroxyl,²33²<DP=34>²CA 03036114 2019-03-07²amino, thiol, and carboxyl. Suitable hydroxy protecting groups include ²trialkylsilyl ²or diarylalkylsilyl groups (e.g., tert-butyldimethylsilyl, tert-²butyldiphenylsily1 or ²trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting ²groups for ²amino, amidine group and guanidyl include t-butoxycarbonyl, benzyloxycarbonyl,²and the like. Suitable thiol protecting groups include -C(0)-R" (wherein R" is ²alkyl,²aryl or aralkyl), p-methoxybenzyl, trityl, and the like. Suitable carboxy ²protecting ²groups include alkyl, aryl or aralkyl esters.²Protecting groups can be introduced and removed according to standard ²techniques known to those skilled in the art and as described herein. The use ²of² protecting groups is described in detail in Greene, T. W. and P. G. M. Wuts,²Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley. The protecting ²group ²can also be polymeric resins.²The main advantages of the present invention are:² 1. Providing a compound of formual I.²2. Providing a composition of novel structure for the prevention and treatment ²²of diseases associated with EZH2 mutations.²The present invention will be further illustrated below with reference to the ²specific examples. It should be understood that these examples are only to ²illustrate²the invention but not to limit the scope of the invention. The experimental ²methods²with no specific conditions described in the following examples are generally ²performed under the conventional conditions, or according to the ²manufacturer's ²instructions. Unless indicated otherwise, parts and percentage are weight ²parts and ²weight percentage.² The experimental materials and reagents used in the following examples are²available from commercially available sources unless otherwise specified.²In each of the examples, the 'H NMR was recorded by Varian Mercury-300 or ²Varian Mercury-400 NMR spectrometer, and the '3C NMR was recorded by Varian²Mercury-400 or Varian Mercury-500 or Varian Mercury-600 NMR spectrometer,² chemical shifts are expressed as 8 (ppm); mass spectrum is recorded by²Finnigan / MAT-95 (El) and Finnigan LCQ / DECA and Micromass Ultra Q-TOF (ESI)²mass spectrometer; reverse phase preparative HPLC separation silica gel is 200-²300²34²<DP=35>²CA 03036114 2019-03-07²mesh.²Among them, names of reagents represented by the chemical formula or the²alphabet abbreviations are as follows:²iPrOH: isopropanol; Et0H: ethanol; DCM: dichloromethane; TFA:² trifluoroacetic acid; MeOH: methanol; NaOH: sodium hydroxide; HC1: hydrogen²chloride; TEA: triethylamine; Raney Ni: Raney Nickel; 1,4-dioxane: 1,4-²dioxane; ²NaH: sodium hydride; H20: water; Pd / C: palladium / carbon; 1-12: hydrogen; HATU: ²²2-(7-oxidizedbenzotriazole)-N,N,N',W-tetramethylurea hexafluorophosphate; DMF: ²²N,N-dimethylformamide; THF: tetrahydrofuran; Boc20: di-tert-butyl dicarbonate;² NBS: N-bromosuccinimide; NCS: N-chlorosuccinimide; NIS: N-iodosuccinimide;²MeCN: acetonitrile; DIPEA: N,N-diisopropylethylamine; NaBH4: Sodium ²borohydride; AcOH: acetic acid; ethyl acetate: ethyl acetate; NaBH3CN: sodium ²cyanoborohydride; K2CO3: potassium carbonate; Cs2CO3: cesium carbonate; nBuLi: ²²n-butyllithium; LiAIH4: lithium aluminum hydride; Pd(dppf)C12:² 11,1-bis(diphenylphosphino)ferrocene]palladium dichloride; KOAc: potassium²acetate. Fumaronitrile: fumaric acid nitrile; P(nBu)3: tri-n-butylphosphine; ²LDA: ²lithium diisopropylamide; LiOH: lithium hydroxide; Mel: methyl iodide; Etl: ²ethyl ²iodide; (CH20)0: paraformaldehyde; HCO2H: formic acid; CH3C0CI: acetyl ²chloride.² Example 1: Preparation of²N-((4,6-Dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-methoxyethyl)-6-²meth ²ylindolizine-7-carboxamide:²- method, ,PrOH²H Brj.²NaBH, ________________________________________________ _ 0 ,² K2CO3 DMF Me0H²method), DMF 0²NaH Mel NaOH A'11N, tii N²DMF N MeO HO'Llt H / H20 HATU DIPEA DMF²ftl compound I²Step 1: Preparation of 1-(2-oxopropy1)-1H-pyrrole-2-carbaldehyde: In a dry² nitrogen-protected 250 mL single-necked flask, compound²<DP=36>²CA 03036114 2019-03-07²1H-pyrrole-2-carbaldehyde (15 g, 158 mmol) was dissolved in 100 mL of DMF, and ²²potassium carbonate (43.6 g, 316 mmol) and bromoacetone (53.7 g, 395 inmol) ²were ²added to the solution, and the mixture was stirred at room temperature ²overnight. The ²reaction mixture was extracted with ethyl acetate (200 mL), washed with water ²(100²mL x 2) and saturated brine (100 mL). The organic phase was dried over ²anhydrous²sodium sulfate, filtered and concentrated to provide a crude product. After ²purified ²by column chromatography (petroleum etherEt0Ac=4:1), brown solid (7g, ²yield:30%) was obtained.²1H NMR (CDC13, 400 MHz) 6 ppm 9.49 (s, 1 H), 7.00 (d, J= 8.0 Hz, 1 H), 6.87² (brs, 1 Fl), 6.32-6.31 (m, 1 H), 5.09 (s, 2 H), 2.23 (s, 3 H).²Step 2: Preparation of ethyl 5-acetyl-6-methylindolizine-7-carboxylate:²Method A: The compound 1-(2-oxopropy1)-1H-pyrrole-2-carbaldehyde (7.0 g,²46.0 mmol) was dissolved in 150 mL of DMF in a dry nitrogen-protected 250 mL ²single-necked flask. Ethyl acetoacetate (17.9 g, 138 mmol) and potassium ²carbonate²(9.52 g, 69 mmol) were added successively, and the mixture was warmed to ²reflux²for two hours. The mixture was extracted with ethyl acetate (200 mL) and water ²(100 ²mLx2). The organic layer was dried over anhydrous sodium sulfate, filtered and ²²concentrated to give a crude product. After purified by column chromatography ²(petroleum etherEt0Ac=10:1), yellow oil (5.4 g, yield:48ÃY0) was obtained and ²stood² for curing.²Method B: The compound 1-(2-oxopropy1)-1H-pyrrole-2-carbaldehyde (7.0 g, ²46.0 mmol) was dissolved in 50 mL of DMF in a dry nitrogen-protected 100 mL ²single-necked flask. Ethyl 2-butynoate (6.3 g, 56 mmol) and cesium carbonate ²(22.7 ²g, 69 mmol) were added successively, and the mixture was warmed to 50 C and²stirred for 4 to 5 hours. The reaction mixture was extracted with ethyl ²acetate (200²mL) and washed with water (100 mLx2) and brine (100 mL). The organic phase was ²²dried over anhydrous sodium sulfate, filtered and concentrated to provide a ²crude ²product. After purified by column chromatography (petroleum ethenEt0Ac=10:1), ²yellow oil (1.4 g, yield:12.4%) was obtained and stood for curing.² 1H NMR (CDC13, 400 MHz) 6 ppm 9.20 (s, 1 H), 7.21 (brs, 1 H), 6.87(t, J=4.0²Hz, 1 H), 6.74 (d, J= 4.0 Hz, 1 H), 4.34 (q, J= 7.2 Hz, 2 El), 2.64 (s, 3 1-²1), 2.44 (s, 3 ²H), 1.39 (t, J= 7.2 Hz, 3 H).²36²<DP=37>²CA 03036114 2019-03-07²Step 3: Preparation of ethyl²5-(1-hydroxyethyl)-6-methylindolizine-7-carboxylate: compound ethyl ²5-acetyl-6-methylindolizine-7-carboxylate (1 g, 4.1 mmol) and 50 mL of ²methanol ²were added to a dry nitrogen-protected 100 mL single-necked flask. Sodium²borohydride (310.2 mg, 8.2 mmol) was added portionwise after cooled to 0 C. ²The²reaction was stirred at room temperature for 3-4 hours, and then the mixture ²was ²extracted with ethyl acetate (200 mL) and washed with water (100 mLx2) and ²brine ²(100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered ²and ²concentrated to provide a crude product. After purified by column ²chromatography² (petroleum ether:Et0Ac=8:1), yellow oil (650 mg, yield:65%) was obtained.²1H NMR (CDC13, 400 MHz) 6 ppm 8.09 (s, 1 H), 8.01 (s, 1 H), 6.84 (t, J= 3.6²Hz, 1 H), 6.67 (d, J= 4.0 Hz, 1 H), 5.75-5.73 (m, 1 H), 4.31 (q, J= 7.2 Hz, 2 ²H),²2.47 (s, 3 H), 1.68 (d, J=8 Hz, 3 H), 1.38 (t, J= 6.8 Hz, 3 H).²Step 4: Preparation of ethyl² 5-(1-methoxyethyl)-6-methylindolizine-7-carboxylate: compound ethyl²5-(1-hydroxyethyl)-6-methylindolizine-7-carboxylate (40 mg, 0.16 mmol) and 15 ²mL ²of DMF were added to a dry nitrogen-protected 50 mL single-necked flask. ²Sodium ²hydride (16.2 mg, 0.24 mmol) was added portionwise after cooled to 0 C. The ²reaction was stirred at room temperature for 30 min, iodomethane (34 mg, 0.24 ²mmol)²was added, and the mixture was stirred at room temperature overnight, and then ²the²mixture was extracted with ethyl acetate (100 mL) and washed with water (50 ²mLx2) ²and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, ²filtered and concentrated to provide a crude product. After purified by column ²²chromatography (petroleum ether:Et0Ac=10:1), yellow oil (20 mg. yield:47.6%) ²was²obtained.²1H NMR (Me0D, 400 MHz) 6 ppm 8.40 (s, 2 H), 6.82 (t, J- 3.2 Hz, 1 H), 6.77²(d, J= 3.6 Hz, 1 H), 5.26 (q, J= 7.8 Hz, 1 H), 3.85 (s, 3 H), 3.19 (s, 3 H), ²2.48 (s, 3²H), 1.59 (d, . / --= 7.8 Hz, 3 H).²Step 5: Preparation of 5-(1-methoxyethyl)-6-methylindolizine-7-carboxylic ²acid:²The compound Ethyl 5-(1-methoxyethyl)-6-methylindolizine-7-carboxylate (20 mg,²0.077 mmol) and 5 mL of methanol were added successively in a 25 mL ²nitrogen-protected one-necked bottle. Sodium hydroxide (12.4 mg, 0.31 mmol) ²was²37²<DP=38>²CA 03036114 2019-03-07²dissolved in 5 mL water, added to the reaction system, and stirred overnight ²under ²room temperature. The mixture was neutralized with diluted hydrochloric acid ²to pH ²5, extracted with dichloromethane (100 mL), washed with water (50 mL x 2) and ²brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, ²filtered²and concentrated to provide pale yellow oil (18 mg, yield: 100%). 1H NMR ²(Me0D,²400 MHz) 6 ppm 8.05 (s, 1 H), 6.81 (t, J = 3.2 Hz, 1 H), 6.66 (t, J = 3.2 Hz, ²1 H), ²5.27 (q, Jr= 7.8 Hz, 1 H), 3.19 (s, 3 H), 2.50 (s, 3 H), 1.60 (d, 1=7.8 Hz, 3 ²H). ²Step 6: Preparation of²N-((4,6-Dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-5-(1-methoxyethyl)-6-²meth²ylindolizine-7-carboxamide: 5-(1-methoxyethyl)-6-methylindolizine-7-carboxylic²acid (18 mg, 0.077 mmol), 3-(aminomethyl)-4,6-lutidine-2(1H)-one hydrochloride ²²(23.5 mg, 0.125 mmol) (the synthesis of which can be found in W02015023915), ²HATU (44 mg, 0.116 mmol), DIPEA (29.9 mg, 0.232 mmol) and DMF 20 mL were ²added sequentially to a 25 mL nitrogen-protected one-necked bottle, stirred at ²room²temperature for 30 min. The mixture was extracted with ethyl acetate (100 mL),²washed with water (50 mLx2) and brine (50 mL). The organic phase was dried ²over ²anhydrous sodium sulfate, filtered and concentrated to provide a crude ²product. After ²purified by column chromatography (dichloromethanol:methanol = 20:1), white ²solid ²was obtained (20mg, yield: 71%). 1H NMR (CDC13, 400 MHz) 6 ppm 7.97 (s, 1 H),²7.38 (s, 1 H), 6.84-6.78 (m, 2 H), 6.53 (d, I = 3.6 Hz, 1 H), 6.37(s, 1 1-1), ²5.10 (q, 1=²7.8 Hz, 1 H), 4.54 (brs, 2 H), 3.19 (s, 3 H), 2.57 (s, 3 H), 2.41 (s, 3 Fl) ²,2.31 (s, 3 H), ²1.60 (d, 1 7.8 Hz, 3 H); MS (ES!) m / z 368 [M+Hr²Example 2: Preparation of²N-((4,6-Dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-ethoxyethyl)-6-²methyl² indolizine-7-carboxamide:²0²o OH 0) 0 oi H5-µ4"C' 0 0 0)²L.,0 NaOH²HO ___________________________________________________________ 7601 N²N DMF N MeOH / H20 HATIJ DIPEA / ²compound 2²Step 1: Preparation of ethyl 5-(1-ethoxyethyl)-6-methylindolizine-7-²carboxylate: ²Ethyl 5-( 1 -ethoxyethyl)-6-methylindolizine-7-carboxylate was prepared by a ²method²similar to Step 4 of Example I except ethyl iodide was used, yield 15%. MS ²(ESI)²38²<DP=39>²CA 03036114 2019-03-07²m / z 276 [M+Hr.²Step 2: Preparation of 5-( I -ethoxyethyl)-6-methylindolizine-7-carboxylic ²acid: ²5-(1-ethoxyethyl)-6-methylindolizine-7-carboxylic acid was prepared by a ²method ²similar to Step 5 of Example 1, yield 95%. MS (ES!) m / z 248 [M+Hr² Step 3: Preparation of²N-((4,6-Dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-ethoxyethyl)-6-²methyl ²indolizine-7-carboxamide: ²N-((4,6-Dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-5-(1-ethoxyethyl)-6-²methyl ²indolizine-7-carboxamide was prepared by a method similar to Step 6 of Example ²1,²yield 35%. 1H NMR (400 MHz, CDCI3) 6 ppm 8.02 (s, 1 H), 7.36 (s, 1 H), 6.99 ²(s, 1²H), 6.77(s, 1 H), 6.50 (s, 1 H), 6.14 (s, 1 H), 5.34 (brs, 1 H), 5.20 (q, J= ²7.8 Hz, 1 H), ²4.51 (brs, 2 H), 3.36-3.34 (m, 1 H), 3.23-3.21 (m, 1 H), 2.48 (s, 3 H), 2.22 ²(s, 6 H), ²1.26 (d, J= 7.6 Hz, 3 H), 0.88 (t, J= 7.8 Hz, 3 H); MS (ES!) m / z 382 [M+H]'.²Example 3: Preparation of² 5-(1-(Allyloxy)ethyl)-N-((4,6-dimethy1-2-oxo-1,2-dihydropyrid in-3-yl)methy 1²6-methylindolizine-7-carboxamide:²f .)²,5. .²0 OH²0 ,FINA-IVH3C1 f 0 0 0²)I A- iyc²' IN? I40H DMF I \ 1.4ii Me0H / H20 --.112.5 / ²go,:k4TFO DIPEA -..ii²compound 3²Step 1: Step 1: Preparation of ethyl²5-( l -(allyloxy)ethyl)-6-methylindolizine-7-carboxylate: Ethyl²5-(1-(allyloxy)ethyl)-6-methylindolizine-7-carboxylate was prepared by a ²method²similar to Step 4 of Example 1 except that allyl chloride was used, yield 49%. ²MS ²(ES!) m / z 288 [M+Hr.²Step 2: Preparation of 5-(l -(allyloxy)ethyl)-6-methylindolizine-7-carboxylic ²acid: 5-(1-(allyloxy)ethyl)-6-methylindolizine-7-carboxylic acid was prepared ²by a² method similar to Step 5 of Example 1, yield 98%. MS (ES!) m / z 260 [M+H] '.²Step 3: Preparation of²5-(1-(allyloxy)ethyl)-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-²met ²hylindolizine-7-carboxamide:²5-(1-(allyloxy)ethyl)-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-²met²39²<DP=40>²CA 03036114 2019-03-07²hylindolizine-7-carboxamide was prepared by a method similar to Step 6 of ²Example ²1, yield 53%. 1H NMR (400 MHz, CDCI3) 6 ppm 8.01 (s, 1 H), 7.37 (s, 1 H), 6.91 ²(s, ²1 H), 6.78(s, 1 H), 6.26 (s, 1 H), 6.14 (s, 1 H), 5.91-5.83 (m, 1 H), 5.23-²5.14 (m, 3 H), ²4.54-4.52 (m, 2 H), 3.86-3.73 (m, 2 H), 2.52 (s, 3 H), 2.36 (s, 3 H), 2.29 (s, ²3 H),² 1.62 (d, J= 7.8 Hz, 3 H); S (ESI) m / z 394 [M+H].²Example 4: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-(prop-2-yn-²1 ²-yloxy)ethyl)indolizine-7-carboxamide:²Ii II ²,0²0 0 0²Ci.i / ZHO² \ D HAT U, DIPEA "1:111- - ¨ ¨² L141 NH DMF N Me0H / H20²1 / 1 / ²compound 4² Step 1: Preparation of ethyl²6-methyl-5-(1-(prop-2-yn-l-yloxy)ethyl)indolizine-7-carboxylate: ethyl ²6-methyl-5-(l-(prop-2-yn-l-yloxy)ethyl)indolizine-7-carboxylate was prepared ²by a ²method similar to step 4 of example 1 except that 3-bromoprop-2-yne was used, ²yield ²35%. MS (ESI) m / z 286 [M+Hr² Step 2: Preparation of²6-methyl-5-(1-(prop-2-yn-l-yloxy)ethyl)indolizine-7-carboxylic acid: ²6-methyl-5-(1-(prop-2-yn-l-yloxy)ethyl)indolizine-7-carboxylic acid was ²prepared ²by a method similar to step 5 of example 1, yield 100%. MS (ESI) m / z 258 [M+H] ²²Step 3: Preparation of²N4(4,6-Dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-(prop-2-yn-²l-yloxy)ethyl)indolizine-7-carboxamide: ²N-((4,6-Dimethy1-2-oxo-1,2-dihydropyridin-3-yHmethyl)-6-methyl-54 -(prop-2-yn-²l-yloxy)ethyl)indolizine-7-carboxamide was prepared by a method similar to ²Step 6²of Example 1, yield 20%. NMR (DMSO-d6, 400 MHz) 6 ppm 8.19 (s, 1 H), 7.83²(s, 1 H), 7.36 (s, 1 H), 6.77 (d, J= 2.8 Hz, 1 H), 6.52 (d, = 3.2 Hz, 1 El), ²5.88 (s, 1²H), 5.46-5.44 (m, 1 H), 4.28-4.27 (m, 2 H), 4.10 (d,1 = 16.0 Hz, 1 H), 3.80 ²(d, = ²16.0 Hz, 1 H), 2.26 (s, 3 H) ,2.21 (s, 3 H), 2.12 (s, 3 H), 1.56 (d, . / = 6.8 ²Hz, 3 H); ²MS (ESI) m / z 392 [M+H].²Example 5: Preparation of²<DP=41>²CA 03036114 2019-03-07²N((4,6-Dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-((2-²methylal²lyl)oxy)ethyl)indolizine-7-carboxam ide:²0²0 OH 0 0 N.0 0 0²I I I²N NsH DMF N Me00 N HATU DIPEA²compound 5²Step 1: Preparation of ethyl² 6-methyl-5-(1-((2-methylallyl)oxy)ethyl)indolizine-7-carboxylate: ethyl²6-methyl-5-(1-((2-methylallyl)oxy)ethyl)pyridazin-7-carboxylate was prepared ²by a ²method similar to step 4 of Example 1 except that 3-chloro-2-methylprop-1-ene ²was ²used, yield 44%. 1H NMR (CDC13, 400 MHz) 6 ppm 8.10 (brs, 1 H), 8.05 (s, 1 H), ²²6.84 (t, J = 2.0 Hz, 1 H), 6.69 (t, J= 2.0 Hz, 1 H), 5.30 (q, J= 6.8 Hz, 1 1-²1), 4.91 (d,²J = 3.9 Hz, 2 H), 4.34 (q, I= 6.4 Hz, 2 H), 3.70 (d, J= 12.0 Hz, 1 H), 3.62 ²(d, 1=²12.0 Hz, 1 1-1), 2.47 (s, 3 H), 1.71 (s, 3 14), 1.65 (d, J= 6.8 Hz, 3 El), ²1.40 (t, J= 6.4²Hz, 3 H).²Step 2: Preparation of²6-methyl-5-(14(2-methy lal lyl)oxy)ethy 1) indolizine-7-carboxyl ic acid:²6-Methy1-5-(1-((2-methylallyl)oxy)ethyl)indolizine-7-carboxylic acid was ²prepared²by a method similar to step 5 of Example 1, yield 94%. 1H NMR (CDC13, 400 MHz) ²²6 ppm 8.26 (s, 1 H), 8.16 (s, 1 H), 6.86 (brs, 1 H), 6.75 (brs, 1 H), 5.32 (q, ²J= 6.8 Hz, ²1 H), 4.91 (d, J= 4.4 Hz, 2 H), 3.72 (d, J= 12.0 Hz, 1 H), 3.66 (d, 1= 12.0 ²Hz, 1 H), ²2.52 (s, 3 H), 1.71 (s, 3 H), 1.65 (d, J = 6.8 Hz, 1 H).² Step 3: Preparation of²N-((4,6-Dimethy1-2-oxo-1,2-di hydropyridin-3 -yOmethy 1)-6-m ethy l-5-(1 -((2-²methal ly ²1)oxy)ethyl)indolizine-7-carboxamide: ²N-((4,6-Dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-((2-²methally ²1)oxy)ethyl)indolizine-7-carboxamide was prepared by a method similar to step ²6 of²Example 1, yield 18%. 1H NMR (CDC13, 400 MHz) 8.02 (s, 1 H), 7.35 (s, 1 H), ²6.93²(s, 1 H), 6.76 (s, 1 H), 6.48 (brs, 1 H), 6.30 (brs, 1 H), 5.20 (q, I = 6.8 ²Hz, I H), 4.90 ²(q, J= 10.8 Hz, 2 H), 4.51 (d, J= 5.6 Hz, 2 H), 3.70 (d, J = 12.0 Hz, I H), ²3.65 (d, J ²= 12.0 Hz, 1 H), 2.52 (s, 3 H), 2.34 (s, 3 H), 2.28 (s, 3 H), 1.69 (s, 3 H), ²1.61 (d, J = ²6.8 Hz, 3 H); MS (ES!) m / z 408 [M+14]'.²41²<DP=42>²CA 03036114 2019-03-07²Example 6: Preparation of²N((4,6-Dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-5-(1- isobutyloxyethyl)-²6-m ²ethylindolizine-7-carboxam ide :²0²0²Ho² ¨ ,²H2 Me0H N MeOH / H20 N HATU DIPEA²compound 6² Step I: Preparation of ethyl²5-(1-isobutyloxyethyl)-6-methylindolizine-7-carboxylate: ethyl ²6-methy1-5-(1-((2-methylallyl)oxy)ethyl)indolizine-7-carboxylate (60 mg, 0.2 ²mmol)) , Raney Ni (6 mg) and 10 ml of methanol were added sequentially to a 25 ²mL ²single-necked flask, exchanged with hydrogen and stirred at room temperature ²for²two hours. The organic phase was concentrated to provide a yellow oily product ²(50²mg, yield: 86%). MS (ESI) m / z 304 [M+1-11+.²Step 2: Preparation of 5-(1-isobutyloxyethyl)-6-methylindolizine-7-carboxylic ²acid: 5-(1-isobutyloxyethyl)-6-methylindolizine-7-carboxylic acid was prepared ²by a ²method similar to step 5 of Example I, yield 89%. MS (ESI) m / z 276 [M+1-1]1.² Step 3: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-5-(1-isobutyloxyethyl)-6-²m ²ethylindolizine-7-carboxamide:²N-((4,6-dimethy1-2-oxo- 1 ,2-dihydropyridin-3-yl)methyl)-5-(1-²isobutyloxyethyl)-6-m ²ethylindolizine-7-carboxamide was prepared by a method similar to Step 6 of² Example I, yield 20%. 1H NMR (DMSO-d6, 400 MHz) 6 ppm 8.17 (s, 1 H), 7.91 (s,²1 H), 7.34 (s, 1 H), 6.76 (brs, 1 II), 6.49(d, J= 2.8 Hz, 1 I-I), 5.88 (s, 1 ²H), 5.20 (q, J ²= 6.8 Hz, I H) ,4.28 (brs, 2 H), 3.20-3.16 (m, 1 H), 2.85-2.82 (m, 1 H), ²2.24(s, 3 H), ²2.21(s, 3 H), 2.12(s, 3 H), 1.69-1.66 (m, 1 H), 1.53 (d, J = 6.8 Hz, 3 H), ²0.82-0.79 (m, ²6 H);MS (ESI) m / z 410 [M+Efl1-.² Example 7: Preparation of²5-((cyc lohex-2-en-l-yloxy)ethyl)-N-((4,6-dimethyl-2-oxo-1,2-di hydro pyrid in-²3-y 1)m²ethyl)-6-methyl indolizine-7-carboxam ide:²42²<DP=43>²CA 03036114 2019-03-07²0²OH alk 0 OCI 0 0²HIs....'4H3C1 0 0 0,0²I²NaOH i²71,o'l²0 NaH, DMF Me0H / H20 \ HATU, DIPEA DMF NI²compound 7²Step 1: Preparation of ethyl²5-(1-(cyclohex-2-en-1-yloxy)ethyl)-6-methylindolizine-7-carboxylate: ethyl ²5-(1-(cyclohex-2-en-l-yloxy)ethyl)-6-methylindolizine-7-carboxylate was ²prepared²by a method similar to Step 4 of Example 1 except that 3-bromo-2-cyclohex-1-²ene²was used, yield 38%. MS (ESI) m / z 328 [M+1-1]²Step 2: Preparation of²5-(1-(cyclohex-2-en-1-yloxy)ethyl)-6-methylindolizine-7-carboxylic acid: ²5-(1-(cyclohex-2-en-1-yloxy)ethyl)-6-methylindolizine-7-carboxylic acid was²prepared by a method similar to step 5 of example 1, yield 66%. MS (ESI) m / z ²300²[M+F11 .²Step 3: Preparation of²5-(1-(cyclohex-2-en-l-yloxy)ethyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-²3-y1 ²)methyl)-6-methylindolizine-7-carboxamide:² 5-(1-(cyclohex-2-en-l-yloxy)ethyl)-6-methylindolizine-7-carboxylic acid was²prepared by a method similar to step 6 of example 1, yield 19%. IH NMR (DMSO-²d6, ²400 MHz) 6 ppm 8.19 (s, 1 H), 7.97 (s, 1 H), 7.34 (s, 1 H), 6.76 (s, 1 H), ²6.49 (s, 1 ²H), 5.88 (s, 1 H), 5.84-5.69 (m, 1 H), 5.42-5.32 (m, 1 H), 4.27 (brs, 1 H), ²3.67 (s, 1 ²H), 2.25 (s, 3 H), 2.21(s, 3 H), 2.12 (s, 3 H), 1.97-1.93 (m, 1 H), 1.86-1.79 ²(m, 2 H),²1.67 (s, 1 H), 1.52 (d, J= 6.8 Hz, 3 H), 1.47-1.46 (m. 1 H), 1.36-1.35 (m, 1 ²H); MS²(ESI) m / z 434 [M+H]'.²Example 8: Preparation of²5-(1-(cyclohexyloxy)ethyl)-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-²y1)methyl) ²-6-methylindolizine-7-carboxamide:²0²0 0,0 0 ?JD² Raney NI NaOH²H&HI I²I \ 1-12 Me0H I 0 Me0H / H2C7 HO -- I -- HATU DIPEA ²DMF² / ² compound 8²Step 1: Preparation of ethyl²5-(1-(cyclohexyloxy)ethyl)-6-methylindolizine-7-carboxylate: ethyl²43²<DP=44>²CA 03036114 2019-03-07²5-(1-(cyclohexyloxy)ethyl)-6-methylindolizine-7-carboxylate was prepared by a ²method similar to step 1 of example 6, yield 80%. MS (ES!) m / z 330 [M+H]+. ²Step 2: Preparation of²5-(1-(cyclohexyloxy)ethyl)-6-methylindolizine-7-carboxylic acid:²5-(l -(cyclohexyloxy)ethyl)-6-methylindolizine-7-carboxylic acid was prepared ²by a²method similar to step 5 of example 1, yield 82%. MS (ES!) m / z 302 [M+Hr. ²Step 3: Preparation of²5-(1-(cyclohexyloxy)ethyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-²yOmethyl ²)-6-methylindolizine-7-carboxamide:²5-(1-(cyclohexyloxy)ethyl)-6-methylindolizine-7-carboxylic acid was prepared ²by a²method similar to step 6 of example 1, yield 5%. 1H NMR (DMSO-d6, 400 MHz) 6 ²ppm 8.18 (brs, 1 I-1), 7.98 (s, 1 H), 7.32 (s, 1 H), 6.75 (s, 1 H), 6.48 (dõI ²= 3.0 Hz, 1 ²H), 5.87 (s, 1 H), 5.35 (q, J = 6.8 Hz, 1 H), 4.26 (d, J = 4.8 Hz, 2 H), 3.23 ²(s, 1 H), ²2.23 (s, 3 H), 2.20 (s, 3 H), 2.11 (s, 3 H), 1.99-1.97 (m, 1 H), 1.66 (s, 1 ²H), 1.50 (d, J² = 6.8 Hz, 3 H), 1.33-1.12 (m, 5 H);MS (ESI) m / z 433 [M+H].²Example 9: Preparation of²5-(1-(benzyloxy)ethyl)-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-²6-m ²ethylindolizine-7-carboxamide:²=²ttiFi Q²3CI 9 am io)²L-o NaOH²-²\,N1 NaTI OMF MeOH / H20 ,61 HATU DIPEA DMF² / If compound 9² Step 1: Preparation of ethyl²5-(1-(benzyloxy)ethyl)-6-methylindolizine-7-carboxylate: ethyl²5-(1-(benzyloxy)ethyl)-6-methylindolizine-7-carboxylate was prepared by a ²method ²similar to step 6 of example 1 except benzyl bromide was used, yield 64%. MS ²(ES!) ²m / z 338 [M+H] f.² Step 2: Preparation of 5-(1-(benzyloxy)ethyl)-6-methylindolizine-7-carboxylic²acid: 5-(1 -(benzyloxy)ethyl)-6-methylindolizine-7-carboxylic acid was ²prepared by a ²method similar to step 5 of example 1, yield 92%. 1H NMR (CDC13, 400 MHz) 6 ²ppm 8.31 (s, 1 H), 8.22 (brs, 1 H), 7.34-7.24 (in, 5 H), 6.89 (t, = 2.8 Hz, 1 ²H), 6.79 ²(t, J = 2.8 Hz, 1 H), 5.37 (q, 1 = 6.8 Hz, 1 H), 4.40 (d, 1= 11.6 Hz, 1 H), ²4.24 (d, 1=²44²<DP=45>²CA 03036114 2019-03-07²11.6 Hz, 1 H), 2.47 (s, 3 H), 1.67 (d, J = 6.8 Hz, 1 H).²Step 3: Preparation of²5-(1-(benzyloxy)ethyl)-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-²6-m ²ethylindolizine-7-carboxamide:²5-(1-(benzyloxy)ethyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-²m²ethylindolizine-7-carboxamide was prepared by a method similar to step 6 of ²example 1, yield 10%. 11l NMR (DMSO-d6, 400 MHz) 6 ppm 11.48 (s, 1 H), 8.18 ²(s, ²1 I-1), 7.97 (s, 1 H), 7.37-7.24 (m, 5 H), 7.11 (s, 1 H), 6.98 (s, 1 H), 6.78 ²(s, 1 H), 6.52 ²(s, 1 H), 5.32 (q, J = 6.8 Hz, 1 H), 4.37-4.34 (m, 1 H), 4.27-4.22 (m, 3 H), ²2.19 (d, J²= 6.8 Hz, 3 H), 2.11 (s, 3 H), 1.58 (d, J = 6.4 Hz, 3 H);MS (ES!) m / z 444 [M-i-²F111.²Example 10: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-((4-²fluorobenzyl))oxy) ²ethyl)-6-methylindolizine-7-carboxamide:²F F²F²40 40 . 40²F²)t _______________________________________ ivirj ,,,, ,,c ,,²0 . .² - ' _²\²,,, . DipEA EmAF l:&111 I '',, NI NaH DMF ²I \ NJ MeOH / H20 .. ²compound I 0² N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-((4-fluorobenzyl)²)oxy)ethyl)-6-methylindolizine-7-carboxamide was prepared by a method similar ²to ²example 9.²Step 1: Preparation of ethyl²5-(14(4-fluorobenzypoxy)ethyl)-6-methylindolizine-7-carboxylate: Yield 63%. MS² (ESI) m / z 356 [M4-1-111-.²Step 1: Preparation of²5-(14(4-fluorobenzypoxy)ethyl)-6-methylindolizine-7-carboxylic acid: Yield ²88%.²MS (ES!) m / z 328 [M+H].²Step 3: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methy1)-5-( l -((4-²fluorobenzyl)oxy)²ethyl)-6-methylindolizine-7-carboxamide: Yield 30%. 111 NMR (400 MHz, CDC13) 6 ²²ppm 11.5(s, 1 H), 8.02(s, 1 H), 7.41(s, 1 H), 7.24-7.17 (m, 2 H), 7.00-6.96 ²(m, 2 H), ²6.78 (t, J = 2.8 Hz, 1 H), 6.51 (t. 1 = 2.8 Hz, 1 H), 5.94 (s, 1 H), 5.24 (q, ²1 = 6.8 Hz, ²1 H), 4.52(d, J = 4.8 Hz, 2 H), 4.30 (d, 1 ---- 12.0 Hz, 1 H), 4.19 (d, J = ²12.0 Hz, 1 H),²<DP=46>²CA 03036114 2019-03-07²2.39 (s, 3 H), 2.25 (s, 3 H), 2.23 (s, 3 H), 1.63 (d, J = 6.8 Hz, 3 H); MS ²(ESI) m / z ²462 1M+1-11.²Example 11: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(142-fluorobenzyWoxy)² ethyl)-6-methylindolizine-7-carboxamide:² F²0 0 0² N NaH, DM:, I 14 Me0H / H,0 I HATU DIPEA DMF²________________________________ HO H14, I N²compound 11²N((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-y1)methyl)-5-(142-fluorobenzyl) ²oxy)ethyl)-6-methylindolizine-7-carboxamide was prepared by a method similar ²to ²example 9.² 10 Step 1: Preparation of ethyl²5-(l-((2-fluorobenzyl)oxy)ethyl)-6-methylindolizine-7-carboxylate: Yield 63%. ²MS ²(ESI) m / z 356 [M+Hr.²Step 2: Preparation of²5-(142-fluorobenzyl)oxy)ethyl)-6-methylindolizine-7-carboxylic acid: Yield ²84%.² 15 MS (ESI) m / z 328 [M4+11 .²Step 3: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-5-(142-fluorobenzypoxy) ²ethyl)-6-methylindolizine-7-carboxamide: Yield 4%. 1H NMR (DMSO-do, 400 MHz) ²6 ppm 8.19 (brs, 1 H), 7.93 (s, 1 H), 7.36-7.34 (in, 3 H), 7.18-7.16 (in, 2 ²H), 6.76 (t, J²20 = 2.8 Hz, 1 H), 6.52 (t, J= 2.8 Hz, 1 H), 5.88 (s, 1 H), 5.45 (q, J= 6.8 ²Hz, 1 H), 4.46²(d, J= 12.0 Hz, 1 H), 4.28-4.25 (m, 3 H), 2.22 (s, 3 H), 2.21 (s, 3 H), 2.12 ²(s, 3 H), ²1.58 (d, J = 6.8 Hz, 3 H);MS (ESI) m / z 462 1M+1-1]²Example 12: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-((3-²fluorobenzyl))oxy)² 25 ethyl)-6-methylindolizine-7-carboxamide:²F²1101 ²0²0 OH io 0 Fj,):7'..-,c 9-F²Br c1 o o o²1,0õ1W...õ NaOH H0,1² I 13 / NaH DMF I N / Me0H / F120²HATU DIPEA, DMF²compound 12²46²<DP=47>²CA 03036114 2019-03-07²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-((3-fluorobenzyl) ²)oxy)ethyl)-6-methylindolizine-7-carboxamide was prepared by a method similar ²to ²example 9.²Step 1: Preparation of ethyl²5-(14(3-fluorobenzyl)oxy)ethyl)-6-methylindolizine-7-carboxylate: Yield 66%. ²MS²(ESI) m / z 356 [M+H].²Step 2: Preparation of²5-(14(3-fluorobenzypoxy)ethyl)-6-methylindolizine-7-carboxylic acid: Yield ²87%. ²MS (ESI) m / z 328 [M+Hr.² Step 3: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-5-(1-((3-²fluorobenzyl)oxy) ²ethyl)-6-methylindolizine-7-carboxamide: Yield 11%. 1H NMR (DMSO-do, 400 MHz) ²6 ppm 12.50 (brs, 1 H), 7.95 (brs, 1 H), 7.40 (s, 1 14), 7.36-7.32 (m, 2 H), ²7.96-6.82 ²(m, 3 H), 6.75 (t, J= 2.8 Hz, 1 H), 6.47 (t, J= 2.8 Hz, 1 H), 5.87 (s, 1 H), ²5.25 (q, J²= 6.8 Hz, 1 H), 4.46 (d, J= 4.0 Hz, 2 H), 4.26 (d, J= 12.0 Hz, 1 H), 4.18 (d, ²J= 12.0²Hz, 1 H), 2.38 (s, 3 H), 2.21 (s, 3 H), 2.18 (s, 3 H), 1.54 (d, J= 6.8 Hz, 3 ²H);MS (ESI) ²m / z 462 [M+H]'.²Example 13: Preparation of²5-(1-((2,6-difluorobenzyl)oxy)ethyl)-N-((4,6-dimethy1-2-oxo-1,2-²dihydropyridine)-3² .. -yflmethyl)-6-methylindolizine-7-carboxamide:² F²F F²cr.:Br 0 0HjNHC²0 0 0²L011cF HoYt²NaH DMF Me0H / H20 \ N. / HATU, DIPEA DMF²compound I A²5-(1-((2,6-difluorobenzyfloxy)ethyl)-N-((4,6-dimethyl-2-oxo-1.2-dihydropyridi ²ne)-3-yl)methyl)-6-methylindolizine-7-carboxamide was prepared by a method ²similar to example 9.² Step 1: Preparation of ethyl²5-(14(2,6-difluorobenzypoxy)ethyl)-6-methylindolizine-7-carboxylate: Yield ²70%. ²MS (ESI) m / z 374 [M+H].²Step 2: Preparation of²5-(14(3-fluorobenzypoxy)ethyl)-6-methylindolizine-7-carboxylic acid: Yield ²78%.²47²<DP=48>²CA 03036114 2019-03-07²MS (ES!) m / z 346 [M-411".²Step 3: Preparation of²5-(14(2,6-difluorobenzypoxy)ethyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-²3-²yOmethyl)-6-methylindolizine-7-carboxamide: Yield 16%. 'N MR (CDC13, 400²MHz) 6 ppm 12.40 (brs, 1 H), 7.95 (brs, 1 H), 7.38 (s, 1 H), 7.30-7.18 (m, 1 1-²1), 6.75²(t, J = 7.8 Hz 3 H), 6.67 (t, J = 2.8 Hz, 1 H), 6.43 (t, J = 2.8 Hz, 1 H), ²5.91 (s, 1 H), ²5.25 (q, J= 6.8 Hz, 1 H), 4.46 (d, J= 4.0 Hz, 2 H), 4.35 (s, 2 H), 2.32 (s, 3 ²H), 2.27 ²(s, 3 H), 2.15 (s, 3 H), 1.58 (d, J= 6.8 Hz, 3 H);MS (ES!) m / z 480 [M+Hr.²Example 14: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-((3-²methoxybenzyl)ox²y)ethyl)-6-methylindolizine-7-carboxamide:²0, , 0,²0 40 .,²*(t:IFI'Cl²NH,²' N . DMF ' N MeOH / H Ho20 N HAT U DIPEA DMF²compound 14²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-5-(1-((3-methoxybenz ²yl)oxy)ethyl)- 6-methylindolizine-7-carboxamide was prepared by a method ²similar² to example 9.²Step 1: Preparation of ethyl²5-(14(2,6-difluorobenzypoxy)ethyl)-6-methylindolizine-7-carboxylate: Yield ²65%.²MS (ES!) m / z 368 [M+Hr.²Step 2: Preparation of²5-(14(3-fluorobenzypoxy)ethyl)-6-methylindolizine-7-carboxylic acid: Yield ²69%.²MS (ES!) tn / z 340 [M+1-1]'.²Step 3: Preparation of²5-0 4(2,6-difluorobenzypoxy)ethyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-²3-²y1)methyl)-6-methylindolizine-7-carboxamide: Yield 13%. 1H NMR (DMSO-d6, 400²MHz) 6 ppm 8.17 (brs, 1 H), 7.97 (brs, 1 H), 7.37 (s, 1 H), 7.26 (brs, 2 H), ²6.84-6.79²(m, 4 H), 6.51 (t, J= 2.8 Hz, 1 H), 5.88 (s, 1 H), 5.32 (q, J= 6.8 Hz, 1 H), ²4.34-4.21 ²(m, 4 H), 3.70 (s, 3 H), 2.21 (s, 3 H), 2.19 (s, 3 H), 2.12 (s, 3 H), 1.58 (d, ²J = 6.8 Hz, ²3 H);MS (ES!) m / z 474 [M+Hr.²Example 15: Preparation of²48²<DP=49>²CA 03036114 2019-03-07²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-(pyridine-²2-²ylmethoxy)ethyl)indolizine-7-carboxam ide:²9²9 HNNHC²NaOH²L'OtC H _________________________ I²NaH, DMF N Me0:o HO H / N HATU DIPEA ²DMF FINAN I N'N² / ²compound 15²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-(pyridin²-2-ylmethoxy)ethyl)indolizine-7-carboxamide was prepared by a method similar ²to²example 9.²Step 1: Preparation of ethyl²6-methy1-5-(1-(pyridin-2-ylmethoxy)ethyl)indolizine-7-carboxylate: Yield 30%. ²MS ²(ESI) m / z 339 [M+Hr.² Step 2: Preparation of²6-methy1-5-(1-(pyridin-2-ylmethoxy)ethyl)indolizine-7-carboxylic acid: yield ²90%. ²MS (ES!) m / z 311 [M+H].²Step 3: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-(pyridine-²2-² ylmethoxy)ethyl)indolizine-7-carboxamide: Yield 20%. 1H NMR (400 MHz, CDC13)²6 ppm 8.62 (d, J= 4.8 Hz, 1H), 7.91-7.84 (m, 2 H), 7.52-7.51 (m, 1 FL), 7.42-²7.39(m, ²1 H), 7.32 (s, 1 H), 7.09 (s, 1 H), 6.76 (d, J= 3.2 Hz, 1 H), 6.48(d, J = 3.2 ²Hz, 1 H), ²6.3 3(s, 1 H), 5.36 (q, J= 6.8 Hz, 1 H), 4.70 (d, J= 12.0 Hz, 1 H), 4.57-4.49 ²(m, 3 H), ²2.52 (s, 3 H), 2.37 (s, 3 H), 2.23 (s, 3 H), 1.70 (d, J = 6.8 Hz, 3 H);MS ²(ES!) m / z 445²[M+H].²Example 16: Preparation of²N4(4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-5-(1-(pyridine-²4-²ylmethoxy)ethypindolizine-7-carboxamide:²II 0,²0ii²HAN4H3CI²0 OH 0 0 0 0² NaOH Holt HN N =-===²u I u I N²N NaH DmF N Me0F14-120 N HATU DIPEA DMF² / ²compound 16² N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-(pyridin²-4-ylmethoxy)ethyl)indolizine-7-carboxamide was prepared by a method similar ²to²49²<DP=50>²CA 03036114 2019-03-07²example 9.²Step 1: Preparation of ethyl²6-methy1-5-(1-(pyridin-4-ylmethoxy)ethypindolizine-7-carboxylate: Yield 37%. ²MS ²(ESI) m / z 339 [M+H]+.² Step 2: Preparation of²6-methy1-5-(1-(pyridin-4-ylmethoxy)ethypindolizine-7-carboxylic acid: yield ²85%. ²MS (ESI) m / z 311 [M+H]+.²Step 3: Preparation of²N4(4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-54 -(pyridine-4-² ylmethoxy)ethyl)indolizine-7-carboxamide: Yield 6%. 1H NMR (400 MHz, CDC13) 6²ppm 8.61 (d, J = 6.4 Hz, 1 H), 7.87 (s, 1 H), 7.60-7.59 (m, 2 H), 7.35 (s, 1 ²H), 7.05 (s, ²1 H), 6.79 (t, J= 2.8 Hz, 1 Fl), 6.52 (t, J= 2.8 Hz, 1 H), 6.43 (s, 1 H), 5.32 ²(q, J= 6.8 ²Hz, 1 H), 4.66-4.46 (m, 4 H), 2.57 (s, 3 H), 2.43 (s, 3 H), 2.27 (s. 3 H), ²1.75 (d, J ²6.8 Hz, 3 H); MS (ESI) m / z 445 [M+Hr² Example 17: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²(thiophene-2 ²-ylmethoxy)ethyl)indolizine-7-carboxamide:²0 s'?²L. n 0 os? ...õ....õ1õ).õ. 0)-² OH NaOH²I N NaH, DMF Me0H / H2C7 HO HATU DIPEA DMF²compound 17²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-(thioph²ene-2-ylmethoxy)ethypindolizine-7-carboxamide was prepared by a method similar²to example 9.²Step 1: Preparation of ethyl²6-methy1-5-(1-(thiophene-2-ylmethoxy)ethyl)indolizine-7-carboxylate: Yield ²39%. ²MS (ESI) m / z 344 [M+H]² Step 2: Preparation of²6-methyl-5-(1-(thiophene-2-ylmethoxy)ethyl)indolizine-7-carboxylie acid: yield ²82%. ²MS (ESI) m / z 316 [M+Hr.²Step 3: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-5-(1-(thiophene-²2²<DP=51>²CA 03036114 2019-03-07²-ylmethoxy)ethyl)indolizine-7-carboxamide: Yield 8%. 1H NMR (400 MHz, CDC13) ²6 ppm 7.40 (s, 1 H), 7.28 (s, 1 H), 6.93 (t, J = 3.0 Hz, 1 H), 6.87-6.81 (m, 3 ²El), 6.55 ²(d, J= 3.0 Hz, 1 Ii), 6.34 (s, 1 H), 5.28 (q, J= 6.8 Hz, 1 H), 4.55-4.52 (m, 3 ²H), 4.38 ²(d, J= 11.8 Hz, 1 H), 2.56 (s, 3 H), 2.40 (s, 3 H), 2.11 (s, 3 H), 1.62 (d, J ²= 6.8 Hz, 3² H); MS (ESI) m / z 450 [M+H].²Example 18: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-(thiazole-²2-y ²Imethoxy)ethypindolizine-7-carboxamide:² \ 1 M Ho DIP DMF1-1²sf...N ST N²0 S / N;A²H NaH DMF (11 HN TH'CI²L 1, -- _² N e0H / H20 0 0 0)²HATU .--"I".....-²\ Ni i,.,:j ²compound 18² N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-5-(1-(thiazol²e-2-ylmethoxy)ethyl)indolizine-7-carboxamide was prepared by a method similar ²to ²example 9.²Step 1: Preparation of ethyl²6-methy1-5-(1-(thiazol-2-ylmethoxy)ethyl)indolizine-7-carboxylate: Yield 45%. ²MS² (ESI) m / z 345 [M+HY.²Step 2: Preparation of²6-methy1-5-(1-(thiazol-2-ylmethoxy)ethyl)indolizine-7-carboxylic acid: yield ²89%.²MS (ESI) m / z 317 [M+H].²Step 3: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-5-(1-(thiazol-2-²y1²methoxy)ethyl)indolizine-7-carboxamide: Yield 11%. 1H NMR (400 MHz, CDC13) 6 ²ppm 12.1 (brs, 1 El), 7.94 (s, 1 H), 7.64 (s, 1 H), 7.24-7.21 (m, 2 H), 6.71 ²(t, J = 3.0 ²Hz, 1 H), 6.42 (d, J = 3.0 Hz, 1 H), 5.88 (s, 1 H), 5.32 (q, J= 6.8 Hz, 1 H), ²4.56 (s, 1 ²H), 4.45 (d, J = 6.4 Hz, 2 14), 2.32 (s, 3 H), 2.23 (s, 3 H), 2.16 (s, 3 H), ²1.62 (d, J --² 6.8 Hz, 3 H); MS (ESI) m / z 451 [M+Hr²Example 19: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-5-(1-(thiophene-²3 ²-ylmethoxy)ethyl)indolizine-7-carboxamide:²51²<DP=52>²CA 03036114 2019-03-07²9²0 09 H,...&,:i.,c,². 0 0²9²NaOH²'0 1 ..--= HO ______________ '=-= _, H,A1 ..........7 ri 1 1 ²."..N²' N NF, DM ' N Me0H / H20 I² N HATU DIPEA DMF²\ / 1 ²compound 19²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-5-(1-(thioph ²ene-3-ylmethoxy)ethyl)indolizine-7-carboxamide was prepared by a method ²similar ²to example 9.² Step 1: Preparation of ethyl²6-methyl-5-(1-(thiophene-3-ylmethoxy)ethyl)indolizine-7-carboxylate: Yield ²34%. ²MS (ES!) m / z 344 [M+H].²Step 2: Preparation of²6-methy1-5-(1-(thiophene-3-ylmethoxy)ethypindolizine-7-carboxylic acid: yield ²71%.² MS (ESI) m / z 316 [M+Hr.²Step 3: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-(thiophene-²3 ²-ylmethoxy)ethyl)indolizine-7-carboxamide: Yield 13%. 1H NMR (400 MHz, CDC13) ²5 ppm 12.30 (brs, I H), 8.06 (s, 1 H), 7.41 (s, 1 H), 7.29-7.24 (m, 1 H), 7.11 ²(brs, 1²H), 6.98 (brs, 1 H), 6.79 (d. J= 3.0 Hz, 1 H), 6.49 (d, J= 3.0 Hz, 1 H), 5.98 ²(s, 1 H),²5.24 (q, J = 6.8 Hz, 1 H), 4.53 (d, J = 6.4 Hz, 2 H), 4.34 (d, J= 11.4 Hz, 1 ²H), 4.26 ²(d, J -= 11.4 Hz, 1 H), 2.34 (s, 3 H), 2.26 (s, 3 H). 2.24 (s, 3 H), 1.61 (d, ²J = 6.8 Hz, 3 ²H); MS (ESI) m / z 450 [M+Hr.²Example 20: Preparation of² N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-methyl-²IH-pyrazol-3-yOmethoxy)ethyl)indolizine-7-carboxam ide:²\²\N \²rlir)²NI? 15.3 il²NH HN ,CI²L.0 0 = 01-1-.11;k_ci 0 0 0 0 ):CCI ei²\ / \ NeH DMr r.) meNoaHOIH,420 HO 1 ......N²)1t DIPEA DMF 1 N?²compound 20²N4(4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-methyl-²IH-pyrazol-3-y1)methoxy)ethyl)indolizine-7-carboxamide was prepared by a ²method² similar to example 9.²Step 1: Preparation of ethyl²52²<DP=53>²CA 03036114 2019-03-07²6-methyl-5-(1-((1-methyl-1H-pyrazol-3-yl)methoxy)ethyl)indolizine-7-²carboxylate:²Yield 43%. MS (ESI) m / z 342 [M+Hr.²Step 2: Preparation of²6-methy1-5-(1-(( 1 -methy1-1H-pyrazol-3-yl)methoxy)ethypindolizine-7-²carboxylic² acid: yield 82%. MS (ESI) m / z 314 [M+Hlt.²Step 3: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-methyl-1H-²p²yrazol-3-yl)methoxy)ethyl)indolizine-7-carboxamide: Yield 16%. 1H NMR (400 ²MHz, CDC13) 6 ppm 12.51 (brs, 1 H), 8.06 (brs, 1 H), 7.39 (s, 1 1-1), 7.29-²7.23 (m, 1²H), 6.78 (d, J= 3.0 Hz, 1 H), 6.47 (d, J = 3.0 Hz, 1 H), 6.07 (brs, 1 H), 5.95 ²(s, 1 H),²5.31 (q, J= 6.8 Hz, 1 H), 4.53 (d, J= 6.4 Hz, 2 H), 4.32 (t, J = 11.4 Hz, 2 ²H), 3.84 (s, ²3 1-1), 2.38 (s, 3 I-1), 2.30 (s, 3 H), 2.22 (s, 3 1-1), 1.61 (d, J = 6.8 Hz, ²3 H); MS (ESI) ²m / z 448 [M+H].²Example 21: Preparation of² N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-methyl-²1H-pyrazol-5-yOmethoxy)ethyl)indolizine-7-carboxamide:²A-..'NFI3CI²Hol 1 ..õ. ' FirsciN²t,²11, NeH DmF 151 / I \ N / Me0H / H20 HAT U DIPEA DMF²compound 2 1²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-methyl-²1H-pyrazol-5-yl)methoxy)ethypindolizine-7-carboxamide was prepared by a method² similar to example 9.²Step 1: Preparation of ethyl²6-methy1-5-(1-((1-methyl-1H-pyrazol-5-yl)methoxy)ethyl)indolizine-7-²carboxylate:²Yield 33%. MS (ESI) m / z 342 [M+Hr²Step 2: Preparation of² 6-methy1-5-(1-((1-methyl-1H-pyrazol-5-yOmethoxy)ethypindolizine-7-carboxylic²acid: yield 81%. MS (ESI) m / z 314 [M+1-11'.²Step 3: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-methyl-1H-²p²yrazol-5-yl)methoxy)ethypindolizine-7-carboxamide: Yield 13%. 1H NMR (400²53²<DP=54>²CA 03036114 2019-03-07²MHz, DMSO-d6) 6 ppm 13.08 (brs, 1 H), 8.20 (brs, 1 H), 7.89 (s, 1 H), 7.38 (s, ²1 H), ²7.32 (s, 1 H), 6.78 (t, J= 3.0 Hz, 1 H), 6.52 (d, J= 3.0 Hz, 1 H), 6.12 (brs, ²1 H), 5.89 ²(s, 1 H), 5.29 (q, J= 6.8 Hz, 1 H), 4.41-4.26 (m,4 H), 3.68 (s, 3 H), 2.38 (s, ²3 H), ²2.21 (s, 3 H), 2.20 (s, 3 H), 1.56 (d, J= 6.8 Hz, 3 H); MS (ESI) m / z 448 [M+Hr² Example 22: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-(4-²(dimethylamino))ph ²enyloxy)ethyl)-6-methylindolizine-7-carboxamide:²NO²Loo 0H F is NO,², 40²0 Raney NI, H2 0 0 ' NH 2 Mel ²K2CO,²I N DMF _________________________________ DMF²Me0H² / I N² / ²Ht:INy'N-1-I3C1²0 0 0 0 0 ?²NaOH HO²I N²Me0H, H,0 HAW D7PEA DMF -²\ NI² / 4b-²att compound 22²Step 1: Preparation of ethyl² 6-methyl-5-(1-(4-nitrophenyloxy)ethypindolizine-7-carboxylate: ethyl²6-methyl-5-(1-(4-nitrophenyloxy)ethyl)indolizine-7-carboxylate was prepared by ²a ²mathed similar to Step 4 of example 1 except that p-nitrofluorobenzene was ²used, ²yield 65%. MS (ESI) m / z 369 [M+F11'.²Step 2: Preparation of ethyl² 5-(1-(4-aminophenyloxy)ethyl)-6-methylindolizine-7-carboxylate: ethyl²6-methy1-5-(1-((4-aminophenyloxy)ethyl)indolizine-7-carboxylate (125 mg, 0.34 ²mmol)), Raney Ni (10 mg) and 10 ml of methanol were added sequentially to a 25 ²²mL single-necked flask, exchanged with hydrogen and stirred at room ²temperature ²for 4 hours, and filtered. The organic phase was concentrated and purified ²through²column chromatography (petroleum ether: ethyl acetate = 4:1) to provide a ²product²as yellow oil (100 mg, yield: 87%). MS (ES1) m / z 339 [M+Hr²Step 3: Preparation of ethyl²5-(1-(4-dimethylaminophenyloxy)ethyl)-6-methylindolizine-7-carboxylate: ethy ²5-( I -(4-aminophenyloxy)ethyl)-6-methylindolizine-7-carboxylate (100 mg, 0.30² mmol) in DMF (1.0 mL) was added with potassium carbonate (104 mg, 0.75 mmol) ²and methyl iodide (94 mg, 0.66 mmol), stirred at room temperature for 2 h. The ²²mixture was extracted with ethyl acetate (100 mL), washed with water (50 mLx2)²54²<DP=55>²CA 03036114 2019-03-07²and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, ²filtered and concentrated to provide a crude product, which was purified ²through ²column chromatography (petroleum ether: ethyl acetate = 4:1) to provide a ²product ²as white solid (40 mg, yield: 36%). MS (ES!) m / z 367 [M+H]² Step 4: Preparation of²5-(1-(4-dimethylaminophenyloxy)ethyl)-6-methylindolizine-7-carboxylic acid: ²5-(1-(4-dimethylaminophenyloxy)ethy1)-6-methylindolizine-7-carboxylic acid was ²²prepared by a method similar to step 5 of example 1, yield 89%. MS (ES!) m / z ²339 ²[M+H]+.² Step 5: Preparation of N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)²-5-(1-(4-(dimethylamino)benzyloxy)ethyl)-6-methylindolizine-7-carboxamide: ²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl) ²-541-(4-(dimethylamino)benzyloxy)ethyl)-6-methylindolizine-7-carboxamide was ²prepared by a method similar to Step 6 of Example 1, yield 6%. ill NMR (400 ²MHz,²DMSO-d6) 6 ppm 11.49 (brs, 1 H), 8.21 (t, J= 3.0 Hz, 1 H), 8.03 (s, 1 H), 7.34 ²(s, 1²H), 7.29 (brs, 2 H), 6.93-6.90 (m, 2 H), 6.80 (t, J = 3.0 Hz, 1 H), 6.51 (d, J ²= 3.0 Hz, ²1 H), 6.12 (q, J 6.8 Hz, 1 H), 5.86 (s, 1 H), 4.25 (d, J = 6.4 Hz, 2 H), 2.95 ²(s,6 H), ²2.34 (s, 3 H), 2.26 (s, 3 H), 2.22 (s, 3 H), 1.73 (dõI = 6.8 Hz, 3 H); MS ²(ES!) m / z ²473 [M+H]' .² Example 23: Preparation of²54(4- bromophenyl)(hydroxy)methyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-²²yl)methyl)-6-methylindolizine-7-carboxamide:²0 0 0 OH²CO ²i(61 / 10 DMF²Br 0Br K INj mecw, Efr²0² 0 OH 1:1H3CI 0 0 OH² H I ___________ 7OC:141 I s²Me0H H20² / I HATU, O'DEA DMF²ite 'compound 21²Step 1: Preparation of ethyl²5-(4-bromobenzoy1)-6-methylindolizine-7-carboxylate: In a dry nitrogen-²protected²100 mL three-necked flask, 1H-pyrrole-2-formaldehyde (2.5 g, 26 mmol), ²2,4-dibromoacetophenone (7.23 g, 26 mmol), ethyl 2-butynoate (3.5 g, 31.2 ²mmol) ²and potassium carbonate (7.18 g, 52 mmol) and 50mL DMF were added ²successively.²<DP=56>²CA 03036114 2019-03-07²The mixture was stirred for 5 hours at 90 C, and cooled to room temperature. ²The ²mixture was extracted with ethyl acetate (200 mL), washed with water (100 ²mLx2) ²and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, ²²filtered and concentrated to provide a crude product, which was purified ²through².. column chromatography (petroleum ether: ethyl acetate = 4:1) to provide a ²product²as yellow oil (2.0 g, yield: 20%). 1H NMR (CDCI3, 400 MHz) 6 ppm 8.29 (s, 1 ²El), ²7.73 (d, J= 7.6 Hz, 2 H), 7.63 (d, J= 7.6 Hz, 2 1-1), 6.99 (s, 1 H), 6.77 (s, ²2 H), 4.36 ²(q, J= 7.2 Hz, 2 H), 2.31 (s, 3 H), 1.42 (t, J= 7.2 Hz, 3 F1).²Step 2: Preparation of ethyl² 54(4-bromophenyl)(hydroxy)methyl)-6-methylindolizine-7-carboxylate: Ethyl²((4-bromophenyl)(hydroxy)methyl)-6-methylindolizine-7-carboxylate was prepared ²²by a method similar to step 3 of example 1, yield 86%. MS (ESI) m / z 388 ²[M+HJE. ²Step 3: Preparation of²54(4-bromophenyl)(hydroxy)methyl)-6-methylindolizine-7-carboxylic acid:² 54(4-bromophenyl)(hydroxy)methyl)-6-methylindolizine-7-carboxylic acid was²prepared by amethod similar to Step 5 of Example 1, yield 83%. 1H NMR (DMSO-²d6, ²400 MHz) 6 ppm 8.13 (s, 1 El), 7.56 (d, J= 7.6 Hz, 2 H), 7.33 (d, J= 7.6 Hz, 2 ²H), ²6.70 (s, 1 H), 6.61-6.55 (m, 2 H), 2.64 (s, 3 H).²Step 4: Preparation of²54(4-13romophenyl)(hydroxy)methyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-²²y1)-6-methylindolizine-7-carboxamide: ²54(4-Bromophenyl)(hydroxy)methyl)-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-²y1)-6-methylindolizine-7-carboxamide was prepared by a method similar to step ²6 of ²example 1, yield 10%. 'H NMR (DMSO-d6, 400 MHz) 6 ppm11.50 (brs, 1 11), 8.25 ²(t,²J= 2.8 Hz, 2 H), 7.63 (d, J= 7.6 Hz, 2 H), 7.38 (s, 1 H), 6.54 (t, J= 2.8 Hz, ²1 El),²6.45 (s, 1 H), 6.41 (t, J= 2.8 Hz, 1 H), 5.88 (s, I H), 4.29 (s, 2 H), 2.37 ²(s, 3 H), 2.33 ²(s, 3 H), 2.22 (s, 3 H); MS (ESI) m / z 494 [M+Hr²Example 24: Preparation of²54(4-bromophenyl)(methoxy)methyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-²y1)methyl)-6-methylindolizine-7-carboxamide:²56²<DP=57>²CA 03036114 2019-03-07²0²0 '."0 NH3CI 0 0 '0²N²LO)c / B,²² DMF Br Me0H H20 Br HATU, DIPEA DMF Br²compound 24²Step 1: Preparation of ethyl²5-44-bromophenyl)(methoxy)methyl)-6-methylindolizine-7-carboxylate: ethyl² 5((4-bromophenyl)(methoxy)methyl)-6-methylindolizine-7-carboxylate was²prepared by a method similar to Step 4 of Example 1, yield 80%. MS (ESI) m / z ²402 ²[M+H1'.²Step 2: Preparation of²54(4-bromophenyl)(methoxy)methyl)-6-methylindolizine-7-carboxylic acid:² 54(4-bromophenyl)(methoxy)methyl)-6-methylindolizine-7-carboxylic acid was²prepared by a method similar to Step 5 of Example 1, yield 83%. MS (ESI) m / z ²374 ²[M+11]-1.²Step 3: Preparation of²5((4-Bromophenyl)(methoxy)methyl)-N-((4,6-dimethyl-2-oxo-1,2-dihy dropyridin-3-²² y1)-6-methylindolizine-7-carboxamide:²5-((4-Bromophenyl)(methoxy)methyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-²²y1)-6-methylindolizine-7-carboxamide was prepared by a method similar to step ²6 of ²example 1, yield 14%. 1H NMR (400 MHz, CDC13) 6 ppm 7.47 (s, 11J), 7.37-7.31 ²(m, ²3 H), 7.18 (d, J = 7.6 Hz, 2 H), 6.99 (brs, 1 H), 6.60 (t, J = 2.8 Hz, 1 H), ²6.48 (t, J =²2.8 Hz, 1 H), 6.29 (s, 1 H), 6.05(s. 1H), 4.56 (d, J= 6.4 Hz, 2 H), 3.36 (s, 3 ²H), 2.55²(s, 3 H), 2.45 (s, 3 H), 2.37 (s, 3 H); MS (ESI) m / z 508 [M+HI.²Example 25: Preparation of²N-((4,6-dimethy1-2-oxo- I ,2-dihydropyridin-3-y pmethyl)-6-methyl-54 I -²phenylethyl)²indolizine-7-carboxamide:² 0 0 0²Pd / C²Ph,PBrTC: nBuL,²I² \-N-) MeOri²0 , HNi5INH,C1 0 0²NaOH²Me0H H,LT) HO = HAT': DIPEA DMF 11-.11'6:1T1² 'Li it-1;A compound 25²Step 1: Preparation of ethyl²5-(1-(4-bromophenyl)viny1)-6-methylindolizine-7-carboxylate: Triphenyl²57²<DP=58>²CA 03036114 2019-03-07²methylphosphonium bromide (329 mg, 0,856 mmol) and 10 mL of tetrahydrofuran ²were added into dry nitrogen-protected 100 ml single-necked bottle, cooled to -²78 C, ²and then nBuLi in tetrahydrofuran (0.5 mL, 1.6 M) was slowly added dropwise. ²After ²warmed to room temperature and stirred for half an hour, ethyl² 5-(4-bromobenzoy1)-6-methylindolizine-7-carboxylate (150 mg, 0.39 mmol) was²added, and then warmed to 50 C and stirred for 3-4 hours, and then 50 mL of ²water ²was slowly added dropwise in an ice bath, extracted with ethyl acetate (100 ²mL). The ²organic phase was preserved and concentrated to provide a crude product, which ²was ²purified through column chromatography (petroleum ether: ethyl acetate = 4:1) ²to²provide a product as yellow viscous liquid (85 mg, yield: 57%). MS (ESI) m / z ²384²[M+F11+.²Step 2: Preparation of ethyl²6-methy1-5-(1-phenylethyl)-6-methylindolizine-7-carboxylate:²5-(1-((4-bromophenyl)ethylene)-6-methylindolizine-7-carboxylate (85 mg, 0.22² mmol)), Pd / C (10 mg) and 10 ml of methanol were added sequentially to a 25 mL²single-necked flask, exchanged with hydrogen and stirred at room temperature ²for ²48 hours, and filtered. The organic phase was concentrated to provide a ²product as ²yellow oil (65 mg, yield: 97%). MS (ESI) m / z 308 [M+Hr.²Step 3: Preparation of 6-methy1-5-(1-phenylethyl)indolizine-7-carboxylic acid:²ethyl 6-methyl-5-(1-phenylethypindolizine-7-carboxylate was prepared by a ²method²similar to Step 5 of example 1, yield 90%. MS (ESI) m / z 280 [M+F11+.²Step 4: Preparation of²N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-²phenylethyl) ²indolizine-7-carboxamide:²N-((4,6-di methy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²phenylethyl)²indolizine-7-carboxamide was prepared by a method similar to Step 6 of Example ²1, ²yield 17%. 1H NMR (400 MHz, CDC13) 8 ppm 10.78 (brs, 1 H), 7.52 (s, 1H), ²7.40-7.22 (m, 5 H), 6.91 (t, J= 2.8 Hz, 1 H), 6.55 (t, J= 2.8 Hz, 1 H), 6.41 ²(t. J= 2.8 ²Hz, 1 H), 5.94 (s, 1 H), 5.04 (q, J= 6.8 Hz, 1 H), 4.54 (d¨ l= 6.4 Hz, 2 H), ²2.41 (s, 3²1-1), 2.39 (s, 3 H), 2.23 (s, 3 H), 1.80 (q, J= 6.8 Hz, 3 H); MS (ESI) m / z 414 ²1114+Hr²Example 26: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-morpholinyl²58²<DP=59>²CA 03036114 2019-03-07²ethyl)indolizine-7-carboxamide:² CLo HNC-0 0²0 N² I N 71(01Pri4 (0N) NACBOHH' )'1D²O².0²(N) H:&i:44.13CI 0 0 ,N²NaOH²j'')YYC² Me0H H,0 HO 'I'=N HATO OIPEA OMF H² / ²compound 26²Step 1: Preparation of isopropyl²6-methyl-5-(1-morphinolinylvinyl)indolizine-7-carboxylate: Ethyl²5-acetyl-6-methylindolizine-7-carboxylate (200 mg, 0.80 mmol), Morpholine(1.0 ²mL)²and 2.0 mL of tetraisopropyl oxytitanium were added successively to a dried ²nitrogen-protected 10 mL microwave tube, heated to 60 C and stirred ²overnight, 10 ²mL of water was added into the reaction system, stirred for 10 minutes and ²concentrated to remove water. The solid was washed with dichloromethane (20 mL ²x²3) and the organic phase was concentrated and used directly in the next step. ²1H²NMR (400 MHz, CDC13) 6 8.09 (s, 1 I-1), 7.48 (brs, 1 H), 6.80 (dd, J= 4.0, 2.6 ²Hz, ²H), 6.66 (dd, J= 4.0, 1.4 Hz, 1 H), 5.22 (sept, J= 6.2 Hz, I H), 4.49 (s, 1 ²H), 4.24 (s, ²1 H), 3.72-3.59 (m, 4 H), 2.99-2.80 (m, 4 H), 2.46 (s, 4 H), 2.46 (s, 3 H), ²1.38 (dõI ²= 6.2 Hz, 6 H); MS (ESI) m / z 329 [M+H1+.² Step 2: Preparation of isopropyl²6-methy1-5-(1-morphinolinylethyl)indolizine-7-carboxyate: in an ice bath, ²sodium ²borohydride (114 mg, 3.0 mmol) was added in portions to a solution of ²isopropyl ²6-methyl-5-(1-morphinolinylvinypindolizine-7-carboxylate (50 mg, 0.15 mmol) in ²²acetic acid, and stirred in room temperature for 4 hours. Most of acetic acid ²was²removed under reduced pressure, and the remaining part was extracted with²dichloromethane (50mLx3), washed with water (30 mLx3) and saturated brine (30 ²mL), filtered to provide a crude product, which was purified through column ²chromatography (petroleum ether: ethyl acetate = 10:1) to provide a product as ²pale ²yellow oil (35 mg, yield: 73%). 1H NMR (400 MHz, CDC13) 6 8.50 (s, 1H), 7.95 ²(s,²1H), 6.80 (s, 1H), 6.65 (s, 1H), 5.21 (dt, J= 6.3 Hz, 1 H), 4.17-4.06 (m, I ²H), 3.68²(brs, 4 H), 2.66 (brs, 2 1-1), 2.50 (s, 3 1-1), 2.26 (brs, 2 H), 1.49 (d, J= ²5.7 Hz, 3 H), ²1.37 (d, J= 6.3 Hz, 6 H); MS (ESI) m / z 331 [M+H]²59²<DP=60>²CA 03036114 2019-03-07²Step 3: Preparation of²6-methyl-5-(1-morphinolinylethyl)indolizine-7-carboxylic acid:²6-methy1-5-(1-morphinolinylethyl)indolizine-7-carboxylic acid was prepared by ²a ²method similar to Step 5 of example 1, yield 63%. MS (ES!) m / z 202 [M-87+H]t² Step 4: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-morphinolin ²²ylethyl)indolizine-7-carboxamide: ²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-5-(1-²morphinolin ²ylethyl)indolizine-7-carboxamide was prepared by a method similar to Step 6 of²Example 1, yield 68%. 1H NMR (400 MHz, CDC13) 6 11.53 (brs, 1 H), 8.44 (brs, I²H), 7.37 (brs, 1 H), 7.22 (brs, 1 H), 6.77 (brs, 1 H), 6.47 (brs, 1 FI), 5.96 ²(s, 1 I-1), ²4.51 (dd, J = 5.9, 3.0 Hz, 2 H), 3.70 (brs, 4 H), 3.48 (q, J = 7.0 Hz, 2 H), ²2.65 (brs, 2 ²H), 2.40 (s, 3 H), 2.35 (s, 3 H), 2.26 (brs, 2 H), 2.24 (s, 3 I-1), 1.24 (brs, ²3 H); MS ²(ES!) m / z 423 [M +Hr.² Example 27: Preparation of²1-chloro-N4(4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²mo ²rphinolinylethyl)indolizine-7-carboxamide:²0²0 C0N) 0²0 N²0 N c0:1²0 0 N²"J-'0 :3N1 '11:3 NaOH²Me0H N20 NO HATU²H I²N DIPEA²DMF / ²CI compound 27 ci²Step 1: Preparation² 1-chloro-6-methyl-5-(1-morphinolinylethyl)indolizine-7-carboxamide:²6-methy1-5-(1-morphinolinylethyl)indolizine-7-carboxamide (450 mg, 1.37mm01)), ²²NCS (183 mg, 1.37mmol) and 10 ml of acetonitrile were added sequentially to a ²100 ²mL single-necked bottle, and stirred at room temperature for 30 hours, which ²was ²purified through column chromatography (petroleum ether: ethyl acetate = 10:1) ²to²provide a product as yellow oil (30 mg, yield: 63%).²1H NMR (500 MHz, CDC13) 6 7.84 (s, 1 H), 6.67 (d, 1=2.9 Hz, 1 II), 5.15 (sept, ²²J= 6.1 Hz, 1 H), 4.03 (q, J= 6.5 Hz, 1 H), 3.66-3.56 (m, 4 H), 2.63-2.52 (m, 2 ²H), ²2.41 (s, 3 H), 2.23-2.10 (m, 2 H), 1.40 (d, J 6.8 Hz, 3 H), 1.31 (d, J = 6.3 ²Hz, 6 H); ²MS (ESI) m / z 364 [M +Hr.²<DP=61>²CA 03036114 2019-03-07²Step 2: Preparation of²I -chloro-6-methy1-5-(1-morphinolinylethyflindolizine-7-carboxylic acid: ²1-chloro-6-methy1-5-(1-morphinolinylethypindolizine-7-carboxylic acid was ²prepared by a method similar to Step 5 of example 1, yield 75%. MS (ESI) m / z ²323 ² [M+H].²Step 3: Preparation of²1-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²mo ²rphinolinylethypindolizine-7-carboxamide:²1-chloro-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²mo²rphinolinylethyl)indolizine-7-carboxamide was prepared by a method similar to ²Step ²6 of Example I. yield 68%. 1H NMR (400 MHz, Me0D) 6 7.33 (s, 1 H), 6.49 (s, 1 ²H), ²6.13 (s, 1 H), 4.44 (s, 2 H), 4.26-4.20 (qm, 4 H), 3.63 (q, I - 6.4 Hz, 1 H), ²3.21 (s, 3 ²H), 2.86-2.84 (m, 2 H), 2.69-2.65 (m, 2 H), 2.36 (s, 3 H), 2.30 (s, 3 H), 1.84 ²(d. J ²6.8 Hz, 3 H); MS (ES1) m / z 457 [M +H].² Example 28: Preparation of²(S)- I -Chloro-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-²5-(1 ²-morphinolinylethyl)pyridazin-7-carboxamide or ²(R)-1-chloro-N-((4,6-dimethy1-2-oxo-1,2-dihydro)pyridin-3-yl)methyl)-6-methyl-²54 ²1-morphinol inylethyl)pyridazin-7-carboxam ide:²1-chloro-N-((4,6-dimethyl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²m ²orphinolinylethypindolizine-7-carboxamide was resolved through chiral ²preparative ²liquid chromatography to provide compound 28 and compound 29.²The separation conditions were: column type: AD-H; column size: 0.46 cm I.D.²x 15 cm L; injection volume: 5 L; mobile phase: Hep / Et0H (0.1% DEA) = 60 / 40² (v / v ); flow rate: 0.5 ml / min; detection conditions: UV = 254 nm; column ²temperature: 25 C.²Compound 28: 111 NMR (400 MHz, Me0D) 6 7.33 (s, 1 H), 6.49 (s, I H), 6.13 ²(s, I H), 4.44 (s, 2 H), 4.26-4.20 (qm, 4 H), 3.63 (q, J= 6.4 Hz, 1 H), 3.21 ²(s, 3 H), ²2.86-2.84 (m, 2 H), 2.69-2.65 (m, 2 H), 2.36 (s, 3 H), 2.30 (s, 3 H), 1.84 (d, ²J= 6.8² Hz, 3 H); MS (ESI) m / z 457 [M 4+1] ; tR = 3. 849 min.²Compound 29: 1H NMR (400 MHz, Me0D) 6 7.33 (s, 1 H), 6.49 (s, 1 11), 6.13²(s, 1 H), 4.44 (s, 2 H), 4.26-4.20 (qm, 4 H), 3.63 (q, J= 6.4 Hz, 1 H), 3.21 ²(s, 3 1-1),²61²<DP=62>²CA 03036114 2019-03-07²2.86-2.84 (m, 2 H), 2.69-2.65 (m, 2 H), 2.36 (s, 3 H), 2.30 (s, 3 H), 1.84 (d, ²1=6.8 ²Hz, 3 H); MS (ESI) m / z 457 [M +Hr ; tR = 4.309 min.²Example 29: Preparation of²2-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²mo² rpholinylethyl)indolizine-7-carboxamide:²Br j, 0 00 I 0 "N²I NBS 11 \,c_tz,1 11140²\ 3 THF K2c03 DmF AUA KA , (-PrOH 11(0,1'04²Br Br Br²CN) (0) HN-IrIVH3C1 c01²N.OH²AcOH I 4 Ille0H I-1,0 HO HATU DIPEA, DMF²\Br Br compound 10²Step 1: 4-bromo-I H-pyrrole-2-carbaldehyde was prepared according to Outlaw, ²etal., Org Lett, 2015, 17, 1822-5. Yield: 80%. IFI NMR (CDCI3, 400 MHz) 6 10.3 ²²(brs, 1 H), 9.46 (s, 1 H), 7.14 (s, 1 H), 6.98 (s, 1 H); MS (ESI) m / z 174 [M ²+H].² Step 2: Preparation of 4-bromo-1-(2-oxopropy1)-1F1-pyrrole-2-carbaldehyde:²4-bromo-1-(2-oxopropy1)-1H-pyrrole-2-carbaldehyde was prepared by a method ²similar to Step 1 of Example 1, yield 75%. MS (ESI) m / z 202 [M-28+Hr.²Step 3: Preparation of ethyl 5-acetyl-2-bromo-6-methylindolizine-7-²carboxylate: ²Ethyl 5-acetyl-2-bromo-6-methylindolizine-7-carboxylate was prepared by a ²method²similar to step 2 of example 1, yield 50%. ifiNMR (400 MHz, CDC13) 6 8.09 (s, ²1²H), 7.24(d, J = 1.3 Hz, 1 H), 6.76(d, J = 1.4 Hz, 1 H), 4.35 (q, J = 7.2 Hz, 2 ²H), ²2.64 (s, 3 H), 2.44 (s, 3 H), 1.40 (t, 1= 7.1 Hz, 3 11); MS (ESI) m / z 324 ²[M+Hr. ²Step 4: Preparation of isopropyl²2-bromo-6-methyl-54 I -morphinolinylethylene)indolizine-7-carboxylate: ²isopropyl² 2-bromo-6-methy1-5-(1-morphinolinylethylene)indolizine-7-carboxylate was²prepared by a method similar to Step 1 of example 26, and was directly used in ²the ²next step reaction. MS (ESI) m / z 407 [M+Hy.²Step 5: Preparation of isopropyl²2-bromo-6-methyl-5-(1-morphinolinylethyl)indolizine-7-carboxylate: isopropyl² 2-bromo-6-methyl-5-(1-morphinolinylethypindolizine-7-carboxylate was prepared²by a method similar to Step 2 of example 1, yield 84%. MS (ESI) m / z 409 [M+111 ².²Step 6: Preparation of²62²<DP=63>²CA 03036114 2019-03-07²2-bromo-6-methyl-5-(1-morphinolinylethyl)indolizine-7-carboxylic acid: ²2-bromo-6-methyl-5-(l -morphinolinylethyl)indolizine-7-carboxylic acid was ²prepared by a method similar to step 5 of example 1, yield 95%. MS (ES!) m / z ²367 ²[M+1-111-.² Step 7: Preparation of²2-bromo-N -((4,6-dimethy1-2-oxo-1,2-dihydropyrid in-3 -yl)methyl)-6-methyl-5-²(1-mo ²rphinolinylethyl)indolizine-7-carboxamide: ²2-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-5-(1-²mo ²rphinolinylethyl)indolizine-7-carboxamide was prepared by a method similar to ²Step²6 of Example 1, yield 56%. 1H NMR (400 MHz, CDC13) 6 14.37 (brs, 1 H), 8.42 ²(s, 1²H), 6.80 (t, 1 = 5.5 Hz, 1 H), 6.56 (brs, 1 H), 6.51 (brs, 1 H), 4.54 (d, 1 - ²6.1 Hz, 2 ²H), 4.16 (q, 1 = 6.7 Hz, 1 H), 3.76 (brs, 4 H), 2.61 (s, 3 H), 2.46 (s, 3 H), ²2.30 (s, 3 ²H), 1.57 (d, 1= 6.8 Hz, 3 H); MS (ESI) m / z 501 [MM].²Example 30: Preparation of²2-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1 -(4-²(dimethyl²am ino))pheny 1 oxy)ethy 1)-6-methy 1 indol izine-7-carboxam i de:²-N-²a².I.²r )²ItIL-²--"-²- H20 ²\ / ² Br Br²Br²---14"- 0²aFIN ',., ' 1 NH3C1 a²HO 1 '''N HATO DIPEA, DMF fir.r,A-N 1CAlt compound 11²Br Br²Step 1: Preparation of isopropyl²2-brom o-5-(1-(4-(dimethy lam ino)piperid in- 1 -y 1)v iny1)-6-methy 1 ind ol ²izin e-7-carboxy² late: isopropyl²2- brom o-5-( I -(4-(dimethy lam ino)piperid in-1-y 1)ethy lene)-6-methy 1 ²indol izine-7-carb²oxylate was prepared by a method similar to Step 1 of example 26. MS (ES!) m / z ²448²[M+1-1]1.²Step 2: Preparation of isopropyl²2-bromo-5-(1-(4-(dimethy lam ino)piperid in-1-y 1)ethyl)-6-m ethy I indolizine-²7-carboxy²late: isopropyl²63²<DP=64>²CA 03036114 2019-03-07²2-bromo-5-(1-(4-(dimethylamino)piperidin-1-yl)ethyl)-6-methylindolizine-7-²carboxy ²late was prepared by a method similar to step 2 of example 26, yield 800 / 0. MS ²(ESI) ²m / z 450 [M+H].²Step 3: Preparation of²2-bromo-5-(1-(4-(dimethylamino)piperidin-1-yl)ethyl)-6-methylindolizine-7-²carboxy²lie acid:²2-bromo-5-(1-(4-(dimethylamino)piperidin- 1 -yl)ethyl)-6-methylindolizine-7-²carboxy²lie acid was prepared by a method similar to step 5 of example 1, yield 56%. ²MS ²(ESI) m / z 408 [M+Hr.² Step 4: Preparation of²2-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-54 I -(4-²(dimethyl ²amino)) Piperidin-1-yl)ethyl)-6-methylindolizine-7-carboxamide: ²2-bromo-N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-5-(1-(4-²(dimethyl ²amino)) Piperidin-1 -ypethyl)-6-methylindolizine-7-carboxamide was prepared by ²a²method similar to Step 6 of Example 1, yield 30%. 1H NMR (400 MHz, DMSO-d6) 6²11.49 (brs, 1 H), 9.37 (brs, 1 H), 8.29 (s, 1 H), 8.24 (t, .1=4.3 Hz, 1 H), ²7.26 (brs, 1 ²H), 6.61 (brs, 1 H), 5.87 (s, 1 H), 4.25 (d, J= 5.0 Hz, 2 1-1), 4.03 (dd, J = ²13.8, 7.3 Hz, ²1 H), 3.47-3.34 (m, 2 H), 3.18-3.02 (m, 2 H), 2.80-2.69 (m, 6 H), 2.19 (s, 3 ²H), 2.11 ²(s, 3 H), 2.04-1.93 (m, 2 H), 1.88-1.80 (m, 2 1-1), 1.41 (d, J= 6.7 Hz, 3 11); ²MS (ESI)²m / z 542 [M+H].²Example 31: Preparation of²2-(benzo[d][1,3]dioxo1-5-y1)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-²3-y1)methyl)-6-methyl-5-(1-morphinolinylethyl)indolizin-7-carboxamide:²C0)²0 0²0 0 >t1 n²101 0->²Nal3H4²Pd(dppf)Ct, '<Otte o(OPHa AcOH²Doxane / H2O.(5 1)²03²0 0 0²0 (²0 N 0 0 N²0 N²0²N NaOH HO²Me0H H20 HATU, DIPEA OMF²o-)²it compound 32 b² Step 1: Preparation of ethyl²64²<DP=65>²CA 03036114 2019-03-07²5-acetyl-2-(benzo[d][1,3]dioxo1-5-y1)-6-methylindolizin-7-carboxylate: In a ²dry ²nitrogen protected 100 mL three-necked flask, ethyl ²5-acetyl-2-bromo-6-methylindolizine-7-carboxylate (200 mg, 0.62 mmol), ²3,4-dimethylenedioxyphenyl boronic acid pinacol ester (200 mg, 0.81 mmol),² Pd(dppf)C12 (20 mg) and potassium acetate (182 mg, 1.86 mmol) and 10 ml²dioxane / 2 ml water were added successively, stirred and refluxed overnight, ²the ²reaction solution was extracted with ethyl acetate (200 mL), washed with water ²(100 ²mLx2) and brine (100 mL). The organic phase was dried over anhydrous sodium ²sulfate, filtered and concentrated to provide a crude product, which was ²purified²through column chromatography (petroleum ether: ethyl acetate = 4:1) to ²provide a²product as yellow oil (140 mg, yield: 62%). MS (ESI) m / z 366 1M+111i.²Step 2: Preparation of isopropyl²2-Benzo[d][1,3]dioxo1-5-y1)-6-methy1-5-(1-morphinolinylvinypindolizine-7-²carboxyl ²ate: crude product, isopropyl²2-Benzo[d][1,31di0xo1-5-y1)-6-methyl-5-(1-morphinolinylvinyl)indolizine-7-²carboxyl²ate was prepared by a method similar to step 1 in example 26. MS (ESI) m / z 449 ²²[M+F11+.²Step 3: Preparation of isopropyl²2-Benzo[d][1,3 ylioxo1-5-y1)-6-methyl-5-(1-morphinolinylethyl)indolizine-7-²carboxyl² ate: isopropyl²2-Benzo[d][1,31dioxo1-5-y1)-6-methyl-5-(1-morphinolinylethyl)indolizine-7-²carboxyl ²ate was prepared by a method similar to Step 2 of example 26, yield 57%. MS ²(ESI) ²m / z 451 [M+1-11+.²Step 4: Preparation of²2-benzo[d111,3]dioxol-5-y1)-6-methy1-5-(1-morphinolinylethyl)indolizine-7-²carboxyl²ic acid: crude product²2-Benzo[d][1,3]clioxol-5-y1)-6-methyl-54 -morphinolinylethyl)indolizine-7-²carboxyl ²ic acid was prepared by a method similar to step 5 of example I. MS (ESI) m / z ²409 ²[M+HF.² Step 5: Preparation of²2-(benzo[d][1,3]dioxo1-5-y1)-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridine-²3-yl)methyl)-6-methyl-5-(1-morphinolinylethyl)indolizin-7-carboxamide:²<DP=66>²CA 03036114 2019-03-07²2-(Benzo[d][1,31dioxo1-5-y1)-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridine-²3-yl)methyl)-6-methyl-5-(1-morphinolinylethyDindolizin-7-carboxamide was ²prepared by a method similar to Step 6 of Example 1, yield 20%. H NMR (Me0D, ²400 MHz) 8 7.54 (s, 1 H), 7.23 (brs, 3 H), 6.88 (s, 1 H), 6.16(s, 1 H). 5.97 ²(s, 3 H),²4.48 (s, 3 H), 3.88 (brs, 4 H), 3.23-3.22 (m, 2 H), 2.39 (brs, 9 H), 2.26 ²(brs, 3 H); MS²(ES!) m / z 543 [M+Hr²Example 32: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morphinolin ²ylethyl)- 2-(4-morphinolinylphenyl)indolizine-7-carboxamide:²0 r²0²0 0 0 go² N-Th N \² / HN0 / NaBH,² To(0,Pr)4 AcOH² / Pd(cIppfpl, KOAc²Doxane / H20.(5 1)²Br²L.NJ²C²², HO 0 0 õLy 1,1²HNICNH,CI HN)IrN)(Y²H²NaOH² / Me0H I120 N \²HATU DIPEA DMF² / ²ft compound 33² Q²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-5-(1-morphi ²nolinylethyl)- 2-(4-morphinolinylphenyDindolizine-7-carboxamide was prepared ²by a ²method similar to example 31.²Step 1: Preparation of ethyl²5-acety1-6-methy1-2-(4-morphinolinylphenyl)indolizine-7-earboxylate: Yield ²12%.²MS (ES!) m / z 407 [M+H]f.²Step 2: Preparation of isopropyl²6-methy1-2-(4-morphinolinylpheny1)-5-(1-morphinolinylvinyl)indolizine-7-²carboxyla ²te: MS (ES!) m / z 490 [M+H]'.² Step 3: Preparation of isopropyl²6-methyl-5-(1-morphinol inylethyl)-2-(4-morphino I inylpheny Dindol izine-7-²carboxyla²te: yield of two steps was 83%. MS (ES!) m / z 492 [M+H]'.²Step 4: Preparation of²66²<DP=67>²CA 03036114 2019-03-07²6-methy1-5-(1-morphinolinylethyl)-2-(4-morphinolinylphenyl)indolizine-7-²carboxyli ²c acid: MS (ES!) m / z 409 [M+Hr²Step 5: Preparation of²N4(4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-5-(1-²morphinolin²ylethyl)- 2-(4-morphinolinylphenyl)indolizine-7-carboxamide: yield of two ²steps was²20%. NMR (Me0D, 400 MHz) 6 7.68-7.66 (m, 3 H), 7.49 (s, I H), 7.13-7.11 ²(m, ²3 H), 6.14 (s, I H), 4.48 (s, 2 H), 3.89-3.83 (m, 10 H), 3.26 (s, 6 H), 2.38 ²(s, 9 I-1), ²2.26 (s, 3 H),1.81-1.76 (m, 2H); MS (ES!) m / z 584 [M+H]²Example 33: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-morphinol ²in²ylethyl)- 2-(pyridin-3-yl)indolizine-7-carboxamide:²C0,1²HO²0 0 -13² HO 0 I N.., HN,²NaBH4² / ²Ti(O / Pr)4 AcOH² / Pd(dppf)C12 KOAc²liozane / H20=(5 1)JN²CN²CL -J 0 0 0 H.Nj 0 N 0 N² NaOH Ho H3C1²H I 11 I 'r² Me0H H20 HATU, OIPEA, OMF / ²compound 34 \²CN CN²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-morphi ²nolinylethyl)- 2-(-3-morphinolinylphenyl)indolizine-7-carboxamide was prepared ²by² a method similar to example 31.²Step I: Preparation of ethyl²5-acetyl-6-methyl-2-(pyridin-3-yl)indolizine-7-carboxylate: Yield 39%. MS ²(ES!)²m / z 323 [M+H].²Step 2: Preparation of isopropyl²6-methy1-5-(1-morphinolinylviny1)-2-(pyridin-3-y1)indolizine-7-carboxylate: MS²(ES!) m / z 406 [M+H].²Step 3: Preparation of isopropyl²6-methy1-5-(1-morphinolinylethyl)-2-(pyridin-3-ypindolizine-7-carboxylate: ²yield of ²two steps was 83%. MS (ES!) m / z 408 [M+H]² Step 4: Preparation of²67²<DP=68>²CA 03036114 2019-03-07²6-methyl-5-(1-morphinolinylethyl)-2-(pyridin-3-y1)indolizine-7-carboxylic ²acid. MS ²(ESI) m / z 366 [M+H].²Step 5: Preparation of²N4(4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-5-(1-²morphinolin²ylethyl)- 2-(pyridin-3-yl)indolizine-7-carboxamide: yield of two steps was ²20%. 1H²NMR (400 MHz. CDC13) 6 ppm 11.48 (brs, 1 H), 8.95 (s. 1 H), 8.79 (brs, 1 H), ²8.44 ²(d, J= 2.8 Hz, 1 1-1), 8.20 (s, 1H), 8.08 (d, J = 2.8 Hz, 1 H), 7.43 (d, J = ²2.8 Hz, 1 H), ²7.30 (s, 1 H), 6.92 (s, 1 H), 5.87 (s, 1 H), 4.26 (d, J= 6.4 Hz, 2 H), 4.06 ²(q, J= 6.8 ²Hz, 1 H),3.59 (brs, 4 H), 2.66 (brs, 2 H), 2.26 (s, 3 II), 2.20-2.16 (m, 5 Fp, ²2.11 (s, 3² H),1.47 (d, J= 6.8 Hz, 1 H); MS (ESI) m / z 500 [M+H].²Example 34: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-5-(1-²morphinolin ²ylethyl)- 2-(pyridin-4-yl)indolizine-7-carboxamide:²(N-J²0 9²HO² 0 0²HO-11 HN / --0 I² I / NA:130HH4²1-1(0,P,4²Pd(dppf)CI, KOAc²Otoxane / H20-.(5 1)²¨N ¨N²0 0²0 0 0² 0 N 0 1,,,r1õ 0 0 IC²0²N, NaOH I NJHCI²FIA.)11 I²Me0H, H20 HATU, DIPEA, DMF²1b compound 35² N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-morphi²nolinylethyl)- 2-(pyridin-4-yl)indolizine-7-carboxamide was prepared by a ²method ²similar to example 31.²Step I: Preparation of ethyl²5-acetyl-6-methyl-2-(pyridin-4-yl)indolizine-7-carboxylate: Yield 34%. MS ²(ESI)² m / z 323 [M+HY.²Step 2: Preparation of isopropyl²6-methyl-5-(1-morphinolinylyiny1)-2-(pyridin-4-ypindolizine-7-carboxylate. MS²(ESI) m / z 406 [M+H].²Step 3: Preparation of isopropyl² 6-methy1-5-(1-morphinolinylethyl)-2-(pyridin-4-y1)indolizine-7-carboxy1ate:²68²<DP=69>²CA 03036114 2019-03-07²two-step yield was 82%. MS (ESI) m / z 408 [M+H1+.²Step 4: Preparation of²6-methyl-5-(1-morphinolinylethyl)-2-(pyridin-4-ypindolizine-7-carboxylic acid. ²MS ²(ESI) m / z 366 [M+H].² Step 5: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-4-yl)methyl)-6-methyl-5-(1-²morphinolin ²ylethyI)- 2-(pyridin-3-yl)indolizine-7-carboxamide: yield of two steps was ²20%. 1H ²NMR (400 MHz, CDCI3) 6 ppm 8.87 (brs, 1 H), 8.54 (d, J = 7.8 Hz, 2 H), 8.22 ²(s, 1 ²1-1), 7.67 (d, .1 = 7.8 Hz, 2 H), 7.30 (s, 1 H), 6.98 (s, 1 H), 5.87 (s, 1 H), ²4.26 (d, J =²6.4 Hz, 2 H), 4.06 (q, J= 6.8 Hz, I H), 3.59 (brs, 4 H), 2.66-2.62 (m, 2 H), ²2.26 (s, 3²H), 2.20-2.17 (m, 5 H), 2.16 (s, 3 H), 1.46 (d, J= 6.8 Hz, 1 H); MS (ESI) m / z ²500 ²[M+Hr.²Example 35: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-morpholinyl² ethyl)-2-phenylindolizine-7-carboxamide:²CI²0 0 , 0 N-²HO'²Ho -)-a ca I IN / õ / ¨`0 I ²1r .²TeOPH4 AcOH²\ / Pd(depf)CI, KOAc²a, Deazane / H,015 1) / \²--- / ²CI (0 ) 0 10)²0 N²Ns NaOH²A) ___________________________ ¨. \ / \ / ² Me0H 1-120 HATU, DIPEA DMF²I compound 36² / \ 0_²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-morpho ²linylethyl)-2-phenylindolizine-7-carboxamide was prepared by a method similar ²to ²example 31.²Step I: Preparation of ethyl 5-acetyl-6-methyl-2-phenylindolizine-7-²earboxylate:²Yield 40%. MS (ESI) m / z 322 [M+Hr.²Step 2: Preparation of isopropyl²6-methyl-5-(1-morphinolinylviny1)-2-phenylindolizine-7-carboxylate. MS (ESI) ²m / z ²405 [M+H]+.² Step 3: Preparation of isopropyl²6-methy1-5-(1-morphinolinylethyl)-2-phenylindolizine-7-carboxylate: yield of ²two²69²<DP=70>²CA 03036114 2019-03-07²steps was 42%. MS (ESI) m / z 407 [M+Hr²Step 4: Preparation of²6-methy1-5-(1-morphinolinylethyl)-2-phenylindolizine-7-carboxylic acid. MS ²(ESI) ²m / z 365 [M+H].² Step 5: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-morphinolin ²²ylethyl)-2-phenylindolizine-7-carboxamide: yield of two steps was 39%. 1H NMR ²(400 MHz, DMSO-d6) 6 ppm 11.47 (s, 1 H), 8.71 (brs, 1 H), 8.18 (s, 1 H), 7.69 ²(d, J ²= 7.8 Hz, 2 H), 7.40 (t, J = 7.8 Hz, 2 H), 7.28-7.22 (m, 2 H), 6.84 (s, 1 H), ²5.87 (s, 1²H), 4.26 (d, J= 6.4 Hz, 2 H), 4.05 (q, J= 6.8 Hz, I H), 3.56 (brs, 4 H), 2.66-²2.61 (m,²2 H), 2.26 (s, 3 H), 2.20 (s, 3 H) 2.20-2.17 (m, 5 H), 2.11 (s, 3 H), 1.45 (d, ².1 = 6.8 Hz,²1 H); MS (ESI) m / z 499 [M-4111.²Example 36: Preparation of²N-((4,6-di methy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-morph ²inol in² ylethyl)- 2-(3-morphinolinylphenyl)indolizine-7-carboxamide:²(0)²0²N - NaBH4²-11(0iPO4 AcOH²Pcf(dpp6012, KOAc²Diezane / H20-(91) N 0 11,N \D²Br²0²COD²0 (N) C 0 VI N²HO 81411:1H'C": I²NaOH N²\²Me0H, H20 HATLE DIPEA DMF²rTh f²N 0 N 0 COMDOUIld 37 .-ErTh0²\²N-((4,6-dimethy1-2-oxo-1.2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-morphi ²nolinylethyl)- 2-(3-morphinolinylphenyl)indolizine-7-carboxamide was prepared ²by a ²method similar to example 31.² Step 1: Preparation of ethyl²5-acety1-6-methy1-2-(3-morphinolinylphenypindolizine-7-carboxylate: Yield 56%. ²²MS (ESI) m / z 407 [M+H].²Step 2: Preparation of isopropyl²6-methyl-5-(1-morphinolinylviny1)-2-(3-morphinolinylphenyl)indolizine-7-²carboxyla² te. MS (ESI) m / z 490 [M+Hf.²<DP=71>²CA 03036114 2019-03-07²Step 3: Preparation of isopropyl²6-methy1-5-(1-morphinolinylethyl)-2-(3-morphinolinylphenyl)indolizine-7-²carboxyla ²te: yield of two steps was 83%. MS (ES!) m / z 492 [M+H]'.²Step 4: Preparation of 6-methy1-5-(1-morphinolinylethyl)² -2-(3-morphinolinylpheny1)-7-carboxylic acid. MS (ES!) m / z 450 [M+H]'.²Step 5: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-54 I -morph inol ²in ²ylethyl)- 2-(3-morphinolinylphenyl)indolizine-7-carboxamide: yield of two ²steps was ²39%. 1HNMR (400 MHz, DMSO-do) 6 ppm 11.50 (s, 1 H), 8.61 (brs, 1 H). 8.21 (s, ²1²H), 7.38-7.26 (m, 2 H), 6.88-6.85 (m, 2 Fl), 5.89 (s, 1 H), 4.33 (s, 2 H), ²4.05 (q, J²6.8 Hz, I H), 3.89-3.83 (m, 8 I-I), 3.25-3.18 (m, 4 H), 2.46 (s, 3 H), 2.45-²2.20 (m, 4 ²H), 2.26 (s, 3 H), 2.20 (s, 3 H), 2.11 (s, 3 H), 1.38 (d, J = 6.8 Hz, 3 H); MS ²(ESI) m / z ²584 [M+H]²Example 37: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-morpholinyl²ethyl)-2-(3,4,5-trimethoxyphenypindolizine-7-carboxamide:²0,²HO J².0-6 0 0 IN²0 0²0 I²N _²1KO / P194 AGOH²Pd(dppfICI, KOAc² Br Doxane / H20=(51) / \ 0 / ²o\ P 0\ io ²0² C ) ) 0 )²²²NOH HO)l(L(²HNrNH201 FiN,A'TF1²a²1 / ²MeOli H20 HATU, OIPEA EWE² / ²E compound 38_\²\ / ²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-morpho ²linylethyl)-2-(3,4,5-trimethoxyphenypindolizine-7-carboxamide was prepared by ²a² method similar to example 31.²Step 1: Preparation of ethyl²5-acetyl-6-methy1-2-(3,4,5-trimethoxyphenyl)indolizine-7-carboxylate: Yield ²47%.²MS (ES!) m / z 412 [M+H].²Step 2: Preparation of isopropyl²71²<DP=72>²CA 03036114 2019-03-07²6-methy1-5-(l-morphinolinylviny1)-2-(3,4,5-trimethoxyphenyl)indolizine-7-²carboxyl ²ate. MS (ES!) m / z 495 [M+H]'.²Step 3: Preparation of isopropyl²6-methy1-5-(1-morphinolinylethyl)-2-(3,4,5-trimethoxyphenypindolizine-7-²carboxyl² ate: yield of two steps was 81%. MS (ES!) m / z 497 [M+H1'.²Step 4: Preparation of²6-methyl-5-(1-morphinolinylethyl)-2-(3,4,5-trimethoxyphenyl)indolizine-7-²carboxyli²c acid. MS (ES!) m / z 455 [M+F11+.²Step 5: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morphinolin²ylethyl)-2-(3,4,5-trimethoxyphenypindolizine-7-carboxamide: yield of two steps ²was ²69%. TH NMR (400 MHz, DMSO-do) 6 ppm 11.48 (brs, 1 H), 8.68 (brs, 1 H). 8.18 ²(brs, 1 H), 7.27 (s, 1 H), 6.93 (s, 2 H), 5.88 (s, 1 H), 4.28 (s, 2 H), 4.08 ²(q, J= 6.8 Hz, ²1 H), 3.87 (s, 6 H), 3.68 (s, 3 H), 3.60 (brs, 4 H), 2.75-2.68 (m, 2 H), 2.27 ²(s, 3 H),²2.21 (s, 5 H), 2.12 (s, 3 H), 1.47 (d, J= 6.8 Hz, 3 H); MS (ES!) m / z 589 ²[M+H]f.²Example 38: Preparation of²2-(2,4-dimethoxypheny1)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyrid in-3 -²yl)methyl)-6 ²-methyl-5-(1-morphinolinylethyl)indolizine-7-carboxamide:²0², 0 N² 0-8²HN 0 N²\ C) 1)(0,PcIn NaBH4² AcOH² / Pel(dppIlCl2, KOAc²Doxarle / H20=t51) / / ²Br²0 0²0 0 / ²o²C 0 0 N 0 N²NaOH²HO iii:Or4H3C"1:6rN²N N=²\ 0 Me0H H20 HATU. DIPEA DMF²compOund 391_²0 0² 2-(2,4-dimethoxypheny1)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)meth²y1)-6-methyl-5-(1-morpholinylethyl)indolizine-7-carboxamide was prepared by a ²method similar to example 31.²Step 1: Preparation of ethyl 5-acetyl²-2-(2,4-dimethoxypheny1)-6-methylindolizine-7-carboxylate: Yield 47%. MS (ES!)²72²<DP=73>²CA 03036114 2019-03-07²m / z 382 [M+Hr.²Step 2: Preparation of isopropyl²2-(2,4-dimethoxypheny1)-6-methy1-5-(1-morphinolinylvinypindolizine-7-²carboxylate. ²MS (ESI) m / z 465 [M+Hr.² Step 3: Preparation of isopropyl²2-(2,4-dimethoxypheny1)-6-methyl-5-(1-morphinolinylethyl)indolizine-7-²carboxylate:²yield of two steps was 65%. MS (ESI) m / z 467 [M+H]²Step 4: Preparation of²2-(2,4-dimethoxypheny1)-6-methyl-5-(1-morphinol inylethyl)indolizine-7-²carboxylic² acid. MS (ESI) m / z 425 [M+H]'.²Step 5: Preparation of²2-(2,4-dimethoxypheny1)-N-((4,6-dimethy1-2-oxo-1,2-dihydropyrid in-3 -yl)methy ²1)-6 ²-methyl-5-(1-morphinolinylethypindolizine-7-carboxamide: yield of two steps ²was ²18%. 1H NMR (400 MHz, DMSO-do) 6 ppm 11.46(s, 1 H), 8.81 (s, 1 H), 8.12(s, 1²1-1), 7.57-7.55 (m. 1 H), 7.25 (s, 1 H), 6.77 (s, 1 H), 6.64-6.59 (m, 2 H). ²5.86 (s, 1 H),²4.26 (s, 2 H), 4.03 (q, J = 6.8 Hz, 1 H), 3.90 (s, 3 H), 3.79 (s, 3 H), 3.60 ²(brs, 4 H), ²2.64-2.59 (m, 2 H).2.24 (s, 3 H), 2.17 (s, 3 H), 2.16-2.15(m, 2 H), 2.11 (s, 3 ²F1), 1.43 ²(d, J= 6.8 Hz, 3 H);MS (ESI) m / z 559 [M+Hr²Example 39: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyrid in-3-yOmethyl)-6-methy 1 -5-(1 -morph ²inolin²ylethyl)- 2-(4-(morphinolinylmethyl)phenyl)indolizine-7-carboxamide:²0 LoN)²²HN / ² / 1.1 NaBH,² / FilOPOn AcOH²\ / pa(cIpp1)02 KOAc²Br Dioxane / H20.(5 1)²i 0 C ) 0 CON) 0 cC)²0 OH N² HO (NCI²NaOH²Me0H H20 HATU, DIPEA, DMF²410²compound 40²\cõ)²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-morphi²73²<DP=74>²CA 03036114 2019-03-07²nolinylethyl)-2-(4-4-(morphinolinylmethyl)phenypindolizine-7-carboxamide was ²prepared by a method similar to example 31.²Step 1: Preparation of ethyl²5-acety1-6-methy1-2-(4-(morphinolinylmethyl)phenypindolizine-7-carboxylate: ²Yield² 62%. MS (ESI) m / z 421 [M+Hr.²Step 2: Preparation of isopropyl²6-methyl-2-(4-(morphinolinylmethyl)pheny1)-5-(1-morphinolinylvinyl)indolizine-²7-c²arboxylate. MS (ESI) m / z 504 [M+Hr.²Step 3: Preparation of isopropyl²6-methyl-5-(1-morphinolinylethyl)-2-(4-(morphinolinylmethyl)phenyl)indolizine-²7-c²arboxylate: yield of two steps was 41%. MS (ESI) m / z 506 [M+H1'.²Step 4: Preparation of 6-methyl-5-(1-morphinolinylethyl)²-2-(4-(morphinolinylmethyl)phenyl)indolizine-7-carboxylic acid. MS (ESI) m / z ²464 ²[M+Hr.² Step 5: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-morphinol ²in ²ylethyl)- 2-(4-(morphinolinylmethyl)phenyl)indolizine-7-carboxamide: yield of ²two ²steps was 43%. 1H NMR (Me0D, 400 MHz) 6 ppm 7.84 (d, J= 7.6 Hz, 2 H), 7.53 (d,²= 7.6 Hz, 2 H), 7.49-7.45 (m, 2 H), 6.14 (s,2 I-1), 4.47 (s, 2 H), 4.44 (s, 2 ²H),²4.06-4.02 (m, 2 H), 3.88-3.86 (m, 2 H), 3.78-3.74 (m, 3 H), 3.41-3.37 (m, 2 ²H),²3.23-3.21 (m, 2 1-1), 2.38-2.34 (m, 8 H), 2.27 (s, 6 H), 1.80 (brs, 3 1-1); MS ²(ESI) m / z ²598 [M+H].²Example 40: Preparation of tert-butyl²7-eyano-5-(7((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-y1)methypcarbamoy1)-6-me² thy1-5-(1-morpholineylethyl)indol izine-2-yDindo I ine-l-carbamate:²74²<DP=75>²CA 03036114 2019-03-07²(N0)²0 0²ON²,Boc²²-N²HN NaBH4²AcOH²PcKappf)CI, KOAc²14-Boc²0²0 C )²)²N HOYY 25:'= ).LC1C²H HN N 3C I Hal N²I NaOH \²MeOH 1-120 HAIL / DIPEA DMF²CN²compound 41 =(²N-Boc²N Boc²Tert-butyl²7-cyano-5-(7((4,6-dimethy1-2-oxo-1,2-dihydropyridi n-3 -y pmethyl)earbamoy1)-6-²me²thy1-5-(1-morphol ineylethy I) indol izine-2-y 1) indol ine-l-carbam ate was ²prepared by a² method similar to example 31.²Step 1: Preparation of tert-butyl²5-(5-acety1-7-(ethoxycarbonyI)-6-methy 1 indolizine-2-y1)-7-cyano indoline-l-²carbamat²e: Yield 66%. MS (ESI) m / z 488 [M+H]1-.²Step 2: Preparation of tert-butyl²7-cyano-5-(7-(isopropoxycarbony1)-6-methy1-5-(1-morphinolinylvinyl)indolizine-²2-y²1)indoline-1 -carboxylate: MS (ESI) m / z 571 [M+Hr²Step 3: Preparation of tert-butyl²7-cyano-5-(7-(isopropoxycarbony1)-6-methyl-5-(1-morph inoliny lethy I) ²indolizine-2-y²1)indoline-I -carboxylate: yield of two steps was 30%. MS (ESI) m / z 573 [M+H]² Step 4: Preparation of²2-(1-(tert-butoxycarbony1)-7-cyanoporphyrin-5-y1)-6-methy1-5-(1-²morphinolinylethy ²1)indolizine-7-carboxylic acid. MS (ESI) m / z 531 [M+H]-1.²Step 5: Preparation of tert-butyl²7-cyano-5-(7-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoy1)-6-²me²thy1-5-(1-morpholineylethyl)indolizine-2-ypindoline-l-carbamate: yield of two ²steps²was 35%. 1H NMR (400 MHz, DMSO-d6) 6 ppm 11.48 (s, 1 H), 8.61 (s, 1 H), 8.20 ²(s, ²1 H), 7.87 (s, 1 H), 7.24 (s, 1 H), 6.80 (s, 1 H), 5.87 (s, 1 H). 4.26 (d, J = ²6.4 Hz, 2 ²H), 4.09-4.05 (m, 3 H), 3.15-3.11 (m, 4 H), 2.29 (brs, 2 H), 2.21 (s, 6 H), ²2.12 (s, 3 ²H), 1.54 (s, 9 H), 1.24 (brs, 3 H); MS (ESI) m / z 665 [M+HI.²<DP=76>²CA 03036114 2019-03-07²Example 41: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-(1-methyl-²IH-pyrazol-5-y1)-5-(1-morpholineylethyl)indolizine-7-carboxamide:²(0)²HNC \P I Nal3H4²N²Pd(dppf)CI, KOAc Ti(0,Pr), AcOH²sr Chozane / H20.(5 1) / 14 / ²0 0²0²( 0 (²0 N 0 N²HN )kr i3CI²Ho ';'1\)01 I N ²Me0H H,0² / HATU DIPEA 11(_² / ² / / compound 42 N²N² N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-(1-methyl-²111-pyrazol-5-y1)-5-(1-morpholineylethyl)indolizine-7-carboxamide was prepared ²by ²a method similar to example 31.²Step 1: Preparation of ethyl²5-acety1-6-methy1-2-(1-methyl-1H-pyrazol-5-ypindolizine-7-carboxylate: Yield ²55%.² MS (ESI) m / z 326 [M+Hr.²Step 2: Preparation of isopropyl²6-methyl-2-(1-methy1-1Fl-pyrazol-5-y1)-5-(1-morphinol inylvinyl)indolizine-7-²carbox²ylate: MS (ESI) m / z 409 [M+H14.²Step 3: Preparation of isopropyl²6-methyl-2-(1-methy1-1H-pyrazol-5-y1)-5-(1-morphinolinylethypindolizine-7-²carbox²ylate: yield of two steps was 54%. MS (ESI) m / z 411 [M+H]4²Step 4: Preparation of²6-methy1-2-(1-methyl-1H-pyrazol-5-y1)-5-(1-morphinolinylethyl)indolizine-7-²carbox ²ylic acid: MS (ESI) m / z 369 [M+Hr² Step 5: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-2-(1-methyl-1 ²Il-p ²yrazol-5-y1)-5-(1-morphinolinylethyl)indolizine-7-carboxamide: Yield of two ²steps²was 32%. NMR (400 MHz, DMSO-d6) 6 ppm 11.48 (s, 1 H), 8.65 (s, 1 H), ²8.21 (s, ²1 H), 7.43 (s, 1 H), 7.32 (s, 1 H), 6.73 (s, 1 H), 6.46(s, 1 H), 5.87 (s, 1 ²H), 4.45 (brs,²2 H), 3.84 (brs, 2 H), 3.72 (s, 3 H), 3.48 (brs, 4 1-1), 2.84 (s, 3 H), 2.38 ²(s, 3 II), 2.31²76²<DP=77>²CA 03036114 2019-03-07²(s, 3 H), 1.55 (s, 3 H); MS (ES!) m / z 503 [M+H]'.²Example 42: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-(1-methyl-²IH-pyrazol-4-y1)-5-(1-morpholinylethyl)indolizine-7-carboxamide:²c) 9 413²[²1 5²N ______________________________________________________ NaBH,²Pd(dppf)CI, KOAc AcOH² B, Doxane / H20.(51)²\N-N,²j 0 CN 0) 0²0 N + 0 0 N²'0 s's=N NaOH Ho & INH,C1 õsr,L,²Me0H, H,0 N HATU. DIPEA ONIF / ² / ²compound 43² N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-(1-methyl-²1H-pyrazol-4-y1)-5-(1-morpholineylethyl)indolizine-7-carboxamide was prepared ²by ²a method similar to example 31.²Step 1: Preparation of ethyl²5-acetyl-6-methyl-2-(1-methyl-11-1-pyrazol-4-ypindolizine-7-carboxylate: Yield ²74%.²MS (ESI) m / z 326 [M+HY.²Step 2: Preparation of isopropyl²6-methyl-2-(l-methyl-1 1-1-pyrazol-4-y1)-5-(1-morphinolinylvinyl)indolizine-7-²carbox²ylate: MS (ES!) m / z 409 [M+H].² Step 3: Preparation of isopropyl²6-methyl-2-(1-methy1-1 H-pyrazol-4-y1)-5-(1-morphinolinylethypindolizine-7-²carbox²ylate: yield of two steps was 30%. MS (ES!) m / z 411 [M+1-11+.²Step 4: Preparation of²6-methyl-2-(1-methyl-1H-pyrazol-4-y1)-5-(1-morphinolinylethyl)indolizine-7-²carbox² ylic acid: MS (ES!) m / z 369 [M+14]+.²Step 5: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-(1-methyl- 1 ²H-p ²yrazol-4-y1)-5-(1-morphinolinylethyl)indolizine-7-carboxamide: Yield 11%. Ili ²NMR²(400 MHz, Me0D) 6 ppm 7.83 (s, I H), 7.69 (s, 1 H), 7.31 (s, 1 H), 6.61 (s, 1 ²H),²6.11 (s, 1 H), 6.46(s, 1 H), 4.57 (s, 2 H), 4.45 (brs, 2 H), 4.07 (q, J= 6.8 ²Hz, 1 H),²77²<DP=78>²CA 03036114 2019-03-07²3.68 (brs, 4 H), 2.70-2.67 (m, 2 H), 2.37 (s, 3 H), 2.30 (s, 2 H), 2.24-2.19 ²(m, 6 H), ²1.52 (d, J= 6.8 Hz, 3 1-1); MS (ESI) m / z 503 [M+Hr.²Example 43: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(2-fluoro-4-²methoxyphen² y1)-6-methy1-5-(1-morphinolinylethyl)indolizine-7-carboxamide:²OH F 0 0 (C)²0 IN²0 0 .13²HO² 0' HN7--\0²NaBH,²F Ti(OiPr),²F Ac0FI²Pd(dppf)C12, KOAc²Br Elmane / H20.(5 1) / ²0 0² 0 / / ,0²C 0² 0 ( ) 0 0 N 0 N²N²"--N²F Me0H 1-120 HO²" F HATU. DIPEA² cJ it compound 4 4²0² / 0²N4(4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-2-(2-fluoro-4-methoxy ²pheny1)-6-methy1-5-(1-morphinolinylethypindolizine-7-carboxamide was prepared ²by a method similar to example 31.² Step 1: Preparation of ethyl²5-acetyl-2-(2-fluoro-4-dimethoxyphenyI)-6-methylindolizine-7-carboxylate: ²Yield ²70%. MS (ESI) m / z 370 [M+Hr²Step 2: Preparation of isopropyl²2-(2-fluoro-4-methoxypheny1)-6-methy1-5-(1-morphinolinylvinyl)indolizine-7-²carbo² xylate: MS (ESI) m / z 453 [M+H]t²Step 3: Preparation of isopropyl²2-(2-fluoro-4-methoxypheny1)-6-methy1-5-(1-morphinolinylethypindolizine-7-²carbox²ylate: yield of two steps was 72%. MS (ESI) m / z 455 [MM].²Step 4: Preparation of²2-(2-fluoro-4-methoxypheny1)-6-methy1-5-(1-morphinolinylethyl)indolizine-7-²carbox²ylic acid: MS (ESI) m / z 413 [Mr²Step 5: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyrid in-3-yl)methyl)-2-(2-fluoro-4-²methoxyphen²y1)-6-methyl-5-(1-morphinolinylethyl)indolizine-7-carboxamide: Yield of the ²two²78²<DP=79>²CA 03036114 2019-03-07²steps was 28%. 1H NMR (400 MHz, DMSO-do) 6 ppm 11.53 (s, 1 H), 8.26 (s, 1 H), ²8.23 (t, J = 2.8 Hz, 1 H), 7.75 (t, J= 7.8 Hz, 1 H), 7.35 (s. 1 H), 6.99-6.90 ²(m, 2 1-1), ²6.87 (s, 1 H), 5.93 (s, 1 H), 4.32 (d, J = 6.4 Hz, 1 H), 4.11 (q, I = 6.8 Hz, ²1 H), 3.86 ²(s, 3 H), 3.63 (brs, 4 H), 2.71-2.69 (m, 2 H), 2.31 (s, 3 H), 2.28 (s, 3 H), ²2.28-2.18 (m,² 2 H), 2.17 (s, 3 H), 1.49 (d, J = 6.8 Hz, 1 1-1); MS (ES!) m / z 547 [M+Hr.²Example 44: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morphinolin ²ylethy1)-2-(1-(piperidin-4-y1)-1H-pyrazol-4-ypindolizine-7-carboxam ide:² 0 0 0 C0)²:²,²-1-0²AIZ nd(dppOCl2, KOAc / i 7,(0 / PHa AcOH²Br Doxane / H20.(5 1) 0 \Pk a a cly ²r'l a²N²BoC N N²0 0²²Bo c I²BoI²0 ²C ) ( ) C )²0 N 0 0 N²0 0 _it²NaOH FM)OCNId,C1 F:5²²CI.41 1²N NCi / AcOEt Hrsi=-1:11 I '''N²µ / Me0H H20 x, HATU DIPEA DMF²¨ N,N²N IN²a a Bo Bo 4 compound ²45²N N c)²I²c O H² Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-morphinol ²in ²ylethyl)-2-(1-(piperidin-4-y1)-1H-pyrazol-4-ypindolizine-7-carboxamide: The ²first ²five steps were similar to Example 31.²Step 1: Preparation of ethyl²5-acetyl-2-(1-(1-(tert-butyloxycarbonyl)piperidin-4-y1)-1H-pyrazol-4-y1)-6-²methylin²dolizine-7-carboxylate: Yield 87%. MS (ES!) m / z 495 [M+Hy.²Step 1: Preparation of isopropyl²2-(1-(1-(tert-Butoxycarbonyl)piperidin-4-y1)-1H-pyrazol-4-y1)-6-methy1-5-(1-²morphi ²nolinylvinyl)indolizine-7-carboxylate: Yield 87%.² Step 3: Preparation of isopropyl²2-(1-(1-(tert-butoxycarbonyppiperidin-4-y1)-1H-pyrazol-4-y1)-6-methyl-5-(1-²morphi²nolinylethyl)indolizine-7-carboxylate: yield of two steps was 12%. MS (ES!) ²m / z ²580 [M+Hr²79²<DP=80>²CA 03036114 2019-03-07²Step 4: Preparation of²2-(1-(1-(tert-butoxycarbonyl)piperidin-4-y1)-1H-pyrazol-4-y1)-6-methy1-5-(1-²morphi ²nolinylethyl)indolizine-7-carboxylic acid: MS (ESI) m / z 451 [M+H]²Step 5: Preparation of tert-butyl²4-(4-(7-((4,6-dimethy1-2-oxo-1,2-dihydropyrid in-3-y 1)methy 1)carbam oy1)-6-²methy1-5²-(1-morphinolinylethyl)indolizine-2-y1)-11-1-pyrazol-1-yl)piperidine-1-²carbamate: ²yield of two steps was 37%. MS (ESI) m / z 672 [M+H1'.²Step 6: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-54 I -morph ²inylet² hyl)-2-(1-(piperidin-4-y1)-1H-pyrazol-4-y1)indolizine-7-carboxamide: Compound²tert-butyl ²4-(4-(7-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoy1)-6-²methyl-5 ²-(1-morpholinylethyl)indolizine-2-y1)-1H-pyrazol-1-yl)piperidine- 1 -carbamate ²(50 ²mg, 0.074 mmol) was dissolved in 5.0 mL ethyl acetate, and ethyl²acetate / hydrochloric acid (5 mL, 3 M) was added and stirred at room ²temperature for²1 hour. The reaction mixture was adjusted to pH = 7 with sodium hydrogen ²carbonate ²solution, and purified by reverse phase HPLC. The solvent was evaporated under ²²reduced pressure and white crystals were obtained by freeze drying (17 mg, ²40%). 11-1 ²NMR (400 MHz, DMSO-d6) 6 ppm 11.48 (s, 1 H), 8.48 (s, 1 H), 8.14 (s, 1 H), ²8.04 (s,²1 H), 7.71 (s, 1 H), 7.22 (s, 1 1-1), 6.60 (s, 1 H), 5.87 (s, 1 H), 4.26-4.24 ²(m, 2 H), 4.02²(q, J = 6.8 Hz, 1 H), 3.59 (brs, 4 H), 3.07-3.04 (m, 2 H),2.63-2.57 (m, 2 I-²I), 2.25 (s, 3 ²H), 2.20 (s, 3 H) 2.12-2.10 (m, 5 H), 1.98-1.95 (m, 2 H), 1.83-1.80 (m, 2 H), ²1.44-1.43 (m, 3 H); MS (ESI) m / z 572 [M+H]²Example 45: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-morphinol ²in²ylethyl)-2-(1,2,3,6-tetrahydropyridin-4-y1)indolizine-7-carboxam ide:²<DP=81>²CA 03036114 2019-03-07² I '' 13-N-Boc²1 / TqoPr). N²1 / Pcadopf)C12 KOAc \ ,ri.²Br Doxane / H20.(5 1)²'Roc²Boc Boc²0 0²õ²a C .) .), C)²0 0 N²,.....i.a.--,²HCl / AcO!² Me0H, H20 \ / HATIJ DIPEA DMF _..._._²N µ...,0²h²--N I N²µ &²compound 46 =\²Boc "¨NH'Boo²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-morphi ²nolinylethyl)- 2-(1,2,3,6-tetrahydropyridin-4-yl)indolizine-7-carboxamide was ²prepared by a method similar to example 44.² Step 1: Preparation of ethyl²5-acetyl-2-(1-(tert-butyloxycarbony1)-1,2,3,6-tetrahydropyridin-4-y1)-6-²methylindoli ²zine-7-carboxylate: Yield 65%. MS (ESI) m / z 427 [M+1-111.²Step 2: Preparation of isopropyl²2-(1-(1-(tert-Butoxycarbony1)-1,2,3,6-tetrahydropyridin-4-y1)-6-methy1-5-(1-²morphin² olinylvinyl)indolizine-7-carboxylate: MS (ESI) m / z 510 [M+1-1] +.²Step 3: Preparation of isopropyl²2-(1-(tert-butoxycarbony1)-1,2,3,6-tetrahydropyridin-4-y1)-6-methy1-5-(1-²morphinoli²nylethyl)indolizine-7-carboxylate: yield of two steps was 54%. MS (ESI) m / z ²512 ²[M-EFIr.² Step 4: Preparation of²2-(1-(tert-butoxycarbony1)-1 .2,3,6-tetrahydropyridin-4-y1)-6-methyl-5-(1-²morphinoli²nylethyl)indolizine-7-carboxylic acid: MS (ESI) m / z 470 [M+1-11'.²Step 5: Preparation of tert-butyl²4-(7-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoy1)-6-methyl-5-²(1².. -morpholinylethyl)indolizine-2-y1)-3,6-dihydropyridine-1(21-1)-²carboxylate:yield of²two steps was 33%. MS (ESI) m / z 604 [M+Hr.²Step 6: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morphinolin ²ylethyl)- 2-(1,2,3,6-tetrahydropyridin-4-ypindolizine-7-carboxamide: yield ²40%. 1H²81²<DP=82>²CA 03036114 2019-03-07²NMR (400 MHz, Me0D) 6 ppm 7.36 (s, 1 H), 6.68 (s, 1 H), 6.19 (s, 1 H), 6.12 ²(s, 1 ²H), 4.45 (s, 2 H), 3.84 (s, 2 H), 3.72 (s, 4 H), 3.48 (s, 2 H), 2.84 (s, 4 H), ²2.38 (s, 3 ²H), 2.31 (s, 3 H), 2.25 (s, 5 H), 1.55 (s, 3 1-1); MS (ESI) m / z 504 [M+1-114²Example 46: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-5-(1-²morphinolin²ylethyl)- 2-(piperidin-4-yl)indolizine-7-carboxamide:²0²(0NJ (:)²² Pd C H2 I NaOH I²1.2² / Me0H Me0H H20²ci²0 0²0 ) C 0 0 N²0 VI²HN NH2Cl²HCl / AcOEt MAN"²N²HATU DIPEA OMF / ²compound 47 )²Boc²\ NH²Step 1: Preparation of isopropyl²2-(1-(tert-Butoxycarbonyl)piperidin-4-y1)-6-methy1-5-(1-²morphinolinylethyl)indolizi² ne-7-carboxylate: isopropyl²2-(1-(tert-butyloxycarbony1)-1,2,3,6-tetrahydropyridin-4-y1)-6-methy1-5-(1-²morphino ²linylethyl)indolizine-7-carboxylate (95 mg, 0.186 mmol)), Pd / C (10 mg) and 10 ²ml ²of methanol were added sequentially to a 25 mL single-necked flask, exchanged ²with hydrogen and stirred at room temperature for 2 hours, and filtered. The ²organic²phase was concentrated to provide a product as yellow oil (90 mg, yield: 95%). ²MS²(ESI) m / z 514 [M+Hr.²Step 2: Preparation of²2-(1-(tert-butoxycarbonyl)piperidin-4-y1)-6-methy1-5-(1-²morphinolinylethyl)indolizi ²ne-7-carboxylic acid:²2-(1-(tert-butoxycarbonyppiperidin-4-y1)-6-methyl-5-(1-²morphinolinylethypindolizi²ne-7-carboxylic acid was prepared by a method similar to step 5 of example 1. ²MS ²(ESI) m / z 472 [M+H].²Step 3: Preparation of tert-butyl²4-(74(4,6-Dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoy1)-6-methyl-54² 1 -morpholinylethyl)indolizine-2-yl)piperidine-1-carboxylate: tert-butyl²82²<DP=83>²CA 03036114 2019-03-07²4-(7-((4,6-Dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoy1)-6-methyl-5-²( ²1 -morpholinylethyl)indolizine-2-yl)piperidine-1 -carboxylate was prepared by ²a ²method similar to Step 6 of Example 1, yield of the two steps was 32%. MS ²(ESI) ²m / z 606 1M+HY.² Step 4: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-morph ²inol in ²ylethyl)- 2-(piperidin-4-ypindolizine-7-carboxamide: ²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morphinolin ²ylethyl)- 2-(piperidin-4-yl)indolizine-7-carboxamide was prepared by a method²similar to Step 6 of Example 1, yield 47%. 1HNMR (400 MHz, Me0D) 6 ppm 7.36²(s, 1 H), 6.13 (s, 1 H), 4.46 (s, 3 H), 3.84 (s, 1 H), 3.76 (s, 4 H), 3.49-²3.49 (m, 3 H), ²3.23-3.16 (m, 7 H), 2.38 (s, 3 H), 2.31 (s, 5 H), 2.33 (s, 3 H), 2.25 (s, 6 ²H), 1.94-1.85 ²(m, 3 H); MS (ESI) m / z 506 [M+11] '.²Example 47: Preparation of² 2-(3,6-dihydro-2H-pyran-4-y1)-N-44,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)-²6-methy1-5-(1-morphinolinylethypindolizine-7-carboxamide:²0²...3t0L²0²)L-Y co)²0 N²-'0 I 0 tb¨Co 3 I HNO t ,²\____ / ' 0 1 _ NalEIH4²1-1(01PO4²Dioxane / H20=(51)²rit²Q²0,²C p, C ) q 1. )²N²\ / Me0H H20²¨ 1 compound 7=-) ²o²2-(3,6-Dihydro-21-1-pyran-4-y1)-N-44,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1 ²)-6-methyl-5-(1-morphinolinylethyl)indolizine-7-carboxamide was prepared by a² method similar to example 31.²Step 1: Preparation of ethyl²5-acety1-2-(3,6-dihydro-21-1-pyran-4-y1)-6-methylindolizine-7-carboxylate: ²Yield²62%. MS (ESI) m / z 328 [M+H]'.²Step 2: Preparation of isopropyl²2-(3,6-dihydro-2H-pyran-4-y1)-6-methy1-5-(1-morphinolinylvinyl)indolizine-7-²carbo²83²<DP=84>²CA 03036114 2019-03-07²xylate: MS (ESI) m / z 411 [M+H].²Step 3: Preparation of isopropyl²2-(3,6-dihydro-2H-pyran-4-y1)-6-methyl-5-(1-morphinolinylethyl)indolizine-7-²carbo ²xylate: yield of two steps was 41%. MS (ESI) m / z 413 [M+H]1.² Step 4: Preparation of²2-(3,6-dihydro-2H-pyran-4-y1)-6-methy1-5-(1-morphinol inylethyl) indo lizine-7-²carbo²xylic acid: MS (ESI) m / z 371 [M+H].²Step 5: Preparation of²2-(3,6-dihydro-2H-pyran-4-y1)-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-²yl)meth²y1)-6-methy1-5-(1-morphinolinylethypindolizine-7-carboxamide: yield of two ²steps²was 43%. I H NMR (400 MHz, Me0D) 6 ppm 7.46 (s, 1 H), 6.21 (s, 1 H), 6.15 (s, ²1 ²H), 4.46 (s, 2 H), 4.29 (s, 2 H), 3.93-3.84 (m, 7 H), 2.54 (s, 2 H), 2.39-2.38 ²(m, 8 H), ²2.38-2.35 (m, 6 H), 1.80 (s, 3 H); MS (ESI) m / z 505 [M+H]²Example 48: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-54 I -morph ²inol in²ylethyl)- 2-(tetrahydro-2H-pyran-4-yl)indolizine-7-carboxamide:²0 (0) (:) J 0²0 N 0 0 (C)Al²Pd / C H²NaOH²===, N²I \ 1'1 / Me0H2 \ N / Me0H \ N / HATU DIPEA DMF²4t compound 49²(:)²Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methy 1)-6-methy 1-5-(1-morph ²inol in²ylethyl)-2-(tetrahydro-2H-pyran-4-yl)indolizine-7-carboxamide was similar to ²the²first three steps of Example 46.²Step 1: Preparation of isopropyl²6-methyl-5-(1-morphinol iny lethy 1)-2-(tetrahydro-2H-pyran-4-yl)indolizine-7-²carbox²ylate: yield 94%. MS (ESI) m / z 415 [M+Hr² Step 2: Preparation of²6-m ethy1-5-(1-morphinolinylethyl)-2-(tetrahydro-2H-pyran-4-y1)indol izine-7-²carbox²ylic acid: MS (ESI) m / z 373 [M+H].²Step 3: Preparation of²84²<DP=85>²CA 03036114 2019-03-07²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morphinolin ²ylethyl)- 2-(tetrahydro-2H-pyran-4-yl)indolizine-7-carboxamide: yield of two ²steps ²was 65%. 1H NMR (400 MHz, Me0D) 6 ppm 7.42 (s, 1 H), 6.15 (s, 1 H), 4.46 (s, 2 ²²II), 4.01 (d, J = 4.8 Hz, 2 H), 3.87-3.82 (m, 4 H), 3.57 (t, 1= 11.6 Hz, 2 H),²3.20-3.01 (m, 2 H), 3.00-2.92 (m, 1 H), 2.38-2.33 (m, 6 I-I), 2.25 (s, 3 H), ²1.94-1.90²(m, 2 H), 1.81-1.75 (m, 5 H); MS (ESI) m / z 507 [M+Hr²Example 49: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-5-(1-(4-²(dimethylamino)pip ²eridin-l-ypethyl)-6-methyl-2-(pyridin-3-y1)indolizine-7-carboxamide:²0 o _is N²HJ²N²NaBH,²Ti(OiPH, / ²AcOH²\ N \ N²e--7s / 4² / ²CI)²0 0 0 N²N²NaOH²HO) HN NH3CI HNAN I²I H N²Me0H, H20 HATU, DIPEA DMF / ²\ N compound 50 \ N²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-(4-(dimethylam in ²o)piperidin-l-ypethyl)-6-methyl-2-(pyridin-3-y1 )indo I izine-7-carboxamide ²was ²prepared by a method similar to example 31.²Step 1: Preparation of isopropyl²5-(1-(4-(dimethylamino)piperidin-l-ypviny1)-6-methyl-2-(pyridin-3-ypindolizine-²7-²carboxylate: MS (ESI) m / z 447 [M+Hr.²Step 2: Preparation of isopropyl²5-(1-(4-(Dimethylamino)piperidin-1-ypethyl)-6-methyl-2-(pyridin-3-²y1)indolizine-7-²carboxylate: yield of two steps was 52%. MS (ESI) m / z 449 [M+Hr.² Step 3: Preparation of²5-(1-(4-(dimethylamino)piperidin-1-yl)ethyl)-6-methyl-2-(pyridin-3-²y1)indolizine-7-²carboxylic acid: MS (ESI) m / z 407 [M+Fl]+.²Step 4: Preparation of²<DP=86>²CA 03036114 2019-03-07²N-((4,6-dimethy1-2-oxo-1.2-dihydropyridin-3-y1)methyl)-5-(1-(4-²(dimethylamino)pip ²eridine-1-ypethyl)-6-methyl-2-(pyridin-3-y1)indolizine-7-carboxamide: Yield of ²the ²two steps was 27%. 1H NMR (400 MHz, DMSO-d6) 6 ppm 11.46 (brs, 1 H), 9.60 ²(brs, ²I H), 9.17 (s, 1 H), 8.74 (brs, 1 H), 8.65 (s, 1 H), 8.55 (brs, 1 H), 8.27 ²(brs, 1 H),²-- 7.78 (brs, 1 El), 7.38 (s, 1 H), 7.08 (s, 1 H), 5.89 (s, 1 H), 4.04 (s, 2 ²H), 3.69-3.57 (m,²211), 3.17 (s, 1 H), 2.74 (s, 6H), 2.38 (s, 3 H), 2.22 (s, 3 H), 2.13 (s, 3 ²H), 1.89-1.81 ²(m, 4 H), 1.49 (brs, 3 H);MS (ESI) m / z 541 [M+1-1]²Example 50: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morphinolin² -- ylethyl)- 2-(thiazol-2-yl)indolizine-7-carboxamide:²0 0 0 ?²0 0²0 ,0t 0 N ²I²N HO² 0 0² / ²1 / PcIKIppf)C12, KOAc, choxane Pd(dppf)CI, KOAc 71(0 / PO4² / ²B_o Dioxane / H20.(51)² SNj' ¨N²S²0 0²(0)²NaBH, N NaOH HO 0 0 N²HhANH,CI u²---²AcOH Me0H, H2O HAM DIPEA DMF 1N)1 / 47² / ²¨N compound 51²S Si²N) S²Step 1: Preparation of ethyl²5-acetyl-6-methyl-2-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)indolizine-7-²carbo ²xylate: ethyl 5-acetyl-2-bromo-6-methylindolizine-7-carboxylate (2.0 g, 6.2 ²mmol),²-- Pd (dppf)C12 (454 mg, 0.62 mmol), pinacol borate (3.15 g, 12.4 mmol) and ²potassium²acetate (1.22 g, 12.4 mmol) were added into a dry 50 mL three-necked flask ²successively, dissolved in I .4-dioxane (50 mL), and stirred under 110 C ²overnight. ²After the reaction was completed, the reaction mixture was extracted with ²ethyl ²acetate (100 mLx3), washed with water (30 mLx2) and saturated brine (30 mL). ²The²-- organic phase was dried over anhydrous sodium sulfate, filtered and ²concentrated to²provide a crude product. After purified by column chromatography (petroleum ²ether: ²ethyl acetate = 10:1), ethyl 5-acetyl-6-methy1-2-(4,4,5,5-tetrarnethy1-1,3,2-²dioxaborolan-2-ypindolizine-7-carboxylate (1.60 g, yield: 70%) was provided. ²MS ²(ESI) m / z 372 [M+Hr² Step 2: Preparation of ethyl²86²<DP=87>²CA 03036114 2019-03-07²5-acetyl-6-methyl-2-(thiazole-2-yl)indolizine-7-carboxylate: the procedure was ²the ²same as step 1 of example 21. Yield: 32%. MS (ESI) m / z 329 [M+Hr.²Step 3: Preparation of isopropyl²6-methy1-5-(1-morphinolinylviny1)-2-(thiazol-2-ypindolizine-7-carboxylate:² isopropyl²6-methy1-5-(1-morphinolinylviny1)-2-(thiazol-2-yOindolizine-7-carboxylate was ²prepared by a method similar to step 1 of example 26. MS (ESI) m / z 412 [M+H]. ²Step 4: Preparation of isopropyl²6-methy1-5-(1-morphinolinylethyl)-2-(thiazol-2-y1)indolizine-7-carboxylate:² isopropyl²6-methy1-5-(1-morphinolinylethyl)-2-(thiazol-2-y1)indolizine-7-carboxylate was ²²prepared by a method similar to step 2 of example 26, yield of two steps was ²63%. ²MS (ESI) m / z 414 [M+Hr.²Step 5: Preparation of²6-methyl-5-(1-morphinolinylethyl)-2-(thiazol-2-y1)indolizine-7-carboxylic ²acid:²6-methyl-5-(1-morphinolinylethyl)-2-(thiazol-2-y1)indolizine-7-carboxylic acid ²was²prepared by a method similar to step 5 of example I. MS (ESI) m / z 372 [M+Hr. ²Step 6: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyrid in-3-yl)methyl)-6-methyl-5-(1-²morphinolin² ylethyl)- 2-(thiazol-2-yl)indolizine-7-carboxamide:²N-((4,6-Dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-²morphinolin ²ylethyl)- 2-(thiazol-2-yl)indolizine-7-carboxamide was prepared by a method ²similar ²to Step 6 of Example 1, yield 15%. 1H NMR (400 MHz, DMSO-d6) 6 ppm 11.48 (brs, ²²1 H), 8.82 (brs, 1 H), 8.24 (s, 1 H), 7.83 (s, 1 H), 7.66 (s, 1 I-1), 7.36 (s, ²1 F1), 6.91 (s,²1 H), 5.87 (s, 1 H), 4.27 (s, 2 II), 4.14-4.12 (m, 1 11), 3.60-3.57 (m, 4 H), ²2.67-2.62²(m, 2 H), 2.40-2.36 (m, 5 H). 2.11 (s, 3 H), 2.05 (s, 3 H), 1.43 (brs, 3 H);MS ²(ESI) ²m / z 506 [M+Hr²Example 51: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-²morphinolin² ylethyl)- 2-(pyridin-2-yl)indolizine-7-carboxamide:²87²<DP=88>²CA 03036114 2019-03-07²jt\ Nõ. ²fi Pd(dppf)CI, KOAc IPr . % / ²6_, Doxane / H.O=T5 1) / N\ ²c_ONj 0 CON)²....1, 0 N.OH HO 1 "...N laCNHCI²HATU DIPEA DMF² =NI it compound 52²c_) ²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-5-(1-morphi ²nolinylethyl)- 2-(pyridin-2-yl)indolizine-7-carboxamide was prepared by a ²method ²similar to example 50.² Step 1: Preparation of ethyl²5-acetyl-6-methyl-2-(pyridin-2-yl)indolizine-7-carboxylate: Yield 37%. MS ²(ESI) ²m / z 323 [M+Hr.²Step 2: Preparation of isopropyl²6-methyl-5-(1-morphinolinylviny1)-2-(pyridin-2-y1)indolizine-7-carboxylate: MS² (ES!) m / z 406 [M+HY.²Step 3: Preparation of isopropyl²6-methy1-5-(1-morphinolinylethyl)-2-(pyridin-2-ypindolizine-7-carboxylate: ²yield of²two steps was 40%. MS (ES!) m / z 408 [M+H]t²Step 4: Preparation of²6-methy1-5-(1-morphinolinylethyl)-2-(pyridin-2-y1)indolizine-7-carboxylate: MS²(ESI) m / z 366 [M+Hr .²Step 5: Preparation of²N-((4,6-dimethy1-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-methyl-5(I -²morphinol in²ylethyl)- 2-(pyridin-2-yl)indolizine-7-carboxamide: yield 28%. II-I NMR (400 ²MHz,²DMSO-d6) .3 ppm 8.87 (brs, 1 H), 8.57 (d, J= 4.8 Hz, 1 H), 8.21 (t, J= 4.8 Hz, ²1 H),²7.79-7.78(m, 2 H), 7.30 (s, 1 H), 7.21 (dd, J= 7.8, 7.4 Hz, 1 1-1), 7.01 (s, I ²H), 5.87 (s, ²1 F1), 4.27 (d, J = 6.4 Hz, 2 H), 4.06 (q, J= 6.8 Hz, 1 H), 3.58 (brs, 4 H), ²2.67-2.64 ²(m, 2 H), 2.42 (s, 3 H), 2.32-2.20 (m, 5 H), 2.16 (s, 3 H), 1.46 (d, 1 = 6.8 ²Hz, 3 H); ²MS (ESI) m / z 500 [M+H].² Example 52: Preparation of²88²<DP=89>²CA 03036114 2019-03-07²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-2-(1-methyl-²IH-imidazole-4-y1)-5-(1-morpholineylethypindolizine-7-carboxamide:²0 0 0 0 Cowl²I HNO²I Nal3H4²\ Pd(dpiA)CI, K(7);:c 11(044 AcOH²D' "ene / H20=l5 1)²0)ck- N²õt0 0N) 0 NaoH 1, ,4 0²HIN ²13¨Inr¨= HO 1',²N ___________________________________________________ yocri²m ________________________________________________________ ---,,,²eoH H20 , HATU DIPEA OMF²compound 53²NZ,N,²N4(4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-2-(1-methyl-²1H-imidazole-4-yI)-5-(1-morpholineylethyl)indolizine-7-carboxamide was ²prepared²by similar method in example 50.²Step 1: Preparation of ethyl²5-acetyl-6-methyl-2-(1-methyl-1H-imidazol-4-ypindo I izine-7-carboxylate: ²Yield ²53%. MS (ESI) m / z 326 [M+H].² Step 2: Preparation of isopropyl²6-methyl-2-(1-methyl-IH-imidazol-4-y1)-5-(1-morphinolinylvinypindolizine-7-²carbo ²xylate: MS (ESI) m / z 409 [M-1-H]'.²Step 3: Preparation of isopropyl²6-methyl-2-(1-methy1-1H-imidazol-4-y1)-5-(1-morpholinylethyl)indolizine-7-²carboxy² late: yield of two steps was 63%. MS (ESI) m / z 411 [M-FH]²Step 4: Preparation of²6-methy1-2-(1-methy1-1H-imidazol-4-y1)-5-(1-morphinolinylethypindolizine-7-²carbo²xylic acid: MS (ESI) m / z 369 [M+Fl]²Step 5: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-2-(1-methyl-1H-²i²midazol-4-y1)-5-(1-morphinolinylethyl)indolizine-7-carboxamide: Yield 5%. I H ²NMR (400 MHz, Me0D) 6 ppm 8.87 (s, 1 H), 7.80 (s, 1 H), 7.47 (s, 1 H), 6.66 ²(s, 1 ²H), 6.16 (s, 1 H), 4.48 (s, 2 H), 3.97 (s, 3 H), 3.88-3.85 (m, 1 H), 3.75 ²(brs, 4 H), ²3.23-3.22 (m, 2 H), 2.39 (s, 3 H), 2.35 (s, 3 H), 2.28-2.26 (m, 5 H), 1.64-²1.62 (m, 3² H);MS (ESI) m / z 503 [M+H].²89²<DP=90>²CA 03036114 2019-03-07²Example 53: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y 1)methy 1)-6-methy1-5-(1-²morphinolin²ylethyl)-2-(4,5,6,7-tetrahydroth azo lo [5,4-c] pyr id in-2-y 1) indo 1 izine-²7-carboxam ide:²0,²0 ty JCIL,²0 (NJ C²0 N²r)-14)--B''' I 1,1² I Boc-N =-s H1,10 I NaBH I -'1,1² / 4 .² / Pd(dppf)Cl2, K57,c -11(01PiC.²= AcOH / ²Oraxane / H20=(51) / ²N.soc Nb²N-Boc²co) 0²0²C )²HO HNA'NH,CI IHN 11² NaOH HCl / AcOEt I² / ² Me0H. H20 HATU DIPEA, DMF² / S²compound 54N. 1²N-Boc LNH² The first five steps of the preparation method of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyrid in-3 -yl)methyl)-6-m ethyl-5 -(1- ²morph i nol in ²ylethyl)- 2-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)indolizine-7-²carboxamide ²are similar to that of example 50, and the last deprotection step is the same ²as that in ²step 6 of example 44.² Step 1: Preparation of tert-butyl²2-(5-acety1-7-(ethoxycarbony1)-6-methy 1 indolizin-2-y1)-6,7-dihydrothiazolo ²[5,4-c] py²ridine-5(4H)-carboxylate: Yield 26%. MS (ESI) m / z 484 [M+Hr.²Step 2: Preparation of tert-butyl²2-(7-(isopropoxycarbony1)-6-methyl-5-(1-morphinolinylv inyl)indolizin-2-y1)-²6,7-dih² ydrothiazolo[5,4-0-pyridin-5(4H)-carboxylate: MS (ESI) m / z 567 [M+Hr²Step 3: Preparation of tert-butyl²2474 isopropoxyearbony1)-6-methyl -5-(1-morph inol inylethy Hind 1 izin-2-y1)-²6,7-dih²ydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate: yield of two steps was 44%. MS ²(ESI)²m / z 569 [M+H]² Step 4: Preparation of²2-(5-(tert-butoxycarbony1)-4,5,6,7-tetrahydrothiazolo [5,4 -c] pyridin-2-y1)-6-²methyl-5²-(1-morpholinylethyl)indolizine-7-carboxylic acid: MS (ESI) m / z 527 [M+H]'.²Step 5: Preparation of tert-butyl²2-(7-(((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoy1)-6-methyl-²54²<DP=91>²CA 03036114 2019-03-07²1-morpholinylethyl)indolizin-2-y1)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-²carbox ²ylate: yield of two steps was 49%. MS (ESI) m / z 661 [M+H]'.²Step 6: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morphinolin²ylethyl)-2-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-ypindolizine-7-²carboxamide:²yield 49%. IFINMR (400 MHz, DMSO-d6) 6 ppm 11.47 (brs, 1 H), 8.78 (brs, 1 H), ²8.21 (t, J = 2.6 Hz, 1 H), 7.32 (s, 1 H), 6.82 (s, 1 H), 5.87 (s, 1 H), 4.27 ²(t, J = 6.2 Hz, ²2 H), 4.06 (q, J= 6.8 Hz, 1 H), 3.94 (m, 2 H), 3.57 (brs, 4 H), 3.09 (t, J= ²7.2 Hz, 2 ²H), 2.73 (brs, 2 Fl), 2.66-2.64 (m, 2 El), 2.26 (s, 3 H), 2.20-2.17 (m, 5 El), ²2.16 (s, 3² H), 1.46 (d, J= 6.8 Hz, 3 H); MS (ESI) m / z 561 [M+H].²Example 54: Preparation of²1-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²mo ²rpholinylethyl)indolizine-7-carboxamide:²0 0² 0 L'N²NBS²HN \²NaBH4²N THF _________ T,(0,T304² / Br²Br²(0, 0²0²C) C ) NH3CI²0 N²NaOH ,²N Me0H H20 HO I "N HATU DIPEA DMF FISA..."HN ²I "² / ²COM pound 55²sr Br²Step 1: Preparation of ethyl 5-acetyl-1-bromo-6-methylindolizine-7-²carboxylate:²in a 100 ml dry single-mouth bottle, ethyl 5-acetyl-6-methylindolizine-7-²carboxylate ²(500 mg, 2 mmol) was dissolved in 20 mL of tetrahydrofuran, bromosuccinimide ²(320 mg, 1.8 mmol) was added portionwise at 0 C, and the mixture was stirred ²at 0 ²C for 20 min. The solvent was evaporated under reduced pressure to dry to ²provide²a crude product, which was purified by column chromatography (petroleum ether:²ethyl acetate = 20: 1) to obtain 141 mg of yellow oil, yield 26%. 1H NMR ²(CDC13, ²400 MHz) 8 ppm 8.15 (s, 1 H), 7.17 (d, J= 2.8 Hz, 1 H), 6.89 (d, = 2.8 Hz, 1 ²H), ²4.37 (q, J = 14 Hz, 2 H), 2.63 (s, 3 H), 2.44 (s, 3 H), 1.42 (t, J= 14 Hz, 3 I-²I).²Step 2: Preparation of isopropyl² 1-bromo-6-methy1-5-(1-morphinolinylvinypindolizine-7-carboxylate: isopropyl²1-bromo-6-methy1-5-(1-morphinolinylvinyl)indolizine-7-carboxylate was prepared²91²<DP=92>²CA 03036114 2019-03-07²by a method similar to Step 1 of example 26. MS (ES!) m / z 407 [M+H]I.²Step 3: Preparation of isopropyl²1-bromo-6-methy1-5-(1-morphinolinylethypindolizine-7-carboxylate: isopropyl ²1-bromo-6-methy1-5-(1-morphinolinylethyl)indolizine-7-carboxylate was prepared²by similar method in Step 2 of example 26, yield 84%. Yield of two steps was ²50%.²MS (ES!) m / z 323 [M-87+Hr²Step 4: Preparation of²1-bromo-6-methy1-5-(1-morphinolinylethypindolizine-7-carboxylic acid: ²1-bromo-6-methy1-5-(1-morphinolinylethyl)indolizine-7-carboxylic acid was² prepared by a method similar to step 3 of example 26. MS (ES!) m / z 280²[M-87+Hr.²Step 5: Preparation of²1 - bromo-N44,6-dimethyl-2-oxo-1,2-dihydropyrid in-3-yl)methy I) -6-methy1-5-²(1-mo²rphinolinylethyl)indolizine-7-carboxamide:²1-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²mo²rphinolinylethyl)indolizine-7-carboxamide was prepared by a method similar to ²Step ²4 of Example 26, yield of two steps was 25%.²1H NMR (400 MHz, CDC213) 6 ppm 11.52 (brs, 1 H), 8.40 (brs, 1 H), 8.34 (s, 1 ²H), 7.15 (s, 1 H), 6.87 (s, 1 H), 5.88 (s, 1 H), 4.27 (t, J= 6.2 Hz, 2 H), ²4.03 (q, =-²6.8 Hz, 1 H), 3.55 (brs, 4 H), 2.62-2.58 (m, 2 H), 2.25 (s, 3 H), 2.20 (s, 3 ²H)²2.17-2.11 (m, 5 H), 1.40 (d, J = 6.8 Hz, 3 H); MS (ESI) m / z 501 [M+11]'.²Example 55: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-²(methyl(tetrahy ²dro-2H-pyran-4-yl)amino)indolizine-7-carboxamide:²CN 01J²H 0 , runku on t eN 1) WA THF, Mel NC _ NH,²) g 1) AcOH NC 11---CO Mel, K,CO,²P(nBu), THF 0-- 2) K2CO3, DMF NI / 2) NaBH,CN 14 / DMF²0²I²7,,,,t1CNH,C1²NC 'N. 111¨CO NaOH 1+3 C² / N 00² EtOH / H20² / HATU DIPEA DMF²COMpOWld 56 \I-1²Step 1: Preparation of (E)-2-((l H-pyrrol-2-yOmethylene)succinonitrile: ²pyrrole-2-carbaldehyde (3 g, 31.5 mmol), fumaronitrile (3.1 g, 39.4 mmol),²92²<DP=93>²CA 03036114 2019-03-07²tributylphosphine (5.8 ml, 37.8 mmol) and anhydrous tetrahydrofuran (80 mL) ²were ²added successivly into a dry 100 mL round bottom flask at room temperature, ²heated ²to reflux under nitrogen and stirred for 8 hours. After the reaction was ²monitored to ²have been finished by TLC, the mixture was concentrated under reduced ²pressure, 30²mL of water was added, and extracted with ethyl acetate (40 mL x 3), the ²organic²phases were combined. The mixture was washed with saturated brine (30 mL x I), ²²dried over anhydrous sodium sulfate, filtered and the filtrate was ²concentrated under ²reduced pressure, purified by column chromatography (pure dichloromethane) to ²provide yellow solids 1.85 g, yield 37%. 1H NMR (CDC13, 400 MHz) 6 ppm 7.49(1²H), 7.27 (d, Jr 8.9 Hz, 1 H), 7.01 (t, J= 3.9 Hz, I H), 6.73 (d, J= 3.9 Hz, 1 ²H), 5.97²(s, 1 H), 4.26 (s, 2 H).²Step 2: Preparation of 5-amino-6-methylindolizine-7-carbonitrile:²(E)-2-((1H-pyrrol-2-yl)methylene) succinonitrile (1.8 g, 11.7 mmol) and TI-IF ²(60 ²mL) were added to a dry 100 mL round bottom flask at room temperature, and LDA²(11.7 mL, 23.4 mmol) was added under -78 C, stirred at this temperature for ²half an²hour, then methyl iodide (1.6 g, 11.7 mmol) was added, warmed to 0 C and ²stirred ²for half an hour, then quenched with saturated aqueous ammonium chloride, ²extracted with ethyl acetate (40 mLx3), combined organic phase was dried over ²sodium sulfate, filtered, and the filtrate was evaporated, and the residue was²dissolved in DMF (60 mL), and potassium carbonate (6.4 g, 46.8 mmol) was ²added,²then the reaction was heated to 70 C and stirred for 16 hours. After the ²reaction was ²completed, 30 mL of water was added and extracted with ethyl acetate (40 mL x ²3), ²organic phases were combined, washed with saturated brine (30 mL x 1), dried ²over ²anhydrous sodium sulfate, filtered, and the filtrate was concentrated under ²reduced²pressure to obtain yellow solids (1.76 g, yield 88%). 1H NMR (CDCI3, 400 MHz) ²6²ppm 7.51 (s, 1 H), 7.19 (brs, 1 F1), 6.96 (t, J= 2.8 Hz, 1 H), 6.67 (d, J= 2.8 ²Hz, I H), ²4.17 (s, 2 H), 2.36 (s, 3 H).²Step 3: Preparation of²6-methy1-5-((tetrahydro-2H-pyran-4-yl)amino)indolizine-7-carbonitrile: in a ²dry 50²mL round bottom flask, 5-amino-6-methylindolizine-7-carbonitrile (300 mg, 1.75²mmol), tetrahydropyranone (350 mg, 3.50 mmol) and acetic acid (3 mL) were ²added ²successivly at room temperature. After heated to 50 C and stirred for 1 hour, ²sodium²93²<DP=94>²CA 03036114 2019-03-07²cyanoborohydride (330 mg, 5.25 mmol) was added and stirred at 50 C. After TLC ²²monitored that the reaction was completed, the mixture was neutralized with ²saturated aqueous solution of sodium hydrogencarbonate, and then extracted ²with ²ethyl acetate (20 mLx 3), and washed with saturated brine (10 mL). The organic².. phase was dried over anhydrous sodium sulfate, filtered, and the filtrate ²was²concentrated under reduced pressure. The residue obtained was purified by ²column ²chromatography (dichloromethane) to afford yellow solids ( 140 mg, yield 31%). ²1H ²NMR (CDC13, 400 MHz) 6 ppm 7.63 (s, 1 H), 7.45 (s, 1 H), 6.90 (brs, 1 H), 6.69 ²(brs, ²1 H), 4.01 (d, J= 9.8 Hz, 2 H), 3.39-3.36 (m, 3 H), 2.40 (s, 3 H), 1.91-1.88 ²(m, 2 11),² 1.65-1.63 (m, 3 FI).²Step 4: Preparation of²6-methyl-5-(methyl(tetrahydro-2H-pyran-4-yl)amino)indolizine-7-carbonitrile: ²in a ²dry 25 mL round bottom flask,²6-methy1-5-((tetrahydro-2H-pyran-4-yl)amino)indolizine-7-carbonitrile (100 mg,² 0.39 mmol), potassium carbonate (108 mg, 0.78 mmol), iodine methane (111 mg,²0.78 mmol) and DMF (2 ml) were added successively at room temperature, and ²replaced with nitrogen for three times, stirred and warmed to 80 C for 16 ²hours. ²After the reaction was monitored to have been finished by TLC, 10 mL of ²saturated ²brine was added, and extracted with ethyl acetate (10 mL x 3), and the organic²phases were combined. The mixture was washed with saturated brine (10 mL x 1),²dried over anhydrous sodium sulfate and filtered. The filtrate was ²concentrated under ²reduced pressure to provide crude product 4 (50mg, yellow sticky liquid), ²which can ²be directly used in the next step, yield: 47%. MS (ESI) m / z 270 [MM].²Step 5: Preparation of²6-methy1-5-(methyl(tetrahydro-2H-pyran-4-yl)amino)indolizine-7-carboxylic ²acid: in²a dry 25 mL round bottom flask, ²6-methyl-5-(methyl(tetrahydro-2H-pyran-4-yl)amino)indolizine-7-carbonitrile ²(50 ²mg, 0.18 mmol), sodium hydroxide (400 mg, 10 mmol) and ethanol / water 1:1²mixture solvent (1 mL) were added successivly at room temperature, heated to ²100 C²and stirred for 16 hours. After TLC monitored that the reaction was completed, ²pH²was adjusted to 1 by 6N hydrochloric acid, and extracted with ethyl acetate ²(10 mL x ²3). The organic phases were combined, dried over anhydrous sodium sulfate, ²filtered,²94²<DP=95>²CA 03036114 2019-03-07²and the filtrate was concentrated under reduced pressure to obtain a crude ²product ²(42mg, dark green solid), which can be directly used in the next step, yield ²81 %. MS ²(ESI) m / z 289 [M+H]+.²Step 6: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-²(methyl(tetrahy²dro-2H-pyran-4-yl)amino)indolizine-7-carboxamide: ²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-²(methyl(tetrahy ²dro-2H-pyran-4-yl)amino)indolizine-7-carboxamide was prepared by a method ²similar to Step 6 of Example I, yield 6%. '1-INMR (CDC13, 400 MHz) 6 ppm 7.40 ²(s,²1 H), 7.33 (s, 1 H), 6.74 (s, 1 H), 6.47 (s, 1 El), 5.94 (s, 1 H), 4.52-4.49 ²(m, 2 H),²3.95-3.89 (m, 2 H), 3.39-3.35 (m, 2 H), 3.14-3.10 (m, 1 H), 2.86 (s, 3 H), ²2.39 (s, 3 ²H), 2.27 (s, 3 H), 2.20 (s, 3 H), 1.77-1.54 (m, 4 H);MS (ESI) m / z 423 [M+H]. ²Example 56: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-²(ethyl(tetrahydr² o-2H-pyran-4-yl)amino)indolizine-7-carboxamide:²t NC o ²Etl, K2CO3 NC . N¨CO NaOH HC) C ,-²,... N¨\ ²I tsi I I²DMF N Et0H / H20 N²0² HN , NH,CI 9 o r²1 H IN 'CIO² HATU DIPEA, DMF '... / 4L-810 compound 57²N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(ethyl(tetr ²ahydro-2H-pyran-4-yl)amino)indolizine-7-carboxamide was prepared by a method ²similar to example 55.² Step 1: Preparation of²5-(ethyl(tetrahydro-2H-pyran-4-yDamino)-6-methylindolizine-7-carbonitrile: ²Yield ²46 %. MS (ESI) m / z 284 [M+H]4.²Step 2: Preparation of²5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-6-methylindolizine-7-carboxylic acid:² Yield 78 %. MS (ESI) m / z 303 [M+H14.²Step 3: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-²(ethyl(tetrahydr ²o-2H-pyran-4-yl)amino)indolizine-7-carboxamide: yield 8%. 1H NMR (CDC13, 400²<DP=96>²CA 03036114 2019-03-07²MHz) 6 ppm 7.35 (s, 1 H). 7.28 (s, 1 H). 6.65 (s, 1 H), 6.39 (s, 1 H), 5.88 ²(s, 1 H), ²4.45-4.44 (m, 2 H), 3.85-3.82 (m, 2 H), 3.31-3.19 (m, 4 I-1), 3.14-3.11 (m, 1 ²H), 2.32 ²(s, 3 H), 2.24 (s, 3 H), 2.17 (s, 3 H), 1.74-1.71 (m, 4 H), 0.90-0.87 (m, 3 ²H);MS (ESI) ²m / z 437 [M+Hr² Example 57: Preparation of²2-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-²(meth ²yl(tetrahydro) -2H-pyran-4-yl)amino)indolizine-7-carboxamide:²CN a ².t. Ff ( ,, LDA THF, Mel NC õ NH2²1) AcOH NC ,2, Ill -0 Mel K2CO3² _______________________________ - ,- ______ I .- __ 1 --.²pogo, TFIF' rE)-1-CN N N²2) K2CO3, DMF q. 2) NaBH3CN \ / DMF²Br Br²Br Br²0²0 1²NC , õ N-CO NaoH \ .t Et0H / H20 HOOC 1 HATDIPEA, DMF²0 HNõ I NCI Hp.,..&NN.,...1²I N²-,2 N 1.....,0²\ / ²Br Br Compound 58 Br²2-Bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(²methyl(tetrahydro-2H-pyran-4-yl)amino)indolizine-7-carboxamide was prepared by ²a²method similar to example 55.²Step 1: Preparation of (E)-2-((4-bromo-I H-pyrrol-2-yOmethylene)succinonitri ²le:²Yield 41%. MS (ESI) m / z 236 [M+H]'.²Step 2: Preparation of 5-amino-2-bromo-6-methylindolizine-7-carbonitrile:² Yield 94%. MS (ESI) m / z 250 [M+H] '.²Step 3: Preparation of²2-bromo-6-methyl-5-((tetrahydro-2H-pyran-4-yl)amino)indolizine-7-carbonitrile: ²²Yield 72%. 1H NMR (CDC13, 400 MHz) 6 ppm 7.54 (s, 1 H), 7.42 (s, 1 H), 6.72 ²(brs. ²1 H), 4.03-3.97 (m, 2 H), 3.41-3.35 (m, 3 H), 2.4 (s, 3 H), 1.90-1.87 (m, 2 ²H),² 1.65-1.63 (m, 2 H).²Step 4: Preparation of²2-bromo-6-methy1-5-(methyl(tetrahydro-2H-pyran-4-yl)amino)indolizine-7-²carbonitr²ile: yield 53 %. MS (ESI) m / z 348 [M+H].²Step 5: Preparation of²2-bromo-6-methy1-5-(methyl(tetrahydro-2H-pyran-4-y1)amino)indolizine-7-²carboxyli²c acid: yield 81 %. MS (ESI) m / z 367 [M+H].²96²<DP=97>²CA 03036114 2019-03-07²Step 6: Preparation of²2-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-²(meth²yl(tetrahydro-2H-pyran-4-yl)amino)indolizine-7-carboxamide: yield 18%. 'N MR²(CDC13, 400 MHz) 8 ppm 11.31 (s, 1 H),7.40 (s, 1 H), 7.23 (s, 1 H), 6.48 (s, 1 ²H),²5.96 (s, 1 H), 4.50 (s, 2 H), 3.98-3.89 (m, 2 H), 3.39-3.30 (m, 3 H), 2.83 (s, ²3 1-1),²2.32 (s, 3 H), 2.24 (s, 3 H), 2.17 (s, 3 II), 1.78-1.59 (m, 4 H);MS (ES1) m / z ²501 ²[M+H].²Example 58: Preparation of²2-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-²(ethyl(tetrahydr² o-2H-pyran- 4-yl)amino)-6-methylindolizine-7-carboxamide:²tN²NC , --... ^1-CO Etl K2CO3 NC , / 1--CO NaoH HOOC ²1 ' I² DMF N Ft0H / H20.-²\ / \ / ²Br Br Br²0²0²1-1,1,11.,1C1 ?j C.²HATU DIPEA DMF / MOW Compound 59²Br²2-Bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetra ²hydro-2H-pyran-4-yl)amino)-6-methylindolizine-7-carboxamide was prepared by a ²method similar to example 55.² Step 1: Preparation of²2-bromo-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-6-methylindolizine-7-²carbonitril ²e: Yield 46 %. MS (ES!) m / z 362 [M+H]'.²Step 2: Preparation of²2-bromo-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-6-methylindolizine-7-²carboxylic² acid: Yield 79 %. MS (ES!) m / z 381 [M+1-11+.²Step 3:. Preparation of²2-bromo-N4(4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-5-²(ethyl(tetrahydr²o-2H-pyran-4-yl)amino)-6-methylindolizine-7-carboxamide: yield 27%. I H NMR²(CDC13, 400 MHz) 8 ppm 11.10 (s, 1 H),7.4I (s, 1 H), 7.23 (s, 1 H), 6.47 (s, 1 ²H),²5.96 (s, 1 1-1), 4.50 (s, 2 H), 3.93-3.92 (m, 2 H), 3.38-3.34 (m, 3 H), 3.25-²3.17 (m, 2²H), 2.39 (s, 3 H), 2.27 (s, 3 H), 2.24 (s, 3 H), 1.76-1.62 (m, 4 H), 0.96 (t, ²J = 7.2 Hz, ²3 H);MS (ES!) m / z 515 [M+Hr.²97²<DP=98>²CA 03036114 2019-03-07²Example 59: Preparation of²2-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-²(ethyl(oxetane-3 ²)-yl)amino)-6-methylindolizine-7-carboxamide:²0.²NC = NH2 1) 7t(tPrO)_. 4 L I²'N²It²\ / NC .1 Eft K2 CO3²NC tr².ro²2) NaBH4 AcOH DMF²q²Br Br Br²0²NaOH ,HOOC 1 =,... N, ___, _ ..,. 1²Et0H / H20²q HA1U, DIPEA DMF \ ii²Br Compound 60² Step 1: Preparation of²5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-6-methylindolizine-7-carbonitrile: in ²a dry ²50 mL three-necked flask, 5-amino-2-bromo-6-methylindolizine-7-carbonitrile ²(300 ²mg, 1.20 mmol) and oxetane (0.6 mL) were dissolved in tetraisopropyl titanium ²oxide (2 mL), and stirred overnight at 65 C. After the reaction was completed, ²I 0 mL²of dichloromethane was added, and a small amount of water was added thereto. ²The²reaction liquid was concentrated under reduced pressure, and then large amount ²of ²floccule was precipitated. The solid was washed with dichloromethane (30 mLx3) ²²and the organic phase was concentrated under reduced pressure. The resultant ²residue ²was redissolved in glacial acetic acid (10 mL) at 0 C, sodium borohydride (121 ²mg,²3.20 mmol) was slowly added, warmed to room temperature and stirred for ²another²1 hour. Water and sodium hydrogencarbonate were added to adjust the pH to 7, ²and ²extracted with ethyl acetate (30 mLx3). The combined organic phase was washed ²with water (10 mLx2) and saturated brine (10 mL). The organic phase was dried ²over ²anhydrous sodium sulfate and filted, and the filtrate was concentrated under ²reduced²pressure to afford yellow oil (160 mg, yield 7%). MS (ESI) m / z 306 [M+H].²Step 2: Preparation of²2-bromo-5-(ethyl(oxetan-3-yl)amino)-6-methylindolizine-7-carbonitrile:the ²procedure was same as step 4 in example 55. Yield: 51 %. MS (ESI) m / z 334 ²[M+1-11f.² Step 3: Preparation of²2-bromo-5-(ethyl(oxetan-3-yl)amino)-6-methylindolizine-7-carboxylic acid: the ²procedure was same as step 5 of example 55. Yield: 68 %. MS (ESI) m / z 353²98²<DP=99>²CA 03036114 2019-03-07²[M+H] .²Step 4: Preparation of²2-bromo-N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-5-(ethyl(oxetane-²3²-yl)amino)-6-methylindolizine-7-carboxamide: the procedure was same as step 6 ²of² example 55. Yield was 22%. 1H NMR (400 MHz, CDCI3) 6 ppm 9.24 (s, 1 H), 7.38²(s, 1 H), 7.18(s, 1 H), 6.52(s, 1 H), 5.92(s, 1 H),5.35 (s, 2 H), 4.73-4.67 ²(m, 3 H), ²4.65-4.47 (m, 3 H), 3.29-3.20 (m, 211), 2.39 (s, 3 11), 2.24(s, 3 H), 2.19 ²(m,3 H), 1.03²(t, J= 7.2 Hz, 3 H);MS (ESI) m / z 487 [M+H]'.²Example 60: Preparation of²5-(azetidin-3-ykethypamino)-2-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-²²3-y1)methyl)-6-methylindolizine-7-carboxamide:²NC .,=_, NH2 1) TOPrO)4, \L1N 80:IC _õ,,,, Ftsil,rN²I²t²\ Ni 2) Na: AcOH N Boc EtDi'mK,2C0²². NC I ...'N 4-rN'Boc ENr02 H / HH²\ / ²g 20 HOOC²I 31 '"'Boc²\ / ²Br Br Br Br²0 0 0 0 0 r²TFA DCM²\ / ti..? 1Lii. Compound ²61²HATU DIPEA DMF²Br Br²Preparation of²5-(azetidin-3-yl(ethypamino)-2-bromo-N-((4,6-dimethyl-2-oxo-1,2-²dihydropyridine-²3-yOmethyl)-6-methylindolizine-7-carboxamide: the procedure of first four ²steps are²same as example 59.²Step 1: Preparation of tert-butyl²3-((2-bromo-7-cyano-6-methylindolizin-5-yl)amino)azetidin-1 -carboxylate: ²Yield ²49%. MS (ES!) m / z 405 [M+Hr.² Step 2: Preparation of tert-butyl²3-42-bromo-7-cyano-6-methylindolizin-5-y1)(ethypam ino)azetidin-l-carboxylate:²Yield 77 %. MS (ES!) m / z 433 [M+H].²Step 3: Preparation of²2-bromo-5-(( l -(tert-butoxycarbonyl)azetidin-3-y1)(ethyl)am ino)-6-methyl ²indolizine-² 7-carboxylic acid: Yield 74 %. MS (ES!) m / z 452 [M+H] I.²Step 4: Preparation of tert-butyl²99²<DP=100>²CA 03036114 2019-03-07²3-((2-bromo-7-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoy1)-6-²m ²ethylindolizine-5-yI)(ethyl)amino)azetidin-1 -carboxylate: yield 31%. MS (ESI) ²m / z ²586 [M+Hr.²Step 5: Preparation of tert-butyl²5-(azetidin-3-yl(ethyl)amino)-2-bromo-N-((4,6-dimethy1-2-oxo-1,2-²dihydropyridine)²-3-yOmethyl)-6-methyl-7-carboxamide: ²3-((2-bromo-7-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoy1)-6-²m ²ethylindolizin-5-yI)(ethyl)amino)azetidine- I -carboxylate (20 mg, 0.034 ²mmol), ²trifluoroacetic acid (1 mL) were added to a dry 50 mL three-necked flask²successively, and dissolved in dichloromethane (1 mL). Reaction was conducted ²for²1 hour at room temperature. The reaction mixture was directly concentrated, ²and ²purified by reverse phase HPLC to provide yellow oil (4mg, yield 25%). 1H NMR ²(Me0D, 400 MHz) 6 ppm 7.58 (s, 1 H), 7.38 (s, 1 IA), 6.63 (s, 1 H), 6.13 (s, 1 ²H), ²4.62-4.61 (m, 1 H), 4.46 (s, 2 H), 4.16-4.14 (m, 2 H), 4.04-3.94 (m, 2 H), ²2.37 (s, 3² H), 2.25 (s, 3 H), 2.19 (s, 3 H), 1.05-1.01 (m, 3 H);MS (ESI) m / z 486 [M+Hr.²Example 61: Preparation of²2-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-²(ethyl(piperidin ²-4-yl)amino)-6-methylindolizine-7-carboxamide:²NC , N²NC H N 1 1)AcOH NG 1 '''= 1.11-C) _____ Etl, K2CO3 t 'CI ²I N²µ / 2) NaBH3CN²Et0H / H² Br Br Br Br²HN NCI Pri--..²,IX 1111111 I '0 HiNie,1 I N OH²N,Boe TFA OCM ,,_ ===,.²\ / -.-²k ²Compound 62²HATU DIPEA DMF² Br Br²20 2-Bromo-N-²((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(pipe²ridin-4-yl)amino)-6-methylindolizine-7-carboxamide was prepared by a method ²similar to example 60.²Step 1: Preparation of tert-butyl²4-((2-bromo-7-cyano-6-methylindolizin-5-yl)amino)piperidin-1 -carboxylate: ²Yield² 28%. MS (ESI) m / z 433 [M+Hr²Step 2: Preparation of tert-butyl²4((2-bromo-7-cyano-6-methylindolizin-5-y1)(ethyl)am ino)piperidin- I -carboxy ²late:²100²<DP=101>²CA 03036114 2019-03-07²Yield 59 %. MS (ESI) m / z 461 [M+H].²Step 3: Preparation of²2-bromo-5-((1-(tert-butoxycarbonyl)piperidin-4-y1)(ethyl)amino)-6-²methylindolizine ²-7-carboxylic acid: Yield 64 %. MS (ESI) m / z 614 [M+1-1]1-.² Step 4: Preparation of tert-butyl²4,6-dimethy1-2-oxo-1,2-dihydropyrid in-3-yOmethyl)carbamoy1)-6-methyl ²indolizine-²5-y1)(ethy Dam ino)piperidine- 1 -carboxylate: yield 43%. MS (ESI) m / z 614 ²[M+H]t ²Step 5: Preparation of²2-bromo-N44,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-5-²(ethyl(piperidin² -4-yl)amino)-6-methylindolizine-7-carboxamide: Yield 35%. 1H NMR (Me0D, 400²MHz) 6 ppm 7.55 (s, 1 H), 7.33 (s, 1 H), 6.58 (s, 1 H), 6.12 (s, 1 H), 4.45 ²(s, 2 H), ²3.10-2.98 (m, 4 H), 2.37 (s, 3 H), 2.25 (s, 6 H), 2.10-2.02 (m, 2 H), 1.72-²1.30 (m, 2 ²H), 0.91 (t, J= 6.9 Hz, 3 H);MS (ESI) m / z 514 [M+Fli'.²Example 62: Preparation of²5-41-acetylpiperidin-4-y1)(ethyDamino)-2-bromo-N-((4,6-dimethyl-2-oxo-1,2-²dihydr²opyridine-3-yOmethyl)-6-methylindolizine-7-carboxamide:²HOOCt,N²HOOC TFA²CH3COCI TEA I N 0²N Dcm² / ²Br Br Br²0²HN NCI 0 0²N²HATU DIPEA DMF LR² / NT ittlt Compound 63²Br²Step 1: Preparation of²2-bromo-5-(ethyl(piperidin-4-yl)amino)-6-methylindolizine-7-carboxylic acid: ²in a² dry 50 mL round bottom flask,²2-bromo-54(1-(tert-butoxycarbonyppiperidin-4-y1)(ethyDamino)-6-²methylindolizine ²-7-carboxylic acid (80 mg, 0.16 mmol), dichloromethane (2 mL), and ²trifluoroacetic ²acid (1 mL) were added successively at room temperature. After stirred at room²temperature for 1 hour, TLC monitored that the reaction was completed. MS ²(ES!)²m / z 380 [M+Fi].²Step 2: Preparation of²54(1-acetylpiperidin-4-y1)(ethypamino)-2-bromo-6-methylindolizine-7-carboxylic²101²<DP=102>²CA 03036114 2019-03-07²acid: in a dry 25 mL round bottom flask,²2-bromo-5-(ethyl(piperidin-4-yl)amino)-6-methylindolizine-7-carboxylic acid ²(60 mg,²0.16 mmol), acetyl chloride (0.2 mL) and THE (1 mL) were added successively at ²²room temperature, and stirred at room temperature for Ih. After the reaction ²was²monitored to have been finished by TLC, 10 mL of saturated sodium bicarbonate ²was²added, and extracted with ethyl acetate (10 mL x 3), and the organic phases ²were ²combined. The mixture was washed with saturated brine (10 mL x 1), dried over ²anhydrous sodium sulfate, filtered and the filtrate was concentrated under ²reduced ²pressure to provide yellow sticky liquid 40 mg, which can be directly used in ²the² next step. MS (ESI) m / z 422 [M+H]4.²Step 3: Preparation of²5-41-acetylpiperidin-4-y1)(ethyl)amino)-2-bromo-N-44,6-dimethyl-2-oxo-1,2-²dihydr²opyridine) -3-yflmethyl)-6-methylindolizine-7-carboxamide:²5-(( 1 -acetylpiperidin-4-y1)(ethyl)amino)-2-bromo-N-((4,6-dimethy1-2-oxo- I ²,2-dihydr² opyridine) -3-yl)methyl)-6-methylindolizine-7-carboxamide was prepared by a²method similar to step 6 of example 1, yield 8%. IFI NMR (CDC13, 400 MHz) 6 ²ppm ²7.40 (s, 1 H), 7.34 (s, 1 H), 6.77 (s, 1 H), 6.57 (s, I 11), 6.52 (s. 1 H), ²4.62-4.54 (m, 3 ²H), 3.78-3.75 (m, I H), 3.37-3.33 (m, 1 H), 3.29-3.16 (m, 2 H), 3.04-3.01 (m, ²I H), ²2.61 (s, 3 11), 2.47 (s, 3 H), 2.17 (s, 3 H), 2.12 (s, 3 H), 1.98-1.88 (m, 2 1-²1), 1.42-1.31²(m, 2 H), 0.96 (t, J= 6.9 Hz, 3 H); MS (ESI) m / z 556 [M+H] '.²Example 63: Preparation of²N-(4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-²pyra ²n-4-yl)amino)-6-methyl-2-phenylindolizine-7-carboxamide:²t²I 'CI NaON HQ I 'N NT:,²Hz .y.--²...)²I NN 0 HQ N ²1,...õ.61²\ / Et0H 1-12.0 \ / 117=6AI) HATU DIPEA²Br / ) Compound 64² Step 1: Preparation of²5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-6-methy1-2-phenylindolizine-7-²carbonitril²e: the procedure was same as step 1 in example 31. Yield: 45%. MS (ESI) m / z ²360 ²[M+Hr .²102²<DP=103>²CA 03036114 2019-03-07²Step 2: Preparation of²-(ethyl(tetrahydro-2H-pyran-4-y 1)amino)-6-methyl-2-phenylindolizine-7-²carboxylic ²acid: the procedure was same as step 5 of example 55. Yield was 68%. MS (ESI) ²m / z ²379 [M+Hr² 5 Step 3: Preparation of²N-(4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-²pyra ²n-4-yl)amino)-6-methyl-2-phenyl indolizine-7-carboxamide: ²N-(4,6-dimethy1-2-oxo-1,2-dihydropyrid in-3-y pmethyl)-5-(ethy 1(tetrahy dro-²2H-pyra ²n-4-yl)amino)-6-methy1-2-phenylindolizine-7-carboxamide was prepared by a²method similar to Step 6 of Example 1, yield 14%. 1H NMR (CDC13, 400 MHz) 6²ppm 11.35 (s, 1 H), 7.69-7.64 (m, 3 H), 7.38-7.33 (m, 4 H), 6.72 (s, 1 H), ²5.95 (s, 1 ²H), 4.52 (s, 2 1-1), 3.99-3.92 (m, 2 I-1), 3.36-3.23 (m, 4 El), 3.22-3.17 (m, ²1 H), 2.40 (s, ²3 H), 2.31 (s, 3 H), 2.24 (s, 3 H),1.60-1.45 (m, 4 H), 0.87-0.83 (m, 3 H); MS ²(ESI) ²m / z 513 [M+H].² Example 64: Preparation of²N-((4,6-dimethy1-2-oxo-1 ,2-dihydropyrid in-3-yl)methy I)-5-(ethy 1(tetrahydro-²2H-pyr²an-4-yl)am ino)-6-methyl-2-(4-morpholinephenyl)indolizine-7-carboxam ide:²NC- 0²Cit,..0²NaOH / NCI² / Pd(dpp()C12 KOAc DOH NTO²\ HATU, DIPEA / \²Dionane / F120.0²Br Compound 65 b²Q ²Q²N((4,6-Dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methy 1)-5-(ethyl(tetrahydro-2² H-pyran-4-y 1)am ino)-6-methy1-2-(4-morpholinephenypindolizine-7-carboxamide²was prepared by a method similar to example 63.²Step 1: Preparation of²5-(ethyl(tetrahydro-2H-pyran-4-yl)am ino)-6-methyl-2-(4-²morpholinephenyl)indolizin²e-7-carbonitrile: Yield 54%. MS (ESI) m / z 445 [M+1-1]1.² Step 2: Preparation of²5-(ethyl(tetrahydro-2H-pyran-4-y 1)am ino)-6-methyl-2-(4-²morpholinephenyl)indolizin²e-7-carboxylic acid: MS (ESI) m / z 464 [M+H].²Step 3: Preparation of²103²<DP=104>²CA 03036114 2019-03-07²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-5-(ethyl(tetrahydro-2H-²pyr ²an-4-yl)amino)-6-methy1-2-(4-morpholinephenypindolizine-7-carboxamide: Yield ²of ²the two steps was 31%. 1H NMR (CDC13, 400 MHz) 6 ppm 11.30 (brs, 1 H), 7.62 ²(s,²1 H), 7.55 (d, J = 7.8 Hz, 2 H), 7.31 (s, 1 1-1), 6.95 (d, J= 7.8 Hz, 2 H), ²6.66 (s, 1 El),²5.94 (s, 1 H), 4.53 (brs, 2 Fl), 3.93-3.88 (m, 6 H), 3.41-3.31 (m, 4 H), 3.24-²3.18 (m, 5²H), 2.40 (s, 3 H), 2.30 (s, 3 H), 2.24 (s, 3 H), 1.67-1.61 (m, 2 H), 0.99 (t, ²J = 7.2 Hz,²3 H); MS (ES!) m / z 598 [M+1-114.²Example 65: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-²pyr² an-4-yl)amino)-6-methyl-2-(1-methyl-IH-pyrazol-5-y1)indolizin-7-carboxamide:²I HN NCI I² NCNC tsi (Co -f0)3 I L---6Na01-1 HON²,² Pd(dppf)C1 E 0²2 KOAc / HATU, DIPEA DMF N²Br² Doxane / H20=(51) / N²Compound 66 I²N i-h²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-5-(ethyl(tetrahydro-2H ²-pyran-4-yl)amino)-6-methyl-2-(1-methy1-111-pyrazol-5-y Dindo lizin-7-carboxam ²ide ²was prepared by a method similar to example 63.² Step 1: Preparation of²5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-6-methyl-2-(1-methyl-1H-pyrazol-5-²ypind ²olizin-7-carbonitrile: Yield 55%. MS (ES!) m / z 364 [M-FH] `.²Step 2: Preparation of²5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-6-methyl-2-(1-methy1-1H-pyrazol-5-²y1)ind² olizine-7-carboxylic acid: yield 31%.²Step 3: Preparation of²N((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yOmethyl)-5-(ethyl(tetrahydro-21-1-²pyr²an-4-yl)amino)-6-methyl-2-(1-methyl-1H-pyrazol-5-ypindolizin-7-carboxamide: ²yield of two step was 23%. 1H NMR (CDC13, 400 MHz) 6 ppm 11.53 (brs, 1 H), ²7.58²(s, 1 H), 7.49 (s, 1 I-1), 7.34 (s, 1 H), 6.57 (s, 1 H), 6.36 (s, 1 H), 5.96 ²(s, 1 H), 4.53 (s,²2 H), 4.19 (s, 3 H), 3.95-3.90 (m, 2 H), 3.39-3.36 (m, 3 H), 3.26-3.19 (m, 2 ²H), 3.02²(s, 1 H), 2.48 (s, 3 H), 2.40 (s, 3 H), 2.25 (s, 3 H), 1.53-1.78 (m, 4 H), ²1.12 (t, J = 7.2²Hz, 3 H); MS (ESI) m / z 517 [M+1-11+.²Example 66: Preparation of²104²<DP=105>²CA 03036114 2019-03-07²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-²pyr²an-4-yl)amino)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)indolizin-7-carboxamide:²0 0²0 A N²NO ²NC ..clo²N ---13:B¨C11 NG I N Ir 0 0 NaOH H ²H7:111:EA4c, F j N '",\ 0² / ² / Pd(dppf)C12 KOAc Et0H H,0² 0ioxane / H,0.(5 1) N Compound 6,7,²Br \"N,²N4(4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-5-(ethyl(tetrahydro-2H²-pyran-4-yl)amino)-6-methyl-2-(1-methyl-1H-pyrazol-4-ypindolizin-7-carboxamide²was prepared by a method similar to example 63.²Step 1: Preparation of²5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-6-methyl-2-(1-methyl-1H-pyrazol-4-²yl)ind ²olizin-7-carbonitrile: Yield 38%. MS (ESI) m / z 364 [M+Hr.² Step 2: Preparation of²5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-6-methy1-2-(1-methyl-1H-pyrazol-4-²yl)ind ²olizine-7-carboxylic acid: yield 31%.²Step 3: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-²pyr² an-4-yl)am ino)-6-methy1-2-(1-methy1-1H-pyrazol-4-yOindol izin-7-carboxamide:²yield of two step was 53%. 1H NMR (CDCI3, 400 MHz) 6 ppm 12.31 (brs, 1 H), ²7.72 ²(s, 1 H), 7.68 (s, 1 H), 7.28 (s, 1 H), 7.26 (s, 1 H), 6.50 (s, 1 H), 5.96 (s, ²1 H), 4.52 (s, ²2 H), 3.93-3.90 (m, 5 H), 3.39-3.16 (m, 5 H), 2.39 (s, 3 H), 2.30 (s, 3 H), ²2.24 (s, 3 ²H), 1.81-1.78 (m, 1 H), 1.33-1.25 (m, 3 H), 0.98 (t, J = 7.0 Hz, 3 H); MS ²(ES!) m / z²517 [M+Hr.²Example 67: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-5-(ethyl(tetrahydro-2H-²pyr ²an-4-ypamino)-6-methyl-2-(thiazol-2-ypindolizin-7-carboxamide:²NC²²0 NC0,B 0²N 0 / ²Pd(dppf)CI, KOAc clioxane Pd(dppf)Cf, KOAc -²NC²B-0 DiaxanerH20--(5²Br dç14 / \.² 0 0²HV )C 11:6CIFI²N 0 NCI²NaOH 1 / ²1 / ²Et0H, H20²HATU, DIPEA DMF²Ni \)! it Compound 68õ)²105²<DP=106>²CA 03036114 2019-03-07²Step 1: Preparation of²5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-6-methy1-2-(4,4,5,5-tetramethyl-1,3,2-²dio ²xane-2-yl)indolizine-7-carbonitrile: the procedure was same as step 1 in ²example 50. ²Yield: 48%. MS (ES!) m / z 410 [M+H].² Step 2: Preparation of²5-(ethyl(tetrahydro-21-1-pyran-4-yl)amino)-6-methyl-2-(thiazol-2-ypindolizine-²7-carb ²onitrile: the procedure is same as step 1 of example 31. Yield: 66%. MS (ES!) ²m / z ²367 [M-1-HI.²Step 3: Preparation of²5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-6-methy1-2-(thiazol-2-y1)indolizine-7-²carb²oxylic acid: the procedure was same as step 5 of example 55. MS (ES!) m / z 386 ²[M+Hr.²Step 4: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-²pyr²an-4-yl)amino)-6-methyl-2-(thiazol-2-yl)indolizine-7-carboxamide: the ²procedure²was same as step 6 in example 1. Yield of two steps was 21%. I H NMR (CDC13, ²400 ²MHz) 8 ppm 8.03 (s, 1 H), 7.80 (s, 1 H), 7.44 (s, 1 1-1), 7.31 (s, 1 H), 7.26 ²(s, 1 H), ²6.83 (s, 1 H), 6.21 (s, I H), 4.46 (s, 2 H), 3.96-3.88 (m, 3 11), 3.41-3.19 ²(m, 4 H), ²2.69 (s, 3 H), 2.26 (s, 6 H), 1.78-1.75 (m, 1 H),1.66-1.57 (m, 3 H), 0.99 (t, ²J= 7.0 Hz,² 3 H); MS (ESI) m / z 520 [M+H]4.²Example 68: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-²(methyl(tetrahy ²dro-2H-pyran-4-yDamino)imidazo[1,5-a]pyridine-7-carboxamide:²ON 11; ²C²H, 1 fumaroname 115cN 1) LDA,THF Mel NCNH2²1) OH NC Fisl¨CC) (CH20),² II , NClif P0139)3, THF )²II- / / 2) K2CO3 DMF i ,,, 2) NaBH,CN ²H00211²0²NC Ni --(0 NaOH² I N²t²\ i Et0H / H20 Fl C²I 14²\²NNLL--\0²HATU DIPEA D ² _________________________________________ ro7²\ i²Compound 69² N-((4,6-Dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(methyl(te²trahydro-2H-pyran-4-yDamino)imidazo[1,5-a]pyridine-7-carboxamide: the ²procedure²106²<DP=107>²CA 03036114 2019-03-07²was similar to example 55.²Step 1: Preparation of (E)-2-((1H-imidazol-5-yl)methylene)succinonitrile: ²Yield²51%. MS (ES!) m / z 159 [M+Hr.²Step 2: Preparation of 5-amino-6-methylimidazo[1,5-a]pyridine-7-carbonitrile:² Yield 38%. MS (ES]) m / z 173 [M+HF.²Step 3: Preparation of²6-methyl-5-((tetrahydro-2H-pyran-4-yl)amino)imidazo[1,5-a]pyridine-7-²carbonitrile:²Yield 7%. MS (ES!) m / z 257 [M+H.r.²Step 4: Preparation of²6-methy1-5-(methyl(tetrahydro-2H-pyran-4-yl)amino)imidazo[1,5-a]pyridine-7-²carbo²nitrile: ²6-Methy1-5-((tetrahydro-2H-pyran-4-yDamino)imidazo[1,5-alpyridine-7-²carbonitrile ²(80 mg, 0.31 mmol), paraformaldehyde (93 mg, 3.12 mmol) were added successivly ²²to a dried 25 mL three-neck flask, dissolved in formic acid (2 mL), and heated ²to²reflux for 3 hours. After the reaction was completed, yellow solids (30 mg) ²were²obtained by thin-layer chromatography plate, yield 36%. MS (ES!) m / z 271 [M+Hr ²²Step 5: Preparation of²6-methyl-5-(methyl(tetrahydro-2H-pyran-4-yDamino)imidazo[1,5-alpyridine-7-²carbo ²xylic acid: MS (ES!) m / z 290 [M+Hr² Step 6: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-²(methyl(tetrahy ²dro-2H-pyran-4-yl)amino)imidazo[1,5-a]pyridine-7-carboxamide: two step yield ²was ²9%. 1H NMR (CDC13, 400 MHz) 6 ppm 11.65 (s, 1 H), 8.15 (s, 1 H), 7.45 (s, 1 ²H), ²7.39-7.37 (m, 2 H), 5.95 (s, 1 H), 4.52 (s, J= 6.2 Hz, 2 H), 3.95 (t, J 6.9 ²Hz, 2 H),²3.39-3.29 (m, 3 H), 2.88 (s, 3 H), 2.38 (s, 3 II), 2.25 (s, 3 H), 2.23(s, 3 ²F1),²1.78-1.59(m, 4 El);MS (ES!) m / z 424 [M+F11+.²Example 69: Preparation of²2-chloro-N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-mo ²²rphinolinylethyl)indolizine-7-carboxamide:²107²<DP=108>²CA 03036114 2019-03-07²0 cO)²H Ncs 9 1-1 13N-1C )1.") )00,0),, o HN / I ii¨µ0²THF L-111. / ²= K2CO3, DMF 04 1(2CO3, f-PrOH ²TI(OiPr),²0 0²0 0²) C) HN NH CI C)²0 0 0 N²JL²NaOH 0 N²AcOH I N Me0H, H20 HO HAT'U, DIPEA, DMF²N²Ci ²Compound 70²2-Chloro-N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-54 ²1-morphinolinylethyl)indolizine-7-carboxamide was prepared by a method similar ²to ²example 29.² Step 1: Preparation of 4-chloro-1H-pyrrole-2-carbaldehyde: Yield 34%. MS²(ESI) m / z 130 [M+H].²Step 2: Preparation of 4-chloro-1-(2-oxopropy1)-1H-pyrrole-2-carbaldehyde:²yield 56%. MS (ESI) m / z 186 [M+H].²Step 3: Preparation of ethyl 5-acetyl-2-chloro-6-methylindolizine-7-²carboxylate:² Yield 58%. MS (ESI) m / z 280 [M+Hr.²Step 4: Preparation of isopropyl²2-chloro-6-methy1-5-(1-morphinolinylvinypindolizine-7-carboxylate: MS (ESI) ²m / z²363 [M+H].²Step 5: Preparation of isopropyl²2-chloro-6-methy1-5-(1-morphinolinylethyl)indolizine-7-carboxylate: yield of ²two²steps was 50%. MS (ESI) m / z 365 [M+H]+.²Step 6: Preparation of²2-chloro-6-methyl-5-(1-morphinolinylethyl)indolizine-7-carboxylic acid: Yield ²75%. ²MS (ES!) m / z 323 [M+H1² Step 7: Preparation of²2-chloro-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²mo ²rphinolinylethyl)indolizine-7-carboxamide: yield 25%. 1H NMR (400 MHz, ²DMSO-d6) 6 7.33 (s, 1 H), 6.49 (s, 1 H), 6.13 (s, 1 H), 4.44 (s, 2 H). 4.23 ²(d, J = 5.6 ²Hz, 1 11), 3.64 (d, J= 10.4 Hz, 1 H), 2.85 (s, 8 H), 2.37 (s, 3 H), 2.29 (s, 3 ²H), 2.24 (s,²3 H), 1.55 (d, J= 6.4 Hz, 3 H); MS (ESI) m / z 457 [M+Hr.²Example 70: Preparation of²108²<DP=109>²CA 03036114 2019-03-07²2-chloro-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-(4-²(dimethyl ²amino))piperidine)ethyl)-6-methylindolizine-7-carboxamide:²0 0²=-'0 N Nal3H4 NaOH²N 0²Ti(01PDa / ²IIHAr ,²CI CI²CI²0²(1-.) HN NH3C1²N I 0 0 N²HO HATU, DIPEA, [IMF N²I H I N²N it= Compound 71²2-Chloro-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-(4-(dim²ethylamino))piperidine)ethyl)-6-methylindolizine-7-carboxamide was prepared by²the same procedure as that in example 29.²Step 1: Preparation of isopropyl²2-chloro-5-(1-(4-(dimethylamino)piperidin-1-ypvinyl)-6-methylindolizine-7-²carboxy ²late: MS (ES!) m / z 404 [M+1-11+.² Step 2: Preparation of isopropyl²2-chloro-5-(1-(4-(dimethylamino)piperidin- I -yl)ethyl)-6-methylindolizine-7-²carboxy²late: yield 36%. MS (ES!) m / z 406 [M+Hr.²Step 3: Preparation of²2-chloro-5-(1-(4-(dimethylamino)piperidin- 1 -ypethyl)-6-methylindolizine-7-²carboxy² lie acid: yield 97%. MS (ES!) m / z 364 [M+1-11'.²Step 4: Preparation of²2-chloro-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-(4-²(dimethyl ²amino))piperidin-l-yl)ethyl)-6-methylindolizine-7-carboxamide: yield 15%. 1H ²NMR ²(400 MHz, DMSO-d6) 6 11.50 (s, 1 H), 9.40 (s, 1 H), 8.25 (m, 2 H), 7.25 (s, 1 ²H),²6.55 (s, I H), 5.87 (s, 1 H), 4.25 (m, 3 H), 4.03 (s,1 H), 3.41 (s, 1 H), 3.09 ²(s, 1 H),²2.74 (m, 8 H), 2.45 (s, 1 I-1), 2.23 (s, 3 H), 2.19 (s, 3 I-1), 2.10 (s, 6 H), ²1.41 (d, J = 5.4 ²Hz, 3 H); MS (ES!) m / z 498 [M+H]+.²Example 71: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morphinolin² ylethypimidazo[1,5-a]pyridine-7-carboxamide:²109²<DP=110>²CA 03036114 2019-03-07²r²LN)²L² 01t.,(7LTI, 0 H B r Njc) ) )C 0²HN 0 ),²0² Crk K2CO3 DM; 0.7.-0115 Method A / -Pr01-7 I T(0 / PO4²0 c 0 Oj 0²0 (N)²0 N 0 0 N²Na01-1²NrH,² AcOH I Me0H H20 HO HATU DIPEA DMF² H H I²N²Nµiy²Compound 72²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-morphi ²nolinylethyl)imidazo[1,5-a]pyridine-7-carboxamide was prepared by a method ²similar to example 26, while the intermediate ethyl²5-acety1-6-methylimidazo[1,5-a]pyridine-7-carboxylate was prepared according ²to²step 2, method A of Example I.²Step 1: Preparation of 1-(2-oxopropy1)-1H-imidazole-5-formaldehyde: yield 8%.²MS (ESI) m / z 153 [M+Hr²Step 2: Preparation of ethyl²5-acety1-6-methylimidazo[1,5-a]pyridine-7-carboxylate: Yield 31%. MS (ES!) m / z²247 [M+H]'²Step 3: Preparation of isopropyl²6-methy1-5-(1-morphinolinylvinypimidazo[1,5-a]pyridine-7-carboxylate: MS (ES!) ²²m / z 330 [M+Hr.² Step 4: Preparation of isopropyl²6-methy1-5-(1-morphinolinylethypim idazo[1,5-a]pyridine-7-carboxylate: yield ²of²two steps was 32%. MS (ES!) m / z 332 [M+H]+.²Step 5: Preparation of²6-methyl-5-(l -morphinol inylethyl)im idazo[1,5-a]pyridine-7-carboxyl ic acid: ²yield² 66%. MS (ESI) m / z 290 [M+H]²Step 6: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyrid in-3-y1 )methyl)-6-methyl-5-(1-²morphinol in²ylethyl)imidazo[1,5-a]pyridine-7-carboxamide: yield 18%. Ili NMR (400 MHz,²DMSO-d6) .3 11.54 (brs, 1 H), 10.04 (brs, 1 H), 8.50 (t, J = 4.9 Hz, 1 H), ²8.14 (s, I H),²7.68 (s, 1 H), 5.89 (s, I H), 4.29 (t, J 7.2 Hz, 2 H), 3.57 (brs, 4 H), 2.66 ²(brs, 2 Fp.²2.29 (s, 3 H), 2.21 (s, 3 H), 2.12 (s, 3 H), 1.45 (d, J= 6.5 Hz, 3 H); MS ²(ES!) m / z²110²<DP=111>²CA 03036114 2019-03-07²424 [M+Fl]'.²Example 72: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morphinolin²ylethyl)imidazo[1,2-a]pyridine-7-carboxamide:²0²ftyy0t, C²9 H Br-j()C²K2003 DM: 0'4715. ,Method A 1-Pr0H INJ -11(0,PO4-". ²IN3²cC )( 0²HN)Ir1H,C1²0²0 W..,²NaBH4jyN NaOH²AcOH I T Me0H H,0 HO HATU DIPEA DME ²HILiril I²NN-1² Compound 71²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-morphi ²nolinylethyl)imidazo[1,2-a]pyridine-7-carboxamide was prepared by a method ²similar to example 72.²Step 1: Preparation of 1-(2-oxopropy1)-1F1-imidazole-2-formaldehyde: yield² 10%. MS (ESI) m / z 153 [M+H] .²Step 2: Preparation of ethyl²5-acetyl-6-methylimidazo[1,2-a]pyridine-7-carboxylate: Yield 17%. MS (ESI) m / z²247 [M+H]4 .²Step 3: Preparation of isopropyl²6-methyl-5-(1-morphinolinylvinyl)imidazo[1,2-a]pyridine-7-carboxylate: MS ²(ESI)²m / z 330 [M+Hr.²Step 4: Preparation of isopropyl²6-methy1-5-(1-morphinolinylethypimidazo[1,2-alpyridine-7-carboxylate: yield of ²²two steps was 50%. MS (ESI) m / z 332 [M+Hr.² Step 5: Preparation of²6-methy1-5-(1-morphinolinylethypimidazo[1,2-a]pyridine-7-carboxylic acid: ²yield ²82%. MS (ESI) m / z 290 [M+F11'.²Step 6: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-morphinol ²in² ylethypimidazo[1,2-alpyridine-7-carboxamide: yield 18%. 1H NMR (400 MHz,²DMSO-d6) 6 11.56 (brs, 1 H), 8.97 (brs, 1 H), 8.62 (t. J= 2.1 Hz. 1 1-1), 8.22 ²(d, J =²111²<DP=112>²CA 03036114 2019-03-07²2.0 Hz, 1 H), 7.73 (s, 1 H), 5.90 (s, I H), 4.32 (d, J = 5.1 Hz, 2 H), 3.57 ²(s, 8 H), 2.36²(s, 3 H), 2.23 (s, 3 H), 2.12 (s, 3 H), 1.44 (d, J= 6.6 Hz, 3 H); MS (ES!) m / z ²424 ²[M+H].²Example 73: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-5-(ethyl(tetrahydro-2H-²pyr²an-4-yl)amino)-6-methyl-2-(1-methyl-1H-imidazol-4-yl)indolizin-7-carboxamide:²r'²NC Br NC NaOH² / ²Pd(dppf)C12 KOAc Et0H, H20² B-0 Doxane / N20-(6²NN²H 0 0 0²NCI 0² / ²HATU, DIPEA, DMF²11 Compound 74²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-21-²1 ²-pyran-4-yl)amino)-6-methyl-2-(1-methyl-1H-imidazol-4-yl)indolizin-7-²carboxamide² was prepared by same method as that in example 67.²Step 1: Preparation of²5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-6-methy1-2-(1-methyl-IH-im idazol-4-²yl)in²dolizin-7-carbonitrile: Yield 43%. MS (ES!) m / z 364 [M+F111.²Step 2: Preparation of²5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-6-methyl-2-(1-methyl-1H-imidazol-4-²yl)in²dolizine-7-carboxylic acid: MS (ES!) m / z 383 [M+H1'.²Step 3: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl ²(tetrahydro-2H-pyran-4-yl)amino)-6-methyl-2-(1-methyl-1H-imidazol-4-²yl)indolizin² e-7-carboxamide: Yield of the two steps was 21%. 1H NMR (CDC13, 400 MHz) 6²ppm 8.86 (s, 1 H), 8.01 (s, 1 H), 7.80 (s, 1 H), 7.38 (s, 1 H), 6.82 (s, 1 H), ²6.12 (s, 1 ²H), 4.46 (s, 2 H), 3.96 (s, 3 H), 3.89-3.84 (m, 2 H), 3.49-3.40 (m, 4 H), 3.25-²3.21 (m, ²1 H), 2.56 (s, 3 H), 2.41 (s, 6 1-1), 2.25-2.20 (m, 2 H), 1.82-1.67 (m, 2 H), ²0.99 (t, J = ²7.0 Hz, 3 H); MS (ESI) m / z 517 [M+Hr.² Example 74: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-2-(3-²((dimethylamino)meth²112²<DP=113>²CA 03036114 2019-03-07²yl)pheny1))-6-methy1-5-(1-morpholineethypindolizine-7-amide:²HO OH²0² / 1( 0 cO,² c IL) C 1 0 N²_1 ²1 Ft ji:),õNPd(dppf)Cl2 -}'-ce."0 *1.N²AcOK Dioxane / H0 ² I 2 \ / . ,²\ Ni²lBr²co / --\ / / 0 . N-² / )___ / ²,,²b I²0 N" 0 I. )²0 _IV² NaOH HO'l .". ²____________________ --. I²Me0H / F1,0 DMF -.. ..... N²"21 / \ ¨² / 3 Vi²Compound 75 , / ²Step 1: Preparation of isopropyl²2-(3-formylpheny1)-6-methyl-5-(1-morpholinylethyl)indolizine-7-formate: ²similar to² step 1 of example 31, yield 25%. MS (ESI) m / z 348 [M+Hr.²Step 2: Preparation of isopropyl²2-(3-((dimethyl)methyl)pheny1)-6-methyl-5-(1-morpholinylethyl)indolizine-7-²carbox ²ylate: isopropyl²2-(3-((dimethyl)methyl)pheny1)-6-methyl-5-(1-morpholinylethypindolizine-7-²carbox² ylate (100 mg, 0.23 mmol), dimethylamine hydrochloride (56 mg, 0.69 mmol),²triethylamine (69 mg, 0.69 mmol), sodium cyanoborohydride (36 mg, 0.58 mmol) ²and dichloromethane (5 ml) were added successively to dry 50 mL round bottom ²flask at room temperature. After stirred at room temperature for 3h, TLC ²monitored ²that the reaction was completed, the mixture was neutralized with saturated ²aqueous²solution of sodium hydrogencarbonate, and then extracted with ethyl acetate ²(20 mLx²3), and washed with saturated brine (10 mL). The organic phase was dried over ²anhydrous sodium sulfate, filtered, and the filtrate was concentrated under ²reduced ²pressure. The obtained residue was purified by column chromatography ²(petroleum ²ether: ethyl acetate=1:I) to afford product, isopropyl²2-(3-((dimethylamine)methyl)pheny1)-6-methyl-5-(1-morpholinylethyl)indolizine-²7-c²arboxylate, yield 52%. MS (ESI) m / z 464 [WM] ' .²Step 3: Preparation of²2-(3-((Dimethylamino)methyl)pheny1)-6-methy1-5-(1-morpholinylethyl)indolizine-²7-²carboxylic acid: similar to step 4 of example 31. MS (ESI) m / z 335 [M+H] .² Step 4: Preparation of²113²<DP=114>²CA 03036114 2019-03-07²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(3-²((dimethylamino)meth ²yl)pheny1)-6-methyl-5-(1-morpholinylethyl)indolizine-7-amide: similar to step ²5 of ²Example 31, yield of the two steps was 18%. 1H NMR (DMSO-d6. 400 MHz) ²811.47(s, 1H),8.70(s, 1H), 8.17 (m, 1H), 7.58-7.60 (m, 2H), 7.34-7.36(m, 111), ²7.29(s,²1H), 7.17-7.18(m, 1H),6.83 (s, 1H), 5.88 (s, 111), 4.26-4.28 (m, 211), 4.06-²4.07(m,²1H), 3.59(m, 21-1), 2.65-2.67(m, 2H),2.26 (s, 3H), 2.18-2.22 (m, 11H), 2.12 ²(s, 31-1), ²1.45-1.47(m, 31-1); MS(ESI) m / z 556 [M+1-11+.²Example 75: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-²((dimethylamino)meth² yl)pheny1))-6-methyl-5-(1-morpholinoethyl)indolizine-7-carboxamide:²(01²ILA '20N12N, O.²--=\ ²-N²01²C H0 5NH²0 N 0 0 N²Ne0H²Et0H / H20²\²N Compound 76 ²-²Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-²((dimethylamino)meth²yl)phenyl) )-6-methyl-5-(1-morpholinoethyl)indolizine-7-carboxamide: same as² example 74.²Step I: Preparation of isopropyl²2-(4-formylpheny1)-6-methyl-5-(1-morpholinoethyl)indolizine-7-earboxylate: ²yield ²34%. MS (ESI) m / z 348 [M+Hr. Step 2: Preparation of isopropyl ²2-(4-((dimethylamino)methyl)pheny1)-6-methyl-5-(1-morpholinoethypindolizine-7-²c² arboxylate: yield 47%. MS (ESI) m / z 464 [M+Hr²Step 3: Preparation of²2-(4-((dimethylamino)methyl)pheny1)-6-methyl-5-(1-morpholinoethyl)indolizine-7-²c²arboxylic acid: MS (ESI) m / z 422 [M]+.²Step 3: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-2-(4-²((dimethylamino)meth²114²<DP=115>²CA 03036114 2019-03-07²yl)pheny1))-6-methy1-5-(1-morpholinoethyl)indolizine-7-carboxamide: Yield of ²the ²two steps was 11 %. 1H-NMR (CDC13, 400 MHz)67.91 (s, 2H), 7.89 (s, 1H), 7.60 ²(s, ²1H), 7.56 (s, 2H), 7.54 (s, 1H), 6.24 (s, 1H), 4.96 (s, 2H), 4.33 (s, 21-1), ²3.91-3.86 (m,²4H), 3.87-3.85 (m, 1H), 2.99-2.98 (m, 11-1), 2.88 (s, 61-1), 2.41 (s, 61-1), ²2.28 (s, 31-1),² 1.96-1.94 (m, 21-1), 1.38-1.32 (in, 3H); MS(ESI) m / z 556 [M+1114.²Example 76: Preparation of²2-(7-cyanoindo1-5-y1)-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-²me ²thy1-5-(1-morpholinoethyl)indolizin-7-carboxamide:² 0 0²0. C %,²r,²0 0 o= ON tt,²j NE430,² I N²CH,COOK 1 4 thoxane / H,0(4 Hopr,4 AcOH.-²Pd(CIPPOCIc -CN²CN²Br²NH²NH²0 CON) (0)²0 N 0 it)²1:1 0 N²NaOH HO²²I N² j\ 1,1_1411, H² HATU DIPEA Compound 77²CN CN VN: CH²NH NH² 2-(7-Cyanoindo1-5-y1)-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)²-6-methyl-5-(1-morpholinoethyl)indolizin-7-carboxamide was prepared according ²to ²example 31.²Step 1: Preparation of ethyl²5-acety1-2-(7-cyanoindole-5-y1)-6-methylindolizin-7-carboxylate: Yield 52%. MS² (ESI) m / z 388 [M+Hr.²Step 2: Preparation of ethyl²isopropy1-2-(7-cyanoindo1-5-y1)-6-methyl-5-(1-morpholinovinyl)indolizine-7-²carbox²ylate: MS (ESI) m / z 471 [M+H]²Step 3: Preparation of ethyl²isopropy1-2-(7-cyanoindo1-5-y1)-6-methyl-5-(1-morpholino-ethyl)indolizine-7-²carbox²ylate: yield of two steps was 69%. MS (ESI) m / z 473 [MH-Hr²Step 4: Preparation of²2-(7-cyanoindo1-5-y1)-6-methyl-5-(1-morpholino)indolizine-7-carboxylic acid: ²MS ²(ESI) m / z 431 [M+Hr.²115²<DP=116>²CA 03036114 2019-03-07²Step 5: Preparation of²2-(7-cyanoindo1-5-y1)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-²me²thy1-5-(1-morpholinoethypindolizine-7-carboxamide: yield of two steps was 10%. ²²1H-NMR (CDC13, 400 MHz)6 12.19 (s, I H), 8.56 (s, 1H), 7.47 (s, 1H), 7.40 (s, ²1H),²7.30 (s, 1H), 6.54 (s, I H), 5.96 (s, 1H), 4.53-4.52 (m, 21-1), 4.06-4.01 (m, ²1H),²3.77-3.69 (m, 6H), 3.17-3.13 (m, 2H), 2.66-2.65 (m, 2H), 2.40 (s, 311), 2.34 ²(s, 3H), ²2.26-2.18 (m, 5H), 1.50-1.49 (m, 3H); MS(ESI) m / z 565 [M+H]'.²Example 77: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-(4-²(dimethylamino)pip²eridine-1-yl)ethyl)-6-methyl-2-(1-methyl-IH-pyrazol-3-ypindolizin-7-²carboxamide:² , 0²0 0 Br -"13²(1:1:11 NaBH4²1 / ²AcOH²PU(dppf)C12 / AcOH²613-0²\ N,²N N,²0 N 0 N²PaCt4H2 ²"1"0 NaOH HO .²1N²HATU, 11²1 / ²-11²N,²Compound 78²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y pmethyl)-5-(1-(4-(dimethylam in ²o)piperidine-1-ypethyl)-6-methyl-2-(1-methyl-1H-pyrazol-3-yl)indolizin-7-²carboxa ²mide was preparated by a method similar to that in example 50.² Step 1: Preparation of ethyl²5-acetyl-6-methyl-2-(1-methyl-IH-pyrazol-3-yl)indolizin-7-carboxylate: Yield ²51%. ²MS (ES1) m / z 326 [M+H]²Step 2: Step 1: Preparation of isopropyl²5-(1-(4-(dimethylamino)piperidin-l-yl)viny1)-6-methyl-2-(1-methyl-IH-pyrazol-3-²y1² )indolizine-7-carboxylate: MS (ESI) m / z 450 [M+H]+.²Step 2: Preparation of isopropyl²5-(1-(4-(dimethylamino)piperidin-l-yDethyl)-6-methyl-2-(1-methyl-1H-pyrazol-3-²y1)²indolizine-7-carboxylate: yield of two steps was 56%. MS (ES1) m / z 452 [M+Hr. ²Step 3: Step 3: Preparation of²116²<DP=117>²CA 03036114 2019-03-07²5-(1-(4-(dimethylamino)piperidin-1-ypethyl)-6-methyl-2-(1-methyl-111-pyrazol-3-²y1) ²indolizine-7-carboxylic acid: MS (ES!) m / z 410 [M+1-11+.²Step 4: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-5-(1-(4-²(dimethylamino)pip²eridine-1-ypethyl)-6-methyl-2-(1-methyl-11-1-pyrazol-3-ypindolizine-7-²carboxamide:²Yield of the two steps was 4%. 1H-NMR (DMSO-16, 400 MHz) 6 8.75 (s, 1H), ²7.73-7.71 (m, 1H), 7.54-7.49 (m, 2H), 7.34 (s, 1H), 7.14 (s, 1H), 6.52 (s, ²1H), 5.93 (s, ²1H), 4.52-4.50 (m, 2H), 4.00 (m, 1H), 3.75 (s, 3H), 3.37-3.35 (m, 1 El), 2.39 ²(s, 3H), ²2.36-2.35 (m, 2H). 2.25-2.23 (m, 61-1), 2.22-2.21 (m, 3H), 2.20-2.17 (m, 2H),²1.98-1.94 (m, 4H), 1.49-1.45 (m, 3H), 0.99-0.96 (m, 3H); MS(ESI) m / z 544 ²[M+H].²Example 78: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-²morpholinyl ²ethyl)-1-(3-cyanophenyl)indolizin-7-amide:² CN Om C Nj²0 0 Hos.¨d²Tp²CN)² / Pd(dppf)CI, / ²CN²O-CN²LON.j L )²0 N (0:3² NaBH, OOH 0² AcOH Me0H / H20 HATU OIPEA²)7--A² CN \ CN Compound 79 CN² Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyrid in-3-yl)methyl)-6-methyl-5-(1-²morpholinyl ²ethyl)-1-(3-cyanophenypindolizin-7-amide was similar to example 31.²Step 1: Preparation of ethyl²5-acetyl-6-methyl-2-(3-cyanophenyl)indolizine-7-carboxylate: Yield 52%. MS ²(ES!)² m / z 374 [M+Hr.²Step 2: Preparation of isopropyl²6-methyl-5-(1-morphinolinylviny1)-1-(3-cyanophenyl)indolizine-7-carboxylate: ²MS²(ES!) m / z 430 [M+11]'.²Step 3: Preparation of isopropyl²6-methyl-5-(1-morphinolinylethy1)3-(3-cyanophenyl)indolizine-7-carboxylate: ²yield²117²<DP=118>²CA 03036114 2019-03-07²of two steps was 72%. MS (ES!) m / z 432 [M+FI11.²Step 4: Preparation of²6-methyl-5-(1-morphinol inylethyl)-1-(3 -cyanophenyl)indol izine-7-carboxyl ic ²acid:²MS (ES!) m / z 388 [M+FIr² Step 5: Preparation of²N-((4,6-dimethy1-2-oxo- l ,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-²morphinolin ²ylethyl)-1-(3-cyanophenyl)indolizine-7-carboxamide: yield of two steps was ²18%. 1H ²NMR (CDC13, 400 MHz) 611.07(s, IH), 8.74(s, 1H), 7.89 (s, 1H), 7.85-7.83(d, ²J=7.2Hz, 1H), 7.53-7.47(m, 2H), 7.34(s, 1H),6.68(s, 1H), 5.96(s,11-0,4.53-4.52 ²(m,²2H), 4.09-4.03 (m, 1H), 3.71 (m, 414), 2.68(s, 2H), 2.40 (s, 3H), 2.34 (s, ²3H),²2.28-2.24 (m, 5H), 1.52-1.50(m, 3H); MS(ESI) m / z 437 [M+1-1]'.²Example 79: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyrid in-3-yl)methyl)-6-methyl-2-(l-methy I-²1 H-imidazole-2-y1)-5-(1-morpholinoethyl)indolizine-7-carboxamide:²(0)²\ / 1-CiProkt \ / AcOH²p-0 Pc1(dppf)C12²0¨ ¨N²¨N,...j²NaOH HO²²....-C I ...... EtOH --' ____ ' N .. =- ",..1-.11 .. ²I ''²HARI DIPEA²q \ / \ / ² )---,N²¨N.,), =PI²¨Nvj ²Compound 80 ,.1²Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-(1-methyl-²1H-imidazole-2-y1)-5-(1-morpholinoethyl)indolizine-7-carboxamide was similar ²to ²example 50.² Step 1: Preparation of ethyl²5-acetyl-6-methyl-2-(1-methyl-IH-imidazol-2-yl)indol izine-7-carboxylate: ²Yield²49%.²MS (ES!) m / z 326 [M+Hr.²Step 2: Preparation of ethyl²isopropyl-6-methyl-2-(1-methyl-1H-imidazo1-2-y1)-5-(1-morpholinovinypindo ²lizine-²118²<DP=119>²CA 03036114 2019-03-07²7-carboxylate: MS (ES!) m / z 409 [M+H].²Step 3: Preparation of ethyl²isopropy1-6-methy1-2-(1-methyl-IH-imidazol-2-y1)-5-(1-²morpholinoethypindolizine-²7-carboxylate: yield 65%. MS (ES!) m / z 411 [M+11] .² Step 4: Preparation of²6-methy1-2-(1-methy1-1H-imidazol-2-y1)-5-(1-morphinoethyl)indolizine-7-²carboxylic ²acid: MS (ES!) m / z 369 [M+H].²Step 5: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-(1-methyl-IH-²i² midazol-2-y1)-5-(1-morphinolinylethypindolizine-7-carboxamide, yield 22%.²1H-NMR (DMSO-d6, 400 MHz) 6 11.48 (s, 114), 8.89 (s, 1H), 8.31-8.28 (m, I H), ²7.78-7.76 (m, 211), 7.45 (s, 1H), 7.09-7.07 (m, 1H), 5.88 (s, 1H), 4.44 (s, ²211), ²4.24-4.22 (m, 1H), 4.18 (s, 3H), 3.63-3.58 (m, 4H), 2.67-2.64 (m, 2H), 2.27-²2.17 (m, ²611), 2.15-2.13 (m, 2H), 2.11 (s, 314), 1.48-1.47 (m, 3H);MS(ESI) m / z 503 ²[M+H]² Example 80: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-morpholine-1-²ethyl)-6 ²-methyl-2-(3-(morpholinemethylene)phenypindolizin-7-amide:²"²- 0 =²0 0 ,el,õ²0, \_ / ) I²k / H ² / Pc1(cIppOpl, KOAc Ti Pro)4 / NaBH4²Br²(0²0 N² 0²I H I jr'. H11:11N011)1I²QQ Compound 81 Q²Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-morpholino-1-²ethyl)-6²-methy1-2-(3-(morpholinomethylene)phenypindolizine-7-carboxamide was similar ²to ²example 3 I .²Step 1: Preparation of ethyl²5-acety1-6-methy1-2-(3-(morpholinemethylene)phenyl)indolizine-7-carboxylate: ²yield² .. 46%. MS (ES!) m / z 420 [M+1-1]'.²119²<DP=120>²CA 03036114 2019-03-07²Step 2: Preparation of isopropyl²5-(1-morpholine-l-viny1)-6-methyl-2-(3-(morpholinemethylene)phenyl)indolizine-²7-²carboxylate: MS (ESI) m / z 504 [M+Hr²Step 3: Preparation of isopropyl²5-(1-morpholine-1-ethy 1)-6-methy1-2-(3-(m orpholinem ethylene)pheny ²pindolizine -7-²carboxy late: yield of two steps was 80%. MS(ESI) m / z 506 [M+111+.²Step 4: Step 4: Preparation of²5-(1-morpholine-1 -ethy 1)-6-methy1-2-(3-(morphinol inylm ethylene)pheny ²pindoliz ine-²7-carboxylic acid: MS (ESI) m / z 377 [M+H]'.² Step 5: Step 5: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-morpholine-1-²ethyl)-6²-methyl -2-(3-(morpholinemethylene)phenyl)indolizine-7-amide: yield of two ²steps²was 19%. 1H NMR (CDC13, 400 MHz) 6 8.67(s, 1 H), 7.57(s, 1 H), 7.50-7.48 (d,²J=7.6,1 H), 7.31-7.23 (m, 1 H), 7.13-7.10(m, 1 H), 6.67(s, 1 5.89(s,1 H),²4.46-4.44 (m, 2 El), 3.40-4.39 (m, 1 H), 3.69 (s, 4 H), 3.64(s. 4 1-1). 3.56 ²(s. 2 H), 2.61²(s, 2 H), 2.50 (s, 4 H), 2.34(s, 3 H), 2.27(s,3 H), 2.23-2.20(m,2 H), 2.18 (s, ²3 H), ²1.46-1.44 (d, J=6.8 Hz,3 H); MS(ESI) m / z 620 [M+Nar.²Example 81: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-1-(1-methyl-IH-²p² yrazol-5-y1)-5-(1-morpholinylethyl)indolizin-7-amide:²0 0 ..t3.13 / I:11km L )²0 N²T,(01Prm AcOH²Br Pd(dppt)C12 KOAc²(0) C,0 0.²4)²C²0-kirkris' j*, HATDUmDFIEK 117,11fil-²meoHn-v)²75--1 Itn" Compound 82²NN²Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-1-(1-methyl-1H-²p²yrazol-5-y1)-5-(1-morpholinylethypindolizine-7-amide was similar to example ²31.² Step 1: Preparation of ethyl²5-acetyl-6-methyl-1-(1-methyl-1H-pyrazol-5-ypindolizine-7-formate: Yield 33%.²120²<DP=121>²CA 03036114 2019-03-07²MS (ES!) m / z 326 [M+H]1-.²Step 2: Preparation of isopropyl²6-methyl-1-(1-methy1-1H-pyrazol-5-y1)-5-(1-morphinolinylvinypindolizine-7-²format ²e: MS (ES!) m / z 409 [M+Hr.² Step 3: Step 3: Preparation of isopropyl²6-methyl-1-(1-methy1-1H-pyrazol-5-y1)-5-(1-morphinolinylethyl)indolizine-7-²format ²e: yield of two steps was 30%. MS (ES!) m / z 411 [M+H]'.²Step 4: Preparation of²6-methyl-1-(1-methy1-1H-pyrazol-5-y1)-5-(1-morphinolinylethylene)indolizine-7-²for² mic acid: MS (ES!) m / z 369 [M+H]1.²Step 5: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-1-(1-methyl-IH-²p ²yrazol-5-y1)-5-(1-morphinolinylethypindolizine-7-carboxamide: Yield of two ²steps²was 16%. 1H NMR (400 MHz, CDCI3) 6 11.46(s, 1H), 8.50(s, 1H), 8.27 (s, 1H),² 7.47(s, 1H), 7.31(s, 1H), 7.03-7.02(d, J = 2.8 Hz, 1H),6.40(s, 1H),²5.85(s,1H),4.25-4.24 (m, 211), 4.09-4.07 (m, 1H), 3.83 (s, 3H), 3.58 (m, 4H), ²2.67-2.62(m, 2H), 2.28 (s, 3F1), 2.18-2.14 (m, 5H), 2.10 (s, 3H), 1.45-1.43(m, ²3H); ²MS(ESI) m / z 503 [M+Hr.²Example 82: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-²morphinolin²ylethyl)-1-phenylindolizine-7-carboxamide:²0 (0:² Pd(cIppf)C1, 0²I n²N N (CD =²NaBH,²H ²AcOH²Br / ²0 0 N²0 L² NaOH N I N MeOH / H HAT20 HO DmUFD'FEA H1:1,,a0-1 I²C,²Compound 83²Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-morphinolin² ylethyl)-1-phenylindolizine-7-carboxylate was similar to example 31.²Step 1: Preparation of ethyl 5-acetyl-6-methy1-1-phenylindolizine-7-²carboxylate:²121²<DP=122>²CA 03036114 2019-03-07²yield 14%. MS (ESI) m / z 322 [M+Ell'.²Step 2: Preparation of isopropyl²6-methyl-5-(1-morphinolinylviny1)-1-phenylindolizine-7-carboxylate: MS (ESI) ²m / z ²405 [M+Hr .² Step 3: Preparation of isopropyl²6-methyl-5-(1-morphinolinylethyl)-1-phenylindolizine-7-carboxylate: yield of ²two ²steps was 38%. MS (ESI) m / z 320 [M+Hr.²Step 4: Preparation of²6-methyl-5-(1-morpholinylethyl)-1-phenylindolizine-7-carboxylic acid: MS (ESI)² m / z 278 [M+Hr.²Step 5: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morphinolin ²ylethyl)-1-phenylindolizine-7-carboxamide: yield of two steps was 17. 'Fl NMR ²(400 ²MHz, CDC13) 6 ppm 11.46(s, 1H), 8.44(s, 1H), 8.27-8.30 (s, 1H), 7.57-7.59(m, ²3H),² 7.40-7.43(m, 2H), 7.20-7.23(m, 1H),7.01-7.02(d,J= 2.8 Hz, 1H),²5.86(s,1H),4.26-4.27 (m, 2H), 4.03-4.08 (m, 1H), 3.55 (brs, 411), 2.58-2.67(m, ²2H), ²2.35 (s, 3H), 2.11-2.17 (m, 5H), 2.07 (s, 3H), 1.39-1.41(m, 311); MS(ESI) m / z ²499 ²[M+Hr.²Example 83: Preparation of²N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-(1-²meth²y1-1H-pyrazol-5-y1)-5-(1-(4-(2,2,2-trifluoroethyl)piperazin-l-²y1)ethyl)indolizine-7-ca ²rboxamide:²122²<DP=123>²CA 03036114 2019-03-07² Soc Er²lac²Boc² 0 0²1 0²)-0 \ NaBH, AcOH² / N²TIOOPN,, 65 C / ²r.CF3²(CF3² L J 0 N²[ 0 n²0 F3c,S,67¨CF,),, 0 'N²õ² EA / HCI I THF, TEA 60 C A. I Et0H / H 0 - I N²- -²F r²0NHc²F-k1²(N 0 0²HATU TEA DMF F112,1²I H I te" Compound 84²0 / ²N²Step 1: Preparation of isopropyl²5-(1-(4-(tert-Butoxycarbonyl)piperazin-l-ypviny1)-6-methyl-2-(1-methyl-1H-²pyrazol ²-5-yl)indolizine-7-formate: similar to step 2 of example 31. MS (ESI) m / z 508 ² [M+Hr.²Step 2: Preparation of isopropyl²5-0 -(4-(tert-butoxycarbonyl)piperazin-l-yl)ethyl)-6-methyl-2-(1-methyl-11-1-²pyrazol ²-5-yl)indolizine -7-formate: similar to step 3 of example 31. MS (ESI) m / z 510 ²²[M+1-I}² Step 3: Synthesis of isopropyl²6-Methyl-2-(1-methy1-1H-pyrazol-5-y1)-5-(1-(piperazin- 1 -yl)ethyl)indolizine-²7-form²ate: isopropyl²5-(1-(4-(tert-butoxycarbonyl)piperazin-l-yl)ethyl)-6-methyl-2-(1-methyl-1H-²pyrazol ²-5-yl)indolizine-7-carboxylate (360 mg (crude), 0.7 mmol) was dissolved in 2 ²mL of²dichloromethane) in a 100 ml dry single-mouth bottle, and trifluoroacetic acid ²(1 ml) ²was added at 0 degree. The mixture was stirred at room temperature for 2 ²hours. ²After the reaction was monitored to have been completed by TLC, NaHCO3 ²solution ²was added and extracted with dichloromethane (50x3 mL). The organic phases ²were ²combined and dried over anhydrous sodium sulfate, flitered and the solvent was²123²<DP=124>²CA 03036114 2019-03-07²removed under reduced pressure to provide yellow oil, which was used in the ²next ²step without purification. MS (ESI) m / z 410 [m+H].²Step 4: Synthesis of isopropyl²6-methyl-2-(1-methyl-IH-pyrazol-5-y1)-5-(1-(4-(2,2,2-trifluoroethyl)piperazine-²1-y1)² ethyl)indolizine-7-carboxylate: isopropyl²6-methyl-2-(1-methy1-1H-pyrazol-5-y1)-5-(1-(piperazin-1-y1)ethyl)indol izine-7-²carbo ²xylate (300 mg (crude), 0.73 mmol) was dissolved in tetrahydrofuran (5 mL) in ²100 ²ml dry single-mouth bottle, and 2,2,2-trifluoroethyl trifluoromethanesulfonate ²(172 ²mg, 0.74 mmol), triethylamine (206 mg, 2.0 mmol) were added. The mixture was²stirred at 60 C for 4 hrs, water was added and extracted by ethyl acetate ²(50x3mL).²The organic phases were combined and dried over anhydrous sodium sulfate. ²After ²filtered, the solvent was removed by evaporation under reduced pressure to ²give ²yellow oil, which was purified through column (ethyl ether: petroleum ether = ²1:3) to ²provide 210 mg pure product (yield-58%). MS (ESL) m / z 492 [M+1-11 .² Step 5: Synthesis of²6-methyl-2-(1-methyl-IH-pyrazol-5-y1)-5-(1-(4-(2,2,2-trifluoroethyl)piperazin-²l-y1)e²thyl)indolizine-7-formic acid: same as step 4 of example 31. MS (ESI) m / z 450 ²[M+Hr.²Step 6: Synthesis of²N-((4-m ethoxy-6-methy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-(1-²meth²y1-1H-pyrazol-5-y1)-5-(1-(4-(2,2,2-trifluoroethyl)piperazin-l-²y1)ethyl)indolizine-7-ca ²rboxamide: same as step 5 of example 31. Yield of two steps was 9%. 1H-NMR ²(CDC13, 400 MHz) 6 ppm8.51(s,1H), 7.64 (s, 1H), 7.45 (s, 1H), 6.84 (s, 1H), ²6.74 (s, ²1H), 6.56 (s, 1H), 6.41(s, 1H), 4.62-4.61 (m, 2H), 4.48-4.46 (m, 1H), 4.10 (s, ²3H),²4.07 (s, 3H), 3.31-3.26 (m, 2H), 3.20-3.14 (m, 2H), 3.07-2.91(m, 4H), 2.68-²2.67 (in,²2H), 2.53 (s, 3H), 2.39 (s, 3H), 1.77 (d, 3H, J=6.911z); MS(ESI) m / z 600 [M+H] ²²Example 84: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-2-(1-methyl-1H-²p ²yrazole-5-y1)-5-(1-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)ethyl)indolizine-7-²carboxa ² mide:²124²<DP=125>²CA 03036114 2019-03-07²r, CF3 F3² r 0²0 t'N) HN NH, 0 0 .. N² HO-jirr, TEA, DMF D Firsi.a) I²\ z²\--N²Compound 85²Step 1: Synthesis of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-(1-methyl-IH-²p ²yrazole-5-y1)-5-(1-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)ethyl)indolizine-7-²carboxa²mide: same as step 5 of example 31. Yield: 8%. 1H-NMR (CDC13, 400 MHz):8.51 ²(s,²1 H), 7.66 (s, 1 H), 7.45 (s, 1 H), 6.93 (s, 1 I-I), 6.75 (s, 1 H), 6.57-6.53 ²(m, 1 H), 4.78 ²(s, 2 H), 4.50 (m, 1 H), 4.11 (s, 3 H), 3.25-3.21 (m, 4 H), 2.94 (m, 4 H), ²2.69 (m, 2 ²H), 2.62 (s, 3 H), 2.56 (s, 3 H), 2.39 (s, 3 H), 1.68 (d, 3 H, J=6.9 Hz); ²MS(ESI) m / z ²584 [M+H]f.² Example 85: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-(1-methyl- 1 ²H-p ²yrazole-3-y1)-5-(1-morpholino)indolizine-7-carboxamide:²0²\ N²0 (N)²Br²N²N H N BH MOH, t²8-0 Pd(dppf)C12,Ac0K 1-1(10Pr), 65 C / ²0²E ) 0²-J ²NH, ( O N NEIGH, Et0HtH0 H0²100 C HARI. TEA, DMF² / ²Compound 86²Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-ypmethyl)-6-methyl-24 I -methyl- I ²H-p²yrazole-3-yI)-5-(1-morpholino)indolizine-7-carboxamide was same as example 31. ²²Step 1: Preparation of ethyl²5-acetyl-6-methyl-2-(1-methyl-IH-pyrazol-3-yl)indolizine-7-formate: Yield 39%. ²²MS (ESI) m / z 326 [M+H]'.²125²<DP=126>²CA 03036114 2019-03-07²Step 2: Preparation of isopropyl²6-methyl-2-(1-methy1-1H-pyrazol-3-y1)-5-(1-morpholinovinypindolizine-7-²carboxyla ²te:²MS (ES!) m / z 409 [M-FH]1-.² Step 3: Preparation of isopropyl²6-methyl-2-(1-methy1-1H-pyrazol-3-y1)-5-(1-morpholinoethypindolizine-7-²carboxyla ²te: yield of two steps was 37%. MS (ESI) m / z 411 [M+H]1-.²Step 4: Preparation of²6-methyl-2-(1-methy1-1H-pyrazol-3-y1)-5-(1-morpholinoethyl)indolizine-7-²carboxyli² c acid: yield 84%. MS (ES!) m / z 369 [M+11.²Step 5: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-(1-methyl-1H-²p ²yrazole -3-yI)-5-(1-morpholinoethyl)indolizine-7-carboxamide: Yield 7%. 1H-NMR ²²(Me0D, 400 MHz):7.57 (s, 1 H), 7.35 (s, 1 H), 6.77 (s, 1 H), 6.49 (s, 1 H), ²6.14 (s, 1²H), 4.46 (s, 2 H), 4.08-4.02 (m, 1 H), 3.92 (s, 3 H), 3.34-3.30 (m, 4 H), 2.69-²2.67 (m,²2 H), 2.37 (s, 3 H), 2.29 (s, 3 H), 2.26 (s, 3 H), 2.25-2.18 (m, 2 H), 1.35-²1.28 (m, 3 ²H); MS(ESI) m / z 503 [M+Hr.²Example 86: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-(1-methyl-IH-²i²midazole- 5-y1)-5-(1-morpholinoethyl)indolizine-7-carboxamide: same as example²50.²0 0 r0,i²\ .. / Pc4cIpp6C12 / AcOK.. / ²N T41-0130. \ / / NaBH² / Ne)²P-0² / 14.4²(0) () 7 0² 0 N ,I1 " ,---- C )²il 2 0 0 N²0 NaOH HO 1 `,N õ.....,,,,,,²'.²1 / ² / ²Q i) Compound 87²N²Step 1: Preparation of ethyl²5-acetyl-6-methyl-2-(1-methy1-1H-im idazol-5-yl)indolizine-7-carboxy late, ²yield² 80%.²126²<DP=127>²CA 03036114 2019-03-07²MS (ES!) m / z 326 [M+Hr²Step 2: Preparation of isopropyl²6-methy1-2-(1-methy1-1H-imidazol-5-y1)-54 -morpholinovinyl)indolizine-7-²carboxy²late: MS (ES 1) m / z 409 [M+H]² Step 3: Preparation of isopropyl²6-methy1-2-(1-methy1-1H-imidazol-5-y1)-5-(1-morpholinoethyl)indolizine-7-²carboxyl ²ate: yield 48%. MS (ES!) m / z 411 [M+Hr.²Step 4: Preparation of²6-methyl-2-(1-methy1-11-1-imidazol-5-y1)-5-(1-morpholinoethyl)indolizine-7-²carboxyl² ic acid: MS (ES!) m / z 369 [M+Hr.²Step 5: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-(1-methyl-1H-²i ²midazol-5-y1)-5-(1-morphinolinylethyl)indolizine-7-carboxamide, yield 10%. ²1H-NMR (DMSO-d6, 400 MHz): 11.48 (s, 1H), 9.17-9.15 (m, 1H), 8.75 (s, 1H). ²8.25²(s, 1H), 7.95-7.93 (m, 1H), 7.38 (s, 1H), 6.86-6.85 (m, 1H), 5.90-5.88 (m, ²1H), 4.62²(s, 2H), 3.99-3.97 (m, 3H), 3.77-3.76 (m, 1H), 3.60-3.59 (m, 4H), 2.70-2.67 ²(m, ²2.42-2.41 (m, 3H), 2.39-2.34 (m, 5H), 2.14-2.12 (m, 3H), 1.54-1.48 (m, 3H). ²MS(ESI) ²m / z 503.2 [M+H]'.²Example 87: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morpholinoe²thyl)-2-(thiazol-5-ypindolizine-7-carboxamide: same as example 50.²0 0 s j:NO j 0²I N H AcOH²Ti OpUe NaBH,,²di3xN)² C .) C0)²0 N = 0 0²HO F4)7,:NH2 P9:ILY:11 .'"-N²I N NaOH² / ²HATU DIEA²N Compound 88 --3²Step 1: Preparation of ethyl²5-methy1-6-methyl-2-(thiazol-5-ypindolizine-7-carboxylate: Yield 33%. MS (ES!)² m / z 329 [M+H]t²127²<DP=128>²CA 03036114 2019-03-07²Step 2: Preparation of isopropyl²6-methy1-5-(1-morpholinoethyl)-2-(thiazol-5-ypindolizine-7-carboxylate: MS ²(ES!) ²m / z 412 [M+H].²Step 3: Preparation of isopropyl²6-methy1-5-(1-morpholinoethyl)-2-(thiazol-5-y1)indolizine-7-carboxylate: yield ²of²two steps was 63%. MS (ES!) m / z 414 [M+H]+.²Step 4: Preparation of²6-methy1-5-(1-morpholinoethyl)-2-(thiazol-5-yDindolizine-7-carboxylic acid: MS ²²(ES!) m / z 372.3 [M+Hr² Step 5: Preparation of²N((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morpholinoe ²thy!)- 2-(thiazol-5-yl)indolizine-7-carboxamide: yield of two steps was 17%.²1H-NMR (CDC13, 400 MHz):11.83 (s.1 H), 8.69 (s,2 H), 7.99 (s,1 H), 7.28-7.30 ²(m,2 ²FI),6.59 (s,1 H),6.96(s,1 H),4.53-4.52(m,2 H),4.06-4.01 (m.11-1), 3.69-²3.68(m,4²H),2.65-2.64 (m,2 H),2.39-2.34(m,6H), 2.26-2.23(m,5 H). 1.50-1.49(m,3H) ; ²MS(ESI)²m / z 506 [M+Hr.²Example 88: Preparation of²N((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-5-(1-²morpholinyl ²ethyl)-2 -(thiazol-4-ypindolizine-7-amide: same as example 50.²0 0 0 0²I CN ) CjL(L² / ²Powpoci,²)=-=1²cc_²N S²CN) (0)²0 N 0² HO),;(1'' N16:7N142 fil-Tho²NeBH4 NaOH²%²AcOH Me0H DIEADMF HATU² N s N,719 =1²Compound 89²Step 1: Preparation of ethyl²5-acetyl-6-methyl-2-(thiazol-4-yl)indolizine-7-carboxylate: Yield 38%. MS ²(ES!) ²m / z 329 [M+H].²128²<DP=129>²CA 03036114 2019-03-07²Step 2: Preparation of isopropyl²6-methy1-5-(1-morpholinylviny1)-2-(thiazol-4-yDindolizine-7-carboxylate: MS ²(ES!) ²m / z 406 [M+H]'.²Step 3: Preparation of isopropyl²6-methy1-5-(1-morpholinylethyl)-2-(thiazol-4-ypindolizine-7-carboxylate: yield ²of²two steps was 35%. MS (ES!) m / z 408 [M+H]²Step 4: Preparation of²6-methy1-5-(1-morpholineethyl)-2-(thiazol-4-y1)indolizine-7-carboxylic acid: ²MS ²(ES!) m / z 366 [M+H].² Step 5: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-5-(1-²morpholinyl ²ethyl)-2-(thiazol-4-y1)indolizine-7-amide: 1H NMR (400 MHz, DMSO-d6) 611.47(s, ²²1H), 9.14-9.13 (d,J= 1.6 Hz, 1H),8.75(s, 1H), 8.20-8.17 (m, 1H), 7.88(d, J = ²1.2 Hz, ²1H), 7.29(s,1H), 6.87(s, 1H), 5.87 (s, 1H), 4.27-4.26(m, 2H), 4.06-4.02(m, ²1H),²3.57(m, 4H), 2.63(m, 2H),2.25 (s, 3H), 2.20-2.15 (m, 5H), 2.11 (s, 3H), 1.46-²1.44(m,²3H); MS(ESI) m / z 506 [M+H]²Example 89: Preparation of²2-(6-aminopyridin-3-y1)-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-²6-²methy1-5-(1-morpholinylethyl)indolizine-7-amide: same as example 31.² H0,B4OH 0²(TiN )cc?0 0²k²coAoppOCl2e / FioNH, TP704²Br N²NH, <NH,²COI²AcOH NaOH 0 re²HATU DIEA²NaBH4 I M.OH / 1-²2 DM,²'I²LNO 0 0 NH,²NH,²tt* Compound 90² (NH,²129²<DP=130>²CA 03036114 2019-03-07²Step 1: Preparation of ethyl²5-acety1-2-(6-aminopyridin-3-yI)-6-methylindolizine-7-carboxylate: Yield 71%. ²MS ²(ESI) m / z 338 [M+H].²Step 2: Preparation of isopropyl²2-(6-aminopyridin-3-y1)-6-methy1-5-(1-morphinolinylvinypindolizine-7-²carboxylate:²MS (ESI) m / z 421 [M+1-1]²Step 3: Preparation of isopropyl²2-(6-aminopyridin-3-y1)-6-methy1-5-(1-morphinolinylethypindolizine-7-²carboxylate: ²yield of two steps was 50%. MS (ESI) m / z 423 [M+Hr.² Step 4: Preparation of²2-(6-aminopyridin-3-y1)-6-methyl-5-(l -morphinolinylethyl)indolizine-7-²carboxylic²acid: MS (EST) m / z 381 [M+H]F.²Step 5: Preparation of²2-(6-aminopyridin-3-y1)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-²6-² methy1-5-(1-morpholinylethyl)indolizine-7-amide: I H NMR (400 MHz, DMSO-d6) 6²11.47(s, 1 H),8.69-8.67(s, 1 H), 8.32-8.26 (m, 2 H), 8.20 (s, 1 II), 7.96(s, 2 ²H), 7.28(s, ²1 H), 7.07-7.05(d, J= 8.8 Hz, 1 H),6.84 (s, 1 El), 5.87 (s, 1 H), 4.27-4.26 ²(m, 2 H), ²4.07-4.05(m, 1 H), 3.59(m, 4 H), 2.26 (s, 3 H), 2.33-2.20 (m, 5 H), 2.11 (s, 3 ²H), ²1.48-1.46(m, 3 H); MS(ESI) m / z 515 [M-I-Hr.² Example 90: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-²morphinolin ²ylethyl)-2-(6,-1-tetrahydropyridin-3-yl)indolizine-7-carboxamide: same as ²example ²44.²130²<DP=131>²CA 03036114 2019-03-07² 401'a , rol²______________________________________ ^,,f Lti' VC:17""iy.L.Aõ--²t" c:To²IN? `li'Dioxane / H20-retlux IA w'c ""'",'²44²(N.-)²I²o²N OH aBH. jt." W .. .,, .. NCM .. m² 7,6 L HO ris- ²\----.²ACOH q HATU OMF 'cL6)² / ¨*N THF PEA²r% ?r-S, ²--(,,²10)²²HNIr"NI,rj,;(²HC, ____. ,...L., , H ²1 / left* Compound 91²_²it²'Cl¨t1²Step 1: Preparation of ethyl²5-acety1-2-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-y1)-6-²methylindolizin ²e-7-carboxylate: Yield 65%. MS (ESI) m / z 507 [M+H].² Step 2: Preparation of isopropyl²2-(6-(4-(tert-butoxycarbonyl)piperazin- 1 -yppyridin-3-y1)-6-methyl-5-(1-²morpholino²vinyl)indolizine-7-carboxylate: MS (ESI) m / z 589 [M+H].²Step 3: Preparation of isopropyl²2-(6-(4-(tert-butoxycarbonyl)piperazin-1-yOpyridin-3-y1)-6-methyl-5-(1-²morpholinoe² thyl)indolizine-7-carboxylate: yield of two steps was 54%. MS (ES1) m / z 591²[MA-1r²Step 4: Preparation of²2-(6-(4-(tert-butoxycarbonyl)piperazin-l-yl)pyridin-3-y1)-6-methyl-5-(1-²morpholinoe ²thyl)indolizine-7-formic acid: MS (ESI) m / z 549 [M+111'.² Step 5: Preparation of tert-butyl²4-(5-(7-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoy1)-6-²methyl-5 ²-(1-morpholinoethypindo1-2-yl)pyridin-2-y1)piperazine-1-carboxylic acid: MS ²(ESI) ²m / z 684 [M+H]+.²Step 6: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morpholinoe²131²<DP=132>²CA 03036114 2019-03-07²thyl)- 2-(6-(piperazin-1-yl)pyridin-3-yl)indolizine-7-carboxamide: three-step ²yield ²was 6%. MS (ES!) m / z 584 [M+1-11`.²Example 91: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-(6-(4-²methylpip² erazine) -1-yl)pyridin-3-y1)-5-(1-morpholinoethyl)indolizine-7-carboxamide:²)' ri 11 jV0²,t)²THF²\=(NN² / ².11²0²0 0 LN- I²7o01 I 'N²HATU DMF t VA0 Compound 92²DIPEA²Q²Step 1: Synthesis of isopropyl²6-methyl-2-(6-(4-methylpiperazin- 1 -yl)pyridin-3-y1)-5-(1-²morpholinoethyl)indolizin²e-7-carboxylate: isopropyl²6-methy1-5-(1-morpholino)-2-(6-(piperazin-1-yppyridin-3-y1)indolizine-7-²carboxylat²e (120 mg, 0.244 mmol) was added to a dry nitrogen-protected 100 ml single-²mouth ²flask, cooled to 0 C, then NaH (24.4 mg. 0.61 mmol) was added, stirred at room ²²temperature for 30 min, and then iodomethane (38.2 mg, 0.269 mmol) was added. ²The reaction was stirred at room temperature for 10 minutes, and 20 ml of ²ethyl²acetate and 10 ml of water were added to the reaction system. The organic ²phase was²seperated and concentrated to provide a crude product (90mg), which was used ²directly in the next step. MS (ES!) m / z 506 [M+Fl]+.²Step 2: Preparation of²6-methy1-2-(6-(4-methylpiperazin-1-yppyridin-3-y1)-5-(1-²morpholinoethyl)indolizin² e-7-carboxylic acid: same as step 4 of example 31. MS (ES!) m / z 464 [M+H].²Example 3: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-(6-(4-²methylpip ²erazine) -1-yl)pyridin-3-y1)-5-(1-morpholinoethypindolizine-7-carboxamide: ²same as ²step 5 of example 31. Three-step yield was 3%.² MS (ES!) m / z 598 [M+H].²132²<DP=133>²CA 03036114 2019-03-07²Example 92: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-5-(1-(4-(dimethy lam ²ino)pip ²eridine-1-ypethyl)-6-methyl-2-(3.4,5-trimethoxyphenyl)-indolizine-7-²carboxamide: ²same as example 31.²0 0²a ,c))1,² LL NaBH4²H ²MOH²¨ \²0 0²\ / p²a²N ,a 0 N²Ne0H Ho s"..N .JTNHN² HATU DIPEA / It'at Compound 91² / ²0 0\²Step 1: Preparation of isopropyl²5-(1-(4-(dimethylamino)piperidin-1-yl)viny1)-6-methyl-2-(3,4,5-²trimethoxypheny1)-i ²ndolizine-7-carboxylate: MS (ESI) m / z 536 [M+H]²Step 2: Preparation of isopropyl².. 5-(1-(4-(Dimethylarnino)piperidin-l-yOethyl)-6-methyl-2-(3,4,5-²trimethoxypheny1)-i²ndolizine-7-carboxylate: yield of two steps was 60%. MS (ESI) m / z 538 [M+H] ²Step 3: Preparation of²5-(1-(4-(dimethylamino)piperidin-l-ypethyl)-6-methyl-2-(3,4,5-²trimethoxypheny1)-i ²ndolizine-7-carboxylic acid: MS (ESI) m / z 496.5 [M+Hr.² Step 4: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-5-(1-(4-²(dimethylamino)pip ²eridine-1-yl)ethyl)-6-methyl-2-(3,4,5-trimethoxyphenyl)-indolizine-7-²carboxamide: ²Yield of the two steps was 29%. 1H-NMR (CDC13, 400 MHz):12.39 (s, 1 H), 8.50 ²(s, ²1 H), 7.31-7.27 (m, 2 H), 6.82-6.79 (m, 2 El), 6.64 (s, 1 H), 5.95 (s, 1 H), ²4.51 (s, 2²H), 4.04-4.03 (m, 1 H), 3.93 (s, 6 H), 3.88 (s, 3 H), 3.44 (s, 1 H), 2.73-2.62 ²(m, 2 H),²2.52 (s, 6 H), 2.43 (s, 3 H). 2.37 (s, 3 H), 2.22 (m, 3 H), 2.18-2.16 (m, 2 ²H), ²1.99-1.94 (m, 2 H), 1.94-1.80 (m. 2 H), 1.77-1.52 (in, 3 H); MS(ESI) m / z 630 ²[M+Hr.²133²<DP=134>²CA 03036114 2019-03-07²Example 93: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-(4-²(dimethylamino)pip²eridine-1-ypethyl)-6-methy1-2-(pyridin-4-ypindolizine-7-carboxamide: same as ²example 31.²HI)²-N 0 N²AcOH²TIO-Opr), / NaBH, _________________ - 0 I T². N NaBH4² / ²¨N² C$ / ²9 a =N²0 0 0 N²HO)L' N N²NaOH \ 14 / 4L=619 Compound 94² / ² / ² Step 1: Step 1: Preparation of isopropyl²5-(1-(4-(dimethylamino)piperidin- 1 -ypethylene)-6-methy1-2-(pyridin-4-²ypindolizine²-7-carboxylate: MS (ES!) m / z 447 [M+H]²Step 2: Preparation of isopropyl²541 -(4-(dimethylamino)piperidin-l-ypethyl)-6-methyl-2-(pyridin-4-²y1)indolizine-7-²carboxylate: yield of two steps was 52%. MS (ES!) m / z 449 [M+H]²Step 3: Preparation of²5-(1-(4-(dimethylamino)piperidin-1-yl)ethyl)-6-methyl-2-(pyridin-4-²ypindolizine-7-²carboxylic acid.² MS (ES!) m / z 407 [M+HF.²Step 4: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-(4-²(dimethylamino)pip ²eridine-1-ypethyl)-6-methyl-2-(pyridin-4-ypindolizine-7-carboxamide: yield of ²the ²two steps was 37%. 1H-NMR (Me0D, 400 MHz):9.14 (s, 1H), 8.66-8.64 (m, 2H),²8.35-8.33 (m, 21-1), 7.52 (s, 1H), 7.23 (s, 1H), 6.16 (s, 1H), 4.47 (s, 2H), ²3.82-3.81 (s, ²1H), 2.99-2.98 (m, 1H), 2.85-2.81 (m, 8H), 2.39 (s, 31-1). 2.35 (s, 3H). 2.29-²2.28 (m, ²21-1), 2.24-2.22(m, 6H), 2.11-1.96 (m, 214), 1.71-1.69 (m, 3H); MS(ESI) m / z ²541.4 ²[M+I-114.²134²<DP=135>²CA 03036114 2019-03-07²Example 94: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-5-(1-²morpholinyl ²ethyl)-1- (3,5-dimethylphenyl)indolizine-7-amide: same as example 31.²OMe²HO Cr)²HO 0 0²0 B0² ...--,0 1 ...... ¨0m. --'-'0 I IL,² N H ...²\ / ² / \ OMe Me \ / i¨OMe ²Me ²co co)²0 N 0 CD²0 0 N UOH ²1 N HO 1 F,11:NH2²NaBH4²1 / ²AcOH²)i--²-0Me 2-OMe Compound 95 ¨OM²Me0 Me0 Me0²r e² Step 1: Preparation of ethyl²5-acety1-6-methy1-2-(3,5-dimethylphenyl)indolizine-7-carboxylate: yield 60%. ²MS ²(ES!) m / z 382 [M+141 .²Step 2: Step 2: Preparation of isopropyl²6-methyl-5-(1-morpholinylviny1)-1-(3,5-dimethylphenypindolizine-7-carboxylate.² MS (ES!) m / z 465 [M+H]+.²Step 3: Step 3: Preparation of isopropyl²6-methyl-5-(1-morpholinylethyl)-1-(3,5-dimethylphenypindolizine-7-carboxylate:²yield of two steps was 55%. MS (ES!) m / z 467 [M+Ht+.²Step 4: Preparation of²6-methyl-5-(1-morphinolinylethyl)-1-(3,5-dimethylphenyl)indolizine-7-²carboxylic²acid: MS (ESI) m / z 425 [M+Hr.²Step 5: Preparation of²N4(4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-morphinolin ²²ylethyl)-1-(3,5-dimethylphenyl)indolizine-7-carboxamide: yield of two steps ²was 6%.² iH NMR (400 MHz, CDC13) 611.56(s, 1 H), 8.62(s, 1 H), 7.66-7.64 (m, 1 H),²7.47-7.45(m,1 H),6.73(s, 2 H), 6.60(s, 1 1-1),6.32(s,1 H), 5.88(s,1 H),4.45-²4.44 ²(d,J=4.8Hz, 2 H), 4.03-4.01 (m, 1 H), 3.79 (s, 6 H), 3.62(s, 4 H), 2.58 (s, 2 ²H), 2.32 ²(s, 3 H), 2.27 (s, 3 H), 2.20-2.13(m, 5 H),1.43-1.41(d,J=6.4 Hz, 2 11); ²MS(ESI) m / z ²559 [M+Hr²135²<DP=136>²CA 03036114 2019-03-07²Example 95: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-morpholinyl ²²ethyl)-1- (3,4-dimethylphenyl)indolizine-7-amide: same as example 31.²0²0 HO \ / =re² HOB¨ I²OMo² / Pd(dppf)C12².0me²²om.²HO HI1,1 0 01-12 N²NaBH4 LIOH² / ²AcOH Me0H / t1,0 HAM 01EA²OMe OMe²Compound / 9(>s Cd"² OMe OM, OMe² Step 1: Preparation of ethyl²5-acety1-6-methy1-2-(3,4-dimethylphenyl)indolizine-7-carboxylate: yield 42%. ²MS (ESI) m / z 382 [M+Hr.²Step 2: Preparation of isopropyl²6-methyl-5-(1-morpholinylviny1)-1-(3,4-dimethylphenypindolizine-7-carboxylate.² MS (ESI) m / z 465 [M+Hr²Step 3: Preparation of isopropyl²6-methyl-5-(1-morpholinylethyl)-1-(3,4-dimethylphenyl)indolizine-7-²carboxylate:²yield of two steps was 55%. MS (ESI) m / z 467 [M+1-11+.²Step 4: Preparation of²6-methyl-5-(1-morphinolinylethyl)-1-(3,4-dimethylphenyl)indolizine-7-²carboxylic²acid: MS (ESI) m / z 425 [M+141+.²Step 5: Preparation of²N-((4,6-dimethy1-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morphinolin²ylethyl)-1-(3,4-dimethylphenyl)indolizine-7-carboxamide: yield of two steps ²was² 13%. 1H NMR (400 MHz, CDC13) 611.08(s, 1 H), 8.59(s, 1 H), 7.25 (s, 1 H),²7.15-7.13(m, 2 H), 7.11(s, 1 H), 7.08(s, 1 H),6.86-6.84(d,J= 8.4 Hz, 1 H), ²6.57(s,1 ²H),5.88(s, 1 H), 4.45-4.44 (d, J = 4.4 Hz, 2 H), 4.01-3.95 (m, 1 H), 3.89(s, 3 ²H), ²3.85(s, 3 H), 3.63 (s, 3 H), 2.59 (s, 2 H), 2.33 (s, 3 H),2.27 (s, 3 H),2.21-²2.15 (m, 5 ²H),1.44-1.42(d,J= 6.4 Flz,3 H); MS(ESI) m / z 559 [M+111'.²136²<DP=137>²CA 03036114 2019-03-07²Example 96: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(3-methoxypheny1)-6-²met ²hy1-5-(1-morpholino)indolizine-7-carboxamide: same as example 31.²RAVetrmsoprop,1² I H __ "lanai'²N² / 60'C overnreght² / ²13r²¨ 0² 0 0² NaBH I 0 0 N²LHDH HO N. N'Th 11:21:C1( HikN² , N c.õ0 H IN² / ² ACOH % HATU DMF / ²¨ THE²\ 0 DIPEA²¨ \ 0²Compound r -0\² Step 1: Preparation of ethyl²5-acetyl-2-(3-methoxypheny1)-6-methylindolizine-7-carboxylate: Yield 72%. ²MS(ESI) m / z 352 [1\4+M'.²Step 2: Preparation of isopropyl²2-(3-methoxypheny1)-6-methy1-5-(1-morpholinylvinypindolizine-7-carboxylate: MS² (ESI) m / z 435 [M-41]*.²Step 3: Preparation of isopropyl²2-(3-methoxypheny1)-6-methyl-5-(1-morpholinylethyl)indolizine-7-carboxylate:²yield of two steps was 52%. MS (ES!) m / z 437 [M+H]²Step 4: Preparation of²2-(3-methoxypheny1)-6-methyl-5-(1-morpholinylethyl)indolizine-7-carboxylic ²acid:²MS (ES!) m / z 395 [M+Hr.²Step 5: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-2-(3-methoxypheny1)-6-²met ²hy1-5-(1-morpholinylethyl)indolizine-7-carboxamide: Yield 50%. 1H-NMR (DMSO,²400 MHz) :1 I .48(s, 1H), 8.23(s,1H),8.19(s, 1H), 7.35-7.23(m, 4H), 6.85(m, ²2H),²5.88(s,1H), 4.28-4.27(m, 2H), 3.85(s, 6H), 3.60(m, 51-1), 2.28(s, 3H), 2.21(s, ²²3H),2.19(s, 3H), 1.55-1.54(m, 31-1); MS(ES1) m / z 529 [M+HF.²Example 97: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-methoxypheny1)-6-²met² hy1-5-(1-morpholinoethyl)indolizine-7-carboxamide: same as example 31.²137²<DP=138>²CA 03036114 2019-03-07²0² 7'0 thl r=a7c 0YyyL,²\²' N thoxane / H20 reflux² / 60 C oxerrught²IL?²Br²0 0² / 0²C )²0²7'"0 .".= N'Th 0 0²0 0 N² L OH NO " 7...a"N)1' µ"-² NaBH N 4 'NINA H!² / ² ACOH HATU DMF / ²THE²DIPEA²0 Compound 98²0 0²Step 1: Preparation of ethyl²5-acetyl-2-(4-methoxypheny1)-6-methylindolizine-7-carboxylate: Yield 60%. MS ²(ES!) m / z 352 [M+H}4.² Step 2: Preparation of isopropyl²2-(4-methoxypheny1)-6-methy1-5-(1-morpholinylvinyl)indolizine-7-carboxylate: ²MS ²(ES!) m / z 435 [M+Hr.²Step 3: Preparation of isopropyl²2-(4-methoxypheny1)-6-methy1-5-(1-morpholinylethypindolizine-7-carboxylate:² yield of two steps was 41%. MS (ES!) m / z 437 [M+FIJ'.²Step 4: Preparation of²2-(4-methoxypheny1)-6-methy1-5-(1-morpholinylethypindolizine-7-carboxylic ²acid:²MS (ES!) m / z 395 [M+H].²Step 5: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-2-(4-methoxypheny1)-6-²met²hy1-5-(1-morpholinylethyl)indolizine-7-carboxamide: Yield of two steps was 7%. ²²1H-NMR (CDC13, 400 MHz) :11.69(s, 1 H), 8.65(s, 1 H), 7.77(s, 1 H), 7.67-²7.66(m, ²2 H), 7.32(s, 1 H), 6.96-6.94(m, 2 H), 6.63(s, 1 H), 5.94(s,1 H), 4.52(m, 2 ²H), 4.09(m, ²1 H), 3.85(s, 3 H), 3.60(m, 4 1-1), 2.67(s, 2 H), 2.28(s, 3 H), 2.21(s,3 ²H),2.15(m, 5 H),² 1.52(m, 3 H); MS(ESI) m / z 529 [M+H]*.²Example 98: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-(4-²methylpip ²erazine)-1-ethyl)-2-bromoindolizine-7-carboxamide: same as example 30.²138²<DP=139>²CA 03036114 2019-03-07²(NINI Jo²0 N²0 0²²I²NaBH,²7,-0-pro1,²Br AcOH²Br²Br²) 0²(²141:NH2 HAõ; N² LiOH HO "c___.z²I H I²Me0H / F120 HATU DIEA²Br Compound 99²Step 1: Step 1: Preparation of isopropyl²6-methy1-5-(1-(4-methylpiperazine)-1-viny1)-2-bromoindolizine-7-carboxylate: ²MS ²(ESI) m / z 420 [M+Hr² Step 2: Step 6: Preparation of isopropyl²6-methyl-5-(1-(4-methylpiperazine)-1-ethyl)-2-bromoindolizine-7-carboxylate: ²yield ²of two steps was 87%. MS (ESI) m / z 424 1M+Hr.²Step 3: Step 1: Preparation of²6-methy1-5-(1-(4-methylpiperazine)-1-ethyl)-2-bromoindolizine-7-carboxylic ²acid:² MS (ESI) m / z 380 [M+Hr.²Step 4: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-(4-²methylpip ²erazine)-1-ethyl)-2-bromoindolizine-7-carboxamide: yield 8%. I H NMR (400 MHz, ²²CDC13) 58.11(s, 1H), 7.28-7.23(m, 1H), 6.77 (s, 111), 6.40(s, 114), 5.90(s, ²1H), 5.86(s,²1H), 4.50-4.35(m, 1H), 4.23-4.22 (d, ,I=5.6HZ, 2H), 3.64-3.58 (m, 4H), 3.08-²3.02 (m,²4H), 2.32 (s, 3H), 2.25(s, 3H), 2.20 (s, 3H), 2.17 (s, 3H), 1.48-1.44 (m, 3H); ²MS(ESI) ²m / z 536 [M+H1+.²Example 99: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-(4-²ethylpiper² azine)-1-ethyl)-2-bromoindolizine-7-carboxamide: same as example 30.²139²<DP=140>²CA 03036114 2019-03-07²)²0 N²O ² 0 N²0 0²'I / IL' CNN) I²NaBH, N² ____________________________ H² / ²Ti-O-pro)4 AcOH²Br Br²Br²0 (NNj 0 0 (61N²LION HO²I²Ma0H / H20 HATU DiEA² / ²Br²Compound 105²Step 1: Preparation of isopropyl²6-methy1-5-(1-(4-ethylpiperazine)-1-viny1)-2-bromoindolizine-7-carboxylate: MS ²²(ESI) m / z 434 [M+H].² Step 2: Preparation of isopropyl²6-methyl-5-(1-(4-ethylpiperazine)-1-ethyl)-2-bromoindolizine-7-carboxylate: ²yield²of two steps was 99%.²MS (ESI) m / z 436 [M+F11 .²Step 3: Preparation of²6-methyl-5-(1-(4-ethylpiperazine)-1-ethyl)-2-bromoindolizine-7-carboxylic ²acid: MS²(ESI) m / z 394 [M+Hr.²Step 4: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyrid in-3-yOmethyl)-6-methyl-5-(1-(4-²ethylpi per²azine)-1-ethyl)-2-bromoindolizine-7-carboxamide: yield of two steps was 60%. ²1H² NMR (400 MHz, Me0D) 6 7.35(s, 1 H), 6.57(s, 1 H), 6.14(s, 1 H), 4.46(s, 2 H),²4.22-4.17(m, 1 H), 3.67-3.63(d, J=13.2 Hz, 1 H), 3.58-3.55 (m, 211), 3.40-²3.37(d, ²J=12.4Hz, I H), 3.25-3.19(m, 41-1), 2.45-2.38(m, 5H), 2.31(s, 3H), 2.25(s, ²3H), ²1.55-1.53(d, J=6.8Hz, 3H) , 1.34-1.31(t, J=7.6Hz, 3H); MS(ESI) m / z 552 [M+Hr.²Example 100: Preparation of²2-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-²(pi²perazine)-1-yl)ethyl)indolizine-7-carboxamide:²140²<DP=141>²CA 03036114 2019-03-07²T ' Boo N²0 C², 0 N² N-B" N NOR, NaOH. Et0H / H20² I / AcOH²-nopro)4 N 80 C²Br / ²Br²Boc² c HN NH2 ( r²HO²TFNDCNI HNja'N²HATU TEA DMF²I N I H I²Br Br Compound 101²Step 1: Preparation of isopropyl²2-bromo-5-(1-(4-(tert-butoxycarbonyl)piperazin- 1 -yl)viny1)-6-²methylindolizine-7-car ²boxylate: same as step 1 of example 30. MS (ES!) m / z 506 [M+Fll'.² Step 2: Preparation of isopropyl²2-bromo-5-(1-(4-(tert-butoxycarbonyl)piperazin-l-yl)ethyl)-6-methy I indol ²izine-7-car ²boxylate: same as step 2 of example 30. Yield of two steps was 33%. MS (ES!) ²m / z ²508 [M+H]'.²Step 3: Preparation of²2-bromo-5-(1-(4-(tert-butoxycarbonyl)piperazin-l-yl)ethyl)-6-methylindolizine-²7-car²boxylic acid: same as step 3 of example 30. MS (ES!) m / z 466 [M+H]'.²Step 4: Preparation of tert-butyl²4-(1-(2-(2,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)aminocarbony1)-6-²meth ²ylindolizine-5-yl)ethyl)piperazine- 1 -carboxylate: same as step 4 of example ²30.² Yield of two steps was 40%. MS (ES!) m / z 600 [M+H]²Step 5: Preparation of²2-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²(pi ²perazine)-1-yl)ethyl)indolizine-7-carboxamide: same as step 5 of example 60. ²Yield: ²53%. 1H-NMR (CDCI3, 400 MHz): 7.34 (s, 1 H), 6.57 (s. 1 H), 6.12 (s, 1 H), ²4.64 (s,²2 H), 4.19-4.18 (m, 1 H), 3.22-3.17 (m, 4 Ft), 2.93-2.90 (m, 2 11). 2.55-2.45 ²(m, 2 H),²2.41 (s, 3 H), 2.30 (s, 3 H), 2.24 (s, 3 FI), 1.51 (d, 3 1-1, J=6.7 Hz); ²MS(ESI) m / z 500 ²[M+Hr²141²<DP=142>²CA 03036114 2019-03-07²Example 101: Preparation of²5-(1-(4-methylpiperazin-1-yl)ethyl)-2-bromo-N-((4,6-dimethyl-2-oxo-1,2-²dihydropyr ²idine-3-yl)methyl)-6-methylindolizine-7-carboxamide:²( C²0 0 N 0 0 N²CH3COCI, TEA, DCM _ Fir)ja'N²7C111 I I H I² / ²Br Compound 102² Step 1: Preparation of²5-(1-(4-methylpiperazin- 1 -yl)ethyl)-2-bromo-N-((4,6-dimethyl-2-oxo-1,2-²dihydropyr ²idin-3-yl)methyl)-6-methylindolizine-7-carboxamide: In a 50 ml dry single-²mouth ²bottle, compound ²2-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²(pi²perazin-1-yl)ethyl)indolizine-7-carboxamide (38 mg, 0.076 mmol) was dissolved ²in²dichloromethane (3 mL), acetyl chloride (140 mg, 1.8 mmol), triethylamine (180 ²mg, ²1.8 mmol) were added and stirred at room temperature for 1 hour. The reaction ²mixture was separated and purified by preparative purification. The solvent ²was ²evaporated under reduced pressure and lyophilized to afford white solids (32 ²mg,²yield: 78%). 111-NMR (CDC13, 400 MHz):8.37 (br, 1 H), 7.24 (s, 1 FI), 6.82 (s, ²1 H),²6.58 (s, 1 H), 6.39 (s, 1 H), 4.54-4.52 (m, 2 H),4.02-3.97 (m, 1 H), 3.82-3.79 ²(m, 1 ²H), 3.47-3.36 (m, 3 H), 2.93-2.84 (m, 4 H), 2.56 (s, 3 H), 2.42 (s, 3 Fp, 2.27 ²(s, 3 ²H),2.06 (s, 3 Fl), 1.49 (d, J=6.7 Hz, 3 Fl); MS(ESI) m / z 542 [M+Hr²Example 102: Preparation of²2-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-5-(1-(4-(2-²hydrox²yacetyl)piperazin-l-yl)ethyl)-6-methylindolizine-7-carboxamide:²142²<DP=143>²CA 03036114 2019-03-07²OH²O²Oyi²HATO DIEA 0 **1,1 NaOH²DMF²I 1,J\²Me0H / 1-120²N / .)² / ²Br²Br²OH OH²0 i(N 11)²N HATU DA A IE -²DmF s' HI'N 0 14²I H I N itg#00 Compound 103²I / ²Br Br²Step 1: Preparation of isopropyl²2-bromo-5-(1-(4-(2-hydroxyacetyl)piperazin-l-yl)ethyl)-6-methy 1 indolizine-7-²carbox ²ylate: same as step 1 of example 102, yield: 48%. MS (ES1) m / z 466 [M+FI14.² Step 2: Preparation of²2-bromo-5-(1-(4-(2-hydroxyacetyl)piperazin-1-yl)ethyl)-6-methylindolizine-7-²carbox ²ylic acid: same as step 4 of example 31. MS (ESI) m / z 424 [M+H]+.²Step 3: Preparation of²2-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-(4-(2-²hydrox²yacetyl)piperazin-1 -yl)ethyl)-6-methylindolizine-7-carboxamide: same as step ²5 of²example 31, yield 5%. 1H NMR (400 MHz, DMSO-do) 6 ppm 8.41(s, 1H),7.31(s, 1H), ²²6.54 (s, 1H), 6.10(s, 1H),4.75 (s, 2H), 4.58 (s, 2H), 4.20(s, I H), 3.58-²3.71(m, 3H), ²3.19-3.24(m, 2H),2.36 (s, 3H), 2.28-2.20 (m, 8H), 2.11 (s, 3H), 1.37-1.32 (m, ²3H); ²MS(ESI) m / z 560 [M-411 .² Example 103: Preparation of²2-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²(4-( ²methylsulfonyl)piperazin- 1 -yl)ethyl)indolizine-7-carboxamide: same as ²example 102.²143²<DP=144>²CA 03036114 2019-03-07²9 9²) 9²ci o 0 N² I Et04 DCM NaOH¨"-² N HO²Br²Br Br²¨S=0²0 r,N,1²f:õ..11,:firNH2 0²letiono, Compound 104²HATU DIEA² / ²Br²Step 1: Preparation of isopropyl²2-bromo-6-methyl-5-(1-(4-(methylsulfonyppiperazin-l-y1)ethyl)indolizine-7-²carboxy ²late: yield 91%. MS (ESI) m / z 488 [M+Hr.² Step²2: 2-bromo-6-methyl-5-(1-(4-(methylsulfonyl)piperazin-1-ypethyl)indolizine-7-²carb²oxylic acid: yield 91%. MS (ESI) m / z 444 [M+Hr²Step 3: Preparation of²2-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²(4-(²methylsulfonyl)piperazin-l-yflethypindolizine-7-carboxamide: yield 29%. 11-1-²NMR²(DMSO-do, 400 MHz): 8.28 (s, 1 H), 8.24-8.21 (m, 1 H), 7.27 (s, 1 H), 6.61 (s, ²1 1-1), ²5.88 (s, 1 H), 4.27-4.26 (m, 2 H), 4.11-4.10 (m, 1 H), 3.12-3.11 (m, 4 H), ²2.89 (s, 3 ²H), 2.89-2.88 (m, 2 H), 2.24-2.21 (m, 5 H).2.21-2.20 (m, 3 H), 2.12 (s, 3 H), ²1.44-1.42 (m, 3 H);MS(ESI) m / z 580 [M+H]'.² Example 104: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-(4-²ethylsulfo ²nyl) piperazine)-1-ethyl)-2-bromoindolizine-7-carboxamide: same as example ²102.²HHCI 0 0 0.O²õ²²H1211. 0 0 N²ciJ OjtJ²LOH HO I __________________________________________ DjEANH,²N ¨ I² / Na2CO, N ma0H / H,0²DMF²Br Br² Br Compound 113'.²Step 1: Preparation of isopropyl²6-methyl-5-(1-(4-ethylsulfonylpiperazine)-1-ethyl)-2-bromoindolizine-7-²carboxylate:²yield 88%. MS (ESI) m / z 500 [M+H]²144²<DP=145>²CA 03036114 2019-03-07²Step 2: Preparation of²6-methyl-5-(1-(4-ethylsulfonylpiperazine)-1-ethyl)-2-bromoindolizine-7-²carboxylic ²acid: yield 76%. MS (ES!) m / z 458 [M+Hr.²Step 3: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-(4-²ethylsulfo²nylpiperazine)- l -ethyl)-2-bromoindolizine-7-carboxamide: yield 88%. 1H NMR ²(400 ²MHz, Me0D) 6 7.97(s, 1H), 7.39(s, 1H). 6.61 (s, 1H), 6.23(s,1H), 4.46(s,1H), ²3.10-3.03(m,1H), 2.99(s,1H), 2.40(s,3H), 2.32 (m, 3H), 2.28 (s, 3H), 1.38-²1.34(m, ²7H), 1.33-1.29(m, 3H); MS(ESI) m / z 592 [M+Hr.² Example 105: Preparation of²2-bromo-N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-5-(1-(4-²( ²3,3,3-trifluoropropyl)piperazin-1-yl)ethyl)indolizine-7-carboxamide:²F F F F.õFõ.,F²F H NCI F F²N²N, NaOH²DIPEA C'1²I )²Me0H / H -..- ²I²\ / Br 20 Microwave I N HO²HATU² i) Br Br²Compound 106 ir²Step 1: Preparation of ethyl²2-bromo-6-methy1-5-(1-(4-(3,3,3-trifluoropropyl)piperazin-1-²y1)ethyl)indolizine-7-ca²rboxylate: in a 100 ml dry single-mouth flask, isopropyl ²2-bromo-6-methyl-5-(1-(piperazine-l-ethyl)ethypindolizine-7-carboxylate ²hydrochloride (170mg, 0.38 mmol) was dissolved in N,N-dimethylformamide (10 ²mL), and 1,1,1-trifluoro-3-iodopropane (170 mg, 0.76 mmol), potassium ²carbonate²(157 mg, 1.14 mmol) were added, the mixture was microwave-stirred at 100 C ²for 2²hours, water was added, and extracted with ethyl acetate (50x3 mL). The ²combined ²organic phase was dried over anhydrous sodium sulfate, filtrated, and solvent ²was ²removed under reduced pressure to give a yellow oil (120 mg, 63%), MS (ES!) ²m / z ²504 [M+H].² Step 2: Synthesis of²2-bromo-6-methy1-5-(1-(4-(3,3,3-trifluoropropyl)piperazin-1-²y1)ethyl)indolizine-7-ca ²rboxylic acid: same as step 2 of example 102. MS (ES!) m / z 462 [M+Hr²145²<DP=146>²CA 03036114 2019-03-07²Step 3: Preparation of²2-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²(4-( ²3,3,3-trifluoropropyl)piperazin-I -yl)ethyl)indolizine-7-carboxamide: same as ²step 3 ²of example 102. Yield: 56%. 11-1 NMR (400 MHz, DMSO-do) 6 11.47(s, I²H),8.24-8.20(m, 2 H), 7.29 (s, 1 H), 6.63 (s, 1 H), 5.88 (s, 1 H), 4.27-4.26 ²(m, 2 H),²4.15-4.13(m, I H), 3.59(m, 3 H), 3.48-3.42(m, 2 H), 3.33-2.81 (m, 4 H), 2.26 ²(s, 3 H), ²2.35 (s, 3 H), 2.25 (s, 6 H), 2.12 (s, 3 H), .45-1.44(m, 3 H): MS(ESI) m / z 596 ²²[M+Hr²Example 106: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-5-(1-(4-(dimethylarn ²ino)pip²eridine-1-ypethyl)-6-methyl-2-(1-methyl-1H-pyrazol-5-yl)indolizine-7-²carboxamide: ²same as example 31.²0)1,i(L.rj,²NaBH, N²AcOH² / -11 1)(,-proi4²N²N²N²e')²NaOH HO ²HATU, DIPEA²Compound 107 / ²Step 1: Step 1: Preparation of isopropyl²5-(1-(4-(dimethylamino)piperidin-1-yl)viny1)-6-methyl-2-(1-methyl-1H-pyrazol-5-²y1²)indolizine-7-carboxylate: MS (ES!) m / z 450 [M+H] +.²Step 2: Preparation of isopropyl²5-(1-(4-(dimethylam ino)piperidin-l-yl)ethyl)-6-m ethyl-2-( I -methyl-1H-²pyrazol-5-y1)²indolizine-7-carboxylate: yield of two steps was 51%. MS (ES!) m / z 452 [M+H]l.² Step 3: Preparation of²5-(1-(4-(dimethylamino)piperidin-1-yl)ethyl)-6-methyl-24 l -methyl-I H-pyrazol-²5-y1) ²indolizine-7-carboxylic acid: MS (ES!) m / z 410.5 [M+Hr.²Step 4: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-(4-²(dimethylamino)pip²eridine-1-yl)ethyl)-6-methyl-2-(1-methyl-1H-pyrazol-5-yl)indolizine-7-²carboxamide:²146²<DP=147>²CA 03036114 2019-03-07²Yield of the two steps was 20%. 1H-NMR (DMSO-d6, 400 MHz):11.54 (s, I H), ²9.45-9.44 (m, 1 H), 8.68-8.67 (m, 1 H). 8.23 (s, 1 H), 7.43-7.32 (m, 2 H), ²6.78-6.75 ²(m, 1 H), 6.43 (s, 1 H), 5.88 (s, 1 H), 4.28-4.26 (m, 2 H), 4.18 (m, 3 H), ²3.43-3.42 (m, ²1 H), 2.78-2.73 (m, 8 H), 2.38-2.36 (m, 3 H), 2.26-2.21 (m, 5 H). 2.16-2.14 ²(m, 6 H),² 1.96-1.94 (m, 2 H), 1.75-1.73 (m, 2 H);MS(ESI) m / z 544 [M+Hr²Example 107: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-(4-²(dimethylamino)pip ²eridine- I -yl)ethyl)-6-methyl-2-(1-methyl-IH-pyrazol-2-y1)indolizi ne-7-²carboxamide: ²same as example 50.²0 0²0 0² / _______________________ ¨²Pd(dppf)CID AcOK AcOH²61)-cOjc N / )²aN²N NaOH HO , ²I²N / NATU, DILA.² / ²N² N cõ)²Compound 108²Step 1: Preparation of isopropyl²5-(1-(4-(dimethylamino)piperidin-1-yl)viny1)-6-methyl-2-(1-methyl-IH-pyrazol-2-²y1 ²)indolizine-7-carboxylate: MS (ESI) m / z 450 [M+H]'.²Step 2: Preparation of isopropyl²5-(1-(4-(dimethylamino)piperidin-1-y Dethyl)-6-m ethy 1-241 -m ethy 1-1H-²pyrazol-2-y1)²indolizine-7-carboxylate: yield of two steps was 45%. MS (ESI) m / z 452 [M+H]²Step 3: Preparation of²5-(1-(4-(dimethylamino)piperid in-l-ypethyl)-6-methyl-2-(1 -methyl-1 H-pyrazol-²2-y1)²indolizine-7-carboxylic acid: MS (ESI) m / z 410 [M+H]'.² Step 4: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-(4-²(dimethylamino)pip ²eridine-1-ypethyl)-6-methyl-2-(1-methyl-1H-pyrazol-2-yl)indolizine-7-²carboxamide: ²Yield of the two steps was 55%. 1H-NMR (Me0D, 400 MHz):8.96 (s, 1H), 7.62 (s, ²1H), 7.58 (s, 2H), 7.07 (s, 1H), 6.19 (s, 1H), 4.49 (s, 2H), 4.47 (s, 1I-1), ²4.07 (s,²3.69-3.67 (m, 1H), 2.96 (s, 6H), 2.41 (s, 3H), 2.37 (s, 3H), 2.28-2.26 (m, ²5H).²147²<DP=148>²CA 03036114 2019-03-07²1.98-1.95 (m, 2H), 1.69-1.67 (m, 2H); MS(ESI) m / z 544 [M+Hr.²Example 108: Preparation of²5-(1-(4-(dimethylamino)piperidin-l-ypethyl)-N-((4-methoxy-6-methyl-2-oxo-1,2-²dih ²ydropyridin-3-yOmethyl)-6-methyl-2-(1-methyl-IH-imidazol-2-yl)indolizine-7-²carbo² xamide: same as step 5 in Example 31, wherein the desired²3-(aminomethyl)-4-methoxy-6-methylpyridine-2(1H)-one was synthesized according ²²to (W02015023915).²0²0 N²HN NH2 0 0 N²HO²A-11² _______________________________________ F 1-² HATU DIPEA s'=== N²rOi 11 Compound 1173²Step 5: Preparation of²5-(1-(4-(dimethylamino)piperidin-l-yl)ethyl)-N-((4-methoxy-6-methyl-2-oxo-1,2-²dih²ydropyridin-3-yl)methyl)-6-methyl-2-(1-methyl-1H-imidazol-2-yl)indolizine-7-²carbo ²xamide, yield 55%. 1H-NMR (Me0D, 400 MHz):8.96 (s, 1H), 7.61-7.60 (m, 1H), ²7.59-7.55 (m, 211), 7.06 (s, 1H), 6.39 (s, 1H), 4.46 (s, 211), 4.33 (s. 1H), ²4.06 (s, 3H), ²3.96 (s, 3H), 3.69-3.67 (m, 1H), 3.23-3.02 (m, 2H), 2.91 (s, 6H), 2.78-2.77 ²(m, 2H),²2.36 (s, 6H), 2.26-2.23 (m, 2H). 1.96-1.93 (m, 2H), 1.65-1.63 (m, 3H); MS(ESI) ²m / z²560 [M+H].²Example 109: Preparation of²N((4-methoxy-6-methy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-2-(1-meth ²²y1-1H-imidazol-2-y1)-5-(1-(4-(2,2,2-trifluoroethy Opiperazin-l-²ypethypindolizine-7-c² arboxamide: same as example 83.²148²<DP=149>²CA 03036114 2019-03-07²Boc Boc² 0 0 Boc ( C²0 N 0 N²I N (N)²NaBH,, AcOH, '"==²N²T1OOPN4,65 ²,N²-N²CF²ri,j,,C F3 (3²9²L) oP N ,3c;'s,or-c F3 111 C NaOH Et0H / F120 ² 0²0 N² EA / HCI, 0 0 THF, TEA, 60 C 80 C ²-===²0² / ²¨N²¨N ¨N²F F²rAF²0²NH2 0 0 LN²HATU, TEA, DMF it'818 Compound 110²Step 1: Synthesis of isopropyl²5-(1-(4-(tert-butoxycarbonyl)piperazin-1-yl)viny1)-6-methyl-2-(1-methyl-1H-²imidazo ²1-2-ypindolizine-7-formate: MS(ES1) m / z 508 [M+H].² Step 2: Synthesis of isopropyl²5-(1-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-6-methyl-2-(1-methyl-1H-²imidazo ²1-2-yl)indolizine-7-formate: yield of the two steps was 45%. MS (ESI) m / z 510 ²[M+Hr.²Step 3: Preparation of isopropyl²6-methyl-2-(1-methy1-1H-pyrazol-5-y1)-5-(1-(piperazin-1-y1)ethyl)indolizine-7-²carbo²xylate: yield 87%. MS (ESI) m / z 410 [M+H]²Step 4: Preparation of isopropyl²6-methyl-2-(1-methy1-1H-imidazol-2-y1)-5-(1-(4-(2,2,2-trifluoroethyppiperazin-²1-y1) ²ethyl)indolizine-7-formate: yield 63%. MS (ESI) m / z 492 [M+H]² Step 5: Preparation of²6-methyl-2-(1-methy1-1H-imidazol-2-y1)-5-(1-(4-(2,2,2-trifluoroethyl)piperazin-² 1-y1) ²indolizine-7-formic acid: MS (ESI) m / z 450 [M+H].²Step 6: Preparation of²N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-(1 -²meth²149²<DP=150>²CA 03036114 2019-03-07²y1-1H²-imidazol-2-y1)-5-(1-(4-(2,2,2-trifluoroethyl)piperazin-l-y1)ethyl)indolizine-²7-carbox²amide: yield of the two steps was 4%. 1H-NMR (CDC13, 400 MHz):8.82 (s, 1H), ²7.72-7.57 (m, 4H), 7.16 (s, 1H), 6.91 (s, 1H), 4.52 (s, 2H), 4.10 (s, 3H), ²4.05 (s, 3H),²3.24-3.12 (m, 6H), 2.98-2.95 (m, 1H), 2.54-2.52 (m, 2H), 2.51 (s, 3H), 2.40 ²(s, 2H),²1.78 (d, J=6.9Hz,3H); MS(ESI) m / z 600 [M+1-1]²Example 110: Preparation of²N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-(1-²meth ²y1-1H-imidazol-2-y1)-5-(1-(4-(2,2,2-trifluoroethyl)piperazin-1-²y1)ethyl)indolizine-7-c² arboxamide: same as step 5 in example 31.²CF, 4,²0 lc)²HO HNTNEI2 0 0 N²EN)² HATU, TEA, DMF li I it'al Compound Ill² / ²õAI²1,111²Step 1: Preparation of²N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-(1-²meth ²y1-1H-imidazol-2-y1)-5-(1-(4-(2,2,2-trifluoroethyl)piperazin-l-²y1)ethyl)indolizine-7-c²arboxamide: yield 4%. 1H-NMR (CDC13, 400 MHz):8.86 (s, 1 H), 7.71-7.54 (s, 4 ²H),²7.12 (s, 1 H), 6.44 (s, 1 H), 4.52 (s, 2 H), 4.05 (s, 3 H), 3.86-3.84 (m, 1 ²H), 3.78-3.71 ²(m, 2 H), 3.24-3.12 (m, 6 H), 2.98-2.95 (m, 2 H), 2.46 (s, 3 H), 2.38 (s, 3 I-²I), 2.34 (s, ²3 H), 1.78 (d, J=6.9 Hz, 3 H); MS(ESI) m / z 584 [M+Hr²Example 1 1 1 : Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-(4-(dimethylarn ²ino)pip²eridine-1-yl)ethyl)-6-methyl-2-(1-methyl-1H-im idazol-2-yl)indo I izine-7-²carboxam id ²e: same as example 50.²150²<DP=151>²CA 03036114 2019-03-07²0 0 0 9 (N)²I B'YV'cl I N.BH4²Pd(dppf)C12 / AcOK / NH Tql pro)4²15¨CI²N.........LysNHz 0 0 N²NEIGH HO N²HAW DIPEA²1 / 1²J N / J1²Compound 11.0H ²Step 1: Preparation of ethyl²5-methyl-2-(1H-imidazol-2-y1)-6-methylindolizine-7-carboxylate: Yield 89%. MS ²(ES!) m / z 312 [M+Hr.² Step 1: Preparation of isopropyl²5-(1-(4-(dimethylamino)piperidin-1-yl)viny1)-2-(1H-im idazol-2-y1)-6-methy 1 ²indolizi ²ne-7-carboxylate: MS (ESI) m / z 395 [M+H].²Step 3: Preparation of isopropyl²5-(1-(4-(dimethylamino)piperidin-1-yl)ethyl)-2-methyl-2-(imidazol-2-y1)-6-²methylin² dolizine-7-carboxylate: yield of two steps was 55%. MS (ES!) m / z 397 [M+Hr²Step 4: Preparation of²5-(1-(4-(dimethylamino)piperidin-1-yl)ethyl)-2-(1H-imidazol-2-y1)-6-²methylindolizi ²ne-7-carboxylic acid: MS (ES!) m / z 355 [M+H].²Step 5: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(1-(4-²(dimethylamino)pip²eridine-1-yl)ethyl)-6-methyl-2-(1-methyl-IH-imidazol-2-y1)indolizine-7-²carboxamid ²e: Yield of the two steps was 13%. 1H-NMR (Me0D, 400 MHz):9.13 (s, 1 H), ²7.55-7.47 (m, 4 H), 7.04 (s, 1 H), 6.13 (s, 1 H). 4.46 (s, 2 H), 4.26-4.25 (m, ²1 H), ²3.88-3.85 (m, 1 H). 3.71 (s, 4 H), 3.23-3.21 (m, 2 H), 2.91-2.81 (m, 2 H), ²2.38 (s, 3²H), 2.31 (s, 3 H). 2.19 (s, 3 H), 1.61-1.59 (m, 3 El); MS(ESI) m / z 489.3 ²[M+111'.²Example 112: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morpholinoe ²thyl)-2-(pyrazol-5-yDindolizine-7-carboxamide: same as example 31.²151²<DP=152>²CA 03036114 2019-03-07²0 0 c0²0 0 OH 0²H 0 N²( )²N I²NaBH.² / ² / -² Pd(dppf)C12 / AcOK AcOH²-NH TIO-pro),²Br² N -NH² / ²N²0²0²C 0 ro,²0 N²tj,,I4H2 0 0 CN)²N. I²0 N²NaOH HO N.²73C, I-1 I² / / HATU DIEA -²H²N²Compound 1 1 3²Step 1: Preparation of ethyl²5-acety1-6-methy1-2-(1H-pyrazol-5-yl)indolizine-7-carboxylate: Yield 31%. MS ²(ES!) ²m / z 312.1 [M+Hr.² Step 2: Preparation of isopropyl²6-methy1-5-(1-morpholinoviny1)-2-(1H-pyrazol-5-y1)indolizine-7-carboxylate: MS²(ES!) m / z 395 [M+H]²Step 3: Step 3: Preparation of isopropyl²6-methyl-5-(l -morpholinoethyl)-2-0 H-pyrazol-5-ypindolizine-7-carboxylate: ²yield² of two steps was 53%. MS (ES!) m / z 397 [M+H]'.²Step 4: Step 4: Preparation of²6-methy1-5-(1-morpholinoethyl)-2-(1H-pyrazol-5-y1)indolizine-7-carboxylic ²acid:²MS (ES!) m / z 355 [M+Hr²Step 5: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morpholinoe²thyl)-2-(1H-pyrazol-5-ypindolizine-7-carboxamide: yield 14%. 1H-NMR (Me0D, ²400 MHz):7.90 (s, 1 H), 7.62 (s, 1 H), 6.80 (s, 1 H), 6.30 (s, 1 H), 4.50 (s, ²2 H). ²3.89-3.88 (in, 4 H), 3.21-3.19 (m, 2 H), 2.43-2.42 (in, 6 H), 2.30-2.26 (in, 5 ²H), ²1.94-1.92 (in, 3 H); MS(ESI) m / z 489 [M+H].² Example 113: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morpholinyl ²ethyl)-2- (1 -ethy1-1H-pyrazole)indolizine-7-carboxamide:²152²<DP=153>²CA 03036114 2019-03-07²J²1-N ²-²Pd(dppf),Cl2, KOAc / TI-0-pro)4 N AcOH² / ²N² / ²N²0²( CD 0 r()²D_Lo 0 N 0 N Ht2&NH2 0 0²I²I LiOH HO²N² / Me0H / H20 HATU DIPEA² / ² / Compound 114 r'! N N ²Step 1: Preparation of ethyl²5-acetyl-6-methyl-2-(1-ethyl-1H-pyrazole)indolizine-7-carboxylate: yield 43%. ²MS ²(ESI) m / z 340 [M+H]4.² Step 2: Preparation of isopropyl²6-methyl-5-(1-morpholinylviny1)-2-(1-ethyl-IH-pyrazole)indolizine-7-²carboxylate:²MS (ESI) m / z 423 [M+Hr.²Step 3: Preparation of isopropyl²6-methyl-5-(1-morpholinylethyl)-2-(I -ethyl-1 H-pyrazole)indolizine-7-²carboxylate:² yield of two steps was 40%. MS (ESI) m / z 425 [M+Hr.²Step 4: Preparation of²6-methyl-5-(1-morpholinylethyl)-2-(1-ethyl-IH-pyrazole)indolizine-7-²carboxylate:²MS (ESI) m / z 383 [M+H]+.²Step 5: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-²morpholinyl²ethyl)-2- (1-ethyl-1H-pyrazole)indolizine-7-carboxamide: yield of two steps ²was ²42%. H NMR (400 MHz, DMSO-d6)6 ppm 11.52(s, 1H), 8.56(s, 1H), 8.17(s, 1H), ²7.46(s, 1H), 7.35 (s, 1H), 6.72(s, 1H), 6.43(s, 1H), 5.88(s,1H), 4.27-4.32 (m, ²9H), ²3.60 (s, 31-1), 2.28 (s, 3H), 2.21(s, 3H), 2.12 (s, 3H), 1.49 (s, 2H), 1.38 ²(t,² 3H), 1.24(s, 2H); MS(ESI) m / z 539 [M+H].²Example 114: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morpholinoe ²thyl)- 2-(4,5,6,7-tetrahydro[2,3-c]pyridin-2-ypindolizine-7-carboxamide: the ²first ²four steps are similar to those of example 31.²153²<DP=154>²CA 03036114 2019-03-07²o o²I WH ²IscAdppf)Cic²p-oCO s Ti0-0Hp04 I N AcOH²CO; / ²S²NH²,0²CCI) LNj r 1²,²I NaOH HOI²(Boc),0 4 ² _______________________________________________ ...²HATU²NH NH NBoc²0 0 N²Ht.)11 HCl / AcOEt 1111-11- I²=== ¨ it=a% Compound 115²1 / ²1 / ² / s / ²NBoc²Step 1: Synthesis of ethyl²5-acety1-6-methy1-2-(4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yDindolizine-7-²format ²e, yield 53%. MS (ESI) m / z 383 [M+H]t² Step 2: Synthesis of ethyl²isopropy1-6-methyl-5-(1-morpholinoviny1)-2-(4,5,6,7-tetrahydrothieno[2,3-²c]pyridine ²-2-yl)indolizine-7-carboxylate: MS (ESI) m / z 466 [M+H]²Step 3: Synthesis of ethyl²isopropy1-6-methy1-5-(1-morpholinoethyl)-2-(4,5,6,7-tetrahydrothieno[2,3-²c]pyridine² -2-yl)indolizine-7-carboxylate: two-step yield of 68%. MS (ESI) m / z 468 [M+Hr²Step 4: Synthesis of²6-methy1-5-(1-morpholinoethyl)-2-(4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-²y1)indol ²izine-7-formic acid: yield 63%. MS (ESI) m / z 426 [M+11]-1.²Step 5: Synthesis of²2-(6-(tert-butoxycarbony1)-4,5,6,7-tetrahydrothieno[2,3-clpyridin-2-y1)-6-²methyl-54²1-morpholinoethyl)indolizine-7-carboxylic acid: To a dry 25 mL three-necked ²flask, ²crude product ²6-methyl-5-(1-morpholinoethyl)-2-(4,5,6,7-tetrahydrothieno[2,3-clpyridin-2-²y1)indol ²izine-7-carboxylic acid (120 mg, 0.28 mmol), Di-tert-butyl dicarbonate (123 ²mg,² 0.56 mmol), sodium hydroxide (22 mg, 0.56 mmol) were added successively,²dissolved in 1.4-dioxane / water (1:1) (3 mL), and stirred for 2 hours at room ²temperature. After the reaction was completed, 1N diluted hydrochloric acid ²was ²added to the reaction mixture to adjust pH=7, and product was extracted with ²ethyl²154²<DP=155>²CA 03036114 2019-03-07²acetate (130 mg, yellow solid), yield: 88%. MS (ESI) m / z 526 [M+H] .²Step 6: Preparation of tert-butyl²2-(7((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y 1)methypcarbamoy1)-6-methyl-5-²(1 ²-morphol inoethyl)indo1-2-y1)-4,5-dihydro-thieno[2,3-c] pyrid ine-6(2H)-²carboxylate:² same as step 5 in example 31. Yield: 24%. MS (ESI) m / z 660 [M+H]²Step 7: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morpholinoe²thyl)-2-(4,5,6,7-tetrahydro[2,3-c]pyridin-2-ypindolizine-7-carboxamide: same ²as ²step 6 in example 44. Yield: 74%.²1H-NMR (Me0D, 400 MHz):8.74 (s, 1 H), 7.33 (s, 1 H), 7.04 (s, 1 H), 6.67 (s, 1²H), 6.11 (s, 1 H). 4.55 (s, 2 H), 4.45-4.42 (m, 4 H), 4.10-4.08 (m, 1 H), 3.67 ²(s. 4 H), ²3.54-3.51 (m, 2 H), 3.03-3.00 (m, 2 H), 2.69-2.67 (m, 2 H), 2.37 (s, 3 1-1), ²2.30 (s, 3 ²H), 2.22 (s, 3 H), 1.51-1.49 (m, 3 H). MS(ESI) m / z 560 [M+Hr.²Example 115: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-5-(1-²morpholinoe²thyl)- 2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)indolizine-7-²carboxamide: same ²as example 53.²0 0 cc)²0 0²N Pd(dppf)C12, K2CO3²1)1-160Pr),,, 65 C / ²B-0 2) NaBH4 AcOH ri²Boc C5xs¨²²rcH²Bo²0 LN) H*N1-12 0 0 L'N)²Na0H, HO²Et0H / H20 1) HATU, TEA DMF 11),41 I²80 C / 2) TFA / DCM / ²--S²,S²1E1B Compound 116²Boo H²Step 1: Synthesis of tert-butyl²2-(5-acetyl-7-(ethoxycarbony1)-6-methylindolizine-2-y1)-6,7-²tetrahydrothieno[3,2-c]²pyridine-5(4H)-formate, yield 29%. MS (ESI) m / z 483 [M+Hr.²Step 2: Synthesis of tert-butyl²2-(7-(isopropoxycarbony1)-6-methy l-5-(1-morphol inoethyl) indolizine-2-y1)-²6,7-tetra²hydrothieno[3,2-clpyridine-5(4H)-carboxylate, yield of two steps was 72%. MS ²(ESI)²155²<DP=156>²CA 03036114 2019-03-07²m / z 568 [M+Hr.²Step 3: Synthesis of²2-(5-(tert-butoxycarbony1)-4,5,6,7-tetrahydrothieno[3,2-clpyridin-2-y1)-6-²methyl-54 ²1-morpholinoethyl)indolizine-7-carboxylic acid, yield 72%. MS (ESI) m / z 526² [M+H]4.²Step 4: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-5-(1-²morpholinoe ²thyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)indolizine-7-carboxamide: ²yield ²of two steps was 6%. 11-1-NMR (CDC13, 400 MHz):7.36 (s, 1H), 7.05 (s, 1H), ²6.12 (s,²1H), 4.59 (s, 21-1), 4.28 (s, 2H), 3.85 (s, 1H), 3.71 (s, 41-1), 3.58-3.55 (m, ²2H),²3.23-3.21 (m, 2H), 3.17-3.15 (m, 2H), 2.77 (s, 2H). 2.38 (s, 3H), 2.31 (s, ²3H), 2.19 (s, ²31-1), 1.58 (d, J=6.9Hz,3H); MS(ESI) m / z 560 [M+Hr²Example 116: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-1-(3-²(dimethylamine)pheny²1)-6-methyl-5-(1-morpholinylethyl)indolizine-7-carboxamide: same as example ²31.²0 (0)²0²õL²0 Pd d 1.1.41 "B(011',1, I NaBH4² / I KOAc Dioxane4120 / AcOH²Br² / ² / 4¨² / NJ--²(0N)² NaOH 0²HATU DIPEA²0 0 N²N Me0H / H,0 HO DMF²HFAII I²I / ² / ²1L'Alo Compound 117²N¨²² / ²Step I: Preparation of ethyl²5-acetyl-1-(3-(dimethylamine)pheny1)-6-methylindolizine-7-carboxylate: yield ²25%. ²MS (ESI) m / z 365 [M+H]'.² Step 2: Preparation of isopropyl²1-(3-(dimethylamine)pheny1)-6-methy1-5-(1-morpholinevinypindolizine-7-²carboxylat ²e: MS (ESI) m / z 448 [M+H].²Step 3: Preparation of isopropyl²1-(3-(dimethylamine)pheny1)-6-methy1-5-(1-morphinolinylethyl)indolizine-7-²carbox² ylate: yield of two steps was 42%. MS (ESI) m / z 450 [M+f1]²156²<DP=157>²CA 03036114 2019-03-07²Step 4: Preparation of²1-(3-(dimethylamine)pheny1)-6-methyl-5-(1-morphol inylethy Dindolizine-7-²earboxyli²c acid: MS (ES!) m / z 408 [M+H].²Step 5: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(3-²(dimethylamine)pheny²l)-6-methyl-5-(1-morpholinylethyl)indolizine-7-carboxamide: yield 27%. 1H NMR ²(400 MHz, CDC13) 8 ppm 11.47(s, 1H), 8.41(s, 1H), 8.24-8.26 (m, 1H), 7.57 (s, ²1H), ²7.19-7.23(m, I H), 6.97-6.98(d,J= 2.8 Hz, 1H),6.61(m, 2H), 5.85(s,1H),4.25-²4.26 (m, ²2H), 4.05-4.07 (m, 1H), 3.58 (m, 4H), 2.88 (s, 6H),2.63-2.66(m, 211), 2.31 (s, ²3H),² 2.11-2.17 (m, 5H), 2.11(s, 3H), 1.43-1.44(m, 3H); MS(ESI) m / z 542 [M+Hr.²Example 117: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morpholinyl ²ethyl)-1- (3-morpholinylphenyl)indolizine-7-carboxamide: same as example 31.².9.²ci- B-00²0,² ," L i 1 c-²,0,3. ,I, 3 .- II 1 ,,,,õ ,I,01 ,,y,l, Ac0,1²11 r -Pd-'d21)-91?( ---"` - ,") ---,--- 1 ²õ ) -õ,Tõ-, - --²mi 100 T Dmane / H20 1\ z_. , = i _.:?\, i²''-- / ²' -0²r., 0.²-0--1-²-"r-- , U L ,I. 1.!"Tuan ?1 õ, 1²1 N ....,N HO²,. 'I; j -;-,--------' ii N'p²_..._.,²N²õAL.)²1.1 . N,²) P²Compound 17² G ,(8,²(70) ²,N,²(N )² Step 1: Preparation of ethyl²5-acety1-6-methy1-1-(3-morphinolinylphenyl)indolizine-7-carboxylate: Yield ²21%. ²MS (ESI) m / z 406 [M+Hr.²Step 2: Preparation of isopropyl²6-methy1-1-(3-morphinolinylpheny1)-5-(1-morphinolinylvinyl)indolizine-7-²carboxyla² te: MS (ES!) m / z 490 [M+H]l.²Step 3: Preparation of isopropyl²6-methyl-I -(3-morphinolinylpheny1)-5-(1-morphinolinylethyl)indolizine-7-²carboxyla²te: MS (ES!) m / z 492 [M+H]4.²Step 4: Preparation of²157²<DP=158>²CA 03036114 2019-03-07²6-methyl-1-(3-morphinolinylpheny1)-5-(1-morphinolinylethypindolizine-7-²carboxyli ²c acid: yield of two steps was 46%. MS (ES!) m / z 450 [M+Hr .²Step 6: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-²morphinolin² ylethyl)-1-(3-morphinolinylphenypindolizine-7-carboxamide: yield 40%. 'N MR²(400 MHz, CDCI3) 8 ppm 11.44(s, 1 H), 8.42-8.41(s, 1 1-1), 8.29 (s, 1 ²H),7.54(s,1 ²H),7.29-7.25(m,1 H), 7.07(s,1 H), 7.03-6.99 (m, 2 H),6.82-6.80(d, I = 6.0 Hz, ²1 H), ²5.86(s,1 H),4.27-4.26 (m, 2 H), 4.08-4.04 (m,1 H),3.73-3.70(m,4 H),3.58-²3.49(m.4 ²H),3.19-3.13 (m,4 H), 2.68-2.63(m, 2 H), 2.29 (s,3 H), 2.18-2.14(m,5 H),2.1 ²1(s,3² H),I.45-1.44(m,3 H); MS(ESI) m / z 584 [M+H1+.²Example 118: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-1-(4-(dimethylamine)pheny ²²0-6-methyl-5-(1-morpholinylethypindolizine-7-carboxamide: same as example 31.²HO OH² ! .,0²[i 1²0 1 0 L²-----0) 1'ryil.,²i Toluene / DMF NaBH4²Br'² 0 ,O,²i 1²It...r.j.., ..õ1,0 , ' NaOH _... fio 1 ==:,N HATU DIEA .. 11,W1,1 ²I X '² I N Me0H,H20 µ ) DMF li²0 --14--- / ²N--)²fe.-Alen Compound 119²1² Step 1: Preparation of ethyl²5-acetyl-1-(4-(dimethylamino)pheny1)-6-methylindolizine-7-carboxylate: Yield ²5%. ²MS (ES1) m / z 365 1M+11]+.²Step 2: Preparation of isopropyl²1-(4-(dimethylamine)pheny1)-6-methyl-5-(1-morpholinevinyl)indolizine-7-²carboxylat² e: MS (ESI) tn / z 448 [M-i-H1'.²Step 3: Preparation of isopropyl²1-(4-(dimethylamine)pheny1)-6-methy1-5-(1-morphinolinylethypindolizine-7-²carbox²ylate: yield of two steps was 25%. MS (ES!) m / z 450 [M+Hr.²Step 4: Preparation of².. 1 -(4-(dimethylam ine)pheny1)-6-methyl-5-(1-morpholinylethy pindol izine-7-²carboxyli²158²<DP=159>²CA 03036114 2019-03-07²c acid: MS (ESI) m / z 408 [M+H1F.²Step 5: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(4-²(dimethylamine)pheny ²1)-6-methyl-5-(1-morpholinylethoxy)indolizine-7-carboxamide: yield 38%. 1H NMR²(400 MHz, CDC13) 6 ppm 8.45(s, I H), 7.59 (s, 1H), 7.41-7.39(m, 21-1), 6.87-²6.84(m,²1H),6.10(s, 1H), 5.85(s,1H),4.66 (s, 2H), 4.10-4.08(m, 1H), 3.67 (m, 4H), 2.94 ²(s, ²6H),2.69-2.68(m, 2H), 2.36 (s, 3H), 2.30-2.23 (m, 5H), 2.20(s, 3H), 1.52-²1.50(m, ²3H); MS(ESI) m / z 542 [M+Hr²Example 119: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-²morpholinyl²ethyl)-1- (4-morpholinylphenyl)indolizine-7-carboxamide: same as example 31.²O.²rN1²1²Pci(dppl)C12 KO AT TgOINNA '011' 'OH²10,10O'C DIOXNZ / H20 -0-,²L11)N²N'B"4²Br / ^N<)-- / ²(²0²0 0 0 - -²0 '01' [²j_ 1, moo HA DPE A 0 0 .N²11I HO 1 ²,1², / "(²A i)²z-N²) italdl Compound 120²Step 1: Preparation of ethyl²5-acetyl-6-methy1-1-(4-morphinolinylphenyl)indolizine-7-carboxylate: Yield ²19%.² MS (ESI) m / z 407 [M+Hr²Step 2: Preparation of isopropyl²6-methyl-1-(4-morphinolinylpheny1)-5-(1-morphinolinylvinypindolizine-7-²carboxyla²te: MS (ESI) m / z 490 [M+Hr²Step 3: Preparation of isopropyl²6-methyl-1-(4-morphinolinylpheny1)-5-(1-morphinolinylethypindolizine-7-²carboxyla²te: yield of two steps was 46%. MS (ESI) m / z 492 [M+I-11F.²Step 4: Preparation of²6-methyl- 1 -(4-morphinolinylpheny1)-5-( I -morph inolinylethyl)indolizine-7-²carboxyli²c acid: MS (ESI) m / z 450 [M+HJ² Step 5: Preparation of²159²<DP=160>²CA 03036114 2019-03-07²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-²morphinolin ²ylethyl)-1-(4-morphinolinylphenyl)indolizine-7-carboxamide: yield of two steps ²was ²14%. H NMR (400 MHz, CDCI3) 6 ppm 8.50(s, 1H), 7.60 (s, 1H), 7.44-7.46(m, ²211), 7.0I-7.04(m, 2H),6.87(d, .J= 2.8 Hz, 111),6.10(s, 1H), 4.45(s,2H),4.07-²4.12 (m,²1H), 3.84-3.86 (m, 4H), 3.67 (m, 4H), 3.14-3.17 (m, 4H), 2.68-2.70(m, 2H), ²2.36 (s,²3H), 2.27-2.31 (m, 5H), 2.23 (s, 3H), 1.50-1.52(m, 3H); MS(ESL) m / z 584 ²[M+H]f. ²Example 120: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-5-(1-²morpholinyl ²ethyl)-1- (3-methoxyphenyl)indolizine -7-amide: same as example 31.²0 0²1`. I fl²Br²H² / Pd(dppfbC12 KOAc me --- Pr.)r / ²AcOH² Br 6,..Dioxane / FLO _ / Me0²(a) (CI) 0²0 N 0 0 0 N² I HO²Lt0H / ² me0² Me0H / H,0 me \ HATU.0IPEA² Me \ Ittlb Compound 121²Step 1: Preparation of ethyl²5-acetyl-6-methyl-2-(3-methoxyphenyl)indolizine-7-carboxylate: Yield 14%. MS ²(ESI) m / z 352 [M+H].²Step 2: Preparation of isopropyl²6-methyl-5-(1-morphinolinylviny1)-1-(3-methoxyphenyl)indolizine-7-carboxylate:²MS (ES!) m / z 435 [M+H].²Step 3: Preparation of isopropyl²6-methy1-5-(1-morphinolinylethyl)-1-(3-methoxyphenypindolizine-7-carboxylate: ²yield of two steps was 79%. MS (ES!) m / z 437 [MM]² Step 4: Preparation of²6-methy1-5-(1-morphinolinylethyl)-1-(3-methoxyphenyl)indolizine-7-carboxylic ²acid: ²MS (ES!) m / z 395 [M+H].²Step 5: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-morphinol ²in²ylethyl)-1-(3-methoxyphenyl)indolizine-7-carboxamide: yield of two steps was ²9%.²1H NMR (400 MHz, CDCI3) 6 ppm 11.16(s, 1 H), 8.41(s, 1 H). 7.61 (s, I H),²160²<DP=161>²CA 03036114 2019-03-07²7.22-7.20 (m, 2 H), 7.06-7.04(m, 2 H), 7.00 (s, 1 H), 6.83(s, 1 11), 6.67-6.65 ²(m,1 H), ²5.81 (s, 1 H), 4.44-4.42 (d,J=5.2 Hz, 2 H), 4.02-3.96 (m, 1 H). 3.74(s, 3 H), ²3.62 (s, ²4 H), 2.58 (s, 2 H), 2.31 (s, 3 H), 2.27 (s, 3 H), 2.21-2.18 (m,2 H), 2.04 ²(s,3 H), ²1.43-1.41 (d,J=6.8 Hz, 3 H); MS(ESI) m / z 551 [M+Hr² Example 121: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morpholinyl ²ethyl)-1- (4-methoxyphenyl)indolizine-7-carboxamide:²0 0²0 LNJ²0 0²C I²Pd(dppf),CI, KOAc TI-O-Prolo AcOH² Br EDIoxane / H20²Me ²0 N Me0 0² 0 0 N²0² I HO ²1JOH / ²MeOH / H20 HATU DIPEA lEt,t Compound U2²DMF² Me0 Me0 Me0²Step 1: Preparation of ethyl² 5-acetyl-6-methyl-2-(4-methoxyphenyl)indolizine-7-carboxylate: Yield 11%. MS²(ESI) m / z 352 [M+1-1]1.²Step 2: Preparation of isopropyl²6-methyl-5-(1-morphinolinylviny1)-1-(4-methoxyphenyl)indolizine-7-carboxylate: ²²MS (ESI) m / z 435 [M+1-11+.² Step 3: Preparation of isopropyl²6-methy1-5-(1-morphinolinylethyl)- -(4-methoxyphenypindolizine-7-carboxylate:²yield 78%. MS (ESI) m / z 437 [M+H]*.²Step 4: Preparation of²6-methy1-5-(1-morphinolinylethyl)-1-(4-methoxyphenypindol izine-7-carboxylic ²acid:² MS (ESI) m / z 395 [M+H]*.²Step 5: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)6-methyl-5-(1-²morpholinyle ²thyl)-1- (4-methoxyphenyl)indolizine-7-carboxamide: 1H NMR (400 MHz, CDC13) 6 ²ppm 8.38 (s, 1 H), 7.61 (s, 1 H), 7.68-7.64 (m, 1 H), 7.55 (s, 1H), 7.48-7.45 ²(m, 1 H),² 7.39-7.36 (d, J=8.8 Hz, 2 H), 7.11-7.09 (m,1 H), 6.87-6.84 (d, J-8.8 Hz,2 H),²161²<DP=162>²CA 03036114 2019-03-07²6.79-6.78(m, 1 H), 4.44-4.42 (d,J-=5.6 Hz, 2H), 4.03-4.01 (d, J-6.8 Hz, 1H), ²3.72(s,²3H), 3.62 (s, 4H), 2.32 (s, 3H), 2.26 (s, 3H), 2.17-2.13 (t,J= 7.6 Hz,2H), ²1.97-1.92 ²(m,2H), 1.42-1.44 (d,J=6.4 Hz, 3H). MS (ES!) m / z 551 [M+1-11'.²Example 122: Preparation of²2-bromo-N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-(py²rrole-1) -yl)ethyl)indolizine-7-carboxamide: same as example 30.²(N) 0 0² NaBH4²I² / Ti pro),, AcOH²Br Br Br²HO HNNH2 ²Q²0²²NaOH I H I²N ibÃ71$ Compound 123²Me0H / H,0 / ² Br Br²Step 1: Step 2: Preparation of isopropyl²2-bromo-6-methyl-5-(1-(pyrrol-l-yl)vinyl)indolizine-7-carboxylate: MS (ES!) ²m / z ² 391 [M+Hr²Step 2: Preparation of isopropyl²2-bromo-6-methy1-5-(1-(pyrrol-1-y1)ethyl)indolizine-7-carboxylate: yield of ²two ²steps was 59%. MS (ES!) m / z 393 [M+1-11'.²Step 3: Preparation of²2-bromo-6-rnethy1-5-(1-(pyrrol-1-ypethyl)indolizine-7-carboxylic acid: MS ²(ESI)²m / z 351 [M+1-11+.²Step 4: Preparation of²2-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²(py²rrol-1-ypethypindolizine-7-carboxamide: Yield 4%. 'H NMR (400 MHz, DMSO-d6)²5 ppm 8.47(s, 1 H), 7.28(s, 1 H), 6.84 (s, 1 H), 6.51 (s, 1 H), 6.10 (s, 1 H), ²4.57 (m, 2²H), 4.05-4.04(m, 1 H),2.69-2.67 (m, 2 H), 2.36 (s, 3 H), 2.29-2.19 (m, 5 H), ²2.18 (s,²3 H),1.78-1.77(m, 4 H), 1.49-1.47(m, 3 H); MS(ESI) m / z 485 [M-411+.²Example 123: Preparation of²2-brom o-5-(1-(4,4-difl uoropiperidin-l-ypethyl)-N-((4,6-dimethyl-2-oxo-1,2-di ²hydro² pyridin-3-yl)methyl)-6-methylindolizine-7-carboxamide: same as example 30.²162²<DP=163>²CA 03036114 2019-03-07²FF²F r² Ck / o (j:ir² Opr), NeB²Br²- \- Br F Br² F F 0 cki²(1,) 7OCNH' 0 )01²NaOH² HO)f HATU DEA7,1141 I N²\Br Compound 124²Step 1: Preparation of isopropyl²2-bromo-5-(1-(4,4-difluoropiperidin-1-yl)viny1)-6-methylindolizine-7-²carboxylate: ²MS (ES!) m / z 441 [M+Hr² Step 2: Preparation of isopropyl²2-bromo-5-(1-(4,4-difluoropiperidin-l-ypethyl)-6-methylindolizine-7-²carboxylate: ²yield of two steps was 7%. MS (ES!) m / z 443 [M+H]²Step 3: Preparation of²2-bromo-5-(1-(4,4-difluoropiperidin-1-ypethyl)-6-inethylindolizine-7-²carboxylic² acid: MS (ES!) m / z 401 [M+H]3.²Step 4: Preparation of²2-bromo-5-(1-(4,4-difluoropiperidin-l-yl)ethyl)-N-((4,6-dimethyl-2-oxo-1,2-²dihydro ²pyridin-3-yOmethyl)-6-methylindolizine-7-earboxamide: yield of two steps was ²51%. ²1H-NMR (Me0D, 400 MHz):7.36 (s, 1 H), 6.59 (s, 1 H), 6.14 (s, 1 H), 4.48 (s, 2 ²H),²4.39 (s, 1 H), 2.96-2.95 (m, 2 FI), 2.55-2.53 (m, 2 H), 2.37 (s, 3 H), 2.30 ²(s, 3 H),²2.35 (s, 3 H), 2.03-2.02 (m, 4 H). 1.60-1.58 (m, 3 H); MS(ESI) m / z 535 [M+Hr . ²²Example 124: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-2-(2-fluoro-5-²methoxyphen ²y1)-6-methy1-5-(1-morpholinoethyl)indolizine-7-carboxamide: same as example ²31.²011 I I()²HO¨BPH F²0 0²_0²PclIcIpp()C1,, 1(2C ,²Br 0²¨0²1²9 cj²o²I N Necn, HOft X²6 5c1L F itgt Compound 125²,² 163²<DP=164>²CA 03036114 2019-03-07²Step I: Preparation of ethyl²5-acety1-2-(2-fluoro-5-methoxyphenyI)-6-methylindolizine-7-carboxylate: Yield ²66%. ²MS (ESI) m / z 370 [M+Hr.²Step 2: Preparation of isopropyl²2-(2-fluoro-5-methoxypheny1)-6-methy1-5-(1-morphinolinylvinyl)indolizine-7-²carbo²xylate. MS (ESI) m / z 453 [M-f-H]'.²Step 3: Preparation of isopropyl²2-(2-fluoro-5-methoxypheny1)-6-methy1-5-(1-morpholinylethyl)indolizine-7-²carboxyl ²ate: yield of two steps was 65%. MS (ESI) m / z 455 [M+H[+.² Step 4: Preparation of²2-(2-fluoro-5-methoxypheny1)-6-methyl-5-(1-morpholinylethypindolizine- 7-²carboxyl ²ic acid: MS (ESI) m / z 413 [M+H]'.²Step 5: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(2-fluoro-5-²methoxyphen²y1)-6-methy1-5-(1-morpholinylethypindolizine-7-carboxamide: yield of two steps²was 32%. 1H-NMR (CDC13, 400 MHz): 12.78 (s, 1H), 8.88 (s, 1H), 7.35 (s, 2H), ²7.18-7.15 (m, I H), 7.07-7.03 (m, I H),6.74-6.72 (m, 2H), 5.98 (s, 1H), 4.54-²4.52 (m, ²2H), 4.07-4.02 (m, I H), 3.83 (s, 3H), 3.69-3.68 (m, 41-1), 2.65-2.64 (m, 2H), ²2.39 (s, ²3H), 2.35 (s, 31-1), 2.27-2.22 (m, 2H), 2.04 (s, 3H), 1.50-1.48 (in, 31-²1);MS(ES1) m / z² 547 [M+F114.²Example 125: Preparation of methyl²7-W4,6-d imethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoy1)-6-methyl-5-(1-²²morpholinylethyl)indolizine-2-carboxylate:²0²) ? IN C )²0 0 N²zpHpi;ez²Br Compound 12()² Step 1: Synthesis of methyl²7-4(4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)carbamoy1)-6-methyl-5-(1-²²morpholinoethyl)indolizine-2-carboxylate: ²2-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²mo ²rpholino)indolizine-7-carboxamide (170 mg, 0.34 mmol), Pd(dpp0C12 (17 mg),²164²<DP=165>²CA 03036114 2019-03-07²triethylamine (69 mg, 0.68 mmol) and 30 ml of methanol were added successively ²²into a 25 mL CO-protected single-mouth flask, stirred to reflux overnight, and ²then ²50 ml of ethyl acetate and 20 ml of water were added. The organic phase was ²seperated and concentrated to provide a crude product, which was purified ²through²column chromatography (petroleum ether: ethyl acetate = 5:1) to provide a ²product²as yellow solids (13 mg, yield: 8%). 1H-NMR (DMSO, 400 MHz) :11.48(s, 1 H), ²8.77(s,1 H),8.25(s, 1 H), 7.48-7.47(m, 1 H), 6.85(m, 1 H), 5.85(s,1 H), 4.39-²4.37(m, ²3 H), 3.85(s, 3 H), 3.60(m, 5 H), 2.28(s, 3 H), 2.21(s, 5 H),2.19(s, 5 H), ²1.55-1.54(m, ²3 H). MS (ESI) m / z 481 [M+Hr.² Example 126: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-2-(morpholin-4-²c ²arbony1)-5 -(1-morpholinoethyl)indolizine-7-carboxamide:²0²0²0 N)²14N.A'rd I N LIOH ______ I ''1,1 N 11:Al² / THE DIPEA DNIF²0 -0²¨0 HO Compound 127²Step 1: Preparation of²7-4(4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)carbamoy1)-6-methyl-5-(1-²²morpholinoethypindolizine-2-carboxylic acid: methyl ²7-((4,6-dimethy1-2-oxo-1,2-dihydropyridine-3-yl)methyl)carbamoy1)-6-methyl-5-²(1-²morpholinoethyl)indolizine-2-carboxylate (50 mg (crude), 0.104 mmol), lithium ²hydroxide (17.5 mg, 0.417 mmol) and 20 ml of THF / 15 ml of water were added² successively to a 50mL single-necked flask, stirred to reflux overnight, 2N²hydrochloric acid was added to adjust pH to 6-7, and 100 ml of ethyl acetate ²was ²added to the reaction system. The organic phase was seperated and evaporated ²to ²provide a crude product (50 mg), which was used directly in the next step.²Step 2: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-(morpholin-4-²c²arbony1)-5-(1-morpholinoethyl)indolizine-7-carboxamide: yield 21%. 1H-NMR ²(Me0D, 400 MHz) : 8.47(s,1 H),7.54(s, 1 H), 6.78(s, 1 H), 6.16(s,1 H), 4.47(s, ²3 H), ²3.79-3.72 (m, 13 H), 3.28(m, 2 H), 2.39(s, 6 H), 2.26(s, 3 H),1 .74(s, 3 H); ²MS(ESI)²165²<DP=166>²CA 03036114 2019-03-07²111 / Z 536 [M+Hr²Example 127: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(4-²dimethylami ²nopiperidinylethyl)-1-phenylindolizine-7-carboxamide: same as example 31.²0 'N²ONO I a 0 N²I N ,p,po 0 I Nal3H4²H 4 ²AcOH² \²0 N 0 0 N²LOH HO²I 11 I²Me0H / H20 / / ²Compound 128² / ²Step 1: Preparation of isopropyl²6-methy1-5-(4-dimethylamidopiperidinylviny1)-1-phenylindolizine-7-carboxylate:²MS (ESI) m / z 446 [M+H]²Step 2: Preparation of isopropyl²6-methyl-5-(4-dimethylamidopiperidinylviny1)-1-phenylindolizine-7-carboxylate: ²²yield of two steps was 91%. MS(ESI) m / z 320 [M+H-C7H16N2r.²Step 3: Preparation of²6-methy1-5-(4-dimethylamidopiperidinylviny1)-1-phenylindolizine-7-carboxylic ²acid: ²MS (ESI) m / z 406 [M+Hr² Step 4: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(4-²dimethylami ²nopiperidinylethyl)-1-phenylindolizine-7-carboxamide: yield of two steps was ²27%. ²11-1 NMR (400 MHz, Me0D) 6 ppm 7.73(s, 1 H), 7.547(d, .1-7.2 Hz, 2 H), 7.41 ²(t, ²J=7.6 Hz, 2 H), 7.236(t, J=7.6 Hz, 1 H), 7.02(s, 1 H), 6.18(s,1 H), 4.47(s, 2 ²H),²3.83(s, 1 H), 3.60 (d, J=12.8 Hz, 1 H), 2.92(s, 2 H), 2.88 (s, 6 H), 2.38-2.36 ²(m, 6 H), ²2.30 (s, 2 H), 2.26 (s, 3 H), 2.21-2.16(m, 2 H) , 2.04-2.00(m. 2 H), L73(d, ²J=6.0 Hz, ²3 H); MS(ESI) m / z 562 [M+H].²Example 128: Preparation of²N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(4-dime²thylaminopiperidinylethyl)-1-phenylindolizine-7-earboxamide: same as example ²108.²166²<DP=167>²CA 03036114 2019-03-07²a²Ho²fLe1.1 Compound 129²Step!: Preparation of²N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(4-²dime ²thylaminopiperidinylethylene)-1-phenylindolizine-7-carboxamide: yield 31%. 1H² NMR (400 MHz, d6-DMS0)03 ppm 11.44(s, 1 H), 8.37(s, 1 H), 8.10(s, 1 H),²7.60-7.56(m, 3 H), 7.42 (t, J=7.2 Hz, 2 H), 7.24-7.21(m, 1 H), 7.00(s, 1 1-1), ²6.11(s,1 ²H), 4.42(d, J=4 Hz, 2 H), 4.11-4.06(m, I H), 3.80(s, 3 H), 3.03 (d, J=6.8 Hz, ²2 H), ²2.86(t, J=10 Hz, 2 H), 2.66 (s, 6 H), 2.60-2.57 (m, 1 H), 2.38 (s, 3 H), 2.28 ²(s, 3 H), ²2.18(s, 4 H) , 1.47(d, J=3.4 Hz, 3 H); MS(ESI) m / z 556 [M+1-11'² Example 129: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y 1)methy 1)-5-(1-(4-(dim ethy lam ²ine)pip²eridine-1-yl)ethyl)-6-methyl-1-(1-methyl-1H-pyrazol-5-ypindolizine-7-²carboxamide:²0 0 a0 N² N __L AcOH ..to 0 N² TathPr), NaBH4 I²1 / I²C-N²0 N 0 0 N²NaOH HATU DIPEA²DMF²HO HI)61-'11 I²Me0H / H20 N² C-N=NL it'aW Compound 130²Step 1: Preparation of isopropyl²5-(1-(4-(dimethylamine)piperidin-l-yl)viny1)-6-methyl-1-(1-methyl-1H-pyrazol-5-²y1)²indolizine-7-carboxylate: MS (ES!) m / z 450 [M+Hr²Step 2: Preparation of isopropyl²5-(1-(4-(dimethylam ine)piperidin-l-yl)ethyl)-6-methyl-1-(1-m ethy 1-1 H-²pyrazol-5-y1)²indolizine-7-carboxylate: yield of two steps was 35%. MS (ES!) m / z 452 [M+H]4.² Step 3: Preparation of²5-(1-(4-(dimethylamine)piperidin-l-ypethyl)-6-methyl-1-(1-methyl-1H-pyrazol-5-²y1)²167²<DP=168>²CA 03036114 2019-03-07²indolizine-7-formic acid: MS(ESI) m / z 282 [M+H-C7F116-1\12r.²Step 4: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyrid in-3-yOmethyl)-5-(1-(4-(dim ethy lam ²ine)pip²eridine-1-y pethyl)-6-methy 1-1-(1-methyl- 1 H-pyrazo 1-5-y izine-7-²carboxam ide:² yield of the two steps was 16%. 1H NMR (400 MHz, CDC13) 6 ppm 8.48(s, 1 H),²8.27 (s, 1 H), 7.47 (s, 1 H), 7.29(s, 1 H), 7.01(d,J =2.4 Hz,1 H),6.40(s,1 H), ²5.85(s,1 ²H),4.25-4.24 (m,2 H), 4.03-4.02 (m,1 H), 3.83(s, 3 H), 2.26(m, 2 H), 2.17-2.02 ²(m, ²13 H), 1.99-1.86(m, 5 H), 1.61-1.59(m,1 H),1.41-1.39(m,3 H); MS(ESI) m / z 544 ²[M+H].² Example 130: Preparation of²2-chloro-5-(1-(4-(dimethylam ino)piperidin- 1-yl)ethyl)-N -((4-methoxy-6-methy ²1-2-ox²o-1,2-dihydropyridin-3-yl)methyl)-6-methylindolizine-7-carboxamide: same as ²example 108.²0²0 1²1-,11-NH,²( I 0²NCI 0 0 N²HO "*.-N DIPEA ,²I H²DMF N²Compound 131² ci ci² Step 1: Preparation of²2-chloro-5-(1-(4-(dimethy lam ino)piperidin- 1 -ypethyl)-N-((4-methoxy-6-²methyl-2-ox ²o-1,2-dihydropyridin-3-yl)methyl)-6-methylindolizine-7-carboxamide: Yield 12%. ²²11-I-NMR (DMSO-d6, 400 MHz) :11.48(s, 1 H), 9.50(s, 1 H ),8.25(s,1 H),8.05(s, ²1 H), ²7.28(s, 1 H), 6.58(s, 1 H), 6.13(s,1 H), 4.22-4.21(m, 2 H), 3.99(s, 6 H), ²3.20(m, 2 H),²2.77-2.76(m, 8 H), 2.28(s, 3 H), 2.21-2.19(m, 7 H), .55-1.54(m, 3 H); MS(ESI) ²m / z²514 [M+11]+.²Example 131: Preparation of²N((4-methoxy-6-methy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-6-methyl-5-(1-morp ²²holinylethyl)-1-phenylindolizine-7-carboxamide: same as example 108.²0 coN) 0 0 C N)²HN HO I NH,²N I²HATU DIPEA, DMF ?² Imo 25 Compound 132²168²<DP=169>²CA 03036114 2019-03-07²Step 1: Preparation of²N-((4-methoxy-6-methy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morp²holinylethyl)-1-phenylindolizine-7-carboxamide: yield of two steps was 24%. 1H ²²NMR (400 MHz, Me0D) ppm 7.68 (s, 1H), 7.54(d, J=7.6Hz, 2H), 7.439(t,²J=7.6Hz, 2H), 7.22(t, J=7.2Hz, 1H), 6.98(s, 1H), 6.29(s,1H), 4.44(s, 2H), 3.91 ²(s,²3H), 3.88-3.86 (m, 1H), 3.74 (s, 41-1), 3.23-3.18(m, 2H), 2.37 (s, 3H), 2.32 ²(s, 3H), ²1.64 (d, J=6.4Hz, 3FI), 1.31(s, 2H); MS(ESI) m / z 515 [M+F11'.²Example 132: Preparation of²N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-1-(1-²meth²y1-1H-pyrazol-5-y1)-5-(1-morpholinylethyl)indolizine-7-carboxamide: same to ²example 108.²0 N (0²0 0 N²HATU DIPEA²H I²_Hr&I-41 I²N²DMF² / 0²i²4-TN,²Compound 133²Step 1: Preparation of²N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-1-(1-meth²y1-1H-pyrazol-5-y1)-5-(1-morpholinylethypindolizine-7-carboxamide: Yield 21%. ²IF1 ²NMR (400 MHz, CDCI3) (3 ppm 11.40(s, 1H), 8.47(s, 1H), 8.05-8.06 (d,j = 3.6 ²Hz, ²1H), 7.46(d,J= 1.2 Hz, 1H), 7.02(d,J = 2.8 Hz, 1H), 6.08(s,1H),²6.38(s,1H),4.19-4.20 (m, 2H), 4.05-4.09 (m, 1H), 3.78 (s, 3H),3.82 (s, ²3H),3.65 (m,²4H), 2.63-2.70(m, 2H), 2.37 (s, 3H). 2.00 (m, 5H), 1.45-1.44(m, 31-1); MS(ESI) ²m / z²542 [M+Hr.²Example 133: Preparation of²N-((4N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl)-2( ²1-methyl-1H-imidazol-5-y1)-5-(1-morpholinoethyl)indolizine-7-carboxamide: same² as example 108.²0 N N²HO HN²)Loil I N² / ²HATU DIPEA²It ( ornnound.,!13²169²<DP=170>²CA 03036114 2019-03-07²Step 1: Synthesis of²N-((4N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-²(1 ²-methyl-1H-imidazol-5-y1)-5-(1-morpholinoethyl)indolizine-7-carboxamide, yield ²²37%. 1H-NMR (Me0D, 400 MHz): 8.91 (s, 1 H), 7.68 (s, 1 H), 7.58 (s, 1 H), 6.93 ²(s,².. 1 H), 6.48 (s, 1 H), 4.47 (s, 2 H), 4.03-3.97(m, 6 H), 3.85-3.74 (m, 1 H), ²3.79 (s, 4 H),²3.23-3.20 (m, 2 H), 2.75-2.68 (m, 2 H), 2.39 (s, 6 H), 1.76-1.75 (m, 3 H); ²MS(ESI) ²m / z 519.5 [M+Hr.²Example 134: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-3 / 1)methyl)-54 1-(4-²(dimethylamino)pip²eridin- 1 -yl)ethyl)-6-methyl-2-(1-methyl-IH-imidazol-5-y1)indolizine-7-²carboxamide:²same as example 31.²0²I N 0 N²)' ² H 0 NaBNL. jita² / ²; TI(1-01.14²²Oyt.1 myON²t.,²NaOH²HATU. DIPEA ².)1.1 / ²Compound 1351²Step 1: Synthesis of isopropyl²5-(1-(4-(dimethylamino)piperidin-l-yl)v iny1)-6-methy1-2-(1-methyl-1H-imidazol-²5-y² I)indolizine-7-formate: MS (ESI) m / z 450 [M+H].²Step 2: Synthesis of isopropyl²5-(1-(4-(dimethylamino)piperidin-l-ypethyl)-6-methyl-2-(1-methyl-IH-imidazol-5-²y²1)indolizine-7-formate: yield of two steps was 29%. MS (ESI) m / z 452 [M+Hr.²Step 3: Synthesis of²5-(1-(4-(dimethylamino)piperidin-l-ypethyl)-6-methyl-2-(1-methyl-IH-imidazol-5-²y²1)indolizine-7-formic acid: MS (ES1) m / z 410 [M+Hr.²Step 4: Synthesis of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-5-(1-(4-(dimethylam ²ino)pip²eridin- 1 -yl)ethyl)-6-methyl-2-(1-methyl-1H-imidazol-5-yl)indolizine-7-²carboxamide:²yield of two steps was 40% . 11-1-NMR (Me0D, 400 MHz): 8.69 (s, 1 H), 8.59 (s, ²1²170²<DP=171>²CA 03036114 2019-03-07²H), 7.56 (s, 1 H), 7.43 (s, 1 H), 6.78 (s, 1 H), 6.12 (s, 1 H), 4.52-4.46 (s, ²2 H). ²4.17-4.13 (m, 1 H), 3.98 (s, 3 H), 3.58-3.56 (m, 1 1-I), 3.30 (s, 4 H), 2.84 ²(s, 6 II), ²2.37 (s, 3 H), 2.32 (s, 3 H), 2.25 (s, 3 H) 2.10-2.07 (m, 2 H). 1.98-1.89 (m, ²2 H), ²1.62-1.54 (m, 3 H); MS(ESI) m / z 544 [M+1-1I.² Example 135: Preparation of²5-(1-(4-(dimethylamino)piperidin-1-ypethyl)-N-((4-methoxy-6-methyl-2-oxo-1,2-²dih ²ydropyridin-3-yl)methyl)-6-methyl-2-(1-methyl-11-1-imidazol-5-y1)indolizine-7-²carbo ²xamide: same as example 108.²'NH2 0 0. aN²0 N²HO² HATu DIPEA "=== N² / ²¨%¨N / ²i:)4 Compound²N ² Step 1: Synthesis of²5-(1-(4-(dimethylam ino)piperidin-l-yl)ethyl)-N-((4-methoxy-6-methy 1-2-oxo-²1,2-dih ²ydropyridin-3-yl)methyl)-6-methyl-2-(1-methy 1-IH-imidazol-5-yl)indolizine-7-²carbo ²xamide: Yield 32 %. 1H-NMR (CDCI3, 400 MHz): 8.59 (s, 1 H), 7.48 (s, 1 H), ²7.42 ²(s, 1 H), 7.34 (s, 1 H), 7.15 (s, 1 H), 6.49 (s, 1 H), 5.93 (s, 1 H), 4.56-²4.55 (m, 2 I-1),²4.01-3.99 (m, 1 H), 3.89 (s, 3 H), 3.75 (s, 3 El), 3.37-3.34 (m. 1 14), 2.53 ²(s, 3 H),²2.37-2.36 (m, 3 H), 2.35 (s, 6 H), 2.02-1.94 (m, 4 H). 1.63-1.57(m, 2 1-1), ²1.55-1.47 ²(m, 3 H); MS(ESI) m / z 560 [M+HI.²Example 136: Preparation of²N((4,6-dimethy1-2-oxo-I,2-dihydropyridin-3-y1)methyl)-6-methyl-2-(1-methyl-1H-²i²midazol-5-y1)-5-(1-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)ethyl)indolizine-7-²carboxa²mide: same as example 83.²Boo (NN) (N) 0 ² I HCI N AcOH Ac²=N .õ)² F N²0²(P) LW) 7..)Y-N"' 0 0 (N)²T10õF 0 N² NaOH ,0),,c(r1, D'I-PE;THI I²N² / A²Compound 137²171²<DP=172>²CA 03036114 2019-03-07²Step I: Synthesis of isopropyl²5-(1-(4-(tert-butoxycarbonyl)piperazin-l-yl)viny1)-6-methyl-2-(1-methyl-1H-²imidazo ²le-5-yl)indolizine-7-carboxylate: MS (ESI) m / z 508 [M+Hr.²Step 2: Synthesis of isopropyl²5-(1-(4-(tert-butoxycarbonyl)piperazin-1-yl)viny1)-6-methyl-2-(1-methyl-1H-²imidazo²le-5-yl)indolizine-7-formate: yield of two steps was 35%. MS (ESI) m / z 510 ²[M+H]. ²Step 3: Synthesis of isopropyl²6-methyl-2-(1-methyl- I H-imidazol-5-y1)-5-(1-(piperazin-l-y1)ethyl)indolizine-²7-carb ²oxylate: MS (ESI) m / z 410 [M+Hr.² Step 4: Synthesis of isopropyl²6-methyl-2-(1-methyl- 1 H-imidazol-5-y1)-5-(1-(4-(2,2,2-²trifluoroethyl)piperazine-1-y²1)ethyl)indolizine-7-carboxylate: yield 33%. MS (ESI) m / z 492 [M+Hr.²Step 5: Synthesis of²6-methyl-2-(1-methyl-1H-imidazol-5-y1)-5-(1-(4-(2,2,2-²trifluoroethyl)piperazine-1-y² 1)ethyl)indolizine-7-carboxylic acid: MS (ESI) m / z 450 [M+Hr.²Step 6: Synthesis of²N-((4,6-dimethy1-2-oxo-1 ,2-dihydropyridin-3-yOmethyl)-6-methyl-2-(1-methyl-IH-²i²midazo-5-y1)-5-(1-(4-(2,2,2-trifluoroethyppiperazin- I -yl)ethypindolizine-7-²carboxa²mide: yield of two steps was 70%. 1H-NMR (Me0D, 400 MHz): 8.96 (s. 1 H), 7.70²(s, 1 H), 7.61 (s, 1 H), 6.18 (s, 1 H), 4.49 (s, 2 H), 4.01 (s, 3 H), 3.35-²3.34 (m, I H),²3.05-2.99 (m, 4 H), 2.94-2.93 (m, 2 H), 2.41-2.38 (m, 6 H), 2.29-2.27 (m, 5 ²H). ²1.87-1.85 (m, 3 H); MS(ESI) m / z 584 [M+I-1]'.²Example 137: Preparation of²N((4-Methoxy-6-methy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-2-( 1-met²hy1-1H-imidazol-5-y1)-5-(1-(4-(2,2,2-trifluoroethyl)piperazin-1-²ypethypindolizine-7²-carboxamide:²F F²ri<F 0 rj<FF²0 CNND HN NH2 cNj²0 0 N²HO²HATO PIDEA²H I 14 C'N²0²Compoundi3 ,²8²Step 1: Synthesis of²172²<DP=173>²CA 03036114 2019-03-07²N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-(1-²meth ²y1-1H-imidazole-5-y1)-5-(1-(4-(2,2,2-trifluoroethyl)piperazin-l-²yl)ethyl)indolizine-7-²carboxamide: yield 62%. 11-1-NMR (CDC13, 400 MHz): 8.96 (s, 1 H), 7.71 (s, 1 ²H), ²7.62 (s, 1 H), 6.47 (s, 1 H), 4.49 (s, 2 H), 4.01-3.99 (m, 6 H), 3.31-3.30(m, ²1 H),²3.30-3.29 (m, 2 H), 3.07-3.04 (m, 4 H), 2.94-2.93 (m, 2 H), 2.42-2.39 (m, 8 ²H),²1.89-1.86 (m, 3 H): MS(ESI) m / z 600.5 [M+El]*.²Example 138: Preparation of²N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morp ²holinoethyl)-2-(thiazol-5-ypindolizine-7-carboxamide: same as example 50.²LO 1 NeBH,² \ ch DI Kan: v I-120 \ / T*D'Pr4-²)(C ___________________________ ²---b²N² C N) cON 0 (CI²DMF _____________________________________ HAW DIPEA k_ics² / ,) , -5²' I? Its-4 c ompound 139² N²Step 1: Synthesis of ethyl²5-acetyl-6-methyl-2-(thiazol-5-yl)indolizine-7-carboxylate: Yield 68%. MS ²(ESI) ²m / z 329 [M+H]4.²Step 2: Synthesis of isopropyl²6-methy1-5-(1-morpholinoviny1)-2-(thiazol-5-ypindolizine-7-carboxylate: MS ²(ESI)²m / z 412 [M-FFIr²Step 3: Synthesis of isopropyl²6-methyl-5-(1-morpholinoethyl)-2-(thiazol-5-y1)indolizine-7-carboxylate: yield ²of ²two steps was 47%. MS (ESI) m / z 414 [M+1-11-1.² Step 4: Synthesis of²6-methy1-5-(1-morpholinoethyl)-2-(thiazol-5-y1)indolizine-7-carboxylic acid: ²MS ²(ESI) m / z 372 [M+1-11'.²Step 5: Synthesis of²N-((4-methoxy-6-methy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²morp²hoethyl)-2-(thiazol-5-y1)indolizine-7-carboxamide: yield of two steps was 24%.²1H-NMR (Me0D, 400 MHz) :8.96(s, 1 H), 8.15(s, 1 H), 7.56(s, 1 H), 6.49(s, 1 ²El),²173²<DP=174>²CA 03036114 2019-03-07²4.47(s,1 H), 3.99(s, 3 H), 3.87-3.86(m, 4 H),3.24-3.20(m, 4 H), 2.41-2.39(m, 6 ²H), ²1.83(m, 3 H); MS(ESI) m / z 522 [M+Hr.²Example 139: Preparation of²N((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-5-(1-(4-(dimethylam ²ino)pip² eridin-1-yl)ethyl)-6-methyl-2-(thiazol-5-y1)indolizine-7-carboxamide: same as²example 31.²:t() a i²0 N-²-n(oHpo4 AcOH²a 0²0 N²0 0 N²LOH -1 "NANH' HATU²DIPE=A "N N² / DMF² / N3 t Compound 14T;)²Step 1: Synthesis of isopropyl²5-(1-(4-(dimethylamino)piperidin-1-yl)viny1)-6-methyl-2-(thiazol-5-²ypindolizine-7-c² arboxylate: MS (ESI) m / z 453 [M+Hr.²Step 2: Synthesis of isopropyl²5-(1-(4-(dimethylamino)piperidin-1 -yl)ethy1)-6-methyl-2-(thiazol-5-²ypindolizine-7-c²arboxylate: yield of two steps was 44%. MS (ESI) m / z 455 [M+H].²Step 3: Synthesis of²5-(1-(4-(dimethylamino)piperidin-1 -yDethyl)-6-methyl-2-(thiazol-5-Aindolizine-²7-c²arboxylic acid: MS (ESI) m / z 413 [M+H]+.²Step 4: Synthesis of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-5-(1-(4-²(dimethylamino))pi²peridin-l-yl)ethyl)-6-methyl-2-(thiazol-5-y1)indolizine-7-carboxamide, two-²step² yield: 10%. 1H-NMR (Me0D, 400 MHz) :8.89(s, 1 H), 8.05(s, I H), 7.39(s, 1 H),²6.77(s, 1 14),6.14(s, 1 H), 4.47(s,2 H), 3.99(s, 2 H), 2.92(s, 1 H),2.85(s, 6 ²H), 2.38(s, ²3 H), 2.32(s, 3 H), 2.28-2.25(m, 5 H), 1.60-1.59(m, 3 H). MS (ESI) miz 547 ²[M+H]+.²Example 140: Preparation of²174²<DP=175>²CA 03036114 2019-03-07²-(1-(4-(dim ethylamino)piperidin-l-yl)ethyl)-N-((4-methoxy-6-methy 1-2-oxo)-²1,2-di ²hydropyridin-3-yl)methyl)-6-methyl-2-(thiazol-5-y1)indolizine-7-carboxamide: ²same²as example 108.²-N-² 0 &--²NH,²HO²HN1 N²I N14 ),XHVIN'² / 0 N²HATU DIPEA DMF \-- / K² / -N3 it Compound i41² 5 Step 1: Synthesis of²5-(1-(4-(dimethyl am ino)p iperidin- 1-y 1)ethyl)-N-((4-m ethoxy-6-methy 1-2-²oxo-1,2-dih ²ydropyridin-3-yl)methyl)-6-methyl-2-(thiazol-5-y1)indolizine -7-carboxamide: ²Yield ²11%. 1H-NMR (Me0D, 400 MHz) :8.89(s, 1 H), 8.05(s, 1 H), 7.39(s, 1 H), 6.74(s, ²²1 H),6.29(s, 1 H), 4.44(s,2 H), 4.16-4.14(s,1 H),3.95(s, 3 H), 3.62-3.59(s, 1 ²H),²3.22(m, 2 H), 2.85(s, 6 H),2.69-2.67(m, 1 H), 2.17(s, 6 H), 2.25-2.28(m, 6 H),²1.60-1.59(m, 3 H); MS(ESI) m / z 563 [M+Hr.²Example 141: Preparation of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-(thiazole-5-²y1)-²5-(1-(4-(2,2,2-trifluoroethyppiperazin-1-ypethypindolizine-7-carboxam ide: ²same as² example 83.²(I N HCI²)²0² B ' 0 N²NaBH, HCI EA JOW²H² Ti(OiPr)4 / ACOH / EA²r,CF, F3C,1 0N F3C1N,N²LN) 0 cNN)MN NH, c²F,CQOTt ²LION 0 0 ²THF I HO²N HATU DIPEA DMF N²-s²Compound 142 tN,²Step 1: Synthesis of isopropyl²5-(1-(4-(tert-butoxycarbonyl)p iperazin-l-y 1)v iny1)-6-methy1-2-(thiazo le-5-²yl)indo 1 izi²ne-7-carboxylate: MS (ESI) m / z 511 [M+H11.² Step 2: Synthesis of isopropyl²5-(1-(4-(tert-butoxycarbonyl)piperazin-l-yl)ethyl)-6-methyl-2-(thiazole-5-²y1)indolizi²175²<DP=176>²CA 03036114 2019-03-07²ne-7-formate: yield of two steps was 34%. MS (ES!) m / z 513 [M+Hr. ²Step 3: Synthesis of isopropyl²6-methy1-5-(1-(piperazin-l-ypethyl)-2-(thiazol-5-ypindolizine-7-carboxylate ²hydrochloride: MS (ES!) m / z 413 [M+H]² Step 4: Synthesis of isopropyl²6-methy1-2-(thiazol-5-y1)-5-(1-(4-(2,2,2-trifluoroethyl)piperazin- 1 -²yl)ethyl)indolizin ²e-7-formate: yield of two steps was 25%. MS (ESI) m / z 495 [m+Hy.²Step 5: Synthesis of²6-Methyl-2-(thiazol-5-y1)-5-(1-(4-(2,2,2-trifluoroethyl)piperazin-1-²y1)ethyl)indolizin² e-7-carboxylic acid: MS (ES!) m / z 453 [M-1-H1+.²Step 6: Synthesis of²N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-(thiazol-5-²y1)-5 ²-(1-(4-(2,2,2-trifluoroethyppiperazin-1-yl)ethyl)indolizine-7-carboxamide: ²yield of ²two steps was 46%. 11-1-NMR (Me0D, 400 MHz) :8.92(s, 1 H), 8.09(s, 1 I-1), ²7.50(s, 1²H), 6.13(s, 1 H), 4.47(s,3 I-I), 3.26-3.22(m,6 H),2.94(m, 4 H), 2.38(s, 3 Fl), ²2.34(s, 3²I-1), 2.25(s, 3 H), 1.77-1.76(m, 3 H); MS(ESI) m / z 587 [M+Hr²Example 142: Preparation of²N-((4-methoxy-6-methy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-2-²(thiazol ²e-5-y1)-5-(1-(4-(2,2,2-trifluoroethyl)piperazin- -yl)ethyl)indol izine-7-²carboxamide:² same to example 108.²F3c,i 0 F3c,1²FIXIIrNH7CNJ²0 0 N²HATU DIPEA DMF \\² tN It C wound 14,34,3.²Step 1: Synthesis of²N((4-methoxy-6-methy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methy I-2-(th ²iazol ²-5-y1)-5-(1-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)ethyl)indol izine-7-²carboxam ide:² yield 38.7%. 1H-NMR (Me0D, 400 MHz) :8.93(s, 1H), 8.09(s, 1H), 7.50(s, 1H),²6.34(s, 1H), 4.52(s,2H), 3.96(s, 3H), 3.26-3.22(m,6H),2.94(m, 4H), 2.38(s, ²3H), ²2.34(s, 3H), 1.77-1.76(m, 3H);MS(ESI) m / z 603 [M+H] h.²Example 143: Preparation of²176²<DP=177>²CA 03036114 2019-03-07²2-Bromo-N4(4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yOmethyl)-6-methyl-5-(1-(4-²methoxypiperidin-1-y1)ethyl)indolizine-7-carboxamide: same as example 30.²,oyt²N²N aBH4 0² MO-Prn)a AcOH²t / Z²Br Br²0 N²HN, NH2HCI HN N²LION t²Me0H / 11,0 i \ HATU, DIPEAMMF² 'Br Compound 14'44r²Step 1: Preparation of isopropyl² 2-bromo-6-methyl-5-(1-(4-methoxypiperidin-1-yl)vinypindolizine-7-carboxylate:²MS (ES!) m / z 436 [M+Hr.²Step 2: Preparation of isopropyl²2-bromo-6-methy1-5-(1-(4-methoxypiperidin-1 -yl)ethyl)indolizine-7-²carboxylate: ²yield of two steps was 74%. MS (ES!) m / z 438 [M+H].² Step 3: Preparation of²2-bromo-6-methy1-5-(1-(4-methoxypiperidin-l-y1)ethyl)indolizine-7-carboxylic ²acid:²MS (ES!) m / z 396 [M+H].²Step 4: Preparation of²2-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyrid in-3-yOmethyl)-6-methyl-5-(1-²(4-²methoxypiperidin- 1 -ypethypindolizine-7-carboxamide: yield of two steps was ²57%.²1H NMR (400 MHz, Me0D-d4) 6 ppm 7.54 (s, 1 H), 6.78 (s, 1 H), 6.13 (s, 1 H), ²5.18-5.14 (m, 1 H), 4.46(s, 2 H), 3.58(s, 1 H), 3.52 (s, 3 H), 3.31 (s, 4 H), ²2.38-2.37(m, 6 H), 2.25 (s, 3 H), 2.13-2.08(m, 2 H), 1.90(d, J=6.8 Hz, 3 H), ²1.29(s, 2 ²H); MS(ESI) m / z 552 [M+Hr² Example 144: Preparation of²2-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-y1)methyl)-5-(1-(4-²hydroxypi ²peridin-1-yl)ethyl)-6-indolizine-7-carboxamide: same as example 30.²177²<DP=178>²CA 03036114 2019-03-07²clE$²OH²OH² TIOrpola eN N BH4 N² / ²Or crji OH Or²²0 1111_²NaOH HATU DIEA 7:õ.j,irvi .J4²0 0²Me0H / H,0 H )CILT DMF²th Br²Compound 145²Step 1: Preparation of isopropyl²2-bromo-5-(1-(4-hydroxypiperidin-l-yl)viny1)-6-methylindolizine-7-carboxylate: ²MS ²(ESI) m / z 421 [M+1-1J.² Step 2: Preparation of isopropyl²2-bromo-5-(1-(4-hydroxypiperidin-1-ypethyl)-6-methylindolizine-7-carboxylate: ²yield of two steps was 41%. MS (ESI) m / z 423 [M+H]'.²Step 3: Preparation of²2-bromo-5-(1-(4-hydroxypiperidin-1-ypethyl)-6-methylindolizine-7-carboxylic ²acid:² MS (ESI) m / z 381 [M+H].²Step 4: Preparation of²2-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3 -yl)methy1)-5-(1-(4-²hydroxypi²peridine-1-yl)ethyl)-6-indolizine-7-carboxamide, yield of two steps was 23%. ²1H²NMR (400 MHz, DMSO-d6) 6 ppm 11.45(s, 1 H), 8.39(s, 1 H), 8.21-8.20 (d, J = ²2.4²Hz, 1 H), 7.23(s, 1 H), 6.58(s, 1 H), 5.87(s, 1 H), 4.56-4.55 (m, 1 H), 4.26-²4.25 (m, 2²H), 3.97-3.96(m, 1 H), 3.02(m, 1 H), 2.41-2.38(m, 2 H),2.32-2.28 (m, 6 H), ²2.21 (s, 3²H), 2.01-1.93 (m, 2 H), 1.78-1.77(m, 1 H),1.65-1.64(m, 1 H), 1.46-1.44(m, 4 ²H).²MS (ESI) m / z 517 [M+H] +.²Example 145: Preparation of²2-bromo-N-((4,6-dimethy1-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-methyl-5-(1-²(44²pyrrolidin-l-Apiperidin-1 -ypethypindolizine-7-carboxamide: same as example ²30.²178²<DP=179>²CA 03036114 2019-03-07²a 0 N² 00 0²\- ,²N N NriBH4²N²T'( 'Pr) 11Z ACOH 1 / ²Br Br²C.:;) 0 o,²L,..² THF , HO ,²N HAT1J HA'141)1' I²Compound 146²Step 1: Synthesis of isopropyl²2-bromo-6-methy1-5-(1-(4-(pyrrolidin-l-y1)piperidin-1-y1)vinypi...

Claims

<DP=1>²² Claims ²²1. A compound of formula I, or a pharmaceutically acceptable salt, an ²enantiomer, a diastereomer, a tautomer, a solvate, a polymorph or a prodrug ²thereof,²²wherein X1 is CR4 or N;²X2 is CR5 or N;²X3 is CR6 or N; and at most one of X1, X2, X3 is N;²R4 is selected from H, a halogen, substituted or unsubstituted C1-C6 alkyl;²R5 or R6 is selected from H, a halogen, -COOH, -CN, substituted or ²unsubstituted 5-8 membered aryl, substituted or unsubstituted 5-8 membered ²heteroaryl, substituted or unsubstituted 5-8 membered aryl fused to ²substituted or ²unsubstituted 5-8 membered heterocyclic group, substituted or unsubstituted 5-²8 ²membered heteroaryl fused to substituted or unsubstituted 5-8 membered ²heterocyclic group, substituted or unsubstituted 5-8 membered aryl fused to ²substituted or unsubstituted 5-8 membered carbocyclic group, substituted or ²unsubstituted 5-8 membered heteroaryl fused to substituted or unsubstituted 5-²8 ²membered carbocyclic group, substituted or unsubstituted 4-8 membered ²saturated or ²unsaturated carbocyclic group, substituted or unsubstituted 4-8 membered ²saturated ²or unsaturated heterocyclic group, substituted or unsubstituted Cl -C6 ²alkylcarbonyl, ²-C(O)O-(substituted or unsubstituted C1-C6 alkyl), -C(O)(NR a R b), ²substituted or ²unsubstituted -(CH2)m NR a R b, substituted or unsubstituted C1-C6 alkyl, ²boronic acid ²group, substituted or unsubstituted C2-C8 alkenyl, substituted or ²unsubstituted ²C2-C8 alkynyl; wherein the heteroaryl or heterocyclic group contains 1-3 ²hetero ²atoms selected from N, O, S, P; m is an integer from 0 to 5; and said ²"substituted" ²means having one or more (e.g., 1, 2, 3, or 4) substituents selected from ²group A;²Wherein R a, R b are each independently selected from H, a halogen, ²substituted ²or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-8 membered ²carbocyclic²² 238²<DP=2>²ring, substituted or unsubstituted 5-8 membered heterocyclic ring, or R a and ²R b are ²bonded to N to form a substituted or unsubstituted 4-8 membered heterocyclic ²ring; ²wherein said heterocyclic ring contains 1-3 hetero atoms selected from N, O, ²S, or P;²²R1 is selected from²R2 is selected from H, a halogen, substituted or unsubstituted C1-C6 alkyl, ²substituted or unsubstituted aryl;² ²R3 is selected from or ; and when R1 is , then ²R3 is²²wherein, R7 is selected from H, substituted or unsubstituted C1-C6 alkyl;²R8 and R9 are each independently selected from H, a substituted or ²unsubstituted²C1-C6 alkyl;² ²Y is selected from or²wherein, R12 and R13 are each independently selected from H, substituted or ²unsubstituted C1-C4 alkyl;²R14 and R15 are each independently selected from H, a halogen, -NH2, -NO2, ²-CF3, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted ²C1-C4 ²alkoxy, substituted or unsubstituted (CH2)NR c R d, or R14 and R15 are joined ²to form a ²substituted or unsubstituted 5-6 membered saturated heterocyclic ring, or R14 ²and R15 ²are linked to form a substituted or unsubstituted 5-6 membered aromatic ring; ²n is an ²integer of 0-4;²R16 is H, a substituted or unsubstituted C1-C4 alkyl;²R17 and R19 are each independently selected from H, a substituted or ²substituted ²C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, -(CH2)n NR c R d; n is ²an ²integer from 0-4;²R18 is selected from H, a halogen, -NH2, -NO2, substituted or substituted C1-²C4²239²<DP=3>²alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted ²²(CH2)n NR c R d; where n is an integer from 0-4;²R20 and R21 are each independently selected from H, a substituted or ²substituted ²C1-C4 alkyl;²R22 is selected from H, a substituted or unsubstituted C1-C4 alkyl; ²² or substituted or unsubstituted C1-C4 alkoxy;²wherein R c, R d are each independently selected from H, a substituted or²unsubstituted C1-C4 alkyl;²Z is selected from N or CH;²R10 and R11 are each independently selected from: H, -OH, a substituted or ²unsubstituted C1-C6 alkyl, -OR e, substituted or unsubstituted 4-8 membered ²heterocyclic group, substituted or unsubstituted 4-8 membered carbocyclic ²group, ²substituted or unsubstituted 5-8 membered aryl, -NR f R g; wherein said ²heterocyclic ²ring contains 1-3 hetero atoms selected from N, O, S, or P; and said ²"substituted" ²means having one or more (e.g., 1, 2, 3 or 4) substituents selected from group ²B;²wherein R e is selected from H, a substituted or unsubstituted C1-C6 alkyl, ²substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ²²alkynyl, substituted or unsubstituted saturated or unsaturated 4-8 membered ²carbocyclic ring, substituted or unsubstituted saturated or unsaturated 4-8 ²membered ²heterocyclic ring, substituted or unsubstituted 5-8 membered aryl, substituted ²or ²unsubstituted 5-8 membered heteroaryl, -(CH2)p(substituted or unsubstituted 5-²8 ²membered aryl), -(CH2)p(substituted or unsubstituted 5-8 membered heteroaryl); ²²wherein the heterocyclic or heteroaryl group comprises 1-3 heteroatoms ²selected ²from N, O, S, or P; p is an integer from 0 to 3; and said "substituted" refers ²to one or ²more of the following (e.g., 1, 2, 3 or 4) substituent: halogen. C1-C4 alkyl, ²C1-C4 ²alkoxy, -NO2, -NR s R t;²wherein R f and R g are each independently selected from: H, a substituted or ²unsubstituted C1-C6 alkyl, wherein the substituent is -OH, C1-C4 alkoxy, or -²NR s R t;²group A substituents are selected from the group consisting of H, =O, -CN, ²-COOH, -NR s R t, a halogen, substituted or unsubstituted C1-C6 ²alkoxycarbonyl, ²unsubstituted or substituted C1-C6 alkyl, substituted or unsubstituted 4-8 ²membered²240²<DP=4>²²heterocyclic group, substituted or unsubstituted C1-C4 alkoxy; wherein the ²heterocyclic group contains 1-3 hetero atoms selected from N, O, S or P;²group B substituents are selected from the group consisting of H, -OH, a ²halogen, unsubstituted or substituted C1-C6 alkyl, -NR s R t, -NO2, ²substituted or ²unsubstituted C1-C6 alkoxycarbonyl, substituted or unsubstituted C1-C6 ²alkylsulfonyl, substituted or unsubstituted C1-C6 alkylcarbonyl, substituted ²or ²unsubstituted C1-C6 alkoxy, substituted or unsubstituted 4-6 membered ²heterocyclic ²ring, substituted or unsubstituted C5-C8 heteroaryl, Boc, benzyl; wherein said ²²heteroaryl comprises 1-3 heteroatoms selected from N, O, S or P;²also, in the group A and group B substituents and R a, R b, the substitution ²means ²having one or more (e.g. 1, 2, 3 or 4) substitutions selected from group C: H, ²a ²halogen, -OH, -CN, C1-C4 alkyl, C1-C4 alkoxy, -NR s R t, 5-8 membered aryl, 4-²8 ²membered heterocyclic group, Boc, C1-C4 acyl; and said substitution is one or ²more ²(e.g., 1, 2, 3 or 4) substituents;²and, in the R7, R8, R9, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, ²R c, R d,²the "substituted" means having one or more (e.g., 1, 2, 3 or 4) substituents ²selected ²from the group D: H, a ahalogen, C1-C4 alkyl, C1-C4 haloalkyl, nitro, -OH, ²amino; ²R s and R t are each independently selected from the group consisting of: H, a ²²C1-C4 alkyl, C1-C4 haloalkyl.²2. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, ²²diastereomer, tautomer, solvate, polymorph or prodrug thereof, wherein R10 is ²a ²substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 ²alkyl.²3. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, ²²diastereomer, tautomer, solvate, polymorph or prodrug thereof, wherein R11 is²selected from the group consisting of -OH, -OR e, -NR f R g, ²²² 241²<DP=5>²wherein R e is selected from the group consisting of substituted or ²unsubstituted ²C1-C4 alkyl, allyl, isobutenyl, propargyl, cyclohexane group, cyclohexenyl,²²wherein, R e1 is selected from the group consisting of H, a halogen, C1-C4 ²alkoxy; and the number of R e1 is 1-3; R e2 is selected from -NO2, -NH2, -N(C ²H3)2; R e3 ²is selected from H, a halogen, -NR s R t, substituted or unsubstituted C1-C4 ²alkyl ²(preferably methyl);²R f is H, a substituted or unsubstituted C1-C4 alkyl;²R g is a C1-C4 alkoxy or -N s R t substituted C1-C4 alkyl;²R h is selected from H, a halogen;²R' is selected from H, an unsubstituted or substituted C1-C4 alkyl, ²substituted or ²unsubstituted C1-C4 alkylcarbonyl, substituted or unsubstituted C1-C4 ²alkoxycarbonyl, substituted or unsubstituted C1-C4 alkylsulfonyl, ²trifluoromethyl²C1-C2 alkyl, difluoromethyl C1-C2 alkyl, -NR s R t , and , wherein R h1 ²is²selected from -OH, -CN, a C1-C4 alkyl;²R j is selected from the group consisting of: -OH, a halogen, C1-C4 alkoxy,²²-NR s R t, ; wherein R j1 is selected from a C1-C4 alkoxy (preferably a²methoxy);²R j' is selected from H or a halogen;²and when R j is a halogen, then R j' is a halogen;²R k is selected from the group consisting of H, -OH, a C1-C4 alkoxy,²R I is selected from the group consisting of H, -NR s R t, preferably H or²dimethylamino;²R m is selected from the group consisting of: H, -NR s R t, preferably H or²dimethylamino;²R n is selected from the group consisting of a trifluoronrethyl C1-C4 alkyl,²preferably CF3CH2-.²242²<DP=6>²4. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, ²²diastereomer, tautomer, solvate, polymorph or prodrug thereof, wherein R5 or ²R6 are ²each independently selected from the group consisting of H, a substituted or ²unsubstituted C 1 -C4 alkyl, -CN, halogen, C1-C4 alkylcarbonyl, R51(C1-C4²alkoxy)carbonyl, R52C(O)- , -COOH, -C(O)(NRaRb),²², R57(C1-C3)alkylalkynyl;²wherein R51 is selected from the group consisting of dimethylamino,²²and wherein Rb is selected from the group consisting of H, a ²C1-C4 alkyl, Boc, C1-C4 acyl;²²R52 is selected from²Ra is selected from H, a substituted or unsubstituted Cl -C4 alkyl; ²Rh is selected from H, a substituted or unsubstituted CI -C4 alkyl,²²cyclopentyl, Rb"(C1-C4)alkyl; wherein X is hetero atom selected from N,²O or S;²R55 is 1-3 substituents selected from the group consisting of H, R551C1-C4 ²alkyl,²halogen, -CN, -NH2, (C1-C4 alkyl)NH-, (R551C1-C4 alkyl) O-, dimethylamino,²243²<DP=7>²²-CH2(Me)2, R551(C1-²C6)aIkyl OC(O)-, -COOH, -C(O)(NRaRb);²wherein R551 is H, -OH, a C1-C4 alkoxy, amino, dimethylamino, methylamino,²diethylamino, methylethylamino, ethylamino,²²; wherein²R541 is selected from H, a C1-C4 alkyl;²R57 is selected from a (C1-C4)alkyl, dimethylamino;²R6 is selected from the group consisting of -OH, a C1-C3 alkoxy,²²dimethylamino,²5. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, ²²diastereomer, tautomer, solvate, polymorph or prodrug thereof, wherein the ²compound of formula I has the structure of formula la below:²²where the said R1, R2, R3, R4, R5, R6 are as described above.²6. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, ²²diastereomer, tautomer, solvate, polymorph or prodrug thereof, wherein the ²compound is selected from the group consisting of²244²<DP=8>²²245²<DP=9>²²246²<DP=10>²²247²<DP=11>²²248²<DP=12>²²249²<DP=13>²²250²<DP=14>²²251²<DP=15>²7. A preparation method for the compound of formula I of claim 1, wherein the ²compound of formula I has the structure shown in formula I-1 and the method ²comprises the steps:²²(1) in the presence of a reducing agent, reducing compound d to form compound ²e, while the reducing agent is selected from the group consisting of sodium ²borohydride, lithium borohydride, potassium borohydride, or combinations ²thereof;²(2) in the presence of a base, reacting compound e with a corresponding ²hydrocarbylation reagent to form compound f, the base is selected from the ²group ²consisting of sodium hydride, potassium t-butoxide, sodium hydroxide, ²potassium ²hydroxide, n-butyl lithium, lithium diisopropylamide, lithium ²hexamethyldisilazide, ²sodium hexamethyldisilazide, potassium hexamethyldisilazide, potassium ²carbonate, ²cesium carbonate, sodium carbonate, or combinations thereof; and the ²alkylating ²agent is selected from the group consisting of halogenated hydrocarbons, ²methanesulfonate, p-toluenesulfonate, trifluoroacetate, triflate, or ²combinations ²thereof;²(3) hydrolyzing compound f to form compound g;²(4) condensing compound g with an amine compound to form compound 1-1,²wherein R2, R3, R7, R8, R9, R10, T1, Re, Rf, X1, X2, X3 and Y are as defined ²above, and Rk is a Cl-C4 linear or branched alkyl;²and / or²a preparation method for the compound of formula 1 of claim 1, wherein the ²compound of formula 1 has the structure shown in formula 1-2 and the method ²comprises the steps:²²(i) in an inert solvent, in the presence of reducing agent, reacting compound ²d²252²<DP=16>²with compound f to form compound i;²(ii) hydrolyzing compound i to form compound j;²(iii) condensing compound g with amine compound to form compound 1-2; ²wherein the R2, R3, R7, R8, R9, R10, Re, Rf, Rk, X1, X2, X3 and Y are as ²described²above;²and / or²a preparation method for the compound of formula I of claim 1, werein the ²compound of formula I has the structure shown in formula I-3 and the method ²comprises the steps:²²(a) in an inert solvent, in the presence of reducing agent, reducing compound ²k to ²form compound I;²(b) in the presence of alkylating agent, reacting compound 1 to form compound ²m, ²and said alkylating agent is selected from the group consisting of X-R10', ²HSO4-R10', ²HO-R10', R10'-O-R10', or combinations thereof;²wherein X is halogen; R10' is a substituted or unsubstituted C1-C6 alkyl, ²substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ²²alkynyl, substituted or unsubstituted saturated or unsaturated 4-8 membered ²heterocyclic group, substituted or unsubstituted saturated or unsaturated 4-8 ²membered carbocyclic group, substituted or unsubstituted 5-8 membered aryl, ²saturated or unsaturated; wherein said heterocyclic ring comprises 1-3 ²heteroatoms ²selected from N, O, S, P; and said "substituted" means having one or more ²(e.g., 1, 2, ²3 or 4) substituents selected from group B as set forth in claim 1;²(c) hydrolyzing compound m to form compound n;²(d) condensing compound n with amine compound to form compound 1-3; ²wherein the R2, R3, R7, R8, R9, R10, Re, Rf, Rk, X1, X2, X3 and Y are as ²described²253²<DP=17>²above.²8. A pharmaceutical composition, comprising:²(1) a compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, ²diastereomer, tautomer, solvate, polymorph or prodrug thereof;²(2) pharmaceutically acceptable carriers.²9. Use of Formula I compound of claim 1, or a pharmaceutically acceptable ²salt, ²enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, ²wherein ²the use is selected from the group consisting of:²(a) preparing a medicament for preventing or treating a disease associated ²with ²EZH2 mutation, activity or expression;²(b) non-therapeutic inhibition of the activity of EZH2 and the mutants thereof ²in ²vitro; and / or²(c) non-therapeutic inhibition of tumor cell proliferation in vitro.²10. The use of claim 9, wherein the disease associated with EZH2 mutation, ²activity or expression is selected from the group consisting of tumor or ²autoimmune ²disease.²254²