BR102019005173A2 - FIVE-ELEMENT AROMATIC RING PIRID COMPOUND, METHOD OF PREPARATION OF THE SAME AND USE OF THE SAME - Google Patents

Abstract

"Five-element aromatic ring pyrido compound, method of preparing and using it" the present invention provides a five-element aromatic ring pyrido compound and a method of preparing and using it. the compound provided in the present invention has an inhibitory effect on wild-type and / or mutant ezh2, and is well positioned to become an innovative antitumor drug or a drug for the treatment of autoimmune diseases.

Description

FIVE-ELEMENT AROMATIC RING PIRID COMPOUND, METHOD OF PREPARATION OF THE SAME AND USE OF THE SAME FIELD OF THE INVENTION

[001] The invention belongs to the field of medicinal chemistry. In particular, the present invention relates to a five-membered aromatic ring pyridine compound or a pharmaceutically acceptable salt thereof, a process of preparing it and using it. The compound of the present invention can be used for the treatment of Drosophila enhancer of diseases related to the homologous Zeste 2 (EZH2), such as malignant tumors.

BACKGROUND OF THE INVENTION

[002] Epigenetics means that the expression of a gene has undergone hereditary changes, while the nucleotide sequence of the gene remains unchanged, which plays an important role in the regulation of cell proliferation, differentiation, survival and apoptosis. An important mechanism for epigenetic regulation is covalent modification of histone. In eukaryotic cells, DNA surrounds histones to form nucleosomes, which is the basic structure of chromatin. In each nucleosome, two molecules of H2A, H2B, H3 and H4 form a histone octamer. A variety of covalent modifications occur at the end of the N-terminal amino acid of each histone, such as methylation, acetylation, phosphorylation, ubiquitination, etc., in order to control gene expression. Enzymes that catalyze histone methylation are called histone methyltransferases (HMTs).

[003] The polycomb protein PRC2 is a complex of multiple proteins that works to catalyze the methylation of lysine (H3K27) at position 27 of histone H3, thereby causing the silencing of related genes. The catalytic subunit of PRC2 is EZH1 or EZH2. EZH1 or EZH2 alone has no catalytic function and must be combined with EED and SUZ12 before being able to exercise methyltransfer. EZH2 is highly expressed in cells of various tumors (such as breast cancer, colorectal cancer, endometrioma, gastric cancer, liver cancer, kidney cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer and cancer of the bladder), and is closely related to a process of tumor cells, such as proliferation, invasion, drug resistance and migration.

[004] In recent years, EZH2 has been found to mutate in 8 to 24% of non-Hodgkin's lymphomas, such as Y641F, Y641N, Y641S, Y641H, A677G and A687V. These mutants potentiated the catalytic functions of dimethylation and trimethylation for histone H3, at position 27 of lysine, compared to wild-type EZH2. Excessive expression or mutation of EZH2 causes an increase in the level of 27 lysine trimethylation products (H3K27me3) of H3, and high levels of H3K27me3 play an important role in the proliferation and survival of tumor cells. Abnormal EZH2 activity leads to the development of tumors. The multiple target genes regulated by EZH2 are tumor suppressor genes, and the silencing of tumor suppressor genes can be an important mechanism. Infrarregulation of EZH2, by siRNA or shRNA, or indirect inhibition of EZH2, by the hydrolase inhibitor SAH 3-deazaneplanocin A (3-DZNep), can significantly reduce the proliferation and invasion of tumor cells in vitro and the growth of tumors in vivo.

[005] EZH2 also plays an important role in the differentiation of T cells. EZH2 reduces the expression of Th1 / Th2 cytokines (such as IFN-γ, IL-4, IL-5, etc.), inhibits T-cell migration of Th1 / Th2, and activates regulatory T cells. In the tumor microenvironment, EZH2 inhibits Th1 chemokines, such as CXCL9 and CXCL10, which is an important mechanism for tumor immune escape.

[006] In summary, there is an urgent need in the art to develop effective drugs capable of inhibiting wild-type and / or mutant EZH2.

SUMMARY OF THE INVENTION

[007] An object of the present invention is to provide a five-membered aromatic ring pyridine compound, a process for preparing it and using it as an EZH2 inhibitor. The compounds of the present invention have a clear relationship of activity and structure, and have an inhibitory effect on wild-type and / or mutant EZH2, thus being expected to be innovative drugs for anti-tumor or autoimmune diseases.

[008] According to a first aspect of the invention, a Compound of Formula I, or a pharmaceutically acceptable salt, an enantiomer, a diastereomer, a tautomer, a solvate thereof, a polymorph or prodrug thereof is provided,

[009] where X1 is CR4 or N;

[0010] X2 is CR5 or N;

[0011] X3 is CR6 or N; and, at most, one of X1, X2, X3 is N;

[0012] R4 is selected from H, a halogen, substituted or unsubstituted C1-C6 alkyl;

[0013] R5 or R6 is selected from H, a halogen, -COOH, -CN, substituted or unsubstituted 5-8 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl, 5-8 membered aryl substituted or unsubstituted fused to the 5 to 8 membered heterocyclic group substituted or unsubstituted, 5 to 8 membered substituted or unsubstituted heteroaryl fused to the substituted or unsubstituted 5 to 8 membered heterocyclic group, 5 to 8 membered substituted or unsubstituted fused to the substituted or unsubstituted 5- to 8-membered carbocyclic group, substituted or unsubstituted 5- to 8-membered substituted or unsubstituted 5- to 8-membered carbocyclic group, saturated or unsaturated 4- to 8-membered carbocyclic group substituted or unsubstituted, substituted or unsubstituted 4- to 8-membered saturated or unsaturated heterocyclic group, substituted or unsubstituted C1-C6 alkylcarbonyl group, -C (O) O- (C1-C6 alkyl su substituted or unsubstituted), -C (O) (NRaRb), - substituted or unsubstituted (CH2) mNRaRb, substituted or unsubstituted C1-C6 alkyl, boronic acid group, substituted or unsubstituted C2-C8 alkenyl, C2 alkynyl -C8 substituted or unsubstituted; wherein the heteroaryl or heterocyclic group contains 1 to 3 heteroatoms selected from N, O, S, P; m is an integer from 0 to 5; and said "substituted" means that it has one or more substituents (for example, 1, 2, 3 or 4) selected from group A;

[0014] where Ra, Rb are each independently selected from H, a halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5- to 8-membered carbocyclic ring, 5-ring heterocyclic ring substituted or unsubstituted 8-membered, or Ra and Rb are attached to N to form a substituted or unsubstituted 4- to 8-membered heterocyclic ring; wherein said heterocyclic ring contains 1 to 3 heteroatoms selected from N, O, S or P;

[0015] R1 is selected from

[0016] R2 is selected from H, a halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted aryl;

e quando R1 é

então R3 é

[0017] R3 is selected from

and when R1 is

then R3 is

[0018] wherein, R7 is selected from H, a substituted or unsubstituted C1-C6 alkyl;

[0019] R8 and R9 are each independently selected from H, a substituted or unsubstituted C1-C6 alkyl;

[0020] Y is selected from

[0021] wherein, R12 and R13 are each independently selected from H, a substituted or unsubstituted C1-C4 alkyl;

[0022] R14 and R15 are each independently selected from H, a halogen, -NH2, -NO2, -CF3, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy (CH2) substituted or unsubstituted nNRcRd, or R14 and R15 are combined to form a 5- to 6-membered saturated heterocyclic ring, or R14 and R15 are linked to form a 5- to 6-membered aromatic ring; n is an integer from 0 to 4;

[0023] R16 is H, a substituted or unsubstituted C1-C4 alkyl;

[0024] R17 and R19 are each independently selected from H, a substituted or substituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, - (CH2) nNRcRd; n is an integer from 0 to 4;

[0025] R18 is selected from H, a halogen, -NH2, -NO2, substituted or substituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, (CH2) nNRc substituted or unsubstituted; where n is an integer from 0 to 4;

[0026] R20 and R21 are each independently selected from H, a substituted or substituted C1-C4 alkyl;

ou alcóxi C1-C4 substituído ou não substituído;[0027] R22 is selected from H, a substituted or unsubstituted C1-C4 alkyl;

or substituted or unsubstituted C1-C4 alkoxy;

[0028] in which Rc, Rd are each independently selected from H, a substituted or unsubstituted C1-C4 alkyl;

[0029] Z is selected from N or CH;

[0030] R10 and R11 are each independently selected from: H, -OH, a substituted or unsubstituted C1-C6 alkyl, -ORe, substituted or unsubstituted 4- to 8-membered heterocyclic group, group substituted or unsubstituted 4- to 8-membered carbocyclic, substituted or unsubstituted 5- to 8-membered aryl, -NRfRg; wherein said heterocyclic ring contains from 1 to 3 heteroatoms selected from N, O, S or P; and said "substituted" means that it has one or more substituents (for example, 1, 2, 3 or 4) selected from group B;

[0031] where Re is selected from H, a substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, 4 to 8 membered carbocyclic ring saturated or substituted or unsubstituted unsaturated, 4- to 8-membered saturated or unsubstituted heterocyclic ring, substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, - (CH2) p (aryl 5- to 8-member substituted or unsubstituted), - (CH2) p (5- to 8-membered substituted or unsubstituted heteroaryl); wherein the heterocyclic or heteroaryl group comprises from 1 to 3 heteroatoms selected from N, O, S or P; p is an integer from 0 to 3; and said "substituted" refers to one or more of the following substituents (for example, 1, 2, 3 or 4): halogen, a C1-C4 alkyl, C1-C4 alkoxy, -NO2, -NRsRt;

[0032] wherein Rf and Rg are each independently selected from: H, a substituted or unsubstituted C1-C6 alkyl, where the substituent is -OH, C1-C4 alkoxy or -NRsRt;

[0033] substituents from group A are selected from the group consisting of H, = O, -CN, -COOH, -NRsRt, a halogen, substituted or unsubstituted C1-C6 alkoxycarbonyl, substituted or unsubstituted C1-C6 alkyl , 4- to 8-membered substituted or unsubstituted heterocyclic group, substituted or unsubstituted C1-C4 alkoxy; wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, S or P;

[0034] substituents from group B are selected from the group consisting of H, -OH, a halogen, substituted or unsubstituted C1-C6 alkyl, -NRsRt, -NO2, substituted or unsubstituted C1-C6 alkoxycarbonyl, C1 alkylsulfonyl -C6 substituted or unsubstituted, substituted or unsubstituted C1-C6 alkylcarbonyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted 4- to 6-membered heterocyclic ring, substituted or unsubstituted C5-C8 heteroaryl, Boc, benzyl; wherein said heteroaryl comprises 1 to 3 heteroatoms selected from N, O, S or P;

[0035] in addition, in group A and in the substituents of group B and Ra, Rb, substitution means having one or more substitutions (for example, 1, 2, 3 or 4) selected from group C: H, one halogen, -OH, -CN, C1-C4 alkyl, C1-C4 alkoxy, -NRsRt, 5-8 membered aryl, 4-8 membered heterocyclic group, Boc, C1-C4 acyl; and said substitution is one or more substituents (for example, 1, 2, 3 or 4);

[0036] and, in R7, R8, R9, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, Rc, Rd, the "substituted" means that it has one or more substituents ( for example, 1, 2, 3 or 4) selected from group D: H, a halogen, C1-C4 alkyl, C1-C4 haloalkyl, nitro, -OH, amino;

[0037] Rs and Rt are each independently selected from the group consisting of: H, a C1-C4 alkyl, C1-C4 haloalkyl.

[0038] In another preferred embodiment, R10 is a substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 alkyl.

[0039] In another preferred mode, R10 is selected from methyl or ethyl.

-ORe, -NRfRg,

[0040] In another preferred mode, R11 is selected from the group consisting of -OH,

-ORe, -NRfRg,

[0041] where Re is selected from the group consisting of a substituted or unsubstituted C1-C4 alkyl, allyl, isobutenyl, propargyl, cyclohexane, cyclohexenyl group,

[0042] where, Re1 is selected from the group consisting of H, a halogen, C1-C4 alkoxy, phenyl; and the number of Re1 is 1 to 3; Re2 is selected from -NO2, -NH2, -N (CH3) 2; Re3 is selected from H, a halogen, -NRsRt, substituted or unsubstituted C1-C4 alkyl (preferably methyl);

[0043] Rf is H, or a substituted or unsubstituted C1-C4 alkyl;

[0044] Rg is a C1-C4 alkoxy or a C1-C4 alkyl substituted with -NsRt, or cyclopentyl;

[0045] Rh is selected from H, a halogen;

em que Rh1 é selecionado a partir de -OH, -CN, uma alquila C1-C4;[0046] Ri is selected from H, a substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkylcarbonyl, substituted or unsubstituted C1-C4 alkoxycarbonyl, substituted or unsubstituted C1-C4 alkylsulfonyl, C1 alkyl -C2 trifluoromethyl, difluoromethyl C1-C2 alkyl, -NRsRt,

wherein Rh1 is selected from -OH, -CN, a C1-C4 alkyl;

em que Rj1 é selecionado a partir de um alcóxi C1-C4 (de preferência, dimetilamino, -OH, -NH2, metóxi);[0047] Rj is selected from the group consisting of: -OH, a halogen, C1-C4 alkoxy, -NRsRt,

wherein R1 is selected from a C1-C4 alkoxy (preferably dimethylamino, -OH, -NH2, methoxy);

[0048] R j 'is selected from H or a halogen;

[0049] and, when Rj is a halogen, then Rj 'is a halogen;

[0050] Rk is selected from the group consisting of H, -OH, a C1-C4 alkoxy,

[0051] R1 is selected from the group consisting of H, -NRsRt, preferably H or dimethylamino;

[0052] Rm is selected from the group consisting of: H, -NRsRt, preferably H or dimethylamino;

[0053] Rn is selected from the group consisting of trifluoromethyl C1-C4 alkyl, preferably CF3CH2-.

R57(C1-C3)alquilalquinila;[0054] In another preferred embodiment, R5 or R6 are each independently selected from the group consisting of: H, a substituted or unsubstituted C1-C4 alkyl, -CN, halogen, C1-C4 alkylcarbonyl , R51 (C1-C4 alkoxy) carbonyl, R52C (O) -, -COOH, -C (O) (NRaRb),

R57 (C1-C3) alkylalkynyl;

e em que Rb é selecionado a partir do grupo que consiste em H, uma alquila C1-C4, Boc, acila C1-C4;[0055] where R51 is selected from the group consisting of dimethylamino,

and wherein Rb is selected from the group consisting of H, a C1-C4 alkyl, Boc, C1-C4 acyl;

[0056] R52 is selected from

[0057] Ra is selected from H, a substituted or unsubstituted C1-C4 alkyl;

ciclopentila, Rb’’(C1-C4)alquila; em que X é um heteroátomo selecionado a partir de N, O ou S;[0058] Rb is selected from H, a substituted or unsubstituted C1-C4 alkyl,

cyclopentyl, Rb '' (C1-C4) alkyl; where X is a heteroatom selected from N, O or S;

R551(C1-C6)alquila OC(O)-, -COOH, -C(O)(NRaRb); em que R551 é H, -OH, um alcóxi C1-C4, amino, dimetilamino, metilamino, dietilamino, metiletilamino, etilamino,

; em que R541 é selecionado a partir de H, uma alquila C1-C4;[0059] R55 is 1 to 3 substituents selected from the group consisting of H, R551C1-C4alkyl, halogen, -CN, -NH2, (R551C1-C4alkyl) NH-, (R551C1-C4alkyl) O-, dimethylamino, -CH2 (Me) 2,

R551 (C1-C6) alkyl OC (O) -, -COOH, -C (O) (NRaRb); where R551 is H, -OH, a C1-C4 alkoxy, amino, dimethylamino, methylamino, diethylamino, methylethylamino, ethylamino,

; wherein R541 is selected from H, a C1-C4 alkyl;

dimetilamino;[0060] R57 is selected from a (C1-C4) alkyl,

dimethylamino;

[0061] Rb '' is selected from the group consisting of -OH, a C1-C3 alkoxy, dimethylamino,

[0062] In another preferred embodiment, the Formula I Compound has the structure of Formula Ia:

[0063] wherein, R1, R2, R3, R4, R5 and R6 are as described above.

[0064] In another preferred embodiment, R2, R4, R7-R9, R12-R22, Ra, Rb, Rc, Rd, Re are replaced by a substituent selected from the group consisting of halogen, a C1-4 alkyl , trifluoromethyl, amino, nitro, -OH.

[0065] In another preferred mode, R7 is H.

[0066] In another preferred mode, R8 = R9 = H.

[0067] In another preferred mode, Z is CH.

[0068] In another preferred mode, R2 is methyl.

[0069] In another preferred mode, the compound is selected from the group consisting of:

[0070] In another preferred modality, the Compound of Formula I is selected from Compound 1 to 151.

[0071] According to the second aspect of the present invention, a process for the preparation of Compound of Formula I, as described in the first aspect of the invention, is provided, wherein the Compound of Formula I has the structure shown in Formula I- 1 and comprises steps:

[0072] in the presence of a reducing agent, reduce the compound d to form the compound and, during the reduction, the agent is selected from the group consisting of sodium borohydride, lithium borohydride, potassium borohydride, or combinations thereof ;

[0073] in the presence of a base, react the compound and with a corresponding hydrocarbilization reagent to form compound f, wherein,

[0074] The base is selected from the group consisting of sodium hydride, sodium t-butoxide, sodium hydroxide, potassium hydroxide, n-butyl lithium, lithium diisopropylamide, lithium hexamethyldisilazide, hexamethyldisilazide of sodium, potassium hexamethyldisilazide, potassium carbonate, cesium carbonate, sodium carbonate, or combinations thereof;

[0075] The alkylating agent is selected from the group consisting of halogenated hydrocarbons, methanesulfonate, p-toluenesulfonate, trifluoroacetate, triflate, or combinations thereof;

[0076] (3) hydrolyze compound f to form compound g;

[0077] (4) condensing compound g with an amine compound to form Compound I-1,

[0078] wherein R2, R3, R7, R8, R9, R10, T1, Re, Rf, X1, X2, X3 and Y are as defined above, and Rk is a straight or branched C1-C4 alkyl.

[0079] In another preferred embodiment, before step (1), the method additionally comprises a step (1 - 1): in an inert solvent, react compound a with b, in the presence of a catalyst, to form the compound d,

[0080] In another preferred embodiment, in step (1 - 1), the inert solvent is selected from the group consisting of isopropanol, ethanol, methanol, tetrahydrofuran, chloroform, N, N-dimethylformamide, N, N-dimethylacetamide , dimethyl sulfoxide, or combinations thereof.

[0081] In another preferred embodiment, in step (1 - 1), the catalyst is selected from the group consisting of alkali, such as cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, triethylamine, 1,8-diazabicicloundec-7-eno or similar, or ammonium acetate, piperidine acetate salt, or combinations thereof.

[0082] In another preferred embodiment, before step (1), the method further comprises step (1 - 1 '): in an inert solvent, using compound a and compound c to conduct the Michael addition reaction, under conditions to form compound d,

[0083] In another preferred embodiment, in step (1 - 1 ′), the solvent is selected from the group consisting of N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, or combinations thereof .

[0084] In another preferred embodiment, in step (1 - 1 ’), alkali is selected from the group consisting of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, or combinations thereof.

[0085] According to the third aspect of the present invention, a process for the preparation of Compound of Formula I, as described in the first aspect of the invention, is provided, wherein the Compound of Formula I has the structure shown in Formula I- 2 and comprises the steps:

[0086] in an inert solvent, in the presence of reducing agent, react compound d with compound f to form compound i;

[0087] hydrolyze compound i to form compound j;

[0088] condensing compound j with amine compound to form compound I-2;

[0089] wherein R2, R3, R7, R8, R9, R10, Re, Rf, Rk, X1, X2, X3 and Y are as described above.

[0090] In another preferred embodiment, in step (i), the inert solvent is selected from the group consisting of titanium tetraisopropyloxide, tetrahydrofuran, acetic acid, trifluoroacetic acid, or combinations thereof.

[0091] In another preferred embodiment, in step (i), the reducing agent is selected from the group consisting of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or combinations thereof.

[0092] According to the fourth aspect of the present invention, a process for the preparation of Formula I Compound, as described in the first aspect of the invention, is provided, wherein the Formula I Compound has the structure shown in Formula I- 3 and comprises the steps:

[0093] in an inert solvent, in the presence of reducing agent, reduce compound k to form compound l;

[0094] in the presence of alkylating agent, react compound 1 to form compound m, and said alkylating agent is selected from the group consisting of X-R10 ', HSO4-R10', HO-R10 ', R10' -O-R10 ', or their combinations;

[0095] where X is halogen; R10 'is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or unsaturated 4- to 8-membered heterocyclic group, 4-carbocyclic group substituted or unsubstituted saturated or unsaturated 8-membered, substituted or unsubstituted, saturated or unsaturated 5- to 8-membered aryl; wherein said heterocyclic ring comprises from 1 to 3 heteroatoms selected from N, O, S, P; and said "substituted" means that it has one or more substituents (for example, 1, 2, 3 or 4) selected from group B, as shown in the first aspect of the present invention;

[0096] (c) hydrolyze compound m to form compound n;

[0097] (d) condensing compound n with amine compound to form compound I-3;

[0098] wherein R2, R3, R7, R8, R9, R10, Re, Rf, Rk, X1, X2, X3 and Y are as described above.

• (1) um composto do primeiro aspecto da presente invenção, ou um sal farmaceuticamente aceitável, enantiômero, diasteroisômero, tautômero, solvato, polimorfo ou pró-fármaco do mesmo; e
• (2) portadores farmaceuticamente aceitáveis.

[0099] According to the fifth aspect of the invention, a pharmaceutical composition is provided, which comprises:

• (1) a compound of the first aspect of the present invention, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof; and
• (2) pharmaceutically acceptable carriers.

• (a) preparação de um medicamento para prevenir ou tratar uma doença associada à mutação, atividade ou expressão de EZH2;
• (b) inibição não terapêutica da atividade de EZH2 e dos seus mutantes in vitro; e/ou
• (c) inibição não terapêutica de proliferação celular tumoral in vitro.

[00100] According to a sixth aspect of the invention, the use of the Compound of Formula I, of the first aspect of the present invention, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, is provided, where usage is selected from the group consisting of:

• (a) preparing a drug to prevent or treat a disease associated with the EZH2 mutation, activity or expression;
• (b) non-therapeutic inhibition of the activity of EZH2 and its mutants in vitro; and / or
• (c) non-therapeutic inhibition of tumor cell proliferation in vitro.

[00101] In another preferred embodiment, the disease associated with the EZH2 mutation, activity or expression is selected from the group consisting of tumor or autoimmune disease.

[00102] In another preferred embodiment, the disease associated with the EZH2 mutation, activity or expression is selected from the group consisting of B-cell lymphoma, malignant rhabdomyoma, synovial sarcoma, breast cancer, colorectal cancer, endometrioma, cancer gastric, liver cancer, kidney cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer or bladder cancer.

[00103] It should be understood that, in the present invention, each of the technical characteristics specifically described above and below (such as those in the Examples) can be combined with each other, which thus constitutes new or preferred technical solutions, that do not need to be specified again in this document.

MODALITIES FOR CARRYING OUT THE INVENTION

[00104] Through extensive and intensive research, the present inventors have revealed, for the first time, unexpectedly, a 5-membered aromatic ring compound of pyrido, a process of preparation and use of it, and the compound of the present invention has an inhibitory effect on wild-type and / or mutant EZH2. The present invention is completed on this basis.

Terms

[00105] Unless otherwise defined, all technical and scientific terms used in this document have the same meaning as that commonly understood by a person of ordinary skill in the technique to which this invention belongs.

[00106] As used in this document, when used in reference to a particular recited amount, the term "about" means that the amount may vary by no more than 1% of the amount recited. For example, as used in this document, the expression “about 100” includes all values between 99 and 101 and (for example, 99.1; 99.2; 99.3; 99.4; etc.).

[00107] As used herein, the terms "containing" or "including (comprising)" may be open, semi-closed or closed forms. In other words, the terms also include situations such as "which essentially consists of ..." or "which consists of ..."

Group definitions

[00108] The definition of standard chemical terms can be found in references (which includes Carey and Sundberg “Advanced Organic Chemistry, 4th Edition”. Volumes A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods, within the skill of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy and pharmacological methods are used. Unless specifically defined, the terms refer to analytical chemistry, organic synthetic chemistry, and the pharmaceutical and pharmaceutical chemistry used herein are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction can be carried out and purified according to the manufacturer's instructions for using the kit, or by methods well known in the art or, as described in the present invention. The above techniques and methods can, in general, be carried out according to conventional methods well known in the art, as described in the various abstracts and in the various more specific references cited and discussed in this specification. In this specification, the group and its substituents can be selected by the person skilled in the art to provide stable structural compounds and portions.

[00109] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[00110] The section titles used in this document are only for organizing articles, and should not be interpreted as limiting the matter. All documents or all parts of the literature cited in this application, which include, but are not limited to, patents, patent applications, articles, books, operating manuals and documents, are hereby incorporated by reference, in their entirety. .

[00111] Certain chemical groups defined in this document are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl refers to an alkyl, as defined below, with a total of 1 to 6 carbon atoms. The total number of carbon atoms in the simplified symbol does not include the carbon that may be present in the substituents in the group.

[00112] In addition, when used in the specification and in the claims of this application, unless otherwise specifically indicated, the following terms have the meaning indicated below.

[00113] In the present application, the term "halogen" means fluoro, chloro, bromo or iodo.

[00114] "Hydroxy" means -OH group.

[00115] "Hydroxyalkyl" means alkyl groups, as defined below, which is replaced by the hydroxy group (-OH).

[00116] "Carbonyl" means group -C (= O) -.

[00117] "Nitro" means -NO2.

[00118] "Cyan" means -CN.

[00119] "Amino" means -NH2.

[00120] "Substituted amino" means amino groups substituted by one or two alkyl, alkylcarbonyl, arylalkyl, heteroarylalkyl, as defined below, for example, monoalkylamino, dialkylamino, alkyl starch, arylalkylamino, heteroarylalkylamino.

[00121] "Carboxyl" means -COOH.

[00122] In the present application, as a group or part of another group (for example, used in a group, such as a halogen substituted alkyl group), the term "alkyl" means a straight or branched chain hydrocarbon group fully saturated, which consists only of carbon atoms and hydrogen atoms, and has, for example, 1 to 12 carbon atoms (preferably 1 to 8, most preferably 1 to 6), and is attached to the remainder of a molecule by a single bond, for example, which includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2 , 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, decila and decila. For the present invention, the term "alkyl" refers to alkyl that contains 1 to 6 carbon atoms.

[00123] In the present application, as a group or part of another group, the term "alkenyl" means a straight or branched chain hydrocarbon group consisting only of carbon atoms and hydrogen atoms, which contain at least one double bond , and, for example, with 2 to 14 carbon atoms (preferably 2 to 10, more preferably 2 to 6), and which is attached to the remainder of a molecule by a single bond, for example, but without limitation, vinyl, propenyl, ally, but-1-enyl, but-2-enyl, pent-1-enyl, pentane-1,4-dienyl, and the like.

[00124] In the present application, as a group or part of another group, the term "cycloalkyl" means a stable non-aromatic monocyclic or polycyclic hydrocarbon group, consisting only of carbon atoms and hydrogen atoms, which may include a system fused ring, bridged ring system or spiro ring system, with 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably, 3 to 8 carbon atoms, and which is saturated or unsaturated and can join the remainder of a molecule by a single bond through any suitable atoms. Unless otherwise specifically stated in the specification, the carbon atoms in the cyclic hydrocarbon groups can be optionally oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2,3-indanyl, 1 , 2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzocycloheptene-6-yl, 6,7,8,9-tetrahydro -5H-benzocycloheptenyl,
5,6,7,8,9,10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo [2,2,1] heptila, 7,7-dimethyl-bicyclo [2,2,1] heptila, bicyclo [ 2,2,1] heptenyl, bicycles [2,2,2] octyl, bicycles [3,1,1] heptyla, bicycles [3,2,1] octyl, bicycles [2,2,2] octenyl, bicycles [ 3.2,1] octenyl, adamantyl, octahydro-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-cyclopentadienyl and the like.

[00125] In the present application, as a group or part of another group, the term "heterocyclyl" means a stable 3 to 20 membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 hetero atoms selected from from the group consisting of nitrogen, phosphorus, oxygen and sulfur. Unless otherwise specifically stated in the specification, the heterocyclic group may be monocyclic, bicyclic, tricyclic or an even more cyclic ring system, which may include the fused ring system, bridged ring system or spiro ring system ; the nitrogen, carbon or sulfur atom can optionally be oxidized; the nitrogen atom can optionally be quaternized; and the heterocyclic group can be partially or completely saturated. The heterocyclic group can be attached to the remaining part of a molecule by means of a carbon atom or a heteroatom, through a single bond. In the heterocyclic group that contains a fused ring, one or more of the rings can be aryl or heteroaryl, as defined hereinafter, as long as the point of attachment to the remaining part of a molecule is a non-aromatic ring atom. For the purposes of the present invention, the heterocyclic group is preferably a spiro or bridged, monocyclic, non-aromatic 4 to 11-membered stable group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur . Most preferably, it is a spiro or bridged group, monocyclic, non-aromatic stable 4 to 8 members, containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro [3,5] nonano-7-yl, 2-oxa-6-aza-spiro [3.3] heptane-6-yl, 2,5-diaza-bicyclo [2,2,1] heptan-2-yl, aza-cyclobutane, pyranyl, tetrahydropyranyl, thiapyranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl , imidazolinyl, imidazolidinyl, quinazolidinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, dihydroindolyl, octahydroindolyl, octahydroxylin, pyrrolidinyl, pyrazolidinyl, phthalimidoyl and the like.

[00126] In the present application, as a group or part of another group, the term "aryl" means a group of conjugated hydrocarbon ring system, with 6 to 18 carbon atoms, preferably with 6 to 10 atoms of carbon. For the purposes of the present invention, an aryl can be a monocyclic, bicyclic, tricyclic ring system or a ring system of even more rings, and can also be fused to a cycloalkyl or heterocyclic group, as defined above, provided that the group aryl connected to the remaining part of a molecule, by a simple bond, through atoms in the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, anthryl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazine-3 (4H) - keto-7-yl, and the like.

[00127] In the present application, the term "arylalkyl" refers to an alkyl, as defined above, replaced by an aryl group, as defined above.

[00128] In the present application, as a group or part of another group, the term "heteroaryl" means a group of conjugated hydrocarbon ring system, with 1 to 15 carbon atoms (preferably with 1 to 10 carbon atoms ) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise indicated in the present invention, a heteroaryl may be a monocyclic, bicyclic, tricyclic ring system or an even more ring system, and may also be fused to a cycloalkyl or heterocyclic group, as defined above, provided that the aryl group connected to the remaining part of the molecule, by a simple bond, through atoms in the aromatic ring. The nitrogen, carbon or sulfur atom in the heteroaryl group can be optionally oxidized; and the nitrogen atom can optionally be quaternized. For the purposes of the present invention, the heterocyclic group is preferably a stable aromatic group of 5 to 12 members, containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. Most preferably, it is a stable aromatic group of 5 to 10 members, containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, or a stable aromatic group of 5 to 6 members, containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, trilin, trilol, trilol, trilol, troll , isoindolyl, indazolyl, isoindazolyl, purinyl, quinolyl, isoquinolyl, diazonaftila, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbonyl, phenantridinyl, phenantrolinyl, acridinyl, phenazinyl, quinothyl, benzothiazolin, isothiazolol , isoxazolyl, phenoxazinyl, phenothiazine, 4,5,6,7-tetrahydrobenzo [b] thienyl, naphthopyridyl, [1,2,4] triazolo [4,3-b] pyridazine, [1,2,4] triazole [4 , 3-a] pyrazine, [1,2,4] triazolo [4,3-c] pyrimidine, [1,2,4] triazolo [4,3-a] pyridine, imidazo [1,2-a] pyridine , imidazo [1,2-b] pyridazine, imidazo [1,2-a] pyrazine, etc.

[00129] In the present application, the term "heteroarylalkyl" refers to an alkyl, as defined above, which is replaced by a heteroaryl, as defined above.

[00130] In the present application, "optional" or "optionally" means that the event or condition subsequently described may or may not occur, and that the description includes both the occurrence and the non-occurrence of the event or condition. For example, "optionally substituted aryl" means that the aryl is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl. The "optional" substituents described in the claims and in the specification of the present invention are selected from the group consisting of an alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro, optionally substituted aryl, optionally substituted heteroaryl , optionally substituted cycloalkyl, optionally substituted heterocyclic hydrocarbon group.

[00131] The terms "part", "structural chemical portion", "chemical portion", "group", and "chemical group", as used herein, refer to a particular fragment or functional group in a molecule. A chemical moiety is generally considered to be a chemical entity that is incorporated into or attached to a molecule.

[00132] "Stereoisomer" refers to a compound that is composed of the same atoms, linked by the same bonds, but with a different three-dimensional structure. The invention will cover several stereoisomers and mixtures thereof.

[00133] When the compound of the present invention contains olefinic double bonds, the compounds of the present invention are intended to comprise geometric E and Z isomers, unless otherwise stated.

[00134] "Tautomer" refers to an isomer formed by the transfer of a proton from an atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention will also be covered within the scope of the invention.

The compounds of the invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral carbon atom can be defined as (R) - or (S) - based on stereochemistry. The invention is intended to include all possible isomers, as well as their racemic and optically pure forms. Racemates, diastereomers or enantiomers can be used as starting materials or intermediates in the preparation of the compounds of the invention. Optically active isomers can be prepared by chiral syntones or chiral reagents, or decomposed using conventional techniques, such as crystallization and chiral chromatography.

[00136] Conventional techniques for the preparation / isolation of individual isomers include chiral synthesis of a suitable optically pure precursor, or decomposition of the racemate (or racemic form of a salt or derivative) using, for example, chiral high performance liquid chromatography . For example, see Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Volume 243, 2004; AM Stalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3: pages 341 to 363, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, pages 809 to 816; Heller, Acc. Chem Res. 1990, 23, page 128.

[00137] In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[00138] "Pharmaceutically acceptable acid addition salt" means a salt formed by an inorganic or organic acid that retains the bioavailability of the free base, without bringing other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipates, glutaric acid salts, malonates, oxalates , maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, besylate, p-toluenesulfonate, alginate, ascorbate, salicylate, aminylsulfate, 4 naphthalene, and the like. These salts can be prepared by methods known in the art.

[00139] "Pharmaceutically acceptable base addition salt" means a salt formed with an inorganic or organic base and capable of maintaining the bioavailability of the free acid, without bringing other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts , aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following salts: primary amines, secondary amines and tertiary amines, substituted amines, which include naturally substituted amines, cyclic amines, and basic ion exchange resins. For example, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, hexylamine bicyclo, lysine, arginine, histidine, caffeine, procinaine, choline, procamine, choline glycosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

[00140] In the present application, "pharmaceutical composition" refers to a formulation of a compound of the invention and a medium, generally accepted in the art, for the delivery of a biologically active compound to a mammal, such as a human. The medium comprises pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to promote the administration of the organism, thus facilitating the absorption of the active ingredients and thereby exercising biological activity.

[00141] The term "pharmaceutically acceptable", as used herein, refers to a substance (such as a vehicle or diluent) that does not affect the biological activity or properties of the compound of the invention, and is relatively non-toxic, that is, the substance can be administered to an individual, without causing undesirable organisms, or interacting with any of the components contained in the composition in an undesirable manner.

[00142] In the present application, "pharmaceutically acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, lubricants, sweeteners, diluents, preservatives, dyes / tinctures, flavoring agents, surfactants, wetting agents, dispersing agents, flavoring agents suspension, stabilizers, isotonic agents, solvents or emulsifiers approved by the relevant government authorities for acceptable use in humans or domestic animals.

[00143] The "tumor" of the present invention includes, but is not limited to, glioma, sarcoma, melanoma, joint chondrocarcinoma, cholangiocarcinoma, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer , pancreatic cancer, squamous cell carcinoma of the lung, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer , bone cancer, esophageal cancer, melanin tumor, kidney cancer, oral cancer and other diseases.

[00144] The terms "prevention", "prevent" and "prevented", as used in this document, include the possibility of reducing the occurrence or progression of a disease or condition, by a patient.

• (i) prevenir a ocorrência de uma doença ou afecção em um mamífero, particularmente quando tal um mamífero é suscetível à doença ou afecção, mas não foi diagnosticado como tendo a doença ou afecção;
• (ii) inibir uma doença ou afecção, isto é, inibir seu desenvolvimento;
• (iii) aliviar a doença ou afecção, isto é, degradar a condição da doença ou enfermidade; ou
• (iv) aliviar os sintomas causados pela doença ou afecção.

[00145] The term “treatment” and other similar synonyms, as used in this document, include the following meanings:

• (i) preventing the occurrence of a disease or condition in a mammal, particularly when such a mammal is susceptible to the disease or condition, but has not been diagnosed as having the disease or condition;
• (ii) inhibiting a disease or condition, that is, inhibiting its development;
• (iii) relieving the disease or condition, that is, degrading the condition of the disease or illness; or
• (iv) relieve symptoms caused by the disease or condition.

[00146] The term "effective amount", "therapeutically effective amount", or "pharmaceutically effective amount", as used herein, refers to an amount of at least one agent or compound which, after administration, is sufficient to relieve one or more symptoms of the disease or condition being treated in any way. The result can be a reduction and / or relief of signs, symptoms or causes, or any other desired change in the biological system. For example, an "effective amount" for treatment is an amount of a composition that comprises a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic. An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.

[00147] The terms "take", "administer", "apply" and the like, as used in this document, refer to a method of delivering compost or composition to a desired location for biological action. These methods include, but are not limited to, oral, duodenal, parenteral injection (which includes intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration. The techniques for administering the compounds and methods described in this document are well known to the person skilled in the art, for example, those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition .; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In a preferred embodiment, the compounds and compositions, discussed in this document, are administered orally.

[00148] The terms "pharmaceutical combination", "drug combination", "combination", "administer other treatments", "administer other therapeutic agents" and the like, as used herein, mean a pharmaceutical treatment obtained by mixing or by combination of more than one active ingredient that includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient, in the form of a single entity or in a single dosage form. The term "non-fixed combination" refers to the simultaneous administration, administration in combination or administration in sequence, at a variable time interval, at least one of the compounds described in this document and at least one synergistic formulation, to the patient, in the form of entities separate. These can also be applied to cocktail therapy, for example, with the administration of three or more active ingredients.

[00149] It will also be understood by the person skilled in the art that, in the methods described below, the functional groups of an intermediate compound may need to be protected by suitable protecting groups. Such functional groups include hydroxyl, amino, thiol, and carboxyl. Suitable hydroxy protecting groups include trialkylasilyl or diarylalkylasilyl groups (e.g., tert-butyladimethylsilyl, tert-butyladiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidine and guanidyl groups include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable thiol protecting groups include -C (O) -R ”(where R” is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, and the like. Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.

[00150] Protection groups can be introduced and removed according to the standard techniques known to the person skilled in the art and as described in this document. The use of protection groups is described in detail in Greene, T. W. and P. G. M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Edition, Wiley. The protection group can also be polymeric resins.

The main advantages of the present invention are:

[00151] Provide a Compound of Formula I.

[00152] Provide an innovative structure composition for the prevention and treatment of diseases associated with EZH2 mutations.

[00153] The present invention will be further illustrated below, with reference to specific examples. It should be understood that these examples are only to illustrate the invention, but not to limit the scope of the invention. Experimental methods without specific conditions described in the following examples are, in general, carried out under conventional conditions, or according to the manufacturer's instructions. Unless otherwise stated, parts and percentage are parts by weight and percentage by weight.

[00154] The experimental materials and reagents used in the following examples are available from commercially available sources, unless otherwise specified.

[00155] In each of the examples, 1H NMR was recorded by the Varian Mercury-300 or Varian Mercury-400 NMR spectrometer, and the 13C NMR was recorded by Varian Mercury-400 or Varian Mercury-500 or NMR spectrometer Varian Mercury-600, chemical shifts are expressed as δ (ppm); the mass spectrum is recorded by a Finnigan / MAT-95 (EI) and Finnigan LCQ / DECA and Micromass Ultra Q-TOF (ESI) mass spectrometer; silica gel separation by preparative reverse phase HPLC is 200 to 300 mesh.

[00156] Among them, the names of the reagents represented by the chemical formula, or by the abbreviations of the alphabet, are as follows:

[00157] iPrOH: isopropanol; EtOH: ethanol; DCM: dichloromethane; TFA: trifluoroacetic acid; MeOH: methanol; NaOH: sodium hydroxide; HCl: hydrogen chloride; TEA: triethylamine; Raney Ni: Raney nickel; 1,4-dioxane: 1,4-dioxane; NaH: sodium hydride; H2O: water; Pd / C: palladium / carbon; H2: hydrogen; HATU: 2- (7-oxidizedbenzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate; DMF: N, N-dimethylformamide; THF: tetrahydrofuran; Boc2O: di-tert-butyl dicarbonate; NBS: N-bromosuccinimide; NCS: N-chlorosuccinimide; NIS: N-iodosuccinimide; MeCN: acetonitrile; DIPEA: N, N-diisopropylethylamine; NaBH4: Sodium borohydride; AcOH: acetic acid; ethyl acetate: ethyl acetate; NaBH3CN: sodium cyanoborohydride; K2CO3: potassium carbonate; Cs2CO3: cesium carbonate; nBuLi: n-butylalithium; LiAlH4: lithium aluminum hydride; Pd (dppf) Cl2: [1,1-bis (diphenylphosphino) ferrocene dichloride] palladium; KOAc: potassium acetate. Fumaronitrile: fumaric acid nitrile; P (nBu) 3: tri-n-butylphosphine; LDA: lithium diisopropylamide; LiOH: lithium hydroxide; MeI: methyl iodide; EtI: ethyl iodide; (CH2O) n: paraformaldehyde; HCO2H: formic acid; CH3COCl: acetyl chloride.

[00158] Example 1: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1-methoxyethyl) -6-methylind olizine- 7-carboxamide:

[00159] Step 1: Preparation of 1- (2-oxopropyl) -1H-pyrrole-2-carbaldehyde: In a 250 ml dry nitrogen-protected single-necked flask, the 1H-pyrrole-2-carbaldehyde compound ( 15 g, 158 mmol) was dissolved in 100 mL of DMF, and potassium carbonate (43.6 g, 316 mmol) and bromoacetone (53.7 g, 395 mmol) were added to the solution, and the mixture was stirred at temperature environment at night. The reaction mixture was extracted with ethyl acetate (200 ml), washed with water (100 ml x 2) and saturated brine (100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product. After purification by column chromatography (petroleum ether: EtOAc = 4: 1), a brown solid (7g, yield: 30%) was obtained.

[00160] 1H NMR (CDCl3, 400 MHz) δ ppm 9.49 (s, 1 H), 7.00 (d, J = 8.0 Hz, 1 H), 6.87 (brs, 1 H) , 6.32 - 6.31 (m, 1 H), 5.09 (s, 2 H), 2.23 (s, 3 H).

[00161] Step 2: Preparation of ethyl 5-acetyl-6-methylindolizine-7-carboxylate:

[00162] Method A: Compound 1- (2-oxopropyl) -1H-pyrrole-2-carbaldehyde (7.0 g, 46.0 mmol) was dissolved in 150 mL of DMF in a dry, single-necked flask protected with nitrogen, 250 mL. Ethyl acetoacetate (17.9 g, 138 mmol) and potassium carbonate (9.52 g, 69 mmol) were added in succession, and the mixture was heated to reflux for two hours. The mixture was extracted with ethyl acetate (200 ml) and water (100 ml × 2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product. After purification by column chromatography (petroleum ether: EtOAc = 10: 1), a yellow oil (5.4 g, yield: 48%) was obtained, and was left to cure.

[00163] Method B: Compound 1- (2-oxopropyl) -1H-pyrrole-2-carbaldehyde (7.0 g, 46.0 mmol) was dissolved in 50 mL of DMF in a dry, single-necked flask protected with nitrogen, 100 mL. Ethyl 2-butinoate (6.3 g, 56 mmol) and cesium carbonate (22.7 g, 69 mmol) were added in succession, and the mixture was heated to 50 ° C and stirred for 4 to 5 hours. The reaction mixture was extracted with ethyl acetate (200 ml) and washed with water (100 ml × 2) and brine (100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product. After purification by column chromatography (petroleum ether: EtOAc = 10: 1), yellow oil (1.4 g, yield: 12.4%) was obtained, and was left to cure.

[00164] 1H NMR (CDCl3, 400 MHz) δ ppm 9.20 (s, 1 H), 7.21 (brs, 1 H), 6.87 (t, J = 4.0 Hz, 1 H) , 6.74 (d, J = 4.0 Hz, 1 H), 4.34 (q, J = 7.2 Hz, 2 H), 2.64 (s, 3 H), 2.44 (s , 3 H), 1.39 (t, J = 7.2 Hz, 3 H).

[00165] Step 3: Preparation of ethyl 5- (1-hydroxyethyl) -6-methylindolizine-7-carboxylate: 5-acetyl-6-methylindolizine-7-carboxylate compound (1 g, 4.1 mmol) and 50 ml of methanol were added to a 100 ml nitrogen-protected dry single neck flask. Sodium borohydride (310.2 mg, 8.2 mmol) was added in portions, after cooling to 0 ° C. The reaction was stirred at room temperature for 3 to 4 hours and then the mixture was extracted with ethyl acetate (200 ml) and washed with water (100 ml × 2) and brine (100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product. After purification by column chromatography (petroleum ether: EtOAc = 8: 1), yellow oil (650 mg, yield: 65%) was obtained.

[00166] 1H NMR (CDCl3, 400 MHz) δ ppm 8.09 (s, 1 H), 8.01 (s, 1 H), 6.84 (t, J = 3.6 Hz, 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 H), 2 , 47 (s, 3 H), 1.68 (d, J = 8 Hz, 3 H), 1.38 (t, J = 6.8 Hz, 3 H).

[00167] Step 4: Preparation of ethyl 5- (1-methoxyethyl) -6-methylindolizine-7-carboxylate: 5- (1-hydroxyethyl) -6-methylindolizine-7-carboxylate (40 mg, 0 , 16 mmol) and 15 mL of DMF were added to a 50 mL nitrogen-protected dry neck flask. Sodium hydride (16.2 mg, 0.24 mmol) was added in portions, after cooling to 0 ° C. The reaction was stirred at room temperature for 30 min., Iodomethane (34 mg, 0.24 mmol) was added, and the mixture was stirred at room temperature overnight, and then the mixture was extracted with ethyl acetate. (100 ml) and washed with water (50 ml × 2) and brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product. After purification by column chromatography (petroleum ether: EtOAc = 10: 1), yellow oil (20 mg, yield: 47.6%) was obtained.

[00168] 1H NMR (MeOD, 400 MHz) δ ppm 8.40 (s, 2 H), 6.82 (t, J = 3.2 Hz, 1 H), 6.77 (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), 2.48 (s , 3 H), 1.59 (d, J = 7.8 Hz, 3 H).

[00169] Step 5: Preparation of 5- (1-methoxyethyl) -6-methylindolizine-7-carboxylic acid: The 5- (1-methoxyethyl) -6-methylindolizine-7-carboxylate compound (20 mg, 0.077 mmol) and 5 mL of methanol were added successively in a 25 mL nitrogen-protected single neck bottle. Sodium hydroxide (12.4 mg, 0.31 mmol) was dissolved in 5 ml of water, added to the reaction system and stirred overnight at room temperature. The mixture was neutralized with hydrochloric acid diluted to pH 5, extracted with dichloromethane (100 ml), washed with water (50 ml × 2) and brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide pale yellow oil (18 mg, yield: 100%). 1H NMR (MeOD, 400 MHz) δ ppm 8.05 (s, 1 H), 6.81 (t, J = 3.2 Hz, 1 H), 6.66 (t, J = 3.2 Hz , 1 H), 5.27 (q, J = 7.8 Hz, 1 H), 3.19 (s, 3 H), 2.50 (s, 3 H), 1.60 (d, J = 7.8 Hz, 3 H).

[00170] Step 6: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1-methoxyethyl) -6-methylind olizine- 7-carboxamide: 5- (1-methoxyethyl) -6-methylindolizine-7-carboxylic acid (18 mg, 0.077 mmol), 3- (aminomethyl) -4,6-lutidine-2 (1H) -a hydrochloride (23 , 5 mg, 0.125 mmol) (the synthesis of which can be found in WO2015023915), HATU (44 mg, 0.116 mmol), DIPEA (29.9 mg, 0.232 mmol) and DMF 20 mL were added sequentially to a bottle single-necked, nitrogen-protected, 25 mL, stirred at room temperature for 30 min. The mixture was extracted with ethyl acetate (100 ml), washed with water (50 ml × 2) and brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product. After being purified by column chromatography (dichloromethanol: methanol = 20: 1), a white solid (20mg, yield: 71%) was obtained. 1H NMR (CDCl3, 400 MHz) δ ppm 7.97 (s, 1 H), 7.38 (s, 1 H), 6.84 - 6.78 (m, 2 H), 6.53 (d , J = 3.6 Hz, 1 H), 6.37 (s, 1 H), 5.10 (q, J = 7.8 Hz, 1 H), 4.54 (brs, 2 H), 3 , 19 (s, 3 H), 2.57 (s, 3 H), 2.41 (s, 3 H), 2.31 (s, 3 H), 1.60 (d, J = 7.8 Hz, 3 H); ESI-MS m / z 368 [M + H] +.

[00171] Example 2: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1-ethoxyethyl) -6-methylindol izine- 7-carboxamide:

[00172] Step 1: Preparation of ethyl 5- (1-ethoxyethyl) -6-methylindolizine-7-carboxylate: Ethyl 5- (1-ethoxyethyl) -6-methylindolizine-7-carboxylate was prepared using a method similar to Step 4, Example 1, except that ethyl iodide was used, yield 15%. ESI-MS m / z 276 [M + H] +.

[00173] Step 2: Preparation of 5- (1-ethoxyethyl) -6-methylindolizine-7-carboxylic acid: 5- (1-ethoxyethyl) -6-methylindolizine-7-carboxylic acid was prepared using a method similar to from Step 5 of Example 1, yield 95%. ESI-MS m / z 248 [M + H] +.

[00174] Step 3: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1-ethoxyethyl) -6-methylindole izine- 7-carboxamide:
N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1-ethoxyethyl) -6-methylindole izine-7-carboxamide was prepared by a method similar to that of Step 6, Example 1, yield 35%. 1H NMR (400 MHz, CDCl3) δ ppm 8.02 (s, 1 H), 7.36 (s, 1 H), 6.99 (s, 1 H), 6.77 (s, 1 H) , 6.50 (s, 1 H), 6.14 (s, 1 H), 5.34 (brs, 1 H), 5.20 (q, J = 7.8 Hz, 1 H), 4, 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 ( s, 6 H), 1.26 (d, J = 7.6 Hz, 3 H), 0.88 (t, J = 7.8 Hz, 3 H); ESI-MS m / z 382 [M + H] +.

[00175] Example 3: Preparation of 5- (1- (Alyloxy) ethyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl 6-methylindolizine- 7-carboxamide:

[00176] Step 1: Step 1: Preparation of 5- (1- (alyloxy) ethyl) -6-methylindolizine-7-carboxylate: 5- (1- (alyloxy) ethyl) -6-methylindolizine-7-carboxylate Ethyl chloride was prepared using a method similar to that of Step 4, Example 1, except that allyl chloride was used, yield 49%. ESI-MS m / z 288 [M + H] +.

[00177] Step 2: Preparation of 5- (1- (alyloxy) ethyl) -6-methylindolizine-7-carboxylic acid: 5- (1- (alyloxy) ethyl) -6-methylindolizine-7-carboxylic acid was prepared by using a method similar to Step 5, Example 1, yield 98%. ESI-MS m / z 260 [M + H] +.

[00178] Step 3: Preparation of 5- (1- (Alyloxy) ethyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6- methyl ndolizine-7-carboxamide:
5- (1- (Alyloxy) ethyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methylndolizine-7-carboxamide was prepared using a method similar to that of Step 6, Example 1, yield 53%. 1H NMR (400 MHz, CDCl3) δ ppm 8.01 (s, 1 H), 7.37 (s, 1 H), 6.91 (s, 1 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 - 5.14 (m, 3 H), 4 , 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, 3 H), 1.62 (d, J = 7.8 Hz, 3 H); ESI-S m / z 394 [M + H] +.

[00179] Example 4: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (prop-2 -in-1-ioxy) ethyl) indolizine-7-carboxamide:

[00180] Step 1: Preparation of ethyl 6-methyl-5- (1- (prop-2-in-1-yloxy) ethyl) indolizine-7-carboxylate: 6-methyl-5- (1- (prop- Ethyl 2-in-1-yloxy) ethyl) indolizine-7-carboxylate was prepared by a method similar to that of Step 4 of Example 1, except that 3-bromoprop-2 -ine was used, yield 35%. ESI-MS m / z 286 [M + H] +.

[00181] Step 2: Preparation of 6-methyl-5- (1- (prop-2-in-1-yloxy) ethyl) indolizine-7-carboxylic acid: 6-methyl-5- (1- (prop- 2-in-1-yloxy) ethyl) indolizine-7-carboxylic was prepared by a method similar to that of Step 5, of Example 1, yield 100%. ESI-MS m / z 258 [M + H] +.

[00182] Step 3: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (prop-2 -in-1-ioxy) ethyl) indolizine-7-carboxamide:
N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (prop-2-in-1-yloxy) ethyl) indolizine-7-carboxamide was prepared by a method similar to that of Step 6 of Example 1, yield 20%. 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.19 (s, 1 H), 7.83 (s, 1 H), 7.36 (s, 1 H), 6.77 (d, J = 2.8 Hz, 1 H), 6.52 (d, J = 3.2 Hz, 1 H), 5.88 (s, 1 H), 5.46 - 5.44 (m, 1 H) , 4.28 - 4.27 (m, 2 H), 4.10 (d, J = 16.0 Hz, 1 H), 3.80 (d, J = 16.0 Hz, 1 H), 2 , 26 (s, 3 H), 2.21 (s, 3 H), 2.12 (s, 3 H), 1.56 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 392 [M + H] +.

[00183] Example 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1 - ((2- methylalkyl) xi) ethyl) indolizine-7-carboxamide:

[00184] Step 1: Preparation of ethyl 6-methyl-5- (1 - ((2-methylalyl) oxy) ethyl) indolizine-7-carboxylate: 6-methyl-5- (1 - ((2-methylalyl) ethyl oxy) ethyl) pyridazin-7-carboxylate was prepared by a method similar to that of Step 4 of Example 1, except that 3-chloro-2-methylprop-1-ene was used, yield 44%. 1H NMR (CDCl3, 400 MHz) δ ppm 8.10 (brs, 1 H), 8.05 (s, 1 H), 6.84 (t, J = 2.0 Hz, 1 H), 6, 69 (t, J = 2.0 Hz, 1 H), 5.30 (q, J = 6.8 Hz, 1 H), 4.91 (d, J = 3.9 Hz, 2 H), 4 , 34 (q, J = 6.4 Hz, 2 H), 3.70 (d, J = 12.0 Hz, 1 H), 3.62 (d, J = 12.0 Hz, 1 H), 2.47 (s, 3 H), 1.71 (s, 3 H), 1.65 (d, J = 6.8 Hz, 3 H), 1.40 (t, J = 6.4 Hz, 3 H).

[00185] Step 2: Preparation of 6-methyl-5- (1 - ((2-methylalyl) oxy) ethyl) indolizine-7-carboxylic acid: 6-methyl-5- (1 - ((2-methylalyl) acid oxy) ethyl) indolizine-7-carboxylic was prepared using a method similar to that of Step 5, Example 1, yield 94%. 1H NMR (CDCl3, 400 MHz) δ ppm 8.26 (s, 1 H), 8.16 (s, 1 H), 6.86 (brs, 1 H), 6.75 (brs, 1 H) , 5.32 (q, J = 6.8 Hz, 1 H), 4.91 (d, J = 4.4 Hz, 2 H), 3.72 (d, J = 12.0 Hz, 1 H ), 3.66 (d, J = 12.0 Hz, 1 H), 2.52 (s, 3 H), 1.71 (s, 3 H), 1.65 (d, J = 6.8 Hz, 1 H).

[00186] Step 3: Preparation of N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1 - ((2- metalyl) ox i) ethyl) indolizine-7-carboxamide:
N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1 - ((2-methyl) ox i) ethyl) indolizine -7-carboxamide was prepared by a method similar to that of Step 6, Example 1, yield 18%. 1H NMR (CDCl3, 400 MHz) 8.02 (s, 1 H), 7.35 (s, 1 H), 6.93 (s, 1 H), 6.76 (s, 1 H), 6 , 48 (brs, 1 H), 6.30 (brs, 1 H), 5.20 (q, J = 6.8 Hz, 1 H), 4.90 (q, J = 10.8 Hz, 2 H), 4.51 (d, J = 5.6 Hz, 2 H), 3.70 (d, J = 12.0 Hz, 1 H), 3.65 (d, J = 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), 1.61 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 408 [M + H] +.

[00187] Example 6: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1-isobutyloxyethyl) -6-meylindolizine- 7-carboxamide:

[00188] Step 1: Preparation of ethyl 5- (1-isobutyloxyethyl) -6-methylindolizine-7-carboxylate: 6-methyl-5- (1 - ((2-methylalyl) oxy) ethyl) indolizine-7-carboxylate of ethyl (60 mg, 0.2 mmol), Raney's Ni (6 mg) and 10 mL of methanol were added sequentially to a single-necked, 25 mL flask, exchanged with hydrogen and stirred at room temperature for two hours. The organic phase was concentrated to provide a yellow oily product (50 mg, yield: 86%). ESI-MS m / z 304 [M + H] +.

[00189] Step 2: Preparation of 5- (1-isobutyloxyethyl) -6-methylindolizine-7-carboxylic acid: 5- (1-isobutyloxyethyl) -6-methylindolizine-7-carboxylic acid was prepared using a method similar to from Step 5 of Example 1, yield 89%. ESI-MS m / z 276 [M + H] +.

[00190] Step 3: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1-isobutyloxyethyl) -6-meylindolizine- 7-carboxamide:
N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1-isobutyloxyethyl) -6-meylindolizine-7-carboxamide was prepared by means of a method similar to that of Step 6, Example 1, yield 20%. 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.17 (s, 1 H), 7.91 (s, 1 H), 7.34 (s, 1 H), 6.76 (brs, 1 H), 6.49 (d, J = 2.8 Hz, 1 H), 5.88 (s, 1 H), 5.20 (q, J = 6.8 Hz, 1 H), 4.28 (brs, 2 H), 3.20 - 3.16 (m, 1 H), 2.85 - 2.82 (m, 1 H), 2.24 (s, 3 H), 2.21 (s , 3 H), 2.12 (s, 3 H), 1.69 - 1.66 (m, 1 H), 1.53 (d, J = 6.8 Hz, 3 H), 0.82 - 0.79 (m, 6 H); ESI-MS m / z 410 [M + H] +.

[00191] Example 7: Preparation of 5 - ((cyclohex-2-en-1-yloxy) ethyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3 -il) m ethyl) -6-methylindolizine-7-carboxamide:

[00192] Step 1: Preparation of ethyl 5- (1- (cyclohex-2-en-1-yloxy) ethyl) -6-methylindolizine-7-carboxylate: 5- (1- (cyclohex-2 Ethyl -en-1-yloxy) ethyl) -6-methylindolizine-7-carboxylate was prepared using a method similar to that of Step 4, Example 1, except that 3-bromo-2-cyclohex-1- and was not used, yield 38%. ESI-MS m / z 328 [M + H] +.

[00193] Step 2: Preparation of 5- (1- (cyclohex-2-en-1-yloxy) ethyl) -6-methylindolizine-7-carboxylic acid: 5- (1- (cyclohex-2 -en-1-yloxy) ethyl) -6-methylindolizine-7-carboxylic acid was prepared by a method similar to that of Step 5 of Example 1, yield 66%. ESI-MS m / z 300 [M + H] +.

[00194] Step 3: Preparation of 5- (1- (cyclohex-2-en-1-yloxy) ethyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridine -3-yl) methyl) -6-methylindolizine-7-carboxamide: 5- (1- (cyclohex-2-en-1-yloxy) ethyl) -6-methylindolizine-7-carboxylic acid was prepared by means of a method similar to that of Step 6, Example 1, yield 19%. 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.19 (s, 1 H), 7.97 (s, 1 H), 7.34 (s, 1 H), 6.76 (s, 1 H), 6.49 (s, 1 H), 5.88 (s, 1 H), 5.84 - 5.69 (m, 1 H), 5.42 - 5.32 (m, 1 H) , 4.27 (brs, 1 H), 3.67 (s, 1 H), 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 (m, 2 H), 1.67 (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 H); ESI-MS m / z 434 [M + H] +.

[00195] Example 8: Preparation of 5- (1- (cyclohexyloxy) ethyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) - 6- methylindolizine-7-carboxamide:

[00196] Step 1: Preparation of ethyl 5- (1- (cyclohexyloxy)) -6-methylindolizine-7-carboxylate: 5- (1- (cyclohexyloxy) ethyl) -6-methylindolizine-7- ethyl carboxylate was prepared using a method similar to that of Step 1 of Example 6, yield 80%. ESI-MS m / z 330 [M + H] +.

[00197] Step 2: Preparation of 5- (1- (cyclohexyloxy) ethyl) -6-methylindolizine-7-carboxylic acid: 5- (1- (cyclohexyloxy) ethyl) -6-methylindolizine-7- carboxylic acid was prepared using a method similar to that of Step 5, Example 1, yield 82%. ESI-MS m / z 302 [M + H] +.

[00198] Step 3: Preparation of 5- (1- (cyclohexyloxy) ethyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) - 6- methylindolizine-7-carboxamide: 5- (1- (cyclohexyloxy) ethyl) -6-methylindolizine-7-carboxylic acid was prepared by a method similar to that of Step 6, Example 1, yield 5%. 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.18 (brs, 1 H), 7.98 (s, 1 H), 7.32 (s, 1 H), 6.75 (s, 1 H), 6.48 (d, J = 3.0 Hz, 1 H), 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 (s, 1 H), 2.23 (s, 3 H), 2.20 (s, 3 H), 2.11 (s, 3 H), 1.99 - 1.97 (m, 1 H), 1.66 (s, 1 H), 1.50 (d, J = 6.8 Hz, 3 H), 1.33 - 1 , 12 (m, 5 H); ESI-MS m / z 433 [M + H] +.

[00199] Example 9: Preparation of 5- (1- (benzyloxy) ethyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6- met ylindolizine-7-carboxamide:

[00200] Step 1: Preparation of ethyl 5- (1- (benzyloxy) ethyl) -6-methylindolizine-7-carboxylate: 5- (1- (benzyloxy) ethyl) -6-methylindolizine-7-carboxylate was prepared by a method similar to that of Step 6 of example 1 except benzyl bromide was used, yield 64%. ESI-MS m / z 338 [M + H] +.

[00201] Step 2: Preparation of 5- (1- (benzyloxy) ethyl) -6-methylindolizine-7-carboxylic acid: 5- (1- (benzyloxy) ethyl) -6-methylindolizine-7-carboxylic acid was prepared by using a method similar to Step 5, Example 1, yield 92%. 1H NMR (CDCl3, 400 MHz) δ ppm 8.31 (s, 1 H), 8.22 (brs, 1 H), 7.34 - 7.24 (m, 5 H), 6.89 (t , J = 2.8 Hz, 1 H), 6.79 (t, J = 2.8 Hz, 1 H), 5.37 (q, J = 6.8 Hz, 1 H), 4.40 ( d, J = 11.6 Hz, 1 H), 4.24 (d, J = 11.6 Hz, 1 H), 2.47 (s, 3 H), 1.67 (d, J = 6, 8 Hz, 1 H).

[00202] Step 3: Preparation of 5- (1- (benzyloxy) ethyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6- met ylindolizine-7-carboxamide:
5- (1- (benzyloxy) ethyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-ylindolizine-7-carboxamide was prepared using a method similar to that of Step 6, Example 1, yield 10%. 1H NMR (DMSO-d6, 400 MHz) δ ppm 11.48 (s, 1 H), 8.18 (s, 1 H), 7.97 (s, 1 H), 7.37 - 7.24 (m, 5 H), 7.11 (s, 1 H), 6.98 (s, 1 H), 6.78 (s, 1 H), 6.52 (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), 2.19 (d, J = 6.8 Hz, 3 H), 2.11 (s, 3 H), 1.58 (d, J = 6.4 Hz, 3 H); ESI-MS m / z 444 [M + H] +.

[00203] Example 10: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1 - (((4-fluorobenzyl)) oxy ) ethyl) -6-methylindolizine-7-carboxamide:

[00204] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1 - (((4-fluorobenzyl)) oxy) ethyl) -6 -methylindolizine-7-carboxamide was prepared using a method similar to that of Example 9.

[00205] Step 1: Preparation of ethyl 5- (1 - ((4-fluorobenzyl) oxy) ethyl) -6-methylindolizine-7-carboxylate: Yield 63%. ESI-MS m / z 356 [M + H] +.

[00206] Step 1: Preparation of 5- (1 - ((4-fluorobenzyl) oxy) ethyl) -6-methylindolizine-7-carboxylic acid: Yield 88%. ESI-MS m / z 328 [M + H] +.

[00207] Step 3: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1 - (((4-fluorobenzyl) oxy) and useful) -6-methylindolizine-7-carboxamide: Yield 30%. 1H NMR (400 MHz, CDCl3) δ ppm 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 (m, 2 H), 6.78 (t, J = 2.8 Hz, 1 H), 6.51 (t, J = 2.8 Hz, 1 H), 5.94 (s, 1 H), 5.24 (q, J = 6.8 Hz, 1 H), 4.52 (d, J = 4.8 Hz, 2 H), 4.30 (d, J = 12.0 Hz, 1 H), 4.19 (d, J = 12.0 Hz, 1 H), 2.39 (s, 3 H), 2.25 (s, 3 H) , 2.23 (s, 3 H), 1.63 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 462 [M + H] +.

[00208] Example 11: Preparation of N - ((4,6-dimethyl-2 oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1 - (((2-fluorobenzyl)) oxy) ethyl) -6-methylindolizine-7-carboxamide:

[00209] N - (((4,6-dimethyl-2 oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1 - (((2-fluorobenzyl)) oxy) ethyl) -6- methylindolizine-7-carboxamide was prepared by a method similar to that of Example 9.

[00210] Step 1: Preparation of ethyl 5- (1 - ((2-fluorobenzyl) oxy) ethyl) -6-methylindolizine-7-carboxylate: Yield 63%. ESI-MS m / z 356 [M + H] +.

[00211] Step 2: Preparation of 5- (1 - ((2-fluorobenzyl) oxy) ethyl) -6-methylindolizine-7-carboxylic acid: 84% yield. ESI-MS m / z 328 [M + H] +.

[00212] Step 3: Preparation of N - ((4,6-dimethyl-2 oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1 - (((2-fluorobenzyl)) oxy) ethyl) -6-methylindolizine-7-carboxamide: Yield 4%. H1 NMR (DMSO-d6, 400 MHz) δ (ppm) 8.19 (brs, 1 H), 7.93 (s, 1 H), 7.36 - 7.34 (m, 3 H), 7 , 18 - 7.16 (m, 2 H), 6.76 (t, J = 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 Hz, 1 H), 4.46 (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 (s, 3 H), 1.58 (d, J = 6.8 Hz, 3 H ); ESI-MS m / z 462 [M + H] +.

[00213] Example 12: Preparation of N - ((4,6-dimethyl-2 oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1 - (((3-fluorobenzyl)) oxy) ethyl) -6-methylindolizine-7-carboxamide:

[00214] N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridine
3-yl) methyl) -5- (1 - ((3-fluorobenzyl)) oxy) ethyl) -6-methylindolizine-7-carboxamide was prepared by a method similar to that of Example 9.

[00215] Step 1: Preparation of ethyl 5- (1 - ((3-fluorobenzyl) oxy) ethyl) -6-methylindolizine-7-carboxylate: Yield 66%. ESI-MS m / z 356 [M + H] +.

[00216] Step 2: Preparation of 5- (1 - ((3-fluorobenzyl) oxy) ethyl) -6-methylindolizine-7-carboxylic acid: Yield 87%. ESI-MS m / z 328 [M + H] +.

[00217] Step 3: Preparation of N - ((4,6-dimethyl-2 oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1 - (((3-fluorobenzyl)) oxy) ethyl) -6-methylindolizine-7-carboxamide: Yield 11%. H1 NMR (DMSO-d6, 400 MHz) δ (ppm) 12.50 (brs, 1 H), 7.95 (brs, 1 H), 7.40 (s, 1 H), 7.36 - 7 , 32 (m, 2 H), 7.96 - 6.82 (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), 5.25 (q, J = 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, J = 12.0 Hz, 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 H); ESI-MS m / z 462 [M + H] +.

[00218] Example 13: Preparation of 5- (1 - ((2,6-difluorobenzyl) oxy) ethyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin) -3 -yl) methyl) -6-methylindolizine-7-carboxamide:

[00219] 5- (1 - ((2,6-difluorobenzyl) oxy) ethyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin) -3-yl) methyl) -6-methylindolizine-7-carboxamide was prepared by a method similar to that of Example 9.

[00220] Step 1: Preparation of ethyl 5- (1 - ((2,6-difluorobenzyl) oxy) ethyl) -6-methylindolizine-7-carboxylate: Yield 70%. ESI-MS m / z 374 [M + H] +.

[00221] Step 2: Preparation of 5- (1 - ((3-fluorobenzyl) oxy) ethyl) -6-methylindolizine-7-carboxylic acid: Yield 78%. ESI-MS m / z 346 [M + H] +.

[00222] Step 3: Preparation of 5- (1 - ((2,6-difluorobenzyl) oxy) ethyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridine) -3 -yl) methyl) -6-methylindolizine-7-carboxamide: Yield 16%. 1H NMR (CDCl3, 400 MHz) δ (ppm) 12.40 (brs, 1 H), 7.95 (brs, 1 H), 7.38 (s, 1 H), 7.30 - 7.18 (m, 1 H), 6.75 (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), 5.91 (s, 1 H), 5.25 (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 H), 2.27 (s, 3 H), 2.15 (s, 3 H), 1.58 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 480 [M + H] +.

[00223] Example 14: Preparation of N - ((4,6-dimethyl-2 oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1 - (((3-methoxybenzyl)) oxy) ethyl) -6-methylindoli zine-7-carboxamide:

[00224] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1 - (((3-methoxybenzyl)) oxy) ethyl) -6 -methylindolizine-7-carboxamide was prepared using a method similar to that of Example 9.

[00225] Step 1: Preparation of ethyl 5- (1 - ((2,6-difluorobenzyl) oxy) ethyl) -6-methylindolizine-7-carboxylate: 65% yield. ESI-MS m / z 368 [M + H] +.

[00226] Step 2: Preparation of 5- (1 - ((3-fluorobenzyl) oxy) ethyl) -6-methylindolizine-7-carboxylic acid: Yield 69%. ESI-MS m / z 340 [M + H] +.

[00227] Step 3: Preparation of 5- (1 - ((2,6-difluorobenzyl) oxy) ethyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridine) -3 -yl) methyl) -6-methylindolizine-7-carboxamide: Yield 13%. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 8.17 (brs, 1 H), 7.97 (brs, 1 H), 7.37 (s, 1 H), 7.26 (brs , 2 H), 6.84 - 6.79 (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), 4.34 - 4.21 (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, J = 6.8 Hz, 3 H); ESI-MS m / z 474 [M + H] +.

[00228] Example 15: Preparation of N - ((4,6-dimethyl-2 oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (pyridine-2- ylmethoxy) ethyl) indolizine-7-carboxamide:

[00229] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (pyridine-2-ylmethoxy) ethyl) indolizine-7-carboxamide was prepared by a method similar to that of Example 9.

[00230] Step 1: Preparation of ethyl 6-methyl-5- (1- (pyridine-2-ylmethoxy) ethyl) indolizine-7-carboxylate: Yield 30%. ESI-MS m / z 339 [M + H] +.

[00231] Step 2: Preparation of 6-methyl-5- (1- (pyridine-2-ylmethoxy) ethyl) indolizine-7-carboxylic acid: Yield 90%. ESI-MS m / z 311 [M + H] +.

[00232] Step 3: Preparation of N - ((4,6-dimethyl-2 oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (pyridine-2- ylmethoxy) ethyl) indolizine-7-carboxamide: Yield 20%. H1 NMR (400 MHz, CDCl3) δ (ppm) 8.62 (d, J = 4.8 Hz, 1H), 7.91 - 7.84 (m, 2 H), 7.52 - 7.51 (m, 1 H), 7.42 - 7.39 (m, 1 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 Hz, 1 H), 6.3 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 (m, 3 H), 2.52 (s, 3 H), 2.37 (s, 3 H), 2.23 (s, 3 H), 1.70 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 445 [M + H] +.

[00233] Example 16: Preparation of N - ((4,6-dimethyl-2 oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (pyridin-4- ylmethoxy) ethyl) indolizin a-7-carboxamide:

[00234] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (pyrid in-4-ylmethoxy) ethyl ) indolizine-7-carboxamide was prepared using a method similar to that of Example 9.

[00235] Step 1: Preparation of ethyl 6-methyl-5- (1- (pyridin-4-ylmethoxy) ethyl) indolizine-7-carboxylate: Yield 37%. ESI-MS m / z 339 [M + H] +.

[00236] Step 2: Preparation of 6-methyl-5- (1- (pyridin-4-ylmethoxy) ethyl) indolizine-7-carboxylic acid: Yield 85%. ESI-MS m / z 311 [M + H] +.

[00237] Step 3: Preparation of N - ((4,6-dimethyl-2 oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (pyridin-4- ylmethoxy) ethyl) indolizin a-7-carboxamide: Yield 6%. 1H NMR (400 MHz, CDCl3) δ (ppm) 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 H), 7.05 (s, 1 H), 6.79 (t, J = 2.8 Hz, 1 H), 6.52 (t, J = 2 , 8 Hz, 1 H), 6.43 (s, 1 H), 5.32 (q, J = 6.8 Hz, 1 H), 4.66 - 4.46 (m, 4 H), 2 , 57 (s, 3 H), 2.43 (s, 3 H), 2.27 (s, 3 H), 1.75 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 445 [M + H] +.

[00238] Example 17: Preparation of N - ((4,6-dimethyl-2 oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (thiophene-2- ylmethoxy) ethyl) indolizine-7-carboxamide:

[00239] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (thiophene-2-ylmethoxy) ethyl) indolizine-7-carboxamide was prepared by a method similar to that of Example 9.

[00240] Step 1: Preparation of ethyl 6-methyl-5- (1- (thiophene-2-ylmethoxy) ethyl) indolizine-7-carboxylate: Yield 39%. ESI-MS m / z 344 [M + H] +.

[00241] Step 2: Preparation of 6-methyl-5- (1- (thiophene-2-ylmethoxy) ethyl) indolizine-7-carboxylic acid: Yield 82%. ESI-MS m / z 316 [M + H] +.

[00242] Step 3: Preparation of N - ((4,6-dimethyl-2 oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (thiophene-2- ylmethoxy) ethyl) indolizine-7-carboxamide: Yield 8%. 1H NMR (400 MHz, CDCl3) δ (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 H), 6.55 (d, J = 3.0 Hz, 1 H), 6.34 (s, 1 H), 5.28 (q, J = 6 , 8 Hz, 1 H), 4.55 - 4.52 (m, 3 H), 4.38 (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 = 6.8 Hz, 3 H); ESI-MS m / z 450 [M + H] +.

[00243] Example 18: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (thiazol-2 -xi film) ethyl) indolizine-7-carboxamide:

[00244] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (thiazol-2-ylmethoxy) ethyl) indolizine-7-carboxamide was prepared by a method similar to that of Example 9.

[00245] Step 1: Preparation of ethyl 6-methyl-5- (1- (thiazol-2-ylmethoxy) ethyl) indolizine-7-carboxylate: Yield 45%. ESI-MS m / z 345 [M + H] +.

[00246] Step 2: Preparation of 6-methyl-5- (1- (thiazol-2-ylmethoxy) ethyl) indolizine-7-carboxylic acid: 89% yield. ESI-MS m / z 317 [M + H] +.

[00247] Step 3: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (thiazol-2 -xii film) ethyl) indolizine-7-carboxamide: Yield 11%. 1H NMR (400 MHz, CDCl3) δ (ppm) 12.1 (brs, 1 H), 7.94 (s, 1 H), 7.64 (s, 1 H), 7.24 - 7.21 (m, 2 H), 6.71 (t, J = 3.0 Hz, 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), 4.56 (s, 1 H), 4.45 (d, J = 6.4 Hz, 2 H), 2.32 (s , 3 H), 2.23 (s, 3 H), 2.16 (s, 3 H), 1.62 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 451 [M + H] +.

[00248] Example 19: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (thiophene-3 -ilm ethoxy) ethyl) indolizine-7-carboxamide:

[00249] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (thiophene-3-ylmethoxy) ethyl) indolizine-7-carboxamide was prepared by a method similar to that of Example 9.

[00250] Step 1: Preparation of ethyl 6-methyl-5- (1- (thiophene-3-ylmethoxy) ethyl) indolizine-7-carboxylate: Yield 34%. ESI-MS m / z 344 [M + H] +.

[00251] Step 2: Preparation of 6-methyl-5- (1- (thiophene-3-ylmethoxy) ethyl) indolizine-7-carboxylic acid: Yield 71%. ESI-MS m / z 316 [M + H] +.

[00252] Step 3: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (thiophene-3 -ilm ethoxy) ethyl) indolizine-7-carboxamide: Yield 13%. 1H NMR (400 MHz, CDCl3) δ (ppm) 12.30 (brs, 1 H), 8.06 (s, 1 H), 7.41 (s, 1 H), 7.29 - 7.24 (m, 1 H), 7.11 (brs, 1 H), 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 (s, 1 H), 5.24 (q, J = 6.8 Hz, 1 H), 4.53 (d, J = 6.4 Hz , 2 H), 4.34 (d, J = 11.4 Hz, 1 H), 4.26 (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, J = 6.8 Hz, 3 H); ESI-MS m / z 450 [M + H] +.

[00253] Example 20: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-methyl-1H- pyrazol-3-yl) methoxy) ethyl) indolizine-7-carboxamide:

[00254] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-methyl-1H-pyrazol-3-yl ) methoxy) ethyl) indolizine-7-carboxamide was prepared by a method similar to that of Example 9.

[00255] Step 1: Preparation of ethyl 6-methyl-5- (1 - ((1-methyl-1H-pyrazol-3-yl) methoxy) ethyl) indolizine-7-carboxylate: Yield 43%. ESI-MS m / z 342 [M + H] +.

[00256] Step 2: Preparation of 6-methyl-5- (1 - (((1-methyl-1H-pyrazol-3-yl) methoxy) ethyl) indolizine-7-carboxylic acid: Yield 82%. ESI-MS m / z 314 [M + H] +.

[00257] Step 3: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-methyl-1H- pyrazol-3-yl) methoxy) ethyl) indolizine-7-carboxamide: Yield 16%. 1H NMR (400 MHz, CDCl3) δ (ppm) 12.51 (brs, 1 H), 8.06 (brs, 1 H), 7.39 (s, 1 H), 7.29 - 7.23 (m, 1 H), 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 (s, 1 H), 5.31 (q, J = 6.8 Hz, 1 H), 4.53 (d, J = 6.4 Hz, 2 H), 4.32 (t , J = 11.4 Hz, 2 H), 3.84 (s, 3 H), 2.38 (s, 3 H), 2.30 (s, 3 H), 2.22 (s, 3 H ), 1.61 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 448 [M + H] +.

[00258] Example 21: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-methyl-1H- pyrazol-5-yl) methoxy) ethyl) indolizine-7-carboxamide:

[00259] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (1-methyl-1H-pyrazole- 5-yl) methoxy) ethyl) indolizine-7-carboxamide was prepared by a method similar to that of Example 9.

[00260] Step 1: Preparation of ethyl 6-methyl-5- (1 - ((1-methyl-1H-pyrazol-5-yl) methoxy) ethyl) indolizine-7-carboxylate: 33% yield. ESI-MS m / z 342 [M + H] +.

[00261] Step 2: Preparation of 6-methyl-5- (1 - (((1-methyl-1H-pyrazol-5-yl) methoxy) ethyl) indolizine-7-carboxylic acid: Yield 81%. ESI-MS m / z 314 [M + H] +.

[00262] Step 3: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-methyl-1H- pyrazol-5-yl) methoxy) ethyl) indolizine-7-carboxamide: Yield 13%. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 13.08 (brs, 1 H), 8.20 (brs, 1 H), 7.89 (s, 1 H), 7.38 (s , 1 H), 7.32 (s, 1 H), 6.78 (t, J = 3.0 Hz, 1 H), 6.52 (d, J = 3.0 Hz, 1 H), 6 , 12 (brs, 1 H), 5.89 (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, 3 H), 2.21 (s, 3 H), 2.20 (s, 3 H), 1.56 (d, J = 6, 8 Hz, 3 H); ESI-MS m / z 448 [M + H] +.

[00263] Example 22: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamino)) phen iloxy) ethyl) -6-methylindolizine-7-carboxamide:

[00264] Step 1: Preparation of ethyl 6-methyl-5- (1- (4-nitrophenyloxy) ethyl) indolizine-7-carboxylate: 6-methyl-5- (1- (4-nitrophenyloxy) ethyl) indolizine- Ethyl 7-carboxylate was prepared using a method similar to that of Step 4, Example 1, except that p-nitrofluorobenzene was used, 65% yield. ESI-MS m / z 369 [M + H] +.

[00265] Step 2: Preparation of ethyl 5- (1- (4-aminophenyloxy) ethyl) -6-methylindolizine-7-carboxylate: 6-methyl-5- (1 - (((4-aminophenyloxy) ethyl) indolizine- Ethyl 7-carboxylate (125 mg, 3.34 mmol), Raney Ni (10 mg) and 10 ml of methanol were added sequentially to a 25 ml single neck flask, exchanged for hydrogen and stirred at temperature room for 4 hours, and filtered. The organic phase was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 4: 1) to provide a product as a yellow oil (100 mg, yield: 87%). ESI-MS m / z 339 [M + H] +.

[00266] Step 3: Preparation of ethyl 5- (1- (4-dimethylaminophenyloxy) ethyl) -6-methylindolizine-7-carboxylate: 5- (1- (4-aminophenyloxy) ethyl) -6-methylindolizine-7- ethyl carboxylate (100 mg, 0.30 mmol) in DMF (1.0 mL) was added with potassium carbonate (104 mg, 0.75 mmol) and methyl iodide (94 mg, 0.66 mmol) , stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate (100 ml), washed with water (50 ml x 2) and brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 4: 1) to provide a product as a white solid ( 40 mg, yield: 36%). ESI-MS m / z 367 [M + H] +.

[00267] Step 4: Preparation of 5- (1- (4-dimethylaminophenyloxy) ethyl) -6-methylindolizine-7-carboxylic acid: 5- (1- (4-dimethylaminophenyloxy) ethyl) -6-methylindolizine-7- carboxylic acid was prepared using a method similar to that of Step 5, Example 1, yield 89%. ESI-MS m / z 339 [M + H] +.

[00268] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamino) benzyloxy ) ethyl) -6-methylindolizine-7-carboxamide:
N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamine) benzyloxy) ethyl) -6-methylindolizine- 7-carboxamide was prepared by a method similar to that of Step 6, Example 1, yield 6%. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.49 (brs, 1 H), 8.21 (t, J = 3.0 Hz, 1 H), 8.03 (s, 1 H ), 7.34 (s, 1 H), 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 = 3.0 Hz, 1 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 (s, 6 H), 2.34 (s, 3 H), 2.26 (s, 3 H), 2.22 (s, 3 H), 1.73 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 473 [M + H] +.

[00269] Example 23: Preparation of 5 - ((4-bromophenyl) (hydroxy) methyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methylindolizine-7-carboxamide:

[00270] Step 1: Preparation of ethyl 5- (4-bromobenzoyl) -6-methylindolizine-7-carboxylate: In a 100 ml three-necked bottle, dried and protected with nitrogen, 1H-pyrrole-2-formaldehyde ( 2.5 g, 26 mmol), 2,4-dibromoacetophenone (7.23 g, 26 mmol), ethyl 2-butanoate (3.5 g, 31.2 mmol) and potassium carbonate (7.18 g, 52 mmol) and 50 mL of DMF were added in succession. The mixture was stirred for 5 hours at 90 ° C and cooled to room temperature. The mixture was extracted with ethyl acetate (200 ml), washed with water (100 ml x 2) and brine (100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 4: 1) to provide a product such as yellow oil ( 2.0 g, yield: 20%). 1H NMR (CDCl3, 400 MHz) δ (ppm) 8.29 (s, 1 H), 7.73 (d, J = 7.6 Hz, 2 H), 7.63 (d, J = 7, 6 Hz, 2 H), 6.99 (s, 1 H), 6.77 (s, 2 H), 4.36 (q, J = 7.2 Hz, 2 H), 2.31 (s, 3 H), 1.42 (t, J = 7.2 Hz, 3 H).

[00271] Step 2: Preparation of ethyl 5 - ((4-bromophenyl) (hydroxy) methyl) -6-methylindolizine-7-carboxylate: (((4-bromophenyl) (hydroxy) methyl) -6-methylindolizine-7- ethyl carboxylate was prepared using a method similar to that of Step 3, Example 1, yield 86%. ESI-MS m / z 388 [M + H] +.

[00272] Step 3: Preparation of 5 - ((4-bromophenyl) (hydroxy) methyl) -6-methylindolizine-7-carboxylic acid: 5 - ((4-bromophenyl) (hydroxy) methyl) -6-methylindolizine- 7-carboxylic was prepared using a method similar to that of Step 5, Example 1, yield 83%. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 8.13 (s, 1 H), 7.56 (d, J = 7.6 Hz, 2 H), 7.33 (d, J = 7.6 Hz, 2 H), 6.70 (s, 1 H), 6.61 - 6.55 (m, 2 H), 2.64 (s, 3 H).

[00273] Step 4: Preparation of 5 - ((4-bromophenyl) (hydroxy) methyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) - 6 -methylindolizine-7-carboxamide:
5 - ((4-bromophenyl) (hydroxy) methyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) - 6-methylindolizine-7-carboxamide was prepared using a method similar to Step 6, Example 1, 10% yield 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 11.50 (brs, 1 H), 8.25 (t , J = 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, 1 H), 6.45 (s, 1 H), 6.41 (t, J = 2.8 Hz, 1 H), 5.88 (s, 1 H), 4.29 (s, 2 H), 2.37 (s, 3 H), 2.33 (s, 3 H), 2.22 (s, 3 H); ESI-MS m / z 494 [M + H] +.

[00274] Example 24: Preparation of 5 - ((4-bromophenyl) (methoxy) methyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methylindolizine-7-carboxamide:

[00275] Step 1: Preparation of ethyl 5 - ((4-bromophenyl) (methoxy) methyl) -6-methylindolizine-7-carboxylate: 5 - ((4-bromophenyl) (methoxy) methyl) -6-methylindolizine- Ethyl 7-carboxylate was prepared using a method similar to that of Step 4, Example 1, yield 80%. ESI-MS m / z 402 [M + H] +.

[00276] Step 2: Preparation of 5 - ((4-bromophenyl) (methoxy) methyl) -6-methylindolizine-7-carboxylic acid: 5 - ((4-bromophenyl) (methoxy) methyl) -6-methylindolizine- 7-carboxylic was prepared using a method similar to that of Step 5, Example 1, yield 83%. ESI-MS m / z 374 [M + H] +.

[00277] Step 3: Preparation of 5 - ((4-bromophenyl) (methoxy) methyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) - 6 -methylindolizine-7-carboxamide:
5 - ((4-bromophenyl) (methoxy) methyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) - 6-methylindolizine-7-carboxamide using a method similar to Step 6, Example 1, yield 14%. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.47 (s, 1H), 7.37 - 7.31 ( m, 3 H), 7.18 (d, J = 7.6 Hz, 2 H), 6.99 (brs, 1 H), 6.60 (t, J = 2.8 Hz, 1 H), 6.48 (t, J = 2.8 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 H), 2.55 (s, 3 H), 2.45 (s, 3 H), 2.37 (s, 3 H); ESI-MS m / z 508 [M + H] +.

[00278] Example 25: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-phenylethyl) indolazine -7-carboxamide:

[00279] Step 1: Preparation of ethyl 5- (1- (4-bromophenyl) vinyl) -6-methylindolizine-7-carboxylate: triphenyl methylphosphonium bromide (329 mg, 0.856 mmol) and 10 mL of tetrahydrofuran nitrogen-protected, 100 ml, single-necked dry, cooled to -78 ° C and then n-BuLi was added to the tetrahydrofuran (0.5 ml, 1.6 M) slowly from drop to drop. After being warmed to room temperature and stirred for half an hour, ethyl 5- (4-bromobenzoyl) -6-methylindolizine-7-carboxylate (150 mg, 0.39 mmol) was added and then heated to 50 ° C and stirred for 3 to 4 hours and then 50 ml of water were added slowly, drop by drop, in an ice bath, extracted with ethyl acetate (100 ml). The organic phase was preserved and concentrated to provide a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 4: 1) to provide a product as a yellow viscous liquid (85 mg, yield: 57% ). ESI-MS m / z 384 [M + H] +.

[00280] Step 2: Preparation of ethyl 6-methyl-5- (1-phenylethyl) -6-methylindolizine-7-carboxylate: 5- (1 - (((4-bromophenyl) ethylene) -6-methylindolizine-7- carboxylate (85 mg, 0.22 mmol)), Pd-C (10 mg) and 10 ml of methanol were added sequentially to a 25 ml single neck flask, exchanged for hydrogen and stirred at room temperature for 48 hours. hours, and filtered. The organic phase was concentrated to provide a product as a yellow oil (65 mg, yield: 97%). ESI-MS m / z 308 [M + H] +.

[00281] Step 3: Preparation of 6-methyl-5- (1-phenylethyl) indolizine-7-carboxylic acid: Ethyl 6-methyl-5- (1-phenylethyl) indolizine-7-carboxylate was prepared by means of a similar method to Step 5, Example 1, 90% yield. ESI-MS m / z 280 [M + H] +.

[00282] Step 4: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-phenylethyl) indolazine -7-carboxamide: N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-phenylethyl) indolazine-7- carboxamide was prepared by a method similar to that of Step 6, Example 1, 17% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 10.78 (brs, 1 H), 7.52 (s, 1H), 7.40 - 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 (t, J = 2.8 Hz, 1 H), 5.94 (s, 1 H), 5.04 (q, J = 6.8 Hz, 1 H), 4.54 (d, J = 6.4 Hz, 2 H), 2.41 (s, 3 H) , 2.39 (s, 3 H), 2.23 (s, 3 H), 1.80 (q, J = 6.8 Hz, 3 H); ESI-MS m / z 414 [M + H] +.

[00283] Example 26: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinylethyl) indolizine -7-carboxamide:

[00284] Step 1: Preparation of isopropyl 6-methyl-5- (1-morphinolinylvinyl) indolizine-7-carboxylate: ethyl 5-acetyl-6-methylindolizine-7-carboxylate (200 mg, 0.80 mmol), Morpholine (1.0 mL) and 2.0 mL of tetraisopropyl oxytitanium were added successively to a 10 mL microwave tube, dried and protected with nitrogen, heated to 60 ° C and stirred overnight, 10 mL of water was added to the reaction system, stirred for 10 minutes and concentrated to remove water. The solid was washed with dichloromethane (20 ml x 3), and the organic phase was concentrated and used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1 H), 7.48 (brs, 1 H), 6.80 (dd, J = 4.0, 2.6 Hz, 1 H) , 6.66 (dd, J = 4.0, 1.4 Hz, 1 H), 5.22 (sept, J = 6.2 Hz, 1 H), 4.49 (s, 1 H), 4 , 24 (s, 1 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), 1.38 (d, J = 6.2 Hz, 6 H); ESI-MS m / z 329 [M + H] +.

[00285] Step 2: Preparation of isopropyl 6-methyl-5 (1-morphinolinylethyl) indolizine-7-carboxylate: in an ice bath, sodium borohydride (114 mg, 3.0 mmol) was added in portions to a solution of isopropyl 6-methyl-5- (1-morphinolinylvinyl) indolizine-7-carboxylate (50 mg, 0.15 mmol) in acetic acid and stirred at room temperature for 4 hours. Most of the acetic acid was removed under reduced pressure and the remainder was extracted with dichloromethane (50mL x 3), washed with water (30 ml x 3) and saturated brine (30 ml), filtered to provide a crude product, which it was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to provide a pale yellow product (35 mg, yield: 73%). 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.95 (s, 1H), 6.80 (s, 1H), 6.65 (s, 1H), 5.21 ( dt, J = 6.3 Hz, 1 H), 4.17 - 4.06 (m, 1 H), 3.68 (brs, 4 H), 2.66 (brs, 2 H), 2.50 (s, 3 H), 2.26 (brs, 2 H), 1.49 (d, J = 5.7 Hz, 3 H), 1.37 (d, J = 6.3 Hz, 6 H) ; ESI-MS m / z 331 [M + H] +.

[00286] Step 3: Preparation of 6-methyl-5- (1-morfinolinylethyl) indolizine-7-carboxylic acid: 6-methyl-5- (1-morfinolinylethyl) indolizine-7-carboxylic acid was prepared by means of a method similar to Step 5, Example 1, 63% yield. ESI-MS m / z 202 [M – 87 + H] +.

[00287] Step 4: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morphinolinylethyl) indolizine- 7-carboxamide:
N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxamide was prepared by means of a method similar to that of Step 6, Example 1, yield 68%. 1H NMR (400 MHz, CDCl3) δ 11.53 (brs, 1 H), 8.44 (brs, 1 H), 7.37 (brs, 1 H), 7.22 (brs, 1 H), 6.77 (brs, 1 H), 6.47 (brs, 1 H), 5.96 (s, 1 H), 4.51 (dd, J = 5.9, 3.0 Hz, 2 H) , 3.70 (brs, 4 H), 3.48 (q, J = 7.0 Hz, 2 H), 2.65 (brs, 2 H), 2.40 (s, 3 H), 2, 35 (s, 3 H), 2.26 (brs, 2 H), 2.24 (s, 3 H), 1.24 (brs, 3 H); ESI-MS m / z 423 [M + H] +.

[00288] Example 27: Preparation of 1-chloro-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- morphololinolinyl) indolizine-7-carboxamide:

[00289] Step 1: Preparation of 1-chloro-6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxamide:
6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxamide (450 mg, 1.37 mmol)), NCS (183 mg, 1.37 mmol) and 10 mL of acetonitrile were added sequentially to a bottle neck 100 mL, and stirred at room temperature for 30 hours, which were purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to provide a product such as yellow oil (30 mg, yield: 63 %).

[00290] 1H NMR (500 MHz, CDCl3) δ 7.84 (s, 1 H), 6.67 (d, J = 2.9 Hz, 1 H), 5.15 (sept, J = 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 H ), 2.41 (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 Hz, 6 H); ESI-MS m / z 364 [M + H] +.

[00291] Step 2: Preparation of 1-chloro-6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxylic acid: 1-chloro-6-methyl-5- (1-morfinolinylethyl) indolizine-7- carboxylic acid was prepared using a method similar to that of Step 5, Example 1, 75% yield. ESI-MS m / z 323 [M + H] +.

[00292] Step 3: Preparation of 1-chloro-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- morphololinolinyl) indolizine-7-carboxamide:
1-chloro-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinolinylethyl) indolizine-7-carboxamide it was prepared using a method similar to that of Step 6, Example 1, 68% yield. H1 NMR (400 MHz, MeOD) δ 7.33 (s, 1 H), 6.49 (s, 1 H), 6.13 (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 (s, 3 H), 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 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 457 [M + H] +.

[00293] Example 28: Preparation of (S) -1-Chloro-N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5 - ((1-morfinolinylethyl) pyridazine-7-carboxamide or (R) -1-chloro-N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6 -methyl-5- (1-m orfinolinylethyl) pyridazine-7-carboxamide:
1-chloro-N - ((4,6-dimethyl) -2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinolinylethyl) indolizine-7- carboxamide was decomposed by means of preparative chiral liquid chromatography to provide Compound 28 and Compound 29.

[00294] The separation conditions were: column type: AD-H; column size: 0.46 cm I.D. × 15 cm L; injection volume: 5 μL; mobile phase: Hep / EtOH (0.1% DEA) = 60/40 (v / v); flow rate: 0.5 mL / min .; detection conditions: UV λ = 254 nm; column temperature: 25 ° C.

[00295] Compound 28: 1H NMR (400 MHz, MeOD) δ 7.33 (s, 1 H), 6.49 (s, 1 H), 6.13 (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 (s, 3 H), 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 (d , J = 6.8 Hz, 3 H); ESI-MS m / z 457 [M + H] +; tR = 3. 849 min.

[00296] Compound 29: 1H NMR (400 MHz, MeOD) δ 7.33 (s, 1 H), 6.49 (s, 1 H), 6.13 (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 (s, 3 H), 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 (d , J = 6.8 Hz, 3 H); ESI-MS m / z 457 [M + H] +; t R = 4.309 min.

[00297] Example 29: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- mor folinylethyl) indolizine-7-carboxamide:

[00298] Step 1: 4-bromo-1H-pyrrole-2-carbaldehyde was prepared according to Outlaw, et al., Org Lett, 2015, 17, pages 1822 to 1825. Yield: 80%. 1H NMR (CDCl3, 400 MHz) δ 10.3 (brs, 1 H), 9.46 (s, 1 H), 7.14 (s, 1 H), 6.98 (s, 1 H); ESI-MS m / z 174 [M + H] +.

[00299] Step 2: Preparation of 4-bromo-1- (2-oxopropyl) -1H-pyrrole-2-carbaldehyde:
4-bromo-1- (2-oxopropyl) -1H-pyrrole-2-carbaldehyde was prepared using a method similar to that of Step 1, Example 1, 75% yield.
ESI-MS m / z 202 [M-28 + H] +.

[00300] Step 3: Preparation of ethyl 5-acetyl-2-bromo-6-methylindolizine-7-carboxylate: Ethyl 5-acetyl-2-bromo-6-methylindolizine-7-carboxylate was prepared using a method similar to Step 2, Example 1, 50% yield. 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1 H), 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 H), 2.64 (s, 3 H), 2.44 (s, 3 H), 1.40 (t, J = 7 , 1 Hz, 3 H); ESI-MS m / z 324 [M + H] +.

[00301] Step 4: Preparation of isopropyl 2-bromo-6-methyl-5- (1-morphinolinethylene) indolizine-7-carboxylate: 2-bromo-6-methyl-5- (1-morphinolinylethylene) indolizine-7- Isopropyl carboxylate was prepared using a method similar to that of Step 1, Example 26 and was used directly in the reaction of the next step.
ESI-MS m / z 407 [M + H] +.

[00302] Step 5: Preparation of isopropyl 2-bromo-6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxylate: 2-bromo-6-methyl-5- (1-morfinolinylethyl) indolizine-7- Isopropyl carboxylate was prepared using a method similar to that of Step 2, Example 1, 84% yield. ESI-MS m / z 409 [M + H] +.

[00303] Step 6: Preparation of 2-bromo-6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxylic acid: 2-bromo-6-methyl-5- (1-morfinolinylethyl) indolizine-7- carboxylic acid was prepared using a method similar to that of Step 5, Example 1, 95% yield. ESI-MS m / z 367 [M + H] +.

[00304] Step 7: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- mor finolinylethyl) indolizine-7-carboxamide:
2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-mor finolinylethyl) indolizine-7-carboxamide it was prepared using a method similar to that of Step 6, Example 1, yield 56%. 1H NMR (400 MHz, CDCl3) δ 14.37 (brs, 1 H), 8.42 (s, 1 H), 6.80 (t, J = 5.5 Hz, 1 H), 6.56 (brs, 1 H), 6.51 (brs, 1 H), 4.54 (d, J = 6.1 Hz, 2 H), 4.16 (q, J = 6.7 Hz, 1 H) , 3.76 (brs, 4 H), 2.61 (s, 3 H), 2.46 (s, 3 H), 2.30 (s, 3 H), 1.57 (d, J = 6 , 8 Hz, 3 H); ESI-MS m / z 501 [M + H] +.

[00305] Example 30: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- ( dimethyl mine)) phenyloxy) ethyl) -6-methylindolizine-7-carboxamide:

[00306] Step 1: Preparation of isopropyl 2-bromo-5- (1- (4- (dimethylamine) piperidin-1-yl) vinyl) -6-methylindolizine-7-carboxylate: 2-bromo-5- ( Isopropyl 1- (4- (dimethylamine) piperidin-1-yl) ethylene) -6-methylindolizine-7-carboxylate was prepared using a method similar to that of Step 1, Example 26. ESI-MS m / z 448 [M + H] +.

[00307] Step 2: Preparation of isopropyl 2-bromo-5- (1- (4- (dimethylamine) piperidin-1-yl) ethyl) -6-methylindolizine-7-carboxyl act: 2-bromo-5- ( Isopropyl 1- (4- (dimethylamine) piperidin-1-yl) ethyl) -6-methylindolizine-7-carboxylate was prepared by a method similar to that of Step 2, Example 26, 80% yield. ESI-MS m / z 450 [M + H] +.

[00308] Step 3: Preparation of 2-bromo-5- (1- (4- (dimethylamine) piperidin-1-yl) ethyl) -6-methylindolizine-7-carboxylic acid: 2-bromo-5- ( 1- (4- (dimethylamine) piperidin-1-yl) ethyl) -6-methylindolizine-7-carboxylic was prepared by a method similar to that of Step 5, of Example 1, 56% yield. ESI-MS m / z 408 [M + H] +.

[00309] Step 4: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- ( dimethyl mine)) piperidin-1-yl) ethyl) -6-methylindolizine-7-carboxamide: 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl ) methyl) -5- (1- (4- (dimethyl mine)) piperidin-1-yl) ethyl) -6-methylindolizine-7-carboxamide was prepared using a method similar to that of Step 6, Example 1, 30% yield. 1H NMR (400 MHz, DMSO-d6) δ 11.49 (brs, 1 H), 9.37 (brs, 1 H), 8.29 (s, 1 H), 8.24 (t, J = 4.3 Hz, 1 H), 7.26 (brs, 1 H), 6.61 (brs, 1 H), 5.87 (s, 1 H), 4.25 (d, J = 5.0 Hz, 2 H), 4.03 (dd, J = 13.8, 7.3 Hz, 1 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 H), 2.11 (s, 3 H), 2.04 - 1.93 (m, 2 H), 1.88 - 1.80 (m, 2 H), 1.41 (d, J = 6.7 Hz, 3 H); ESI-MS m / z 542 [M + H] +.

[00310] Example 31: Preparation of 2- (benzo [d] [1,3] dioxol-5-yl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridine3-yl ) methyl) -6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxamide:

[00311] Step 1: Preparation of ethyl 5-acetyl-2- (benzo [d] [1,3] dioxol-5-yl) -6-methylindolizine-7-carboxylate: In a 100 ml three-necked flask , dry and protected with nitrogen, ethyl 5-acetyl-2-bromo-6-methylindolizine-7-carboxylate (200 mg, 0.62 mmol), 3.4-dimethylenedioxyphenyl boronic acid pinacol ester (200 mg, 0 , 81 mmol), Pd (dppf) Cl2 (20 mg) and potassium acetate (182 mg, 1.86 mmol) and 10 ml of dioxane / 2 ml of water were added in succession, stirred and refluxed overnight, the reaction solution was extracted with ethyl acetate (200 ml), washed with water (100 ml x 2) and brine (100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 4: 1) to provide a product such as yellow oil ( 140 mg, yield: 62%).
ESI-MS m / z 366 [M + H] +.

[00312] Step 2: Preparation of isopropyl 2-Benzo [d] [1,3] dioxol-5-yl) -6-methyl-5- (1-morphinolinylvinyl) indolizine-7-carboxylate: crude product, 2 -Benzo [d] [1,3] dioxol-5-yl) -6-methyl-5- (1-morphinolinylvinyl) indolizine-7-carboxylate of isopropyl was prepared using a method similar to that of Step 1, Example 26. ESI-MS m / z 449 [M + H] +.

[00313] Step 3: Preparation of isopropyl 2-Benzo [d] [1,3] dioxol-5-yl) -6-methyl-5- (1-morpholinylethyl) indolizine-7-carboxylate: 2-Benzo [ d] [1,3] dioxol-5-yl) -6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxylate isopropyl was prepared using a method similar to that of Step 2, Example 26, 57% yield. ESI-MS m / z 451 [M + H] +.

[00314] Step 4: Preparation of 2-benzo acid [d] [1,3] dioxol-5-yl) -6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxylic acid: 2-Benzo acid [ d] [1,3] dioxol-5-yl) -6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxylic The crude product was prepared using a method similar to that of Step 5, Example 1 ESI-MS m / z 409 [M + H] +.

[00315] Step 5: Preparation of 2- (benzo [d] [1,3] dioxol-5-yl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridine3-yl ) methyl) -6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxamide:
2- (Benzo [d] [1,3] dioxol-5-yl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6- methyl-5- (1-morphinolinylethyl) indolizine-7-carboxamide was prepared by a method similar to that of Step 6, Example 1, 20% yield. H1 NMR (MeOD, 400 MHz) δ 7.54 (s, 1 H), 7.23 (brs, 3 H), 6.88 (s, 1 H), 6.16 (s, 1 H), 5.97 (s, 3 H), 4.48 (s, 3 H), 3.88 (brs, 4 H), 3.23 - 3.22 (m, 2 H), 2.39 (brs, 9 H), 2.26 (brs, 3 H); ESI-MS m / z 543 [M + H] +.

[00316] Example 32: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morphinolinylethyl) - 2 - (4-morphinolinylphenyl) indolizine-7-carboxamide:

[00317] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 2- (4-morfinolinylphenyl) ) indolizine-7-carboxamide was prepared by a method similar to that of Example 31.

[00318] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2- (4-morphinolinylphenyl) indolizine-7-carboxylate: Yield 12%. ESI-MS m / z 407 [M + H] +.

[00319] Step 2: Preparation of isopropyl 6-methyl-2- (4-morphinolinylphenyl) -5- (1-morphinolinylvinyl) indolizine-7-carboxylate: ESI-MS m / z 490 [M + H] +.

[00320] Step 3: Preparation of isopropyl 6-methyl-5- (1-morphinolinylethyl) -2- (4-morphinolinylphenyl) indolizine-7-carboxylate: the yield of the two steps was 83%. ESI-MS m / z 492 [M + H] +.

[00321] Step 4: Preparation of 6-methyl-5- (1-morphinolinylethyl) -2- (4-morphinolinylphenyl) indolizine-7-carboxylic acid: ESI-MS m / z 409 [M + H] +.

[00322] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morphinolinylethyl) - 2 - (4-morphinolinylphenyl) indolizine-7-carboxamide: the yield of the two stages was 20%. 1H NMR (MeOD, 400 MHz) δ 7.68 - 7.66 (m, 3 H), 7.49 (s, 1 H), 7.13 - 7.11 (m, 3 H), 6, 14 (s, 1 H), 4.48 (s, 2 H), 3.89 - 3.83 (m, 10 H), 3.26 (s, 6 H), 2.38 (s, 9 H ), 2.26 (s, 3 H), 1.81 - 1.76 (m, 2H); ESI-MS m / z 584 [M + H] +.

[00323] Example 33: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morphinolinylethyl) - 2 - (pyridin-3-yl) indolizine-7-carboxamide:

[00324] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morphinolinylethyl) - 2 - (- 3- morfinolinylphenyl) indolizine-7-carboxamide was prepared by a method similar to that of Example 31.

[00325] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2- (pyridin-3-yl) indolizine-7-carboxylate: Yield 39%. ESI-MS m / z 323 [M + H] +.

[00326] Step 2: Preparation of isopropyl 6-methyl-5- (1-morphinolinylvinyl) -2- (pyridin-3-yl) indolizine-7-carboxylate: ESI-MS m / z 406 [M + H] + .

[00327] Step 3: Preparation of isopropyl 6-methyl-5- (1-morphinolinylethyl) -2- (pyridin-3-yl) indolizine-7-carboxylate: the yield of the two steps was 83%. ESI-MS m / z 408 [M + H] +.

[00328] Step 4: Preparation of 6-methyl-5- (1-morphinolinylethyl) -2- (pyridin-3-yl) indolizine-7-carboxylic acid: ESI-MS m / z 366 [M + H] +.

[00329] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morphinolinylethyl) - 2 - (pyridin-3-yl) indolizine-7-carboxamide: the yield of the two stages was 20%. 1H NMR (400 MHz, CDCl3) δ (ppm) 11.48 (brs, 1 H), 8.95 (s, 1 H), 8.79 (brs, 1 H), 8.44 (d, J = 2.8 Hz, 1 H), 8.20 (s, 1H), 8.08 (d, J = 2.8 Hz, 1 H), 7.43 (d, J = 2.8 Hz, 1 H), 7.30 (s, 1 H), 6.92 (s, 1 H), 5.87 (s, 1 H), 4.26 (d, J = 6.4 Hz, 2 H), 4.06 (q, J = 6.8 Hz, 1 H), 3.59 (brs, 4 H), 2.66 (brs, 2 H), 2.26 (s, 3 H), 2.20 - 2.16 (m, 5 H), 2.11 (s, 3 H), 1.47 (d, J = 6.8 Hz, 1 H); ESI-MS m / z 500 [M + H] +.

[00330] Example 34: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morphinolinylethyl) - 2 - (pyridin-4-yl) indolizine-7-carboxamide:

[00331] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 2- (pyridin-4 -yl) indolizine-7-carboxamide was prepared by a method similar to that of Example 31.

[00332] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2- (pyridin-4-yl) indolizine-7-carboxylate: Yield 34%. ESI-MS m / z 323 [M + H] +.

[00333] Step 2: Preparation of isopropyl 6-methyl-5- (1-morphinolinylvinyl) -2- (pyridin-4-yl) indolizine-7-carboxylate. ESI-MS m / z 406 [M + H] +.

[00334] Step 3: Preparation of isopropyl 6-methyl-5- (1-morphinolinylethyl) -2- (pyridin-4-yl) indolizine-7-carboxylate: the yield of the two steps was 82%. ESI-MS m / z 408 [M + H] +.

[00335] Step 4: Preparation of 6-methyl-5- (1-morphinolinylethyl) -2- (pyridin-4-yl) indolizine-7-carboxylic acid. ESI-MS m / z 366 [M + H] +.

[00336] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-4-yl) methyl) -6-methyl-5- (1-morphinolinylethyl) - 2 - (pyridin-3-yl) indolizine-7-carboxamide: the yield of the two stages was 20%. 1H NMR (400 MHz, CDCl3) δ ppm 8.87 (brs, 1 H), 8.54 (d, J = 7.8 Hz, 2 H), 8.22 (s, 1 H), 7, 67 (d, J = 7.8 Hz, 2 H), 7.30 (s, 1 H), 6.98 (s, 1 H), 5.87 (s, 1 H), 4.26 (d , J = 6.4 Hz, 2 H), 4.06 (q, J = 6.8 Hz, 1 H), 3.59 (brs, 4 H), 2.66 - 2.62 (m, 2 H), 2.26 (s, 3 H), 2.20 - 2.17 (m, 5 H), 2.16 (s, 3 H), 1.46 (d, J = 6.8 Hz, 1 H); ESI-MS m / z 500 [M + H] +.

[00337] Example 35: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinylethyl) -2 -phenylindolizine-7-carboxamide:

[00338] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinylethyl) -2-phenylindolizine-7- carboxamide was prepared using a method similar to that of Example 31.

[00339] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2-phenylindolizine-7-carboxylate: Yield 40%. ESI-MS m / z 322 [M + H] +.

[00340] Step 2: Preparation of isopropyl 6-methyl-5- (1-morphinolinylvinyl) -2-phenylindolizine-7-carboxylate. ESI-MS m / z 405 [M + H] +.

[00341] Step 3: Preparation of isopropyl 6-methyl-5- (1-morphinolinylethyl) -2-phenylindolizine-7-carboxylate: the yield of the two steps was 42%. ESI-MS m / z 407 [M + H] +.

[00342] Step 4: Preparation of 6-methyl-5- (1-morphinolinylethyl) -2-phenylindolizine-7-carboxylic acid. ESI-MS m / z 365 [M + H] +.

[00343] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morphinolinylethyl) -2 -phenylindolizine-7-carboxamide: the yield of the two stages was 39%. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.47 (s, 1 H), 8.71 (brs, 1 H), 8.18 (s, 1 H), 7.69 (d, J = 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) , 5.87 (s, 1 H), 4.26 (d, J = 6.4 Hz, 2 H), 4.05 (q, J = 6.8 Hz, 1 H), 3.56 (brs , 4 H), 2.66 - 2.61 (m, 2 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, J = 6.8 Hz, 1 H); ESI-MS m / z 499 [M + H] +.

[00344] Example 36: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morphinolinylethyl) - 2 - (3-morphinolinylphenyl) indolizine-7-carboxamide:

[00345] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 2- (3-morfinolinylphenyl) ) indolizine-7-carboxamide was prepared by a method similar to that of Example 31.

[00346] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2- (3-morphinolinylphenyl) indolizine-7-carboxylate: Yield 56%. ESI-MS m / z 407 [M + H] +.

[00347] Step 2: Preparation of isopropyl 6-methyl-5- (1-morphinolinylvinyl) -2- (3-morphinolinylphenyl) indolizine-7-carboxylate. ESI-MS m / z 490 [M + H] +.

[00348] Step 3: Preparation of isopropyl 6-methyl-5- (1-morphinolinylethyl) -2- (3-morphinolinylphenyl) indolizine-7-carboxylate: the yield of the two steps was 83%. ESI-MS m / z 492 [M + H] +.

[00349] Step 4: Preparation of 6-methyl-5- (1-morphinolinylethyl) -2- (3-morphinolinylphenyl) -7-carboxylic acid. ESI-MS m / z 450 [M + H] +.

[00350] Step 5: Preparation of N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 2- (3-morphinolinylphenyl) indolizine-7-carboxamide: the yield of the two stages was 39%. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.50 (s, 1 H), 8.61 (brs, 1 H), 8.21 (s, 1 H), 7.38 - 7.26 (m, 2 H), 6.88 - 6.85 (m, 2 H), 5.89 (s, 1 H), 4.33 (s, 2 H), 4.05 (q, J = 6 , 8 Hz, 1 H), 3.89 - 3.83 (m, 8 H), 3.25 - 3.18 (m, 4 H), 2.46 (s, 3 H), 2.45 - 2.20 (m, 4 H), 2.26 (s, 3 H), 2.20 (s, 3 H), 2.11 (s, 3 H), 1.38 (d, J = 6, 8 Hz, 3 H); ESI-MS m / z 584 [M + H] +.

[00351] Example 37: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinylethyl) -2 - (3,4,5-trimethoxyphenyl) indolizine-7-carboxamide:

[00352] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinylethyl) -2- (3,4 , 5-trimethoxyphenyl) indolizine-7-carboxamide was prepared by a method similar to that of Example 31.

[00353] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2- (3,4,5-trimethoxyphenyl) indolizine-7-carboxylate: Yield 47%. ESI-MS m / z 412 [M + H] +.

[00354] Step 2: Preparation of isopropyl 6-methyl-5- (1-morphinolinylvinyl) -2- (3,4,5-trimethoxyphenyl) indolizine-7-carboxylate. ESI-MS m / z 495 [M + H] +.

[00355] Step 3: Preparation of isopropyl 6-methyl-5- (1-morphinolinylethyl) -2- (3,4,5-trimethoxyphenyl) indolizine-7-carboxylate: the yield of the two steps was 81%. ESI-MS m / z 497 [M + H] +.

[00356] Step 4: Preparation of 6-methyl-5- (1-morphinolinylethyl) -2- (3,4,5-trimethoxyphenyl) indolizine-7-carboxylic acid.
ESI-MS m / z 455 [M + H] +

[00357] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 2- (3,4,5-trimethoxyphenyl) indolizine-7-carboxamide: the yield of the two stages was 69%. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (brs, 1 H), 8.68 (brs, 1 H), 8.18 (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 (q, J = 6.8 Hz, 1 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 (s, 3 H), 2.21 (s, 5 H), 2.12 (s, 3 H), 1.47 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 589 [M + H] +.

[00358] Example 38: Preparation of 2- (2,4-dimethoxyphenyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-m ethyl-5- (1-morphinolinylethyl) indolizine-7-carboxamide:

[00359] 2- (2,4-dimethoxyphenyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyrin-3-yl) methyl) -6-methyl-5- ( 1-morpholinylethyl) indolizine-7-carboxamide was prepared by a method similar to that of Example 31.

[00360] Step 1: Preparation of ethyl 5-acetyl -2- (2,4-dimethoxyphenyl) -6-methylindolizine-7-carboxylate: Yield 47%. ESI-MS m / z 382 [M + H] +.

[00361] Step 2: Preparation of isopropyl 2- (2,4-dimethoxyphenyl) -6-methyl-5- (1-morphinolinylvinyl) indolizine-7-carboxylate. ESI-MS m / z 465 [M + H] +.

[00362] Step 3: Preparation of 2- (2,4-dimethoxyphenyl) -6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxylate isopropyl: the yield of the two steps was 65%. ESI-MS m / z 467 [M + H] +.

[00363] Step 4: Preparation of 2- (2,4-dimethoxyphenyl) -6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxylic acid.
ESI-MS m / z 425 [M + H] +.

[00364] Step 5: Preparation of 2- (2,4-dimethoxyphenyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-m ethyl-5- (1-morphinolinylethyl) indolizine-7-carboxamide: the yield of the two stages was 18%. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.46 (s, 1 H), 8.81 (s, 1 H), 8.12 (s, 1 H), 7.57 - 7.55 (m, 1 H), 7.25 (s, 1 H), 6.77 (s, 1 H), 6.64-6.59 (m, 2 H), 5.86 (s, 1 H) , 4.26 (s, 2 H), 4.03 (q, J = 6.8 Hz, 1 H), 3.90 (s, 3 H), 3.79 (s, 3 H), 3, 60 (brs, 4 H), 2.64 - 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 H), 1.43 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 559 [M + H] +.

[00365] Example 39: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morphinolinylethyl) - 2- (4- (morfinolinylmethyl) phenyl) indolizine-7-carboxamide:

[00366] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinolinylethyl) -2- (4 - 4- (morphinolinylmethyl) phenyl) indolizine-7-carboxamide was prepared by a method similar to that of Example 31.

[00367] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2- (4- (morphinolinylmethyl) phenyl) indolizine-7-carboxylate: Yield 62%. ESI-MS m / z 421 [M + H] +.

[00368] Step 2: Preparation of isopropyl 6-methyl-2- (4- (morphinolinylmethyl) phenyl) -5- (1-morfinolinylvinyl) indolizine-7-carboxyl act. ESI-MS m / z 504 [M + H] +.

[00369] Step 3: Preparation of 6-methyl-5- (1-morphinolinylethyl) -2- (4- (morphinolinylmethyl) phenyl) indolizine-7-carboxyl isopropyl act: the yield of the two steps was 41%. ESI-MS m / z 506 [M + H] +.

[00370] Step 4: Preparation of 6-methyl-5- (1-morphinolinylethyl) -2- (4- (morfinolinylmethyl) phenyl) indolizine-7-carboxylic acid. ESI-MS m / z 464 [M + H] +.

[00371] Step 5: Preparation of N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 2- (4- (morphinolinylmethyl) phenyl) indolizine-7-carboxamide: the yield of the two stages was 43%. 1H NMR (MeOD, 400 MHz) δ ppm 7.84 (d, J = 7.6 Hz, 2 H), 7.53 (d, J = 7.6 Hz, 2 H), 7.49 - 7 , 45 (m, 2 H), 6.14 (s, 2 H), 4.47 (s, 2 H), 4.44 (s, 2 H), 4.06 - 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 H), 3.23 - 3 , 21 (m, 2 H), 2.38 - 2.34 (m, 8 H), 2.27 (s, 6 H), 1.80 (brs, 3 H); ESI-MS m / z 598 [M + H] +.

[00372] Example 40: Preparation of 7-cyano-5- (7 - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) carbamoyl) -6-methyl Tert-butyl -5- (1-morpholineylethyl) indolizin-2-yl) indoline-1-carbamate:

[00373] 7-cyano-5- (7 - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) carbam oil) -6-methyl-5- (1 tert-butyl -morpholylethyl) indolizin-2-yl) indoline-1-carbamate was prepared by a method similar to that of Example 31.

[00374] Step 1: Preparation of tert-butyl 5- (5-acetyl-7- (ethoxycarbonyl) -6-methylindolizin-2-yl) -7-cyanoindoline-1-carbamate: 66% yield. ESI-MS m / z 488 [M + H] +.

[00375] Step 2: Preparation of tert-butyl 7-cyano-5- (7- (isopropoxycarbonyl) -6-methyl-5- (1-morphinolinylvinyl) indolizin-2-yl) i ndoline-1-carboxylate: ESI -MS m / z 571 [M + H] +.

[00376] Step 3: Preparation of tert-butyl 7-cyano-5- (7- (isopropoxycarbonyl) -6-methyl-5- (1-morphinolinylethyl) indolizin-2-yl) in dolina-1-carboxylate: o yield of the two stages was 30%. ESI-MS m / z 573 [M + H] +.

[00377] Step 4: Preparation of 2- (1- (tert-butoxycarbonyl) -7-cyanoporphyrin-5-yl) -6-methyl-5- (1-morphinolinylethyl) ind olizine-7-carboxylic acid. ESI-MS m / z 531 [M + H] +.

[00378] Step 5: Preparation of 7-cyano-5- (7 - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) carbamoyl) -6 -m ethyl-5- (1-morpholineylethyl) indolizin-2-yl) indoline-1-carbamate: the yield of the two stages was 35%. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (s, 1 H), 8.61 (s, 1 H), 8.20 (s, 1 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 = 6.4 Hz, 2 H), 4.09 - 4.05 (m, 3 H), 3.15 - 3.11 (m, 4 H), 2.29 (brs, 2 H), 2.21 (s, 6 H), 2, 12 (s, 3 H), 1.54 (s, 9 H), 1.24 (brs, 3 H); ESI-MS m / z 665 [M + H] +.

[00379] Example 41: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl1H-pyrazole- 5-yl) -5- (1-morpholineylethyl) indolizine-7-carboxamide:

[00380] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl-1H-pyrazol-5-yl ) -5- (1-morpholineylethyl) indolizine-7-carboxamide was prepared by a method similar to that of Example 31.

[00381] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2- (1-methyl-1H-pyrazol-5-yl) indolizine-7-carboxylate: Yield 55%. ESI-MS m / z 326 [M + H] +.

[00382] Step 2: Preparation of isopropyl 6-methyl-2- (1-methyl-1H-pyrazol-5-yl) -5- (1-morphinolinylvinyl) indolizine-7-carboxylate: ESI-MS m / z 409 [M + H] +.

[00383] Step 3: Preparation of isopropyl 6-methyl-2- (1-methyl-1H-pyrazol-5-yl) -5- (1-morphinolinylethyl) indolizine-7-carboxylate: the yield of the two steps was 54%. ESI-MS m / z 411 [M + H] +.

[00384] Step 4: Preparation of 6-methyl-2- (1-methyl-1H-pyrazol-5-yl) -5- (1-morphinolinylethyl) indolizine-7-carboxylic acid: ESI-MS m / z 369 [M + H] +.

[00385] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl-1H- pyrazol-5-yl) -5- (1-morphinolinylethyl) indolizine-7-carboxamide: The yield of the two stages was 32%. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (s, 1 H), 8.65 (s, 1 H), 8.21 (s, 1 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 H), 4.45 (brs, 2 H), 3.84 (brs, 2 H), 3.72 (s, 3 H), 3.48 (brs, 4 H), 2.84 (s, 3 H), 2.38 (s, 3 H), 2.31 (s, 3 H), 1.55 (s, 3 H); ESI-MS m / z 503 [M + H] +.

[00386] Example 42: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl1H-pyrazole- 4-yl) -5- (1-morpholinylethyl) indolizine-7-carboxamide:

[00387] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl-1H-pyrazol-4-yl ) -5- (1-morpholineylethyl) indolizine-7-carboxamide was prepared by a method similar to that of Example 31.

[00388] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2- (1-methyl-1H-pyrazol-4-yl) indolizine-7-carboxylate: Yield 74%. ESI-MS m / z 326 [M + H] +.

[00389] Step 2: Preparation of isopropyl 6-methyl-2- (1-methyl-1H-pyrazol-4-yl) -5- (1-morphinolinylvinyl) indolizine-7-carboxylate: ESI-MS m / z 409 [M + H] +.

[00390] Step 3: Preparation of isopropyl 6-methyl-2- (1-methyl-1H-pyrazol-4-yl) -5- (1-morphinolinylethyl) indolizine-7-carboxylate: the yield of the two steps was 30%. ESI-MS m / z 411 [M + H] +.

[00391] Step 4: Preparation of 6-methyl-2- (1-methyl-1H-pyrazol-4-yl) -5- (1-morphinolinylethyl) indolizine-7-carboxylic acid: ESI-MS m / z 369 [M + H] +.

[00392] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl-1H- pyrazol-4-yl) -5- (1-morphinolinylethyl) indolizine-7-carboxamide: Yield 11%. 1H NMR (400 MHz, MeOD) δ ppm 7.83 (s, 1 H), 7.69 (s, 1 H), 7.31 (s, 1 H), 6.61 (s, 1 H) , 6.11 (s, 1 H), 6.46 (s, 1 H), 4.57 (s, 2 H), 4.45 (brs, 2 H), 4.07 (q, J = 6 , 8 Hz, 1 H), 3.68 (brs, 4 H), 2.70 - 2.67 (m, 2 H), 2.37 (s, 3 H), 2.30 (s, 2 H ), 2.24 - 2.19 (m, 6 H), 1.52 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 503 [M + H] +.

[00393] Example 43: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -2- (2-fluoro-4-methoxyphenyl) - 6 -methyl-5- (1-morphinolinylethyl) indolizine-7-carboxamide:

[00394] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -2- (2-fluoro-4-methoxyphenyl) -6-methyl-5 - (1-morphinolinylethyl) indolizine-7-carboxamide was prepared by a method similar to that of Example 31.

[00395] Step 1: Preparation of ethyl 5-acetyl-2- (2-fluoro-4-dimethoxyphenyl) -6-methylindolizine-7-carboxylate: Yield 70%. ESI-MS m / z 370 [M + H] +.

[00396] Step 2: Preparation of isopropyl 2- (2-fluoro-4-methoxyphenyl) -6-methyl-5- (1-morphinolinylvinyl) indolizine-7-carboxylate: ESI-MS m / z 453 [M + H] +.

[00397] Step 3: Preparation of 2- (2-fluoro-4-methoxyphenyl) -6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxylate isopropyl: the yield of the two steps was 72%. ESI-MS m / z 455 [M + H] +.

[00398] Step 4: Preparation of 2- (2-fluoro-4-methoxyphenyl) -6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxylic acid: ESI-MS m / z 413 [M] +.

[00399] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -2- (2-fluoro-4-methoxyphenyl) - 6 -methyl-5- (1-morphinolinylethyl) indolizine-7-carboxamide: The yield of the two stages was 28%. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (s, 1 H), 8.26 (s, 1 H), 8.23 (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 (m, 2 H), 6.87 (s, 1 H) , 5.93 (s, 1 H), 4.32 (d, J = 6.4 Hz, 1 H), 4.11 (q, J = 6.8 Hz, 1 H), 3.86 (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), 2 , 28 - 2.18 (m, 2 H), 2.17 (s, 3 H), 1.49 (d, J = 6.8 Hz, 1 H); ESI-MS m / z 547 [M + H] +.

[00400] Example 44: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morphinolinylethyl) - 2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) indolizine-7-carboxamide:

[00401] Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morphinolinylethyl) -2- ( 1- (piperidin-4-yl) -1H-pyrazol-4-yl) indolizine-7-carboxamide: The first five steps were similar to those in Example 31.

[00402] Step 1: Preparation of 5-acetyl-2- (1- (1- (tert-butyloxycarbonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -6-methylin dolizine-7-carboxylate ethyl: Yield 87%. ESI-MS m / z 495 [M + H] +.

[00403] Step 1: Preparation of 2- (1- (1- (tert-Butoxycarbonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -6-methyl-5- (1-morpholinolinylvinyl) indolizine -7-isopropyl carboxylate: Yield 87%.

[00404] Step 3: Preparation of 2- (1- (1- (tert-butoxycarbonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -6-methyl-5- (1-morphin olinylethyl) indolizine -7-isopropyl carboxylate: the yield of the two stages was 12%. ESI-MS m / z 580 [M + H] +.

[00405] Step 4: Preparation of 2- (1- (1- (tert-butoxycarbonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -6-methyl-5- (1-morphin olinylethyl) acid indolizine-7-carboxylic: ESI-MS m / z 451 [M + H] +.

[00406] Step 5: Preparation of 4- (4- (7 - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) carbamoyl) -6-methyl-5 - (1-Morphinolinylethyl) indolizin-2-yl) -1H-pyrazol-1-yl) tert-butyl piperidine-1-carbamate: the yield of the two stages was 37%. ESI-MS m / z 672 [M + H] +.

[00407] Step 6: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinylethyl) -2 - (1- (piperidin-4-yl) -1H-pyrazol-4-yl) indolizine-7-carboxamide: Compound 4- (4- (7 - ((4,6-dimethyl-2-oxo-1, Tert-Butyl 2-dihydropyridin-3-yl) methyl) carbamoyl) -6-methyl-5- (1-morpholinylethyl) indolizin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carbamate (50 mg, 0.074 mmol) was dissolved in 5.0 mL of ethyl acetate and ethyl acetate / hydrochloric acid (5 mL, 3 M) was added and stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH = 7, with sodium hydrogen carbonate solution, and purified by reverse phase HPLC. The solvent evaporated under reduced pressure and white crystals were obtained by freeze drying (17 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (s, 1 H), 8.48 (s, 1 H), 8.14 (s, 1 H), 8.04 (s, 1 H), 7.71 (s, 1 H), 7.22 (s, 1 H), 6.60 (s, 1 H), 5.87 (s, 1 H), 4.26 - 4.24 (m, 2 H), 4.02 (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 H), 2.25 (s, 3 H), 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), 1.44 - 1.43 (m, 3 H); ESI-MS m / z 572 [M + H] +.

[00408] Example 45: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 2- (1,2,3,6-tetrahydropyridin-4-yl) indolizine-7-carboxamide:

[00409] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morphinolinylethyl) - 2- (1,2 , 3,6-tetrahydropyridin-4-yl) indolizine-7-carboxamide was prepared by a method similar to that of Example 44.

[00410] Step 1: Preparation of ethyl 5-acetyl-2- (1- (tert-butyloxycarbonyl) -1,2,3,6-tetrahydropyridin-4-yl) -6-methylindolizine-7-carboxylate: Yield 65%. ESI-MS m / z 427 [M + H] +.

[00411] Step 2: Preparation of 2- (1- (1- (tert-Butoxycarbonyl) -1,2,3,6-tetrahydropyridin-4-yl) -6-methyl-5- (1-morphin olinylvinyl) indolizine -7-isopropyl carboxylate: ESI-MS m / z 510 [M + H] +.

[00412] Step 3: Preparation of 2- (1- (tert-butoxycarbonyl) -1,2,3,6-tetrahydropyridin-4-yl) -6-methyl-5- (1-morfinolini letil) indolizine-7- isopropyl carboxylate: the yield of the two stages was 54%. ESI-MS m / z 512 [M + H] +.

[00413] Step 4: Preparation of 2- (1- (tert-butoxycarbonyl) -1,2,3,6-tetrahydropyridin-4-yl) -6-methyl-5- (1-morfinolini letil) indolizine-7 acid -carboxylic: ESI-MS m / z 470 [M + H] +.

[00414] Step 5: Preparation of 4- (7 - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) carbamoyl) -6-methyl-5- (1 - morpholinylethyl) indolizin-2-yl) -3,6-dihydropyridine-1 (2H)-tert-butylcarboxylate: the yield of the two stages was 33%. ESI-MS m / z 604 [M + H] +.

[00415] Step 6: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 2- (1,2,3,6-tetrahydropyridin-4-yl) indolizine-7-carboxamide: 40% yield. 1H NMR (400 MHz, MeOD) δ ppm 7.36 (s, 1 H), 6.68 (s, 1 H), 6.19 (s, 1 H), 6.12 (s, 1 H) , 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) , 2.38 (s, 3 H), 2.31 (s, 3 H), 2.25 (s, 5 H), 1.55 (s, 3 H); ESI-MS m / z 504 [M + H] +.

[00416] Example 46: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 2- (piperidin-4-yl) indolizine-7-carboxamide:

[00417] Step 1: Preparation of 2- (1- (tert-butoxycarbonyl) piperidin-4-yl) -6-methyl-5- (1-morphinolinylethyl) indolizine -7-isopropyl carboxylate: 2- (1- ( isopropyl tert-butyloxycarbonyl) -1,2,3,6-tetrahydropyridin-4-yl) -6-methyl-5- (1-morphinolinethyl) indolizine-7-carboxylate (95 mg, 0.186 mmol), Pd / C (10 mg) and 10 ml of methanol were added, in sequence, to a single neck flask, of 25 ml, exchanged for hydrogen and stirred at room temperature for 2 hours, and filtered. The organic phase was concentrated to provide a product such as yellow oil (90 mg, yield: 95%). ESI-MS m / z 514 [M + H] +.

[00418] Step 2: Preparation of 2- (1- (tert-butoxycarbonyl) piperidin-4-yl) -6-methyl-5- (1-morphinolinylethyl) indolizine -7-carboxylic acid: 2- (1- ( tert-butoxycarbonyl) piperidin-4-yl) -6-methyl-5- (1-morphinolinylethyl) indolizine -7-carboxylic acid was prepared using a method similar to that of Step 5, Example 1. ESI-MS m / z 472 [M + H] +.

[00419] Step 3: Preparation of 4- (7 - ((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) carbamoyl) -6-methyl-5- (1 -morpholinethyl) indolizin-2-yl) tert-butyl piperidine-1-carboxylate: 4- (7 - ((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) carbamoyl) -6-methyl-5- (1-morpholinylethyl) indolizin-2-yl) tert-butyl piperidine-1-carboxylate was prepared using a method similar to that of Step 6 of Example 1, the yield of the two steps was 32%. ESI-MS m / z 606 [M + H] +.

[00420] Step 4: Preparation of N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 2- (piperidin-4-yl) indolizine-7-carboxamide: N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morphinolinylethyl) - 2- (piperidin-4-yl) indolizine-7-carboxamide was prepared by a method similar to that of Step 6, of Example 1, yield of 47%. 1H NMR (400 MHz, MeOD) δ ppm 7.36 (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 - 3.49 (m, 3 H), 3.23 - 3.16 (m, 7 H), 2.38 (s, 3 H), 2 , 31 (s, 5 H), 2.33 (s, 3 H), 2.25 (s, 6 H), 1.94 - 1.85 (m, 3 H); ESI-MS m / z 506 [M + H] +.

[00421] Example 47: Preparation of 2- (3,6-dihydro-2H-pyran-4-yl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridine- 3-yl) - 6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxamide:

[00422] 2- (3,6-dihydro-2H-pyran-4-yl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) -6- methyl-5- (1-morphinolinylethyl) indolizine-7-carboxamide was prepared by a method similar to that of Example 31.

[00423] Step 1: Preparation of ethyl 5-acetyl-2- (3,6-dihydro-2H-pyran-4-yl) -6-methylindolizine-7-carboxylate: Yield 62%. ESI-MS m / z 328 [M + H] +.

[00424] Step 2: Preparation of isopropyl 2- (3,6-dihydro-2H-pyran-4-yl) -6-methyl-5- (1-morphinolinylvinyl) indolizine-7-carboxylate: ESI- MS m / z 411 [M + H] +.

[00425] Step 3: Preparation of isopropyl 2- (3,6-dihydro-2H-pyran-4-yl) -6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxylate: the yield of the two stages was 41%. ESI-MS m / z 413 [M + H] +.

[00426] Step 4: Preparation of 2- (3,6-dihydro-2H-pyran-4-yl) -6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxylic acid: ESI-MS m / z 371 [M + H] +.

[00427] Step 5: Preparation of 2- (3,6-dihydro-2H-pyran-4-yl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin- 3-yl) methyl) -6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxamide: the yield of the two steps was 43%. 1H NMR (400 MHz, MeOD) δ ppm 7.46 (s, 1 H), 6.21 (s, 1 H), 6.15 (s, 1 H), 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 (m, 8 H), 2 , 38 - 2.35 (m, 6 H), 1.80 (s, 3 H); ESI-MS m / z 505 [M + H] +.

[00428] Example 48: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morphinolinylethyl) - 2- (tetrahydro-2H-pyran-4-yl) indolizine-7-carboxamide:

[00429] Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morphinolinylethyl) -2- ( tetrahydro-2H-pyran-4-yl) indolizine-7-carboxamide was similar to that of the first three steps of Example 46.

[00430] Step 1: Preparation of isopropyl 6-methyl-5- (1-morphinolinylethyl) -2- (tetrahydro-2H-pyran-4-yl) indolizine-7-carboxylate: 94% yield. ESI-MS m / z 415 [M + H] +.

[00431] Step 2: Preparation of 6-methyl-5- (1-morphinolinylethyl) -2- (tetrahydro-2H-pyran-4-yl) indolizine-7-carboxylic acid: ESI-MS m / z 373 [M + H] +.

[00432] Step 3: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 2- (tetrahydro-2H-pyran-4-yl) indolizine-7-carboxamide: the yield of the two stages was 65%. 1H NMR (400 MHz, MeOD) δ ppm 7.42 (s, 1 H), 6.15 (s, 1 H), 4.46 (s, 2 H), 4.01 (d, J = 4 , 8 Hz, 2 H), 3.87 - 3.82 (m, 4 H), 3.57 (t, J = 11.6 Hz, 2 H), 3.20 - 3.01 (m, 2 H), 3.00 - 2.92 (m, 1 H), 2.38 - 2.33 (m, 6 H), 2.25 (s, 3 H), 1.94 - 1.90 (m , 2 H), 1.81 - 1.75 (m, 5 H); ESI-MS m / z 507 [M + H] +.

[00433] Example 49: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamino) pip eridin -1-yl) ethyl) -6-methyl-2- (pyridin-3-yl) indolizine-7-carboxamide:

[00434] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl ) -6-methyl-2- (pyridin-3-yl) indolizine-7-carboxamide was prepared by a method similar to that of Example 31.

[00435] Step 1: Preparation of isopropyl 5- (1- (4- (dimethylamino) piperidin-1-yl) vinyl) -6-methyl-2- (pyridin-3-yl) indolizine-7-c arboxylate: ESI-MS m / z 447 [M + H] +

[00436] Step 2: Preparation of isopropyl 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -6-methyl-2- (pyridin-3-yl) indolizine-7-carboxylate: the yield of the two stages was 52%. ESI-MS m / z 449 [M + H] +.

[00437] Step 3: Preparation of 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -6-methyl-2- (pyridin-3-yl) indolizine-7-carboxylic acid: ESI -MS m / z 407 [M + H] +.

[00438] Step 4: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamino) pip eridin -1-yl) ethyl) -6-methyl-2- (pyridin-3-yl) indolizine-7-carboxamide: The yield of the two stages was 27%. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.46 (brs, 1 H), 9.60 (brs, 1 H), 9.17 (s, 1 H), 8.74 (brs, 1 H), 8.65 (s, 1 H), 8.55 (brs, 1 H), 8.27 (brs, 1 H), 7.78 (brs, 1 H), 7.38 (s, 1 H), 7.08 (s, 1 H), 5.89 (s, 1 H), 4.04 (s, 2 H), 3.69 - 3.57 (m, 2 H), 3.17 (s, 1 H), 2.74 (s, 6H), 2.38 (s, 3 H), 2.22 (s, 3 H), 2.13 (s, 3 H), 1.89 - 1.81 (m, 4 H), 1.49 (brs, 3 H); ESI-MS m / z 541 [M + H] +.

[00439] Example 50: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 2- (thiazol-2-yl) indolizine-7-carboxamide:

[00440] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indolizine-7-carboxylate: Ethyl 5-acetyl-2-bromo-6-methylindolizine-7-carboxylate (2.0 g, 6.2 mmol), Pd (dppf) Cl2 (454 mg, 0.62 mmol), pinacol borate (3, 15 g, 12.4 mmol) and potassium acetate (1.22 g, 12.4 mmol) were added successively in a dry 50-neck three-neck flask, dissolved in 1,4-dioxane (50 ml) and stirred at 110 ° C overnight. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (100 ml × 3), washed with water (30 ml × 2) and saturated brine (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product. After purification by column chromatography (petroleum ether: ethyl acetate = 10: 1), 5-acetyl-6-methyl-2- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) ethyl indolizine-7-carboxylate (1.60 g, yield: 70%) was provided. ESI-MS m / z 372 [M + H] +.

[00441] Step 2: Preparation of ethyl 5-acetyl-6-methyl-2- (thiazol-2-yl) indolizine-7-carboxylate: the procedure was the same as that of Step 1 of Example 21. Yield of: 32%. ESI-MS m / z 329 [M + H] +.

[00442] Step 3: Preparation of isopropyl 6-methyl-5- (1-morphinolinylvinyl) -2- (thiazol-2-yl) indolizine-7-carboxylate: 6-methyl-5- (1-morfinolinylvinyl) -2 - Isopropyl (thiazol-2-yl) indolizine-7-carboxylate was prepared by a method similar to that of Step 1 of Example 26. ESI-MS m / z 412 [M + H] +.

[00443] Step 4: Preparation of isopropyl 6-methyl-5- (1-morphinolinylethyl) -2- (thiazol-2-yl) indolizine-7-carboxylate: 6-methyl-5- (1-morfinolinylethyl) -2 - Isopropyl (thiazol-2-yl) indolizine-7-carboxylate was prepared by a method similar to that of Step 2 of Example 26, the yield of the two steps was 63%. ESI-MS m / z 414 [M + H] +.

[00444] Step 5: Preparation of 6-methyl-5- (1-morphinolinylethyl) -2- (thiazol-2-yl) indolizine-7-carboxylic acid: 6-Methyl-5- (1-morphinolinylethyl) -2 - (thiazol-2-yl) indolizine-7-carboxylic acid was prepared by a method similar to that of Step 5, Example 1.
ESI-MS m / z 372 [M + H] +.

[00445] Step 6: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 2- (thiazol-2-yl) indolizine-7-carboxamide: N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morphinolinylethyl) - 2- (thiazol-2-yl) indolizine-7-carboxamide was prepared by a method similar to that of Step 6, Example 1, 15% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (brs, 1 H), 8.82 (brs, 1 H), 8.24 (s, 1 H), 7.83 (s, 1 H), 7.66 (s, 1 H), 7.36 (s, 1 H), 6.91 (s, 1 H), 5.87 (s, 1 H), 4.27 (s, 2 H), 4.14 - 4.12 (m, 1 H), 3.60 - 3.57 (m, 4 H), 2.67 - 2.62 (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); ESI-MS m / z 506 [M + H] +.

[00446] Example 51: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 2- (pyridin-2-yl) indolizine-7-carboxamide:

[00447] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 2- (pyridin-2 -yl) indolizine-7-carboxamide was prepared by a method similar to that of Example 50.

[00448] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2- (pyridin-2-yl) indolizine-7-carboxylate: Yield 37%. ESI-MS m / z 323 [M + H] +.

[00449] Step 2: Preparation of isopropyl 6-methyl-5- (1-morphinolinylvinyl) -2- (pyridin-2-yl) indolizine-7-carboxylate: ESI-MS m / z 406 [M + H] + .

[00450] Step 3: Preparation of isopropyl 6-methyl-5- (1-morphinolinylethyl) -2- (pyridin-2-yl) indolizine-7-carboxylate: the yield of the two steps was 40%. ESI-MS m / z 408 [M + H] +.

[00451] Step 4: Preparation of 6-methyl-5- (1-morphinolinylethyl) -2- (pyridin-2-yl) indolizine-7-carboxylate: ESI-MS m / z 366 [M + H] +.

[00452] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 2- (pyridin-2-yl) indolizine-7-carboxamide: 28% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.87 (brs, 1 H), 8.57 (d, J = 4.8 Hz, 1 H), 8.21 (t, J = 4, 8 Hz, 1 H), 7.79 - 7.78 (m, 2 H), 7.30 (s, 1 H), 7.21 (dd, J = 7.8, 7.4 Hz, 1 H ), 7.01 (s, 1 H), 5.87 (s, 1 H), 4.27 (d, J = 6.4 Hz, 2 H), 4.06 (q, J = 6.8 Hz, 1 H), 3.58 (brs, 4 H), 2.67 - 2.64 (m, 2 H), 2.42 (s, 3 H), 2.32 - 2.20 (m, 5 H), 2.16 (s, 3 H), 1.46 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 500 [M + H] +.

[00453] Example 52: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl1H-imidazole- 4-yl) -5- (1-morpholineylethyl) indolizine-7-carboxamide:

[00454] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl-1H-imidazol-4-yl ) -5- (1-morpholineylethyl) indolizine-7-carboxamide was prepared by a similar method in Example 50.

[00455] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2- (1-methyl-1H-imidazol-4-yl) indolizine-7-carboxylate: Yield 53%. ESI-MS m / z 326 [M + H] +.

[00456] Step 2: Preparation of 6-methyl-2- (1-methyl-1H-imidazol-4-yl) -5- (1-morphinolinylvinyl) indolizine-7-carboxyl isopropyl act: ESI-MS m / z 409 [M + H] +.

[00457] Step 3: Preparation of isopropyl 6-methyl-2- (1-methyl-1H-imidazol-4-yl) -5- (1-morpholinylethyl) indolizine-7-carboxylate: the yield of the two steps was 63%. ESI-MS m / z 411 [M + H] +.

[00458] Step 4: Preparation of 6-methyl-2- (1-methyl-1H-imidazol-4-yl) -5- (1-morphinolinylethyl) indolizine-7-carboxylic acid: ESI-MS m / z 369 [M + H] +.

[00459] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl-1H- imid azol-4-yl) -5- (1-morphinolinylethyl) indolizine-7-carboxamide: Yield 5%. 1H NMR (400 MHz, MeOD) δ ppm 8.87 (s, 1 H), 7.80 (s, 1 H), 7.47 (s, 1 H), 6.66 (s, 1 H) , 6.16 (s, 1 H), 4.48 (s, 2 H), 3.97 (s, 3 H), 3.88 - 3.85 (m, 1 H), 3.75 (brs , 4 H), 3.23 - 3.22 (m, 2 H), 2.39 (s, 3 H), 2.35 (s, 3 H), 2.28 - 2.26 (m, 5 H), 1.64 - 1.62 (m, 3 H); ESI-MS m / z 503 [M + H] +.

[00460] Example 53: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 2- (4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) indolizine-7-carboxamide:

[00461] The first five steps of the N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- morfinolinileti l) - 2- (4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) indolizine-7-carboxamide are similar to those in Example 50, and the last deprotection step is the same than that in Step 6 of Example 44.

[00462] Step 1: Preparation of 2- (5-acetyl-7- (ethoxycarbonyl) -6-methylindolizin-2-yl) -6,7-dihydrothiazolo [5,4-c] pyridine-5 (4H ) tert-butyl carboxylate: Yield 26%. ESI-MS m / z 484 [M + H] +.

[00463] Step 2: Preparation of 2- (7- (isopropoxycarbonyl) -6-methyl-5- (1-morphinolinylvinyl) indolizin-2-yl) -6,7-dihydro-thiazole [5.4-c] tert-butyl pyridine-5 (4H) -carboxylate: ESI-MS m / z 567 [M + H] +.

[00464] Step 3: Preparation of 2- (7- (isopropoxycarbonyl) -6-methyl-5- (1-morphinolinylethyl) indolizin-2-yl) -6,7-dihyd rotiazolo [5,4-c] tert-butyl pyridine-5 (4H) -carboxylate: the yield of the two stages was 44%. ESI-MS m / z 569 [M + H] +.

[00465] Step 4: Preparation of 2- (5- (tert-butoxycarbonyl) -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) -6-methyl-5- ( 1-morpholinethyl) indolizine-7-carboxylic: ESI-MS m / z 527 [M + H] +.

[00466] Step 5: Preparation of 2- (7 - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) carbamoyl) -6-methyl-5- ( 1-morpholinethyl) indolizin-2-yl) -6,7-dihydrothiazolo [5,4-c] pyridine-5 (4H) -carboxylate tert-butyl: the yield of the two stages was 49%. ESI-MS m / z 661 [M + H] +.

[00467] Step 6: Preparation of N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 2- (4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) indolizine-7-carboxamide: 49% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.47 (brs, 1 H), 8.78 (brs, 1 H), 8.21 (t, J = 2.6 Hz, 1 H), 7.32 (s, 1 H), 6.82 (s, 1 H), 5.87 (s, 1 H), 4.27 (t, J = 6.2 Hz, 2 H), 4.06 (q, J = 6.8 Hz, 1 H), 3.94 (m, 2 H), 3.57 (brs, 4 H), 3.09 (t, J = 7.2 Hz, 2 H) , 2.73 (brs, 2 H), 2.66 - 2.64 (m, 2 H), 2.26 (s, 3 H), 2.20 - 2.17 (m, 5 H), 2 , 16 (s, 3 H), 1.46 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 561 [M + H] +.

[00468] Example 54: Preparation of 1-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- mor folinylethyl) indolizine-7-carboxamide:

[00469] Step 1: Preparation of ethyl 5-acetyl-1-bromo-6-methylindolizine-7-carboxylate: in a single 100 ml dry bottle, 5-acetyl-6-methylindolizine-7-carboxylate ethyl (500 mg, 2 mmol) was dissolved in 20 mL of tetrahydrofuran, bromosuccinimide (320 mg, 1.8 mmol) was added to the portion at 0 ° C, and the mixture was stirred at 0 ° C for 20 min. The solvent was evaporated under reduced pressure to dry, to provide a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain 141 mg of yellow oil, yield 26%. 1H NMR (CDCl3, 400 MHz) δ ppm 8.15 (s, 1 H), 7.17 (d, J = 2.8 Hz, 1 H), 6.89 (d, J = 2.8 Hz , 1 H), 4.37 (q, J = 14 Hz, 2 H), 2.63 (s, 3 H), 2.44 (s, 3 H), 1.42 (t, J = 14 Hz , 3 H).

[00470] Step 2: Preparation of isopropyl 1-bromo-6-methyl-5- (1-morphinolinylvinyl) indolizine-7-carboxylate: 1-bromo-6-methyl-5- (1-morfinolinylvinyl) indolizine-7- isopropyl carboxylate was prepared using a method similar to that of Step 1 of Example 26.
ESI-MS m / z 407 [M + H] +.

[00471] Step 3: Preparation of isopropyl 1-bromo-6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxylate: 1-bromo-6-methyl-5- (1-morfinolinylethyl) indolizine-7- isopropyl carboxylate was prepared by a similar method in Step 2 of Example 26, 84% yield. The yield of the two stages was 50%. ESI-MS m / z 323 [M – 87 + H] +.

[00472] Step 4: Preparation of 1-bromo-6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxylic acid: 1-bromo-6-methyl-5- (1-morfinolinylethyl) indolizine-7- acid carboxylic acid was prepared using a method similar to that of Step 3, Example 26. ESI-MS m / z 280 [M – 87 + H] +.

[00473] Step 5: Preparation of 1-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- mor finolinylethyl) indolizine-7-carboxamide:
1-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-mor finolinylethyl) indolizine-7-carboxamide was prepared using a method similar to that of Step 4, Example 26, the yield of the two steps was 25%.

[00474] 1H NMR (400 MHz, CDCl3) δ ppm 11.52 (brs, 1 H), 8.40 (brs, 1 H), 8.34 (s, 1 H), 7.15 (s, 1 H), 6.87 (s, 1 H), 5.88 (s, 1 H), 4.27 (t, J = 6.2 Hz, 2 H), 4.03 (q, J = 6 , 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 H ) 2.17 - 2.11 (m, 5 H), 1.40 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 501 [M + H] +.

[00475] Example 55: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (methyl (tetrahydro2H-pyran- 4-yl) amino) indolizine-7-carboxamide:

[00476] Step 1: Preparation of (E) -2 - ((1H-pyrrol-2-yl) methylene) succinonitrile: pyrrole-2-carbaldehyde (3 g, 31.5 mmol), fumaronitrile (3.1 g, 39.4 mmol), tributylphosphine (5.8 ml, 37.8 mmol) and anhydrous tetrahydrofuran (80 ml) were added successively in a 100 ml round-bottomed dry flask at room temperature, heated to refluxing under nitrogen, and stirring for 8 hours. After monitoring that the reaction was completed by means of TLC, the mixture was concentrated under reduced pressure, 30 ml of water were added, and extracted with ethyl acetate (40 ml × 3), the organic phases were combined. The mixture was washed with saturated brine (30 ml × 1), dried over anhydrous sulfate, filtered, and the filtrate was concentrated under reduced pressure, purified by column chromatography (pure dichloromethane) to provide 1.855 g of yellow solids, 37% yield. 1H NMR (CDCl3, 400 MHz) δ ppm 7.49 (1 H), 7.27 (d, J = 8.9 Hz, 1 H), 7.01 (t, J = 3.9 Hz, 1 H), 6.73 (d, J = 3.9 Hz, 1 H), 5.97 (s, 1 H), 4.26 (s, 2 H).

[00477] Step 2: Preparation of 5-amino-6-methylindolizine-7-carbonitrile: (E) -2 - ((1H-pyrrol-2-yl) methylene) succinonitrile (1.8 g, 11.7 mmol) and THF (60 ml) were added to a dry 100 ml round-bottom flask at room temperature, and LDA (11.7 ml, 23.4 mmol) was added under -78 ° C, stirred at that temperature , for half an hour, then methyl iodide (1.6 g, 11.7 mmol) was added, heated to 0 ° C and stirred for half an hour, then cooled with saturated aqueous ammonium chloride, extracted with acetate ethyl (40 mL × 3), the combined organic phase was dried over sodium sulfate, filtered, and the filtrate was evaporated, and the residue was dissolved in DMF (60 mL), and potassium carbonate (6.4 g, 46.8 mmol) was added, then the reaction was heated to 70 ° C and stirred for 16 hours. After the reaction was completed, 30 mL of water was added and extracted with ethyl acetate (40 mL × 3), the organic phases were combined, washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate , filtered, and the filtrate was concentrated under reduced pressure to obtain yellow solids (1.76 g, 88% yield). 1H NMR (CDCl3, 400 MHz) δ ppm 7.51 (s, 1 H), 7.19 (brs, 1 H), 6.96 (t, J = 2.8 Hz, 1 H), 6, 67 (d, J = 2.8 Hz, 1 H), 4.17 (s, 2 H), 2.36 (s, 3 H).

[00478] Step 3: Preparation of 6-methyl-5 - ((tetrahydro-2H-pyran-4-yl) amino) indolizine-7-carbonitrile: in a 50 ml round-bottom dry flask, 5-amino-6 -methylindolizine-7-carbonitrile (300 mg, 1.75 mmol), tetrahydropyranone (350 mg, 3.50 mmol) and acetic acid (3 mL) were added in succession at room temperature. After heating to 50 ° C and stirring for 1 hour, sodium cyanoborohydride (330 mg, 5.25 mmol) was added and stirred at 50 ° C. After TLC monitored that the reaction was complete, the mixture was neutralized with a saturated aqueous solution of sodium hydrogen carbonate and then extracted with ethyl acetate (20 mL × 3) and washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by means of column chromatography (dichloromethane) to provide yellow solids (140 mg, 31% yield). 1H NMR (CDCl3, 400 MHz) δ ppm 7.63 (s, 1 H), 7.45 (s, 1 H), 6.90 (brs, 1 H), 6.69 (brs, 1 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 ( m, 2 H), 1.65 - 1.63 (m, 3 H).

[00479] Step 4: Preparation of 6-methyl-5- (methyl (tetrahydro-2H-pyran-4-yl) amino) indolizine-7-carbonitrile: in a dry round-bottomed flask of 25 mL, 6-methyl- 5 - ((tetrahydro-2H-pyran-4-yl) amino) indolizine-7-carbonitrile (100 mg, 0.39 mmol), potassium carbonate (108 mg, 0.78 mmol), iodine-methane (111 mg , 0.78 mmol) and DMF (2 ml) were added, subjectively, at room temperature, and replaced with nitrogen three times, stirred and heated to 80oC, for 16 hours. After monitoring that the reaction was completed by means of TLC, 10 ml of saturated brine were added and extracted with ethyl acetate (10 ml × 3), and the organic phases were combined. The mixture was washed with saturated brine (10 ml × 1), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to provide crude product 4 (50 mg, yellow sticky liquid), which can be used directly in the next step, yield: 47%. ESI-MS m / z 270 [M + H] +.

[00480] Step 5: Preparation of 6-methyl-5- (methyl (tetrahydro-2H-pyran-4-yl) amino) indolizine-7-carboxylic acid: in a 25 ml, 6-methyl round-bottom dry flask -5- (methyl (tetrahydro-2H-pyran-4-yl) amino) indolizine-7-carbonitrile (50 mg, 0.18 mmol), sodium hydroxide (400 mg, 10 mmol) and solvent with ethanol / 1: 1 water (1 mL) was added successively at room temperature, heated to 100oC and stirred for 16 hours. Subsequently, TLC monitored that the reaction was completed, the pH was adjusted to 1 by means of 6N hydrochloric acid, and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product (42mg, dark green solid), which can be used directly in the next step, yield 81 %.
ESI-MS m / z 289 [M + H] +.

[00481] Step 6: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (methyl (tetrahydro2H-pyran- 4-yl) amino) indolizine-7-carboxamide: N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (methyl ( tetrahydro2H-pyran-4-yl) amino) indolizine-7-carboxamide was prepared by a method similar to that of Step 6 of Example 1, yield of 6%. 1H NMR (CDCl3, 400 MHz) δ ppm 7.40 (s, 1 H), 7.33 (s, 1 H), 6.74 (s, 1 H), 6.47 (s, 1 H) , 5.94 (s, 1 H), 4.52 - 4.49 (m, 2 H), 3.95 - 3.89 (m, 2 H), 3.39 - 3.35 (m, 2 H), 3.14 - 3.10 (m, 1 H), 2.86 (s, 3 H), 2.39 (s, 3 H), 2.27 (s, 3 H), 2.20 (s, 3 H), 1.77 - 1.54 (m, 4 H); ESI-MS m / z 423 [M + H] +.

[00482] Example 56: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (ethyl (tetrahydro-2 H -pyran-4-yl) amino) indolizine-7-carboxamide:

[00483] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (ethyl (tetrahydro-2H-pyran-4-yl ) amino) indolizine-7-carboxamide was prepared by a method similar to that of Example 55.

[00484] Step 1: Preparation of 5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -6-methylindolizine-7-carbonitrile: Yield 46%. ESI-MS m / z 284 [M + H] +.

[00485] Step 2: Preparation of 5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -6-methylindolizine-7-carboxylic acid: Yield 78%. ESI-MS m / z 303 [M + H] +.

[00486] Step 3: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (ethyl (tetrahydro-2 H -pyran-4-yl) amino) indolizine-7-carboxamide: 8% yield. 1H NMR (CDCl3, 400 MHz) δ ppm 7.35 (s, 1 H), 7.28 (s, 1 H), 6.65 (s, 1 H), 6.39 (s, 1 H) , 5.88 (s, 1 H), 4.45 - 4.44 (m, 2 H), 3.85 - 3.82 (m, 2 H), 3.31 - 3.19 (m, 4 H), 3.14 - 3.11 (m, 1 H), 2.32 (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 H); ESI-MS m / z 437 [M + H] +.

[00487] Example 57: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (methyl ( tetrahydro) -2H-pyran-4-yl) amino) indolizine-7-carboxamide:

[00488] 2-Bromo-N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (methyl (tetrahydro-2H- pyran-4-yl) amino) indolizine-7-carboxamide was prepared by a method similar to that of Example 55.

[00489] Step 1: Preparation of (E) -2 - ((4-bromo-1H-pyrrol-2-yl) methylene) succinonitrile: Yield 41%.
ESI-MS m / z 236 [M + H] +.

[00490] Step 2: Preparation of 5-amino-2-bromo-6-methylindolizine-7-carbonitrile: 94% yield.
ESI-MS m / z 250 [M + H] +.

[00491] Step 3: Preparation of 2-bromo-6-methyl-5 - ((tetrahydro-2H-pyran-4-yl) amino) indolizine-7-carbonitrile: Yield 72%. 1H NMR (CDCl3, 400 MHz) δ ppm 7.54 (s, 1 H), 7.42 (s, 1 H), 6.72 (brs, 1 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 H), 1.65 - 1.63 (m, 2 H).

[00492] Step 4: Preparation of 2-bromo-6-methyl-5- (methyl (tetrahydro-2H-pyran-4-yl) amino) indolizine-7-carbonitrile: 53% yield. ESI-MS m / z 348 [M + H] +.

[00493] Step 5: Preparation of 2-bromo-6-methyl-5- (methyl (tetrahydro-2H-pyran-4-yl) amino) indolizine-7-carboxylic acid: 81% yield. ESI-MS m / z 367 [M + H] +.

[00494] Step 6: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (methyl ( tetrahydro-2H-pyran-4-yl) amino) indolizine-7-carboxamide: 18% yield. 1H NMR (CDCl3, 400 MHz) δ ppm 11.31 (s, 1 H), 7.40 (s, 1 H), 7.23 (s, 1 H), 6.48 (s, 1 H) , 5.96 (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, 3 H), 2.32 (s, 3 H), 2.24 (s, 3 H), 2.17 (s, 3 H), 1.78 - 1.59 (m, 4 H); ESI-MS m / z 501 [M + H] +.

[00495] Example 58: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro2H-piran- 4-yl) amino) -6-methylindolizine-7-carboxamide:

[00496] 2-Bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4- il) amino) -6-methylindolizine-7-carboxamide was prepared by a method similar to that of Example 55.

[00497] Step 1: Preparation of 2-bromo-5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -6-methylindolizine-7-carbonitrile: Yield 46%. ESI-MS m / z 362 [M + H] +.

[00498] Step 2: Preparation of 2-bromo-5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -6-methylindolizine-7-carboxylic acid: Yield 79%. ESI-MS m / z 381 [M + H] +.

[00499] Step 3: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H- pyran-4-yl) amino) -6-methylindolizine-7-carboxamide: 27% yield. 1H NMR (CDCl3, 400 MHz) δ ppm 11.10 (s, 1 H), 7.41 (s, 1 H), 7.23 (s, 1 H), 6.47 (s, 1 H) , 5.96 (s, 1 H), 4.50 (s, 2 H), 3.93 - 3.92 (m, 2 H), 3.38 - 3.34 (m, 3 H), 3 , 25 - 3.17 (m, 2 H), 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, J = 7.2 Hz, 3 H); ESI-MS m / z 515 [M + H] +.

[00500] Example 59: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (oxethane-3) -yl) amino) -6-methylindolizine-7-carboxamide:

[00501] Step 1: Preparation of 5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -6-methylindolizine-7-carbonitrile: in a dry three-necked, 50 mL, 5-amino- 2-bromo-6-methylindolizine-7-carbonitrile (300 mg, 1.20 mmol) and oxetane (0.6 mL) were dissolved in tetraisopropyl titanium oxide (2 mL), and stirred overnight at 65oC. After the reaction was completed, 10 ml of dichloromethane was added, and a small amount of water was added to it. The reaction liquid was concentrated under reduced pressure, and then a large amount of flocculents were precipitated. The solid was washed with dichloromethane (30 ml × 3), and the organic phase was concentrated under reduced pressure. The resulting residue was redissolved in glacial acetic acid (10 ml) at 0 ° C, sodium borohydride (121 mg, 3.20 mmol) was added slowly, warmed to room temperature and stirred for an additional hour. Water and sodium hydrogen carbonate were added to adjust the pH to 7 and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with water (10 ml × 2) and saturated brine (10 ml). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to provide yellow oil (160 mg, 7% yield). ESI-MS m / z 306 [M + H] +.

[00502] Step 2: Preparation of 2-bromo-5- (ethyl (oxetan-3-yl) amino) -6-methylindolizine-7-carbonitrile: the procedure was the same as in Step 4, in Example 55. Yield of: 51%. ESI-MS m / z 334 [M + H] +.

[00503] Step 3: Preparation of 2-bromo-5- (ethyl (oxetan-3-yl) amino) -6-methylindolizine-7-carboxylic acid: the procedure was the same as Step 5 of Example 55. Yield of: 68%. ESI-MS m / z 353 [M + H] +.

[00504] Step 4: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (oxethane-3 - il) amino) -6-methylindolizine-7-carboxamide: the procedure was the same as in Step 6 of Example 55. Yield was 22%. 1H NMR (400 MHz, CDCl3) δ ppm 9.24 (s, 1 H), 7.38 (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 (m, 3 H), 4.65 - 4.47 (m, 3 H), 3 , 29 - 3.20 (m, 2 H), 2.39 (s, 3 H), 2.24 (s, 3 H), 2.19 (m, 3 H), 1.03 (t, J = 7.2 Hz, 3 H); ESI-MS m / z 487 [M + H] +.

[00505] Example 60: Preparation of 5- (azetidin-3-yl (ethyl) amino) -2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin3-yl) methyl) -6-methylindolizine-7-carboxamide:

[00506] Preparation of 5- (azetidin-3-yl (ethyl) amino) -2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl ) -6-methylindolizine-7-carboxamide: the procedure of the first four steps was the same as in Example 59.

[00507] Step 1: Preparation of tert-butyl 3 - ((2-bromo-7-cyano-6-methylindolizine-5-yl) amino) azetidine-1-carboxylate: Yield 49%. ESI-MS m / z 405 [M + H] +.

[00508] Step 2: Preparation of tert-butyl 3 - ((2-bromo-7-cyano-6-methylindolizin-5-yl) (ethyl) amino) azetidine-1-carboxylate: 77% yield. ESI-MS m / z 433 [M + H] +.

[00509] Step 3: Preparation of 2-bromo-5 - ((1- (tert-butoxycarbonyl) azetidin-3-yl) (ethyl) amino) -6-methylindolizine -7-carboxylic acid: Yield 74%. ESI-MS m / z 452 [M + H] +.

[00510] Step 4: Preparation of 3 - ((2-bromo-7 - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) carbamoyl) -6-methylindolizine -5-yl) (ethyl) amino) tert-butyl azetidine-1-carboxylate: 31% yield. ESI-MS m / z 586 [M + H] +.

[00511] Step 5: Preparation of 5- (azetidin-3-yl (ethyl) amino) -2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin) -3 tert-butyl -yl) methyl) -6-methyl-7-carboxamide: 3 - ((2-bromo-7 - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- il) methyl) carbamoyl) -6-methylindolizine-5-yl) (ethyl) amino) azetidine-1-carboxylate (20 mg, 0.034 mmol), trifluoroacetic acid (1 mL) were added to a dry three-necked flask of 50 ml, successively, and dissolved in dichloromethane (1 ml). The reaction was carried out for 1 hour at room temperature. The reaction mixture was directly concentrated and purified by means of reverse phase HPLC to provide yellow oil (4 mg, 25% yield). 1H NMR (MeOD, 400 MHz) δ ppm 7.58 (s, 1 H), 7.38 (s, 1 H), 6.63 (s, 1 H), 6.13 (s, 1 H) , 4.62 - 4.61 (m, 1 H), 4.46 (s, 2 H), 4.16 - 4.14 (m, 2 H), 4.04 - 3.94 (m, 2 H), 2.37 (s, 3 H), 2.25 (s, 3 H), 2.19 (s, 3 H), 1.05 - 1.01 (m, 3 H); ESI-MS m / z 486 [M + H] +.

[00512] Example 61: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (piperidin4-yl) amino) -6-methylindolizine-7-carboxamide:

[00513] 2-bromo-N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (piperidin-4-yl) amino) - 6-methylindolizine-7-carboxamide was prepared by a method similar to that of Example 60.

[00514] Step 1: Preparation of tert-butyl 4 - ((2-bromo-7-cyano-6-methylindolizine-5-yl) amino) piperidine-1-carboxylate: Yield 28%. ESI-MS m / z 433 [M + H] +.

[00515] Step 2: Preparation of tert-butyl 4 - ((2-bromo-7-cyano-6-methylindolizin-5-yl) (ethyl) amino) piperidine-1-carboxylate: 59% yield. ESI-MS m / z 461 [M + H] +.

[00516] Step 3: Preparation of 2-bromo-5 - ((1- (tert-butoxycarbonyl) piperidin-4-yl) (ethyl) amino) -6-methylindolizin a-7-carboxylic acid: Yield 64%. ESI-MS m / z 614 [M + H] +.

[00517] Step 4: Preparation of 4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) carbamoyl) -6-methylindolizine-5-yl) (ethyl) amino) piperidine- Tert-butyl 1-carboxylate: 43% yield.
ESI-MS m / z 614 [M + H] +.

[00518] Step 5: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (piperidin4-yl) amino) -6-methylindolizine-7-carboxamide: 35% yield. 1H NMR (MeOD, 400 MHz) δ ppm 7.55 (s, 1 H), 7.33 (s, 1 H), 6.58 (s, 1 H), 6.12 (s, 1 H) , 4.45 (s, 2 H), 3.10 - 2.98 (m, 4 H), 2.37 (s, 3 H), 2.25 (s, 6 H), 2.10 - 2 , 02 (m, 2 H), 1.72 - 1.30 (m, 2 H), 0.91 (t, J = 6.9 Hz, 3 H); ESI-MS m / z 514 [M + H] +.

[00519] Example 62: Preparation of 5 - ((1-acetylpiperidin-4-yl) (ethyl) amino) -2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-di- hi dropiridin-3-yl) methyl) -6-methylindolizine-7-carboxamide:

[00520] Step 1: Preparation of 2-bromo-5- (ethyl (piperidin-4-yl) amino) -6-methylindolizine-7-carboxylic acid: in a 50 ml round-bottom dry flask, 2-bromo acid -5 - ((1- (tert-butoxycarbonyl) piperidin-4-yl) (ethyl) amino) -6-methylindolizin a-7-carboxylic acid (80 mg, 0.16 mmol), dichloromethane (2 mL) and trifluoroacetic acid (1 mL) were added successively at room temperature. After stirring at room temperature for 1 hour, TLC monitored that the reaction was complete. ESI-MS m / z 380 [M + H] +.

[00521] Step 2: Preparation of 5 - (((1-acetylpiperidin-4-yl) (ethyl) amino) -2-bromo-6-methylindolizine-7-carboxylic acid: in a 25 ml round-bottom dry flask, 2-bromo-5- (ethyl (piperidin-4-yl) amino) -6-methylindolizine-7-carboxylic acid (60 mg, 0.16 mmol), acetyl chloride (0.2 mL) and THF (1 mL) they were added successively at room temperature and stirred at room temperature for 1h. After monitoring that the reaction was completed by means of TLC, 10 ml of saturated sodium bicarbonate were added and extracted with ethyl acetate (10 ml × 3), and the organic phases were combined. The mixture was washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to provide a yellow sticky liquid, 40 mg, which can be used directly in the next step . ESI-MS m / z 422 [M + H] +.

[00522] Step 3: Preparation of 5 - ((1-acetylpiperidin-4-yl) (ethyl) amino) -2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-di- hi dropiridine) -3-yl) methyl) -6-methylindolizine-7-carboxamide: 5 - ((1-acetylpiperidin-4-yl) (ethyl) amino) -2-bromo-N - ((4,6-dimethyl -2-oxo-1,2-dihydropyridine) -3-yl) methyl) -6-methylindolizine-7-carboxamide was prepared using a method similar to that of Step 6, Example 1, yield 8% . 1H NMR (CDCl3, 400 MHz) δ ppm 7.40 (s, 1 H), 7.34 (s, 1 H), 6.77 (s, 1 H), 6.57 (s, 1 H) , 6.52 (s, 1 H), 4.62 - 4.54 (m, 3 H), 3.78 - 3.75 (m, 1 H), 3.37 - 3.33 (m, 1 H), 3.29 - 3.16 (m, 2 H), 3.04 - 3.01 (m, 1 H), 2.61 (s, 3 H), 2.47 (s, 3 H) , 2.17 (s, 3 H), 2.12 (s, 3 H), 1.98 - 1.88 (m, 2 H), 1.42 - 1.31 (m, 2 H), 0 , 96 (t, J = 6.9 Hz, 3 H); ESI-MS m / z 556 [M + H] +.

[00523] Example 63: Preparation of N- (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) ) amino) -6-methyl-2-phenylindolizine-7-carboxamide:

[00524] Step 1: Preparation of 5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -6-methyl-2-phenylindolizine-7-carbonitrile: the procedure was the same as Step 1 in Example 31. Yield: 45%. ESI-MS m / z 360 [M + H] +.

[00525] Step 2: Preparation of 5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -6-methyl-2-phenylindolizine-7-carboxylic acid: the procedure was the same as in Step 5 of Example 55 Yield was 68%. ESI-MS m / z 379 [M + H] +.

[00526] Step 3: Preparation of N- (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl ) amino) -6-methyl-2-phenylindolizine-7-carboxamide:
N- (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -6-methyl- 2-phenylindolizine-7-carboxamide was prepared by a method similar to that of Step 6, Example 1, yield 14%. 1H NMR (CDCl3, 400 MHz) δ ppm 11.35 (s, 1 H), 7.69 - 7.64 (m, 3 H), 7.38 - 7.33 (m, 4 H), 6 , 72 (s, 1 H), 5.95 (s, 1 H), 4.52 (s, 2 H), 3.99 - 3.92 (m, 2 H), 3.36-3.23 (m, 4 H), 3.22 - 3.17 (m, 1 H), 2.40 (s, 3 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); ESI-MS m / z 513 [M + H] +.

[00527] Example 64: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4- il) amino) -6-methyl-2- (4-morpholinephenyl) indolizine-7-carboxamide:

[00528] N - (((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (t-hydroxy-2H-pyran-4-yl) amino) -6-methyl-2- (4-morpholinephenyl) indolizine-7-carbox amide was prepared by a method similar to that of Example 63.

[00529] Step 1: Preparation of 5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -6-methyl-2- (4-morpholinephenyl) indolizine-7-carbonitrile: Yield 54%. ESI-MS m / z 445 [M + H] +.

[00530] Step 2: Preparation of 5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -6-methyl-2- (4-morpholinephenyl) indolizine-7-carboxylic acid: ESI-MS m / z 464 [M + H] +.

[00531] Step 3: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4- il) amino) -6-methyl-2- (4-morpholinephenyl) indolizine-7-carboxamide: The yield of the two stages was 31%. 1H NMR (CDCl3, 400 MHz) δ ppm 11.30 (brs, 1 H), 7.62 (s, 1 H), 7.55 (d, J = 7.8 Hz, 2 H), 7, 31 (s, 1 H), 6.95 (d, J = 7.8 Hz, 2 H), 6.66 (s, 1 H), 5.94 (s, 1 H), 4.53 (brs , 2 H), 3.93 - 3.88 (m, 6 H), 3.41 - 3.31 (m, 4 H), 3.24 - 3.18 (m, 5 H), 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, J = 7 , 2 Hz, 3 H); ESI-MS m / z 598 [M + H] +.

[00532] Example 65: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4- il) amino) -6-methyl-2- (1-methyl-1H-pyrazol-5-yl) indolizine-7-carboxamide:

[00533] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (t-hydroxy-2H-pyran-4-yl) amino) -6-methyl-2- (1-methyl-1H-pyrazol-5-yl) indolizine-7-c arboxamide was prepared by a method similar to that of Example 63.

[00534] Step 1: Preparation of 5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -6-methyl-2- (1-methyl-1H-pyrazol-5-yl) indolizine-7- carbonitrile: Yield 55%. ESI-MS m / z 364 [M + H] +.

[00535] Step 2: Preparation of 5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -6-methyl-2- (1-methyl-1H-pyrazol-5-yl) indolizine-7 -carboxylic: 31% yield.

[00536] Step 3: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4- il) amino) -6-methyl-2- (1-methyl-1H-pyrazol-5-yl) indolizine-7-carboxamide: the two-step yield was 23%. 1H NMR (CDCl3, 400 MHz) δ ppm 11.53 (brs, 1 H), 7.58 (s, 1 H), 7.49 (s, 1 H), 7.34 (s, 1 H) , 6.57 (s, 1 H), 6.36 (s, 1 H), 5.96 (s, 1 H), 4.53 (s, 2 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 H), 3.02 (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), 1.12 (t, J = 7.2 Hz, 3 H); ESI-MS m / z 517 [M + H] +.

[00537] Example 66: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4- il) amino) -6-methyl-2- (1-methyl-1H-pyrazol-4-yl) indolizine-7-carboxamide:

[00538] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (t-hydroxy-2H-pyran-4-yl) amino) -6-methyl-2- (1-methyl-1H-pyrazol-4-yl) indolizine-7-c arboxamide was prepared by a method similar to that of Example 63.

[00539] Step 1: Preparation of 5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -6-methyl-2- (1-methyl-1H-pyrazol-4-yl) indolizine-7- carbonitrile: Yield 38%. ESI-MS m / z 364 [M + H] +.

[00540] Step 2: Preparation of 5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -6-methyl-2- (1-methyl-1H-pyrazol-4-yl) indolizine-7 -carboxylic: 31% yield.

[00541] Step 3: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4- il) amino) -6-methyl-2- (1-methyl-1H-pyrazol-4-yl) indolizine-7-carboxamide: the yield of the two steps was 53%. 1H NMR (CDCl3, 400 MHz) δ ppm 12.31 (brs, 1 H), 7.72 (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, 1 H), 4.52 (s, 2 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), 2.24 (s, 3 H), 1 , 81 - 1.78 (m, 1 H), 1.33 - 1.25 (m, 3 H), 0.98 (t, J = 7.0 Hz, 3 H); ESI-MS m / z 517 [M + H] +.

[00542] Example 67: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4- il) amino) -6-methyl-2- (thiazol-2-yl) indolizine-7-carboxamide:

[00543] Step 1: Preparation of 5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -6-methyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxa no-2-yl) indolizine-7-carbonitrile: the procedure was the same as Step 1 in Example 50. Yield: 48%. ESI-MS m / z 410 [M + H] +.

[00544] Step 2: Preparation of 5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -6-methyl-2- (thiazol-2-yl) indolizine-7-carbon itrila: the procedure was same as Step 1 of Example 31. Yield: 66%. ESI-MS m / z 367 [M + H] +.

[00545] Step 3: Preparation of 5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -6-methyl-2- (thiazol-2-yl) indolizine-7-carboxylic acid: the procedure was the same as in Step 5 of Example 55. ESI-MS m / z 386 [M + H] +.

[00546] Step 4: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4- il) amino) -6-methyl-2- (thiazol-2-yl) indolizine-7-carboxamide: the procedure was the same as Step 6 in Example 1. The yield of the two steps was 21%. 1H NMR (CDCl3, 400 MHz) δ ppm 8.03 (s, 1 H), 7.80 (s, 1 H), 7.44 (s, 1 H), 7.31 (s, 1 H) , 7.26 (s, 1 H), 6.83 (s, 1 H), 6.21 (s, 1 H), 4.46 (s, 2 H), 3.96-3.88 (m , 3 H), 3.41 - 3.19 (m, 4 H), 2.69 (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, J = 7.0 Hz, 3 H); ESI-MS m / z 520 [M + H] +.

[00547] Example 68: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (methyl (tetrahydro-2H- pyran-4-yl) amino) imidazo [1,5-a] pyridine-7-carboxamide:

[00548] N - (((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl -5- (methyl (tetrahydro-2H-pyran-4-yl ) amino) imidazo [1,5-a] pyridine-7-carboxamide: the procedure was similar to that of Example 55.

[00549] Step 1: Preparation of (E) -2 - ((1H-imidazol-5-yl) methylene) succinonitrile: Yield 51%.
ESI-MS m / z 159 [M + H] +.

[00550] Step 2: Preparation of 5-amino-6-methylimidazo [1,5-a] pyridine-7-carbonitrile: Yield 38%.
ESI-MS m / z 173 [M + H] +.

[00551] Step 3: Preparation of 6-methyl-5 - ((tetrahydro-2H-pyran-4-yl) amino) imidazo [1,5-a] pyridine-7-carbonitrile: Yield 7%. ESI-MS m / z 257 [M + H] +.

[00552] Step 4: Preparation of 6-methyl-5- (methyl (tetrahydro-2H-pyran-4-yl) amino) imidazo [1,5-a] pyridine-7-carbo nitrile
6-Methyl-5 - ((tetrahydro-2H-pyran-4-yl) amino) imidazo [1,5-a] pyridine-7-carbonitrile (80 mg, 0.31 mmol), paraformaldehyde (93 mg, 3, 12 mmol) were added successively to a dry flask with three necks, of 25 mL, dissolved in formic acid (2 mL) and heated, so that it would reflux, for 3 hours. After the reaction was completed, yellow solids (30 mg) were obtained by means of a thin layer chromatography plate, yield of 36%. ESI-MS m / z 271 [M + H] +.

[00553] Step 5: Preparation of 6-methyl-5- (methyl (tetrahydro-2H-pyran-4-yl) amino) imidazo [1,5-a] pyridine-7-carboxylic acid: ESI-MS m / z 290 [M + H] +.

[00554] Step 6: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (methyl (tetrahydro-2H- pyran-4-yl) amino) imidazo [1,5-a] pyridine-7-carboxamide: the yield of the two stages was 9%. 1H NMR (CDCl3, 400 MHz) δ ppm 11.65 (s, 1 H), 8.15 (s, 1 H), 7.45 (s, 1 H), 7.39 - 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 Hz, 2 H), 3 , 39 - 3.29 (m, 3 H), 2.88 (s, 3 H), 2.38 (s, 3 H), 2.25 (s, 3 H), 2.23 (s, 3 H), 1.78 - 1.59 (m, 4 H); ESI-MS m / z 424 [M + H] +.

[00555] Example 69: Preparation of 2-chloro-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- morphololinolinyl) indolizine-7-carboxamide:

[00556] 2-chloro-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morphinolinylethyl) indolizine-7 -carboxamide was prepared by a method similar to that of Example 29.

[00557] Step 1: Preparation of 4-chloro-1H-pyrrole-2-carbaldehyde: Yield 34%. ESI-MS m / z 130 [M + H] +.

[00558] Step 2: Preparation of 4-chloro-1- (2-oxopropyl) -1H-pyrrole-2-carbaldehyde: 56% yield.
ESI-MS m / z 186 [M + H] +.

[00559] Step 3: Preparation of ethyl 5-acetyl-2-chloro-6-methylindolizine-7-carboxylate: Yield 58%.
ESI-MS m / z 280 [M + H] +.

[00560] Step 4: Preparation of isopropyl 2-chloro-6-methyl-5- (1-morphinolinylvinyl) indolizine-7-carboxylate: ESI-MS m / z 363 [M + H] +.

[00561] Step 5: Preparation of isopropyl 2-chloro-6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxylate: the yield of the two steps was 50%. ESI-MS m / z 365 [M + H] +.

[00562] Step 6: Preparation of 2-chloro-6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxylic acid: 75% yield. ESI-MS m / z 323 [M + H] +.

[00563] Step 7: Preparation of 2-chloro-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- morphololinylethyl) indolizine-7-carboxamide: 25% yield. 1H NMR (400 MHz, DMSO-d6) δ 7.33 (s, 1 H), 6.49 (s, 1 H), 6.13 (s, 1 H), 4.44 (s, 2 H ), 4.23 (d, J = 5.6 Hz, 1 H), 3.64 (d, J = 10.4 Hz, 1 H), 2.85 (s, 8 H), 2.37 ( s, 3 H), 2.29 (s, 3 H), 2.24 (s, 3 H), 1.55 (d, J = 6.4 Hz, 3 H); ESI-MS m / z 457 [M + H] +.

[00564] Example 70: Preparation of 2-chloro-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- ( dimethylamino)) piperidine) ethyl) -6-methylindolizine-7-carboxamide:

[00565] 2-chloro-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamino)) piperidine) ethyl) -6-methylindolizine-7-carboxamide was prepared by the same procedure as that in Example 29.

[00566] Step 1: Preparation of 2-chloro-5- (1- (4- (dimethylamino) piperidin-1-yl) vinyl) -6-methylindolizine-7-carboxyl isopropyl act: ESI-MS m / z 404 [M + H] +.

[00567] Step 2: Preparation of isopropyl 2-chloro-5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -6-methylindolizine-7-carboxylate: 36% yield. ESI-MS m / z 406 [M + H] +.

[00568] Step 3: Preparation of 2-chloro-5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -6-methylindolizine-7-carboxylic acid: 97% yield. ESI-MS m / z 364 [M + H] +.

[00569] Step 4: Preparation of 2-chloro-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- ( dimethylamino))) piperidin-1-yl) ethyl) -6-methylindolizine-7-carboxamide: 15% yield. 1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1 H), 9.40 (s, 1 H), 8.25 (m, 2 H), 7.25 (s, 1 H ), 6.55 (s, 1 H), 5.87 (s, 1 H), 4.25 (m, 3 H), 4.03 (s, 1 H), 3.41 (s, 1 H ), 3.09 (s, 1 H), 2.74 (m, 8 H), 2.45 (s, 1 H), 2.23 (s, 3 H), 2.19 (s, 3 H ), 2.10 (s, 6 H), 1.41 (d, J = 5.4 Hz, 3 H); ESI-MS m / z 498 [M + H] +.

[00570] Example 71: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) imidazo [1,5-a] pyridine-7-carboxamide:

[00571] N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) imidazo [1,5-a ] pyridine-7-carboxamide was prepared using a method similar to that of Example 26, while the ethyl 5-acetyl-6-methylimidazo [1,5-a] pyridine-7-carboxylate was prepared according to Step 2, Method A of Example 1.

[00572] Step 1: Preparation of 1- (2-oxopropyl) -1H-imidazole-5-formaldehyde: 8% yield. ESI-MS m / z 153 [M + H] +.

[00573] Step 2: Preparation of ethyl 5-acetyl-6-methylimidazo [1,5-a] pyridine-7-carboxylate: Yield 31%. ESI-MS m / z 247 [M + H] +.

[00574] Step 3: Preparation of isopropyl 6-methyl-5- (1-morphinolinylvinyl) imidazo [1,5-a] pyridine-7-carboxylate: ESI-MS m / z 330 [M + H] +.

[00575] Step 4: Preparation of isopropyl 6-methyl-5- (1-morphinolinylethyl) imidazo [1,5-a] pyridine-7-carboxylate: the yield of the two steps was 32%. ESI-MS m / z 332 [M + H] +.

[00576] Step 5: Preparation of 6-methyl-5- (1-morphinolinylethyl) imidazo [1,5-a] pyridine-7-carboxylic acid: 66% yield. ESI-MS m / z 290 [M + H] +.

[00577] Step 6: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) imidazo [1,5-a] pyridine-7-carboxamide: 18% yield. 1H NMR (400 MHz, DMSO-d6) δ 11.54 (brs, 1 H), 10.04 (brs, 1 H), 8.50 (t, J = 4.9 Hz, 1 H), 8 , 14 (s, 1 H), 7.68 (s, 1 H), 5.89 (s, 1 H), 4.29 (t, J = 7.2 Hz, 2 H), 3.57 ( brs, 4 H), 2.66 (brs, 2 H), 2.29 (s, 3 H), 2.21 (s, 3 H), 2.12 (s, 3 H), 1.45 ( d, J = 6.5 Hz, 3 H); ESI-MS m / z 424 [M + H] +.

[00578] Example 72: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) imidazo [1,2-a] pyridine-7-carboxamide:

[00579] N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) imidazo [1,2-a ] pyridine-7-carboxamide was prepared by a method similar to that of Example 72.

[00580] Step 1: Preparation of 1- (2-oxopropyl) -1H-imidazole-2-formaldehyde: 10% yield. ESI-MS m / z 153 [M + H] +.

[00581] Step 2: Preparation of ethyl 5-acetyl-6-methylimidazo [1,2-a] pyridine-7-carboxylate: Yield 17%. ESI-MS m / z 247 [M + H] +.

[00582] Step 3: Preparation of isopropyl 6-methyl-5- (1-morphinolinylvinyl) imidazo [1,2-a] pyridine-7-carboxylate: ESI-MS m / z 330 [M + H] +.

[00583] Step 4: Preparation of isopropyl 6-methyl-5- (1-morphinolinylethyl) imidazo [1,2-a] pyridine-7-carboxylate: the yield of the two steps was 50%. ESI-MS m / z 332 [M + H] +.

[00584] Step 5: Preparation of 6-methyl-5- (1-morphinolinylethyl) imidazo [1,2-a] pyridine-7-carboxylic acid: 82% yield. ESI-MS m / z 290 [M + H] +.

[00585] Step 6: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) imidazo [1,2-a] pyridine-7-carboxamide: 18% yield. 1H NMR (400 MHz, DMSO-d6) δ 11.56 (brs, 1 H), 8.97 (brs, 1 H), 8.62 (t, J = 2.1 Hz, 1 H), 8 , 22 (d, J = 2.0 Hz, 1 H), 7.73 (s, 1 H), 5.90 (s, 1 H), 4.32 (d, J = 5.1 Hz, 2 H), 3.57 (s, 8 H), 2.36 (s, 3 H), 2.23 (s, 3 H), 2.12 (s, 3 H), 1.44 (d, J = 6.6 Hz, 3 H); ESI-MS m / z 424 [M + H] +.

[00586] Example 73: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4- il) amino) -6-methyl-2- (1-methyl-1H-imidazol-4-yl) indolizine-7-carboxamide:

[00587] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (t-hydroxy-2H-pyran-4-yl) amino) -6-methyl-2- (1-methyl-1H-imidazol-4-yl) indolizine-7-carboxamide was prepared by the same method as that in Example 67.

[00588] Step 1: Preparation of 5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -6-methyl-2- (1-methyl-1H-imidazol-4-yl) indolizine-7- carbonitrile: 43% yield. ESI-MS m / z 364 [M + H] +.

[00589] Step 2: Preparation of 5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -6-methyl-2- (1-methyl-1H-imidazol-4-yl) indole-7-acid -carboxylic: ESI-MS m / z 383 [M + H] +.

[00590] Step 3: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4- il) amino) -6-methyl-2- (1-methyl-1H-imidazol-4-yl) indolizine-7-carboxamide: The yield of the two steps was 21%. 1H NMR (CDCl3, 400 MHz) δ ppm 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), 6.12 (s, 1 H), 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 - 3.21 (m, 1 H), 2.56 (s, 3 H), 2.41 (s, 6 H), 2.25 - 2.20 (m, 2 H), 1.82 - 1.67 (m, 2 H), 0.99 (t, J = 7.0 Hz, 3 H); ESI-MS m / z 517 [M + H] +.

[00591] Example 74: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -2- (3 - (((dimethylamino) methyl) phenyl) ) -6-methyl-5- (1-morpholineethyl) indolizine-7-amide:

[00592] Step 1: Preparation of 2- (3-formylphenyl) -6-methyl-5- (1-morpholinylethyl) indolizine-7-isopropyl formate: similar to Step 1 of Example 31, 25% yield. ESI-MS m / z 348 [M + H] +.

[00593] Step 2: Preparation of 2- (3 - ((dimethyl) methyl) phenyl) -6-methyl-5- (1-morpholinylethyl) indolizine-7-carboxylate: 2- (3 - ((dimethyl) methyl) phenyl) -6-methyl-5- (1-morpholinylethyl) indolizine-7-carboxylate isopropyl (100 mg, 0.23 mmol), dimethylamine hydrochloride (56 mg, 0.69 mmol), triethylamine (69 mg , 0.69 mmol), sodium cyanoborohydride (36 mg, 0.58 mmol) and dichloromethane (5 ml) were added successively to the 50 ml round-bottom dry flask at room temperature. After stirring at room temperature for 3h, TLC monitored that the reaction was complete, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and then extracted with ethyl acetate (20 mL × 3) and washed with brine. saturated (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to provide the product, 2- (3 - ((dimethylamine) methyl) phenyl) -6-methyl-5- ( Isopropyl 1-morpholinylethyl) indolizine-7-carboxylate, 52% yield. ESI-MS m / z 464 [M + H] +.

[00594] Step 3: Preparation of 2- (3 - ((Dimethylamino) methyl) phenyl) -6-methyl-5- (1-morpholinylethyl) indolizine-7-carboxylic acid: similar to Step 4 of Example 31. ESI -MS m / z 335 [M + H] +.

[00595] Step 4: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -2- (3 - (((dimethylamino) methyl) phenyl) -6-methyl-5- (1-morpholinylethyl) indolizine-7-amide: similar to Step 5, of Example 31, the yield of the two steps was 18%. 1H NMR (DMSO-d6, 400 MHz) δ 11.47 (s, 1H), 8.70 (s, 1H), 8.17 (m, 1H), 7.58 - 7.60 (m, 2H ), 7.34 - 7.36 (m, 1H), 7.29 (s, 1H), 7.17 - 7.18 (m, 1H), 6.83 (s, 1H), 5.88 ( s, 1H), 4.26 - 4.28 (m, 2H), 4.06 - 4.07 (m, 1H), 3.59 (m, 2H), 2.65 - 2.67 (m, 2H), 2.26 (s, 3H), 2.18 - 2.22 (m, 11H), 2.12 (s, 3H), 1.45 - 1.47 (m, 3H); ESI-MS m / z 556 [M + H] +.

[00596] Example 75: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -2- (4 - ((dimethylamino) methyl) phenyl) ) -6-methyl-5- (1-morpholinoethyl) indolizine-7-carboxamide:

[00597] Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -2- (4 - ((dimethylamino) methyl) phenyl)) -6 -methyl-5- (1-morpholinoethyl) indolizine-7-carboxamide: same as Example 74.

[00598] Step 1: Preparation of isopropyl 2- (4-formylphenyl) -6-methyl-5- (1-morpholinoethyl) indolizine-7-carboxylate: 34% yield. ESI-MS m / z 348 [M + H] +. Step 2: Preparation of isopropyl 2- (4 - ((dimethylamino) methyl) phenyl) -6-methyl-5- (1-morpholinoethyl) indolizine-7-carboxylate: 47% yield. ESI-MS m / z 464 [M + H] +.

[00599] Step 3: Preparation of 2- (4 - ((dimethylamino) methyl) phenyl) -6-methyl-5- (1-morpholinoethyl) indolizine-7-carboxylic acid: ESI-MS m / z 422 [M ] +.

[00600] Step 3: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -2- (4 - (((dimethylamino) methyl) phenyl) ) -6-methyl-5- (1-morpholinoethyl) indolizine-7-carboxamide: The yield of the two stages was 11%. 1H NMR (CDCl3, 400 MHz) δ 7.91 (s, 2H), 7.89 (s, 1H), 7.60 (s, 1H), 7.56 (s, 2H), 7.54 ( s, 1H), 6.24 (s, 1H), 4.96 (s, 2H), 4.33 (s, 2H), 3.91 - 3.86 (m, 4H), 3.87 - 3 , 85 (m, 1H), 2.99 - 2.98 (m, 1H), 2.88 (s, 6H), 2.41 (s, 6H), 2.28 (s, 3H), 1, 96 - 1.94 (m, 2H), 1.38 - 1.32 (m, 3H); ESI-MS m / z 556 [M + H] +.

[00601] Example 76: Preparation of 2- (7-cyanoindol-5-yl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6 -me til-5- (1-morpholinoethyl) indolizine-7-carboxamide:

[00602] 2- (7-cyanoindol-5-yl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyrin-3-yl) methyl) -6-methyl-5 - (1-morpholinoethyl) indolizine-7-carboxamide was prepared according to Example 31.

[00603] Step 1: Preparation of ethyl 5-acetyl-2- (7-cyanoindol-5-yl) -6-methylindolizine-7-carboxylate: Yield 52%. ESI-MS m / z 388 [M + H] +.

[00604] Step 2: Preparation of isopropyl-2- (7-cyanoindol-5-yl) -6-methyl-5- (1-morpholinovinyl) indolizine-7-carboxylate: ESI-MS m / z 471 [ M + H] +.

[00605] Step 3: Preparation of isopropyl-2- (7-cyanoindol-5-yl) -6-methyl-5- (1-morpholino-ethyl) indolizine-7-carboxyl ethyl: the yield of the two steps was 69%. ESI-MS m / z 473 [M + H] +.

[00606] Step 4: Preparation of 2- (7-cyanoindol-5-yl) -6-methyl-5- (1-morpholino) indolizine-7-carboxylic acid: ESI-MS m / z 431 [M + H] +.

[00607] Step 5: Preparation of 2- (7-cyanoindol-5-yl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6 -me til-5- (1-morpholinoethyl) indolizine-7-carboxamide: the yield of the two stages was 10%. 1H NMR (CDCl3, 400 MHz) δ 12.19 (s, 1H), 8.56 (s, 1H), 7.47 (s, 1H), 7.40 (s, 1H), 7.30 ( s, 1H), 6.54 (s, 1H), 5.96 (s, 1H), 4.53 - 4.52 (m, 2H), 4.06 - 4.01 (m, 1H), 3 , 77 - 3.69 (m, 6H), 3.17 - 3.13 (m, 2H), 2.66 - 2.65 (m, 2H), 2.40 (s, 3H), 2.34 (s, 3H), 2.26 - 2.18 (m, 5H), 1.50 - 1.49 (m, 3H); ESI-MS m / z 565 [M + H] +.

[00608] Example 77: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamino) pip eridin -1-yl) ethyl) -6-methyl-2- (1-methyl-1H-pyrazol-3-yl) indolizine-7-carboxamide:

[00609] N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl ) -6-methyl-2- (1-methyl-1H-pyrazol-3-yl) indolizine7-carboxamide was prepared by a method similar to that in Example 50.

[00610] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2- (1-methyl-1H-pyrazol-3-yl) indolizine-7-carboxylate: Yield 51%.

[00611] ESI-MS m / z 326 [M + H] +.

[00612] Step 2: Step 1: Preparation of 5- (1- (4- (dimethylamino) piperidin-1-yl) vinyl) -6-methyl-2- (1-methyl-1H-pyrazol-3-yl) in isopropyl dolizine-7-carboxylate: ESI-MS m / z 450 [M + H] +.

[00613] Step 2: Preparation of 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -6-methyl-2- (1-methyl-1H-pyrazol-3-yl) ind olizine- Isopropyl 7-carboxylate: the yield of the two stages was 56%. ESI-MS m / z 452 [M + H] +.

[00614] Step 3: Step 3: Preparation of 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -6-methyl-2- (1-methyl-1H-pyrazol-3-yl acid ) olizine-7-carboxylic: ESI-MS m / z 410 [M + H] +.

[00615] Step 4: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamino) pip eridin -1-yl) ethyl) -6-methyl-2- (1-methyl-1H-pyrazol-3-yl) indolizine-7-carboxamide: The yield of the steps was 4%. 1H NMR (DMSO-d6, 400 MHz) δ 8.75 (s, 1H), 7.73 - 7.71 (m, 1H), 7.54 - 7.49 (m, 2H), 7.34 (s, 1H), 7.14 (s, 1H), 6.52 (s, 1H), 5.93 (s, 1H), 4.52 - 4.50 (m, 2H), 4.00 ( m, 1H), 3.75 (s, 3H), 3.37 - 3.35 (m, 1H), 2.39 (s, 3H), 2.36 - 2.35 (m, 2H), 2 , 25 - 2.23 (m, 6H), 2.22 - 2.21 (m, 3H), 2.20 - 2.17 (m, 2H), 1.98 - 1.94 (m, 4H) , 1.49 - 1.45 (m, 3H), 0.99 - 0.96 (m, 3H); ESI-MS m / z 544 [M + H] +.

[00616] Example 78: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinylethyl) -1 - (3-cyanophenyl) indolizine-7-amide:

[00617] Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinylethyl) -1- (3 -cyanophenyl) indolizine-7-amide was similar to that of Example 31.

[00618] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2- (3-cyanophenyl) indolizine-7-carboxylate: Yield 52%. ESI-MS m / z 374 [M + H] +.

[00619] Step 2: Preparation of isopropyl 6-methyl-5- (1-morphinolinylvinyl) -1- (3-cyanophenyl) indolizine-7-carboxylate: ESI-MS m / z 430 [M + H] +.

[00620] Step 3: Preparation of isopropyl 6-methyl-5- (1-morphinolinylethyl) 3- (3-cyanophenyl) indolizine-7-carboxylate: the yield of the two steps was 72%. ESI-MS m / z 432 [M + H] +.

[00621] Step 4: Preparation of 6-methyl-5- (1-morphinolinylethyl) -1- (3-cyanophenyl) indolizine-7-carboxylic acid: ESI-MS m / z 388 [M + H] +.

[00622] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 1- (3-cyanophenyl) indolizine-7-carboxamide: the yield of the two stages was 18%. 1H NMR (CDCl3, 400 MHz) δ 11.07 (s, 1H), 8.74 (s, 1H), 7.89 (s, 1H), 7.85 - 7.83 (d, J = 7 , 2Hz, 1H), 7.53 - 7.47 (m, 2H), 7.34 (s, 1H), 6.68 (s, 1H), 5.96 (s, 1H), 4.53 - 4.52 (m, 2H), 4.09 - 4.03 (m, 1H), 3.71 (m, 4H), 2.68 (s, 2H), 2.40 (s, 3H), 2 , 34 (s, 3H), 2.28 - 2.24 (m, 5H), 1.52 - 1.50 (m, 3H); ESI-MS m / z 437 [M + H] +.

[00623] Example 79: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl1H-imidazole- 2-yl) -5- (1-morpholinoethyl) indolizine-7-carboxamide:

[00624] Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl1H-imidazol-2-yl ) -5- (1-morpholinoethyl) indolizine-7-carboxamide was similar to that of Example 50.

[00625] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2- (1-methyl-1H-imidazol-2-yl) indolizine-7-carboxylate: Yield 49%.

[00626] ESI-MS m / z 326 [M + H] +.

[00627] Step 2: Preparation of isopropyl-6-methyl-2- (1-methyl-1H-imidazol-2-yl) -5- (1-morpholinovinyl) indolizine-7-ethyl carboxylate: ESI-MS m / z 409 [M + H] +.

[00628] Step 3: Preparation of isopropyl-6-methyl-2- (1-methyl-1H-imidazol-2-yl) -5- (1-morpholinoethyl) indolizine-7-c arboxylate: 65% yield . ESI-MS m / z 411 [M + H] +.

[00629] Step 4: Preparation of 6-methyl-2- (1-methyl-1H-imidazol-2-yl) -5- (1-morphinoethyl) indolizine-7-carboxylic acid: ESI-MS m / z 369 [ M + H] +.

[00630] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl-1H- imid azol-2-yl) -5- (1-morphinolinylethyl) indolizine-7-carboxamide, 22% yield. 1H NMR (DMSO-d6, 400 MHz) δ 11.48 (s, 1H), 8.89 (s, 1H), 8.31-8.28 (m, 1H), 7.78 - 7.76 (m, 2H), 7.45 (s, 1H), 7.09 - 7.07 (m, 1H), 5.88 (s, 1H), 4.44 (s, 2H), 4.24 - 4.22 (m, 1H), 4.18 (s, 3H), 3.63 - 3.58 (m, 4H), 2.67 - 2.64 (m, 2H), 2.27 - 2, 17 (m, 6H), 2.15 - 2.13 (m, 2H), 2.11 (s, 3H), 1.48 - 1.47 (m, 3H); ESI-MS m / z 503 [M + H] +.

[00631] Example 80: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1-morpholine-1-ethyl) -6 -m ethyl-2- (3- (morpholinamethylene) phenyl) indolizine-7-amide:

[00632] Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1-morpholino-1-ethyl) -6-methyl -2- (3- (morpholinamethylene) phenyl) indolizine-7-carboxamide was similar to that of Example 31.

[00633] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2- (3- (morpholinamethylene) phenyl) indolizine-7-carboxylate: 46% yield. ESI-MS m / z 420 [M + H] +.

[00634] Step 2: Preparation of isopropyl 5- (1-morpholine-1-vinyl) -6-methyl-2- (3- (morpholinamethylene) phenyl) indolizine-7-carb oxylate: ESI-MS m / z 504 [M + H] +.

[00635] Step 3: Preparation of isopropyl 5- (1-morpholine-1-ethyl) -6-methyl-2- (3- (morpholinamethylene) phenyl) indolizine-7-carbo xylate: the yield of the two steps was 80%. ESI-MS m / z 506 [M + H] +.

[00636] Step 4: Step 4: Preparation of 5- (1-morpholine-1-ethyl) -6-methyl-2- (3- (morphinolinylmethylene) phenyl) indolizine-7-carboxylic acid: ESI-MS m / z 377 [M + H] +.

[00637] Step 5: Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1-morpholine-1-ethyl ) -6-methyl ethyl -2- (3- (morpholinamethylene) phenyl) indolizine-7-amide: the yield of the two stages was 19%. 1H NMR (CDCl3, 400 MHz) δ 8.67 (s, 1 H), 7.57 (s, 1 H), 7.50 - 7.48 (d, J = 7.6, 1 H), 7.31 - 7.23 (m, 1 H), 7.13 - 7.10 (m, 1 H), 6.67 (s, 1 H), 5.89 (s, 1 H), 4, 46 - 4.44 (m, 2 H), 3.40 - 4.39 (m, 1 H), 3.69 (s, 4 H), 3.64 (s, 4 H), 3.56 ( s, 2 H), 2.61 (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, 3 H), 1.46 - 1.44 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 620 [M + Na] +.

[00638] Example 81: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (1-methyl-1H- pyrazol-5-yl) -5- (1-morpholinylethyl) indolizine-7-amide:

[00639] Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (1-methyl-1H-pyre-zol- 5-yl) -5- (1-morpholinylethyl) indolizine-7-amide was similar to that of Example 31.

[00640] Step 1: Preparation of ethyl 5-acetyl-6-methyl-1- (1-methyl-1H-pyrazol-5-yl) indolizine-7-formate: 33% yield. ESI-MS m / z 326 [M + H] +.

[00641] Step 2: Preparation of 6-methyl-1- (1-methyl-1H-pyrazol-5-yl) -5- (1-morphinolinylvinyl) indolizine-7-isopropyl formate: ESI-MS m / z 409 [M + H] +.

[00642] Step 3: Step 3: Preparation of 6-methyl-1- (1-methyl-1H-pyrazol-5-yl) -5- (1-morphinolinylethyl) indolizine-7-isopropyl formate: the yield of the two steps was 30%. ESI-MS m / z 411 [M + H] +.

[00643] Step 4: Preparation of 6-methyl-1- (1-methyl-1H-pyrazol-5-yl) -5- (1-morphinolinylethylene) indolizine-7-formic acid: ESI-MS m / z 369 [M + H] +.

[00644] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (1-methyl-1H- pyrazol-5-yl) -5- (1-morphinolinylethyl) indolizine-7-carboxamide: The yield of the two stages was 16%. 1H NMR (400 MHz, CDCl3) δ 11.46 (s, 1H), 8.50 (s, 1H), 8.27 (s, 1H), 7.47 (s, 1H), 7.31 ( s, 1H), 7.03 - 7.02 (d, J = 2.8 Hz, 1H), 6.40 (s, 1H), 5.85 (s, 1H), 4.25 - 4.24 (m, 2H), 4.09 - 4.07 (m, 1H), 3.83 (s, 3H), 3.58 (m, 4H), 2.67 - 2.62 (m, 2H), 2.28 (s, 3H), 2.18 - 2.14 (m, 5H), 2.10 (s, 3H), 1.45 - 1.43 (m, 3H); ESI-MS m / z 503 [M + H] +.

[00645] Example 82: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 1-phenylindolizine-7-carboxamide:

[00646] Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) -1-phenylindolizine -7-carboxylate was similar to that of Example 31.

[00647] Step 1: Preparation of ethyl 5-acetyl-6-methyl-1-phenylindolizine-7-carboxylate: 14% yield.
ESI-MS m / z 322 [M + H] +.

[00648] Step 2: Preparation of isopropyl 6-methyl-5- (1-morphinolinylvinyl) -1-phenylindolizine-7-carboxylate: ESI-MS m / z 405 [M + H] +.

[00649] Step 3: Preparation of isopropyl 6-methyl-5- (1-morphinolinylethyl) -1-phenylindolizine-7-carboxylate: the yield of the two steps was 38%. ESI-MS m / z 320 [M + H] +.

[00650] Step 4: Preparation of 6-methyl-5- (1-morpholinylethyl) -1-phenylindolizine-7-carboxylic acid: ESI-MS m / z 278 [M + H] +.

[00651] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 1-phenylindolizine-7-carboxamide: the yield of the two steps was 17. 1H NMR (400 MHz, CDCl3) δ ppm 11.46 (s, 1H), 8.44 (s, 1H), 8.27- 8.30 (s, 1H), 7.57 - 7.59 (m, 3H), 7.40 - 7.43 (m, 2H), 7.20 - 7.23 (m, 1H), 7, 01 - 7.02 (d, J = 2.8 Hz, 1H), 5.86 (s, 1H), 4.26 - 4.27 (m, 2H), 4.03 - 4.08 (m, 1H), 3.55 (brs, 4H), 2.58 - 2.67 (m, 2H), 2.35 (s, 3H), 2.11 - 2.17 (m, 5H), 2.07 (s, 3H), 1.39 - 1.41 (m, 3H); ESI-MS m / z 499 [M + H] +.

[00652] Example 83: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl- 1 H-pyrazol-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carbo xamide:

[00653] Step 1: Preparation of 5- (1- (4- (tert-butoxycarbonyl) piperazin-1-yl) vinyl) -6-methyl-2- (1-methyl-1H-pyrazol-5-yl) indolizine -7-isopropyl formate: similar to that of Step 2 of Example 31.
ESI-MS m / z 508 [M + H] +.

[00654] Step 2: Preparation of 5- (1- (4- (tert-butoxycarbonyl) piperazin-1-yl) ethyl) -6-methyl-2- (1-methyl-1H-pyrazol-5-yl) indolizine -7-isopropyl formate: similar to Step 3 of Example 31.
ESI-MS m / z 510 [M + H] +.

[00655] Step 3: Synthesis of isopropyl 6-methyl-2- (1-methyl-1H-pyrazol-5-yl) -5- (1- (piperazin-1-yl) ethyl) indolizine-7-format : 5- (1- (4- (tert-butoxycarbonyl) piperazin-1-yl) ethyl) -6-methyl-2- (1-methyl-1H-pyrazol-5-yl) indolizine-7-carboxylate ( 360 mg (crude), 0.7 mmol) was dissolved in 2 ml of dichloromethane) in a 100 ml dry single-mouthed bottle, and trifluoroacetic acid (1 ml) was added at 0 degrees. The mixture was stirred at room temperature for 2 hours. After monitoring that the reaction was completed by TLC, the NaHCO3 solution was added and extracted with dichloromethane (50 × 3 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to provide yellow oil, which was used in the next step, without purification. ESI-MS m / z 410 [M + H] +.

[00656] Step 4: Synthesis of 6-methyl-2- (1-methyl-1H-pyrazol-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl ) isopropyl ethyl) indolizine-7-carboxylate: 6-methyl-2- (1-methyl-1H-pyrazol-5-yl) -5- (1- (piperazin-1-yl) ethyl) indolizine-7-carbox Isopropylylate (300 mg (crude), 0.73 mmol) was dissolved in tetrahydrofuran (5 ml), in a 100 ml dry single-mouthed bottle, and 2,2,2-trifluoroethyl trifluoromethanesulfonate (172 mg, 0.74 mmol), triethylamine (206 mg, 2.0 mmol) were added. The mixture was stirred at 60 ° C for 4 hours, water was added, and extracted with ethyl acetate (50 × 3 mL). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was removed by evaporation, under reduced pressure, to provide yellow oil, which was purified through a column (ethyl ether: petroleum ether = 1: 3) to provide 210 mg of pure product (yield of -58%). ESI-MS m / z 492 [M + H] +.

[00657] Step 5: Synthesis of 6-methyl-2- (1-methyl-1H-pyrazol-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1- il) ethyl) indolizine-7-formic: the same as in Step 4 of Example 31. ESI-MS m / z 450 [M + H] +.

[00658] Step 6: Synthesis of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl- 1 H-pyrazol-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carbo xamide: the same as in Step 5, of the Example 31. The yield of the two stages was 9%. 1H NMR (CDCl3, 400 MHz) δ ppm 8.51 (s, 1H), 7.64 (s, 1H), 7.45 (s, 1H), 6.84 (s, 1H), 6.74 (s, 1H), 6.56 (s, 1H), 6.41 (s, 1H), 4.62 - 4.61 (m, 2H), 4.48 - 4.46 (m, 1H), 4.10 (s, 3H), 4.07 (s, 3H), 3.31 - 3.26 (m, 2H), 3.20 - 3.14 (m, 2H), 3.07 - 2, 91 (m, 4H), 2.68 - 2.67 (m, 2H), 2.53 (s, 3H), 2.39 (s, 3H), 1.77 (d, 3H, J = 6, 9 Hz); ESI-MS m / z 600 [M + H] +.

[00659] Example 84: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl-1H- pyrazol-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide:

[00660] Step 1: Synthesis of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl-1H- pyrazol-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide a: the same as in Step 5, Example 31. Yield: 8%. 1H NMR (CDCl3, 400 MHz): 8.51 (s, 1 H), 7.66 (s, 1 H), 7.45 (s, 1 H), 6.93 (s, 1 H), 6.75 (s, 1 H), 6.57 - 6.53 (m, 1 H), 4.78 (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), 2.69 (m, 2 H), 2.62 (s, 3 H), 2, 56 (s, 3 H), 2.39 (s, 3 H), 1.68 (d, 3 H, J = 6.9 Hz); ESI-MS m / z 584 [M + H] +.

[00661] Example 85: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl-1H- pyrazol-3-yl) -5- (1-morpholino) indolizine-7-carboxamide:

[00662] Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl-1H-pyre-zol- 3-yl) -5- (1-morpholino) indolizine-7-carboxamide was the same as in Example 31.

[00663] Step 1: Preparation of 5-acetyl-6-methyl-2- (1-methyl-1H-pyrazol-3-yl) indolizine-7-ethyl format: Yield 39%. ESI-MS m / z 326 [M + H] +.

[00664] Step 2: Preparation of isopropyl 6-methyl-2- (1-methyl-1H-pyrazol-3-yl) -5- (1-morpholinovinyl) indolizine-7-carboxylate:

[00665] ESI-MS m / z 409 [M + H] +.

[00666] Step 3: Preparation of isopropyl 6-methyl-2- (1-methyl-1H-pyrazol-3-yl) -5- (1-morpholinoethyl) indolizine-7-carboxylate: the yield of the two steps was 37%. ESI-MS m / z 411 [M + H] +.

[00667] Step 4: Preparation of 6-methyl-2- (1-methyl-1H-pyrazol-3-yl) -5- (1-morpholinoethyl) indolizine-7-carboxylic acid: 84% yield. ESI-MS m / z 369 [M + H] +.

[00668] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl-1H- pyrazol-3-yl) -5- (1-morpholinoethyl) indolizine-7-carboxamide: Yield 7%. 1H NMR (MeOD, 400 MHz): 7.57 (s, 1 H), 7.35 (s, 1 H), 6.77 (s, 1 H), 6.49 (s, 1 H), 6.14 (s, 1 H), 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 - 2.67 (m, 2 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 - 1.28 (m, 3 H); ESI-MS m / z 503 [M + H] +.

[00669] Example 86: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl-1H- imid azol-5-yl) -5- (1-morpholinoethyl) indolizine-7-carboxamide: the same as in Example 50.

[00670] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2- (1-methyl-1H-imidazol-5-yl) indolizine-7-carboxylate, 80% yield.

[00671] ESI-MS m / z 326 [M + H] +.

[00672] Step 2: Preparation of isopropyl 6-methyl-2- (1-methyl-1H-imidazol-5-yl) -5- (1-morpholinovinyl) indolizine-7-carboxylate: ESI-MS m / z 409 [M + H] +.

[00673] Step 3: Preparation of isopropyl 6-methyl-2- (1-methyl-1H-imidazol-5-yl) -5- (1-morpholinoethyl) indolizine-7-carboxylate: 48% yield. ESI-MS m / z 411 [M + H] +.

[00674] Step 4: Preparation of 6-methyl-2- (1-methyl-1H-imidazol-5-yl) -5- (1-morpholinoethyl) indolizine-7-carboxylic acid: ESI-MS m / z 369 [M + H] +.

[00675] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl-1H- imid azol-5-yl) -5- (1-morphinolinylethyl) indolizine-7-carboxamide, 10% yield. 1H NMR (DMSO-d6, 400 MHz): 11.48 (s, 1H), 9.17 - 9.15 (m, 1H), 8.75 (s, 1H), 8.25 (s, 1H ), 7.95 - 7.93 (m, 1H), 7.38 (s, 1H), 6.86 - 6.85 (m, 1H), 5.90 - 5.88 (m, 1H), 4.62 (s, 2H), 3.99 - 3.97 (m, 3H), 3.77 - 3.76 (m, 1H), 3.60 - 3.59 (m, 4H), 2, 70 - 2.67 (m, 2H), 2.42 - 2.41 (m, 3H), 2.39 - 2.34 (m, 5H), 2.14 - 2.12 (m, 3H), 1.54 - 1.48 (m, 3H). ESI-MS m / z 503.2 [M + H] +.

[00676] Example 87: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinoethyl) -2 - (thiazol-5-yl) indolizine-7-carboxamide: the same as in Example 50.

[00677] Step 1: Preparation of ethyl 5-methyl-6-methyl-2- (thiazol-5-yl) indolizine-7-carboxylate: 33% yield. ESI-MS m / z 329 [M + H] +.

[00678] Step 2: Preparation of isopropyl 6-methyl-5- (1-morpholinoethyl) -2- (thiazol-5-yl) indolizine-7-carboxylate: ESI-MS m / z 412 [M + H] + .

[00679] Step 3: Preparation of isopropyl 6-methyl-5- (1-morpholinoethyl) -2- (thiazol-5-yl) indolizine-7-carboxylate: the yield of the two steps was 63%. ESI-MS m / z 414 [M + H] +.

[00680] Step 4: Preparation of 6-methyl-5- (1-morpholinoethyl) -2- (thiazol-5-yl) indolizine-7-carboxylic acid: ESI-MS m / z 372.3 [M + H] +.

[00681] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinoethyl) - 2 - (thiazol-5-yl) indolizine-7-carboxamide: the yield of the two stages was 17%. 1H NMR (CDCl3, 400 MHz): 11.83 (s, 1 H), 8.69 (s, 2 H), 7.99 (s, 1 H), 7.28 - 7.30 (m, 2 H), 6.59 (s, 1 H), 6.96 (s, 1 H), 4.53 - 4.52 (m, 2 H), 4.06 - 4.01 (m, 1H) , 3.69 - 3.68 (m, 4 H), 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); ESI-MS m / z 506 [M + H] +.

[00682] Example 88: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinylethyl) -2 - (thiazol-4-yl) indolizine-7-amide: the same as in Example 50.

[00683] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2- (thiazol-4-yl) indolizine-7-carboxylate: Yield 38%. ESI-MS m / z 329 [M + H] +.

[00684] Step 2: Preparation of isopropyl 6-methyl-5- (1-morpholinylvinyl) -2- (thiazol-4-yl) indolizine-7-carboxylate: ESI-MS m / z 406 [M + H] + .

[00685] Step 3: Preparation of isopropyl 6-methyl-5- (1-morpholinethyl) -2- (thiazol-4-yl) indolizine-7-carboxylate: the yield of the two steps was 35%. ESI-MS m / z 408 [M + H] +.

[00686] Step 4: Preparation of 6-methyl-5- (1-morpholineethyl) -2- (thiazol-4-yl) indolizine-7-carboxylic acid: ESI-MS m / z 366 [M + H] +.

[00687] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinylethyl) -2 - (thiazol-4-yl) indolizine-7-amide: 1H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 9.14-9.13 (d, J = 1.6 Hz, 1H), 8.75 (s, 1H), 8.20-8.17 (m, 1H), 7.88 (d, J = 1.2 Hz, 1H), 7.29 (s, 1H ), 6.87 (s, 1H), 5.87 (s, 1H), 4.27 - 4.26 (m, 2H), 4.06 - 4.02 (m, 1H), 3.57 ( m, 4H), 2.63 (m, 2H), 2.25 (s, 3H), 2.20 - 2.15 (m, 5H), 2.11 (s, 3H), 1.46 - 1 , 44 (m, 3H); ESI-MS m / z 506 [M + H] +.

[00688] Example 89: Preparation of 2- (6-aminopyridin-3-yl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6 - methyl-5- (1-morpholinylethyl) indolizine-7-amide: the same as in Example 31.

[00689] Step 1: Preparation of ethyl 5-acetyl-2- (6-aminopyridin-3-yl) -6-methylindolizine-7-carboxylate: 71% yield. ESI-MS m / z 338 [M + H] +.

[00690] Step 2: Preparation of isopropyl 2- (6-aminopyridin-3-yl) -6-methyl-5- (1-morphinolinylvinyl) indolizine-7-carboxylate: ESI-MS m / z 421 [M + H ] +.

[00691] Step 3: Preparation of 2- (6-aminopyridin-3-yl) -6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxylate: the yield of the two steps was 50%. ESI-MS m / z 423 [M + H] +.

[00692] Step 4: Preparation of 2- (6-aminopyridin-3-yl) -6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxylic acid: ESI-MS m / z 381 [M + H] +.

[00693] Step 5: Preparation of 2- (6-aminopyridin-3-yl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6 - methyl-5- (1-morpholinylethyl) indolizine-7-amide: 1H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1 H), 8.69-8.67 (s, 1 H ), 8.32-8.26 (m, 2 H), 8.20 (s, 1 H), 7.96 (s, 2 H), 7.28 (s, 1 H), 7.07 - 7.05 (d, J = 8.8 Hz, 1 H), 6.84 (s, 1 H), 5.87 (s, 1 H), 4.27 - 4.26 (m, 2 H) , 4.07 - 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 H), 1.48 - 1.46 (m, 3 H); ESI-MS m / z 515 [M + H] +.

[00694] Example 90: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 2- (6, -1-tetrahydropyridin-3-yl) indolizine-7-carboxamide: the same as in Example 44.

[00695] Step 1: Preparation of ethyl 5-acetyl-2- (6- (4- (tert-butoxycarbonyl) piperazin-1-yl) pyridin-3-yl) -6-methylindolizine-7-carboxylate: Yield 65%. ESI-MS m / z 507 [M + H] +.

[00696] Step 2: Preparation of 2- (6- (4- (tert-butoxycarbonyl) piperazin-1-yl) pyridin-3-yl) -6-methyl-5- (1-morpholinovinyl) indolizine-7- isopropyl carboxylate: ESI-MS m / z 589 [M + H] +.

[00697] Step 3: Preparation of 2- (6- (4- (tert-butoxycarbonyl) piperazin-1-yl) pyridin-3-yl) -6-methyl-5- (1-morpholinoethyl) indolizine-7- isopropyl carboxylate: the yield of the two stages was 54%. ESI-MS m / z 591 [M + H] +.

[00698] Step 4: Preparation of 2- (6- (4- (tert-butoxycarbonyl) piperazin-1-yl) pyridin-3-yl) -6-methyl-5- (1-morpholinoethyl) indolizine-7 -formic: ESI-MS m / z 549 [M + H] +.

[00699] Step 5: Preparation of 4- (5- (7 - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) carbamoyl) -6-methyl- 5- (1-morpholinoethyl) indol-2-yl) pyridin-2-yl) tert-butyl piperazine-1-carboxylic: ESI-MS m / z 684 [M + H] +.

[00700] Step 6: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinoethyl) - 2 - (6- (piperazin-1-yl) pyridin-3-yl) indolizine-7-carboxamide: the yield of the three steps was 6%. ESI-MS m / z 584 [M + H] +.

[00701] Example 91: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (6- (4-methylpiper azine) -1-yl) pyridin-3-yl) -5- (1-morpholinoethyl) indolizine-7-carboxamide:

[00702] Step 1: Synthesis of 6-methyl-2- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -5- (1-morpholinoethyl) indolizine-7-isopropyl carboxylate: 6- Isopropyl methyl-5- (1-morpholino) -2- (6- (piperazin-1-yl) pyridin-3-yl) indolizine-7-carboxylate (120 mg, 0.244 mmol) was added to a dry flask with nitrogen protection, single-mouthed, 100 mL, cooled to 0 ° C, then NaH (24.4 mg, 0.61 mmol) was added, stirred at room temperature for 30 min., and then iodomethane (38.2 mg, 0.269 mmol) was added. The reaction was stirred at room temperature for 10 minutes, and 20 ml of ethyl acetate and 10 ml and water were added to the reaction system. The organic phase was separated and concentrated to provide a crude product (90 mg), which was used directly in the next step. ESI-MS m / z 506 [M + H] +.

[00703] Step 2: Preparation of 6-methyl-2- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -5- (1-morpholinoethyl) indolizine-7-carboxylic acid: the same as Step 4 of Example 31. ESI-MS m / z 464 [M + H] +.

[00704] Example 3: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (6- (4-methylpiper azine) -1-yl) pyridin-3-yl) -5- (1-morpholinoethyl) indolizine-7-carboxamide: the same as in Step 5 of Example 31. The three step yield was 3%.

[00705] ESI-MS m / z 598 [M + H] +.

[00706] Example 92: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamino) pip eridin -1-yl) ethyl) -6-methyl-2- (3,4,5-trimethoxyphenyl) -indolizine-7-carboxamide: the same as in Example 31.

[00707] Step 1: Preparation of 5- (1- (4- (dimethylamino) piperidin-1-yl) vinyl) -6-methyl-2- (3,4,5-trimethoxyphenyl) -indol izine-7-carboxylate isopropyl: ESI-MS m / z 536 [M + H] +.

[00708] Step 2: Preparation of 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -6-methyl-2- (3,4,5-trimethoxyphenyl) -indolezine-7-carboxylate isopropyl: the yield of the two stages was 60%. ESI-MS m / z 538 [M + H] +.

[00709] Step 3: Preparation of 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -6-methyl-2- (3,4,5-trimethoxyphenyl) -indoli zine-7- carboxylic: ESI-MS m / z 496.5 [M + H] +.

[00710] Step 4: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamino) pip eridin -1-yl) ethyl) -6-methyl-2- (3,4,5-trimethoxyphenyl) -indolizine-7-carboxamide: The yield of the two stages was 29%. 1H NMR (CDCl3, 400 MHz): 12.39 (s, 1 H), 8.50 (s, 1 H), 7.31 - 7.27 (m, 2 H), 6.82-6, 79 (m, 2 H), 6.64 (s, 1 H), 5.95 (s, 1 H), 4.51 (s, 2 H), 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 (m, 2 H), 2.52 ( s, 6 H), 2.43 (s, 3 H). 2.37 (s, 3 H), 2.22 (m, 3 H), 2.18 - 2.16 (m, 2 H), 1.99 - 1.94 (m, 2 H), 1, 94 - 1.80 (m, 2 H), 1.77 - 1.52 (m, 3 H); ESI-MS m / z 630 [M + H] +.

[00711] Example 93: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamino) pip eridin -1-yl) ethyl) -6-methyl-2- (pyridin-4-yl) indolizine-7-carboxamide: the same as in Example 31.

[00712] Step 1: Step 1: Preparation of isopropyl 5- (1- (4- (dimethylamino) piperidin-1-yl) ethylene) -6-methyl-2- (pyridin-4-yl) indolizine-7-carboxylate isopropyl: ESI-MS m / z 447 [M + H] +.

[00713] Step 2: Preparation of isopropyl 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -6-methyl-2- (pyridin-4-yl) indolizine-7-carboxylate: the yield of the two stages was 52%. ESI-MS m / z 449 [M + H] +.

[00714] Step 3: Preparation of 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -6-methyl-2- (pyridin-4-yl) indolizine-7-carboxylic acid.

[00715] ESI-MS m / z 407 [M + H] +.

[00716] Step 4: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamino) pip eridin -1-yl) ethyl) -6-methyl-2- (pyridin-4-yl) indolizine-7-carboxamide: the yield of the two stages was 37%. 1H NMR (MeOD, 400 MHz): 9.14 (s, 1H), 8.66-8.64 (m, 2H), 8.35 - 8.33 (m, 2H), 7.52 (s , 1H), 7.23 (s, 1H), 6.16 (s, 1H), 4.47 (s, 2H), 3.82 - 3.81 (s, 1H), 2.99 - 2, 98 (m, 1H), 2.85 - 2.81 (m, 8H), 2.39 (s, 3H). 2.35 (s, 3H), 2.29 - 2.28 (m, 2H), 2.24 - 2.22 (m, 6H), 2.11 - 1.96 (m, 2H), 1, 71 - 1.69 (m, 3H); ESI-MS m / z 541.4 [M + H] +.

[00717] Example 94: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinylethyl) -1 - (3,5-dimethylphenyl) indolizine-7-amide: the same as in Example 31.

[00718] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2- (3,5-dimethylphenyl) indolizine-7-carboxylate: 60% yield. ESI-MS m / z 382 [M + H] +.

[00719] Step 2: Step 2: Preparation of isopropyl 6-methyl-5- (1-morpholinylvinyl) -1- (3,5-dimethylphenyl) indolizine-7-carboxylate.

[00720] ESI-MS m / z 465 [M + H] +.

[00721] Step 3: Step 3: Preparation of isopropyl 6-methyl-5- (1-morpholinylethyl) -1- (3,5-dimethylphenyl) indolizine-7-carboxylate: the yield of the two steps was 55%. ESI-MS m / z 467 [M + H] +.

[00722] Step 4: Preparation of 6-methyl-5- (1-morphinolinylethyl) -1- (3,5-dimethylphenyl) indolizine-7-carboxylic acid: ESI-MS m / z 425 [M + H] +.

[00723] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 1- (3,5-dimethylphenyl) indolizine-7-carboxamide: the yield of the two stages was 6%. 1H NMR (400 MHz, CDCl3) δ11.56 (s, 1 H), 8.62 (s, 1 H), 7.66 - 7.64 (m, 1 H), 7.47 - 7.45 ( m, 1 H), 6.73 (s, 2 H), 6.60 (s, 1 H), 6.32 (s, 1 H), 5.88 (s, 1 H), 4.45 - 4.44 (d, J = 4.8 Hz, 2 H), 4.03 - 4.01 (m, 1 H), 3.79 (s, 6 H), 3.62 (s, 4 H), 2.58 (s, 2 H), 2.32 (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 H); ESI-MS m / z 559 [M + H] +.

[00724] Example 95: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinylethyl) -1 - (3,4-dimethylphenyl) indolizine-7-amide: the same as in Example 31.

[00725] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2- (3,4-dimethylphenyl) indolizine-7-carboxylate: 42% yield.

[00726] ESI-MS m / z 382 [M + H] +.

[00727] Step 2: Preparation of isopropyl 6-methyl-5- (1-morpholinylvinyl) -1- (3,4-dimethylphenyl) indolizine-7-carboxylate. ESI-MS m / z 465 [M + H] +.

[00728] Step 3: Preparation of isopropyl 6-methyl-5- (1-morpholinylethyl) -1- (3,4-dimethylphenyl) indolizine-7-carboxylate: the yield of the two steps was 55%. ESI-MS m / z 467 [M + H] +.

[00729] Step 4: Preparation of 6-methyl-5- (1-morphinolinylethyl) -1- (3,4-dimethylphenyl) indolizine-7-carboxylic acid: ESI-MS m / z 425 [M + H] +.

[00730] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 1- (3,4-dimethylphenyl) indolizine-7-carboxamide: the yield of the two stages was 13%. 1H NMR (400 MHz, CDCl3) δ11.08 (s, 1 H), 8.59 (s, 1 H), 7.25 (s, 1 H), 7.15 - 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), 6.57 (s, 1 H), 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 H), 3.85 (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 - 2.15 (m, 5 H), 1.44 - 1.42 (d, J = 6.4 Hz, 3 H); ESI-MS m / z 559 [M + H] +.

[00731] Example 96: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -2- (3-methoxyphenyl) -6-methyl-5 - (1-morpholino) indolizine-7-carboxamide: the same as in Example 31.

[00732] Step 1: Preparation of ethyl 5-acetyl-2- (3-methoxyphenyl) -6-methylindolizine-7-carboxylate: Yield 72%. ESI-MS m / z 352 [M + H] +.

[00733] Step 2: Preparation of isopropyl 2- (3-methoxyphenyl) -6-methyl-5- (1-morpholinylvinyl) indolizine-7-carboxylate: ESI-MS m / z 435 [M + H] +.

[00734] Step 3: Preparation of 2- (3-methoxyphenyl) -6-methyl-5- (1-morpholinylethyl) indolizine-7-carboxylate isopropyl: the yield of the two steps was 52%. ESI-MS m / z 437 [M + H] +.

[00735] Step 4: Preparation of 2- (3-methoxyphenyl) -6-methyl-5- (1-morpholinylethyl) indolizine-7-carboxylic acid: ESI-MS m / z 395 [M + H] +.

[00736] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -2- (3-methoxyphenyl) -6-methyl-5 - (1-morpholinylethyl) indolizine-7-carboxamide: Yield 50%. 1H- NMR (DMSO, 400 MHz): 11.48 (s, 1H), 8.23 (s, 1H), 8.19 (s, 1H), 7.35 - 7.23 (m, 4H) , 6.85 (m, 2H), 5.88 (s, 1H), 4.28 - 4.27 (m, 2H), 3.85 (s, 6H), 3.60 (m, 5H), 2.28 (s, 3H), 2.21 (s, 3H), 2.19 (s, 3H), 1.55 - 1.54 (m, 3H); ESI-MS m / z 529 [M + H] +.

[00737] Example 97: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -2- (4-methoxyphenyl) -6-methyl-5 - (1-morpholinoethyl) indolizine-7-carboxamide: the same as in Example 31.

[00738] Step 1: Preparation of ethyl 5-acetyl-2- (4-methoxyphenyl) -6-methylindolizine-7-carboxylate: Yield 60%. ESI-MS m / z 352 [M + H] +.

[00739] Step 2: Preparation of isopropyl 2- (4-methoxyphenyl) -6-methyl-5- (1-morpholinylvinyl) indolizine-7-carboxylate: ESI-MS m / z 435 [M + H] +.

[00740] Step 3: Preparation of isopropyl 2- (4-methoxyphenyl) -6-methyl-5- (1-morpholinylethyl) indolizine-7-carboxylate: the yield of the two steps was 41%. ESI-MS m / z 437 [M + H] +.

[00741] Step 4: Preparation of 2- (4-methoxyphenyl) -6-methyl-5- (1-morpholinylethyl) indolizine-7-carboxylic acid: ESI-MS m / z 395 [M + H] +.

[00742] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -2- (4-methoxyphenyl) -6-methyl-5 - (1-morpholinylethyl) indolizine-7-carboxamide: The yield of the two stages was 7%. 1H NMR (CDCl3, 400 MHz): 11.69 (s, 1 H), 8.65 (s, 1 H), 7.77 (s, 1 H), 7.67 - 7.66 (m, 2 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 H), 4.09 (m, 1 H), 3.85 (s, 3 H), 3.60 (m, 4 H), 2.67 (s, 2 H), 2, 28 (s, 3 H), 2.21 (s, 3 H), 2.15 (m, 5 H), 1.52 (m, 3 H); ESI-MS m / z 529 [M + H] +.

[00743] Example 98: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4-methylpiper azine) -1-ethyl) -2-bromoindolizine-7-carboxamide: the same as in Example 30.

[00744] Step 1: Step 1: Preparation of isopropyl 6-methyl-5- (1- (4-methylpiperazine) -1-vinyl) -2-bromoindolizine-7-carboxylate: ESI-MS m / z 420 [M + H] +.

[00745] Step 2: Step 6: Preparation of isopropyl 6-methyl-5- (1- (4-methylpiperazine) -1-ethyl) -2-bromoindolizine-7-carboxylate: the yield of the two steps was 87% . ESI-MS m / z 424 [M + H] +.

[00746] Step 3: Step 1: Preparation of 6-methyl-5- (1- (4-methylpiperazine) -1-ethyl) -2-bromoindolizine-7-carboxylic acid: ESI-MS m / z 380 [M + H] +.

[00747] Step 4: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4-methylpiper azine) -1-ethyl) -2-bromoindolizine-7-carboxamide: 8% yield. 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.28 - 7.23 (m, 1H), 6.77 (s, 1H), 6.40 (s, 1H), 5, 90 (s, 1H), 5.86 (s, 1H), 4.50 - 4.35 (m, 1H), 4.23 - 4.22 (d, J = 5.6HZ, 2H), 3, 64 - 3.58 (m, 4H), 3.08 - 3.02 (m, 4H), 2.32 (s, 3H), 2.25 (s, 3H), 2.20 (s, 3H) , 2.17 (s, 3H), 1.48 - 1.44 (m, 3H); ESI-MS m / z 536 [M + H] +.

[00748] Example 99: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4-ethylpiperaz in) -1-ethyl) -2-bromoindolizine-7-carboxamide: the same as in Example 30.

[00749] Step 1: Preparation of isopropyl 6-methyl-5- (1- (4-ethylpiperazine) -1-vinyl) -2-bromoindolizine-7-carboxylate: ESI-MS m / z 434 [M + H] +.

[00750] Step 2: Preparation of 6-methyl-5- (1- (4-ethylpiperazine) -1-ethyl) -2-bromoindolizine-7-carboxylate: the yield of the two stages was 99%.

[00751] ESI-MS m / z 436 [M + H] +.

[00752] Step 3: Preparation of 6-methyl-5- (1- (4-ethylpiperazine) -1-ethyl) -2-bromoindolizine-7-carboxylic acid: ESI-MS m / z 394 [M + H] + .

[00753] Step 4: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4-ethylpiperaz ina) -1-ethyl) -2-bromoindolizine-7-carboxamide: the yield of the two stages was 60%. 1H NMR (400 MHz, MeOD) δ 7.35 (s, 1 H), 6.57 (s, 1 H), 6.14 (s, 1 H), 4.46 (s, 2 H), 4.22 - 4.17 (m, 1 H), 3.67 - 3.63 (d, J = 13.2 Hz, 1 H), 3.58 - 3.55 (m, 2H), 3, 40 - 3.37 (d, J = 12.4Hz, 1H), 3.25 - 3.19 (m, 4H), 2.45 - 2.38 (m, 5H), 2.31 (s, 3H ), 2.25 (s, 3H), 1.55 - 1.53 (d, J = 6.8 Hz, 3H), 1.34 - 1.31 (t, J = 7.6 Hz, 3H); ESI-MS m / z 552 [M + H] +.

[00754] Example 100: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (pip erazine) -1-yl) ethyl) indolizine-7-carboxamide:

[00755] Step 1: Preparation of isopropyl 2-bromo-5- (1- (4- (tert-butoxycarbonyl) piperazin-1-yl) vinyl) -6-methylindolizine-7-carboxylate: the same as in Step 1, of Example 30. ESI-MS m / z 506 [M + H] +.

[00756] Step 2: Preparation of isopropyl 2-bromo-5- (1- (4- (tert-butoxycarbonyl) piperazin-1-yl) ethyl) -6-methylindolizine-7-c arboxylate: same as in Step 2 , from Example 30. The yield of the two stages was 33%. ESI-MS m / z 508 [M + H] +.

[00757] Step 3: Preparation of 2-bromo-5- (1- (4- (tert-butoxycarbonyl) piperazin-1-yl) ethyl) -6-methylindolizine-7-c arboxylic acid: the same as in Step 3, of Example 30. ESI-MS m / z 466 [M + H] +.

[00758] Step 4: Preparation of 4- (1- (2- (2,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) aminocarbonyl) -6-methyl lindolizine-5 tert-butyl -yl) ethyl) piperazine-1-carboxylate: the same as in Step 4 of Example 30. The yield of the two steps was 40%. ESI-MS m / z 600 [M + H] +.

[00759] Step 5: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (pip erazine) -1-yl) ethyl) indolizine-7-carboxamide: the same as in Step 5 of Example 60. Yield: 53%. 1H NMR (CDCl3, 400 MHz): 7.34 (s, 1 H), 6.57 (s, 1 H), 6.12 (s, 1 H), 4.64 (s, 2 H), 4.9 - 4.18 (m, 1 H), 3.22 - 3.17 (m, 4 H), 2.93 - 2.90 (m, 2 H), 2.55 - 2.45 ( m, 2 H), 2.41 (s, 3 H), 2.30 (s, 3 H), 2.24 (s, 3 H), 1.51 (d, 3 H, J = 6.7 Hz) ; ESI-MS m / z 500 [M + H] +.

[00760] Example 101: Preparation of 5- (1- (4-methylpiperazin-1-yl) ethyl) -2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyr din-3-yl) methyl) -6-methylindolizine-7-carboxamide:

[00761] Step 1: Preparation of 5- (1- (4-methylpiperazin-1-yl) ethyl) -2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyr din-3-yl) methyl) -6-methylindolizine-7-carboxamide: In a 50 ml dry single-mouthed bottle, the compound 2-bromo-N - ((4,6-dimethyl-2-oxo-1 , 2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (pip erazin-1-yl) ethyl) indolizine-7-carboxamide (38 mg, 0.076 mmol) was dissolved in dichloromethane ( 3 mL), acetyl chloride (140 mg, 1.8 mmol), triethylamine (180 mg, 1.8 mmol) were added and stirred at room temperature for 1 hour. The reaction mixture was separated and purified by means of preparative purification. The solvent evaporated under reduced pressure and lyophilized to provide white solids (32 mg, yield: 78%). 1H NMR (CDCl3, 400 MHz): 8.37 (br, 1 H), 7.24 (s, 1 H), 6.82 (s, 1 H), 6.58 (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 (m, 1 H ), 3.47 - 3.36 (m, 3 H), 2.93 - 2.84 (m, 4 H), 2.56 (s, 3 H), 2.42 (s, 3 H), 2.27 (s, 3 H), 2.06 (s, 3 H), 1.49 (d, J = 6.7 Hz, 3 H); ESI-MS m / z 542 [M + H] +.

[00762] Example 102: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- ( 2-hydroxylacetyl) piperazin-1-yl) ethyl) -6-methylindolizine-7-carboxamide:

[00763] Step 1: Preparation of isopropyl 2-bromo-5- (1- (4- (2-hydroxyacetyl) piperazin-1-yl) ethyl) -6-methylindolizine-7-carboxylate: the same as in Step 1 , from Example 102, yield: 48%. ESI-MS m / z 466 [M + H] +.

[00764] Step 2: Preparation of 2-bromo-5- (1- (4- (2-hydroxyacetyl) piperazin-1-yl) ethyl) -6-methylindolizine-7-carboxylic acid: the same as in Step 4, of Example 31. ESI-MS m / z 424 [M + H] +.

[00765] Step 3: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- ( 2-hydroxylacetyl) piperazin-1-yl) ethyl) -6-methylindolizine-7-carboxamide: the same as in Step 5, Example 31, 5% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (s, 1H), 7.31 (s, 1H), 6.54 (s, 1H), 6.10 (s, 1H), 4 , 75 (s, 2H), 4.58 (s, 2H), 4.20 (s, 1H), 3.58 - 3.71 (m, 3H), 3.19 - 3.24 (m, 2H ), 2.36 (s, 3H), 2.28 - 2.20 (m, 8H), 2.11 (s, 3H), 1.37 - 1.32 (m, 3H); ESI-MS m / z 560 [M + H] +.

[00766] Example 103: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: the same as in Example 102.

[00767] Step 1: Preparation of 2-bromo-6-methyl-5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) indolizine-7-carboxyl isopropyl act: 91% yield. ESI-MS m / z 488 [M + H] +.

[00768] Step 2: 2-Bromo-6-methyl-5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) indolizine-7-carboxylic acid: 91% yield. ESI-MS m / z 444 [M + H] +.

[00769] Step 3: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4- (methylsulfonyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: 29% yield. 1H NMR (DMSO-d6, 400 MHz): 8.28 (s, 1 H), 8.24-8.21 (m, 1 H), 7.27 (s, 1 H), 6.61 ( s, 1 H), 5.88 (s, 1 H), 4.27 - 4.26 (m, 2 H), 4.11 - 4.10 (m, 1 H), 3.12 - 3, 11 (m, 4 H), 2.89 (s, 3 H), 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), 1.44 - 1.42 (m, 3 H); ESI-MS m / z 580 [M + H] +.

[00770] Example 104: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4-ethylsulfonyl ) piperazin) -1-ethyl) -2-bromoindolizine-7-carboxamide: the same as in Example 102.

[00771] Step 1: Preparation of isopropyl 6-methyl-5- (1- (4-ethylsulfonylpiperazin) -1-ethyl) -2-bromoindolizine-7-carboxylate: 88% yield. ESI-MS m / z 500 [M + H] +.

[00772] Step 2: Preparation of 6-methyl-5- (1- (4-ethylsulfonylpiperazin) -1-ethyl) -2-bromoindolizine-7-carboxylic acid: 76% yield. ESI-MS m / z 458 [M + H] +.

[00773] Step 3: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4-ethylsulfonyl piperazin) -1-ethyl) -2-bromoindolizine-7-carboxamide: 88% yield. 1H NMR (400 MHz, MeOD) δ 7.97 (s, 1H), 7.39 (s, 1H), 6.61 (s, 1H), 6.23 (s, 1H), 4.46 ( s, 1H), 3.10 - 3.03 (m, 1H), 2.99 (s, 1H), 2.40 (s, 3H), 2.32 (m, 3H), 2.28 (s , 3H), 1.38 - 1.34 (m, 7H), 1.33 - 1.29 (m, 3H); ESI-MS m / z 592 [M + H] +.

[00774] Example 105: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4- (3,3,3-trifluoropropyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide:

[00775] Step 1: Preparation of ethyl 2-bromo-6-methyl-5- (1- (4- (3,3,3-trifluoropropyl) piperazin-1-yl) ethyl) indolizine-7-c arboxylate: in a 100 ml dry single-mouthed flask, isopropyl 2-bromo-6-methyl-5- (1- (piperazin-1-ethyl) ethyl) indolizine-7-carboxylate (170 mg, 0.38 mmol) was dissolved in N, N-dimethylformamide (10 mL), and 1,1,1-trifluoro-3-iodopropane (170 mg, 0.76 mmol), potassium carbonate (157 mg, 1.14 mmol) were added, the mixture was stirred in a microwave at 100 ° C for 2 hours, water was added, and extracted with ethyl acetate (50 × 3 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to provide a yellow oil (120 mg, 63%), ESI-MS m / z 504 [M + H] +.

[00776] Step 2: Synthesis of 2-bromo-6-methyl-5- (1- (4- (3,3,3-trifluoropropyl) piperazin-1-yl) ethyl) indolizine-7-c arboxylic acid: a same as in Step 2, Example 102. ESI-MS m / z 462 [M + H] +.

[00777] Step 3: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4- (3,3,3-trifluoropropyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: same as in Step 3, Example 102. Yield: 56%. 1H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1 H), 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 (m, 2 H), 4.15 - 4.13 (m, 1 H), 3.59 (m, 3 H), 3.48 - 3.42 (m, 2 H), 3.33 - 2.81 (m, 4 H), 2.26 (s, 3 H), 2.35 (s, 3 H ), 2.25 (s, 6 H), 2.12 (s, 3 H), 1.45 - 1.44 (m, 3 H); ESI-MS m / z 596 [M + H] +.

[00778] Example 106: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamino) pip eridin -1-yl) ethyl) -6-methyl-2- (1-methyl-1H-pyrazol-5-yl) indolizine-7-carboxamide: the same as in Example 31.

[00779] Step 1: Step 1: Preparation of 5- (1- (4- (dimethylamino) piperidin-1-yl) vinyl) -6-methyl-2- (1-methyl-1H-pyrazol-5-yl) in isopropyl dolizine-7-carboxylate: ESI-MS m / z 450 [M + H] +.

[00780] Step 2: Preparation of 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -6-methyl-2- (1-methyl-1H-pyrazol-5-yl) ind olizine- Isopropyl 7-carboxylate: the yield of the two stages was 51%. ESI-MS m / z 452 [M + H] +.

[00781] Step 3: Preparation of 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -6-methyl-2- (1-methyl-1H-pyrazol-5-yl) ind olizine acid -7-carboxylic: ESI-MS m / z 410.5 [M + H] +.

[00782] Step 4: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamino) pip eridin -1-yl) ethyl) -6-methyl-2- (1-methyl-1H-pyrazol-5-yl) indolizine-7-carboxamide: The yield of the two stages was 20%. 1H NMR (DMSO-d6, 400 MHz): 11.54 (s, 1 H), 9.45-9.44 (m, 1 H), 8.68-8.67 (m, 1 H), 8.23 (s, 1 H), 7.43 - 7.32 (m, 2 H), 6.78 - 6.75 (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), 3.43 - 3.42 (m, 1 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 (m, 6 H), 1.96 - 1.94 (m, 2 H), 1.75 - 1.73 (m, 2 H); ESI-MS m / z 544 [M + H] +.

[00783] Example 107: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamino) pip eridin -1-yl) ethyl) -6-methyl-2- (1-methyl-1H-pyrazol-2-yl) indolizine-7-carboxamide: the same as in Example 50.

[00784] Step 1: Preparation of 5- (1- (4- (dimethylamino) piperidin-1-yl) vinyl) -6-methyl-2- (1-methyl-1H-pyrazol-2-yl) in dolizine- Isopropyl 7-carboxylate: ESI-MS m / z 450 [M + H] +.

[00785] Step 2: Preparation of 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -6-methyl-2- (1-methyl-1H-pyrazol-2-yl) ind olizine- Isopropyl 7-carboxylate: the yield of the two stages was 45%. ESI-MS m / z 452 [M + H] +.

[00786] Step 3: Preparation of 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -6-methyl-2- (1-methyl-1H-pyrazol-2-yl) ind olizine acid -7-carboxylic: ESI-MS m / z 410 [M + H] +.

[00787] Step 4: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamino) pip eridin -1-yl) ethyl) -6-methyl-2- (1-methyl-1H-pyrazol-2-yl) indolizine-7-carboxamide: The yield of the two stages was 55%. 1H NMR (MeOD, 400 MHz): 8.96 (s, 1H), 7.62 (s, 1H), 7.58 (s, 2H), 7.07 (s, 1H), 6.19 ( s, 1H), 4.49 (s, 2H), 4.47 (s, 1H), 4.07 (s, 3H), 3.69 - 3.67 (m, 1H), 2.96 (s , 6H), 2.41 (s, 3H), 2.37 (s, 3H), 2.28 - 2.26 (m, 5H). 1.98 - 1.95 (m, 2H), 1.69 - 1.67 (m, 2H); ESI-MS m / z 544 [M + H] +.

[00788] Example 108: Preparation of 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -N - ((4-methoxy-6-methyl-2-oxo-1,2-di- hi dropiridin-3-yl) methyl) -6-methyl-2- (1-methyl-1H-imidazol-2-yl) indolizine-7-carboxylic acid: the same as in Step 5, in Example 31, where 3 - The desired (aminomethyl) -4-methoxy-6-methylpyridin-2 (1H) -one was synthesized according to document No. (WO2015023915).

[00789] Step 5: Preparation of 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -N - ((4-methoxy-6-methyl-2-oxo-1,2-di- hi dropiridin-3-yl) methyl) -6-methyl-2- (1-methyl-1H-imidazol-2-yl) indolizine-7-carboxy, 55% yield. 1H NMR (MeOD, 400 MHz): 8.96 (s, 1H), 7.61 - 7.60 (m, 1H), 7.59 - 7.55 (m, 2H), 7.06 (s , 1H), 6.39 (s, 1H), 4.46 (s, 2H), 4.33 (s, 1H), 4.06 (s, 3H), 3.96 (s, 3H), 3 , 69 - 3.67 (m, 1H), 3.23 - 3.02 (m, 2H), 2.91 (s, 6H), 2.78 - 2.77 (m, 2H), 2.36 (s, 6H), 2.26 - 2.23 (m, 2H). 1.96 - 1.93 (m, 2H), 1.65 - 1.63 (m, 3H); ESI-MS m / z 560 [M + H] +.

[00790] Example 109: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl- 1 H-imidazol-2-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carb oxamide: the same as in Example 83.

[00791] Step 1: Synthesis of 5- (1- (4- (tert-butoxycarbonyl) piperazin-1-yl) vinyl) -6-methyl-2- (1-methyl-1H-imidaz ol-2-yl) indolizine-7-isopropyl formate: ESI-MS m / z 508 [M + H] +.

[00792] Step 2: Synthesis of 5- (1- (4- (tert-butoxycarbonyl) piperazin-1-yl) ethyl) -6-methyl-2- (1-methyl-1H-imidazol -2-yl) indolizine -7-isopropyl format: the yield of the two stages was 45%. ESI-MS m / z 510 [M + H] +.

[00793] Step 3: Preparation of isopropyl 6-methyl-2- (1-methyl-1H-pyrazol-5-yl) -5- (1- (piperazin-1-yl) ethyl) indolizine-7-carboxylate : 87% yield. ESI-MS m / z 410 [M + H] +.

[00794] Step 4: Preparation of 6-methyl-2- (1-methyl-1H-imidazol-2-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl ) and useful) isopropyl indolizine-7-formate: 63% yield. ESI-MS m / z 492 [M + H] +.

[00795] Step 5: Preparation of 6-methyl-2- (1-methyl-1H-imidazol-2-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1- il) i ndolizine-7-formic: ESI-MS m / z 450 [M + H] +.

[00796] Step 6: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl- 1 H-imidazol-2-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carbo xamide: the yield of the two stages was 4 %. 1H NMR (CDCl3, 400 MHz): 8.82 (s, 1H), 7.72 - 7.57 (m, 4H), 7.16 (s, 1H), 6.91 (s, 1H), 4.52 (s, 2H), 4.10 (s, 3H), 4.05 (s, 3H), 3.24 - 3.12 (m, 6H), 2.98 - 2.95 (m, 1H), 2.54 - 2.52 (m, 2H), 2.51 (s, 3H), 2.40 (s, 2H), 1.78 (d, J = 6.9 Hz, 3H); ESI-MS m / z 600 [M + H] +.

[00797] Example 110: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl- 1 H-imidazol-2-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carb oxamide: the same as in Step 5, in the Example 31.

[00798] Step 1: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl- 1 H-imidazol-2-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carb oxamide: 4% yield. 1H NMR (CDCl3, 400 MHz): 8.86 (s, 1 H), 7.71 - 7.54 (s, 4 H), 7.12 (s, 1 H), 6.44 (s, 1 H), 4.52 (s, 2 H), 4.05 (s, 3 H), 3.86-3.84 (m, 1 H), 3.78 - 3.71 (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 H), 2.34 (s, 3 H), 1.78 (d, J = 6.9 Hz, 3 H); ESI-MS m / z 584 [M + H] +.

[00799] Example 111: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamino) pip eridin -1-yl) ethyl) -6-methyl-2- (1-methyl-1H-imidazol-2-yl) indolizine-7-carboxamide: the same as in Example 50.

[00800] Step 1: Preparation of ethyl 5-methyl-2- (1H-imidazol-2-yl) -6-methylindolizine-7-carboxylate: Yield 89%. ESI-MS m / z 312 [M + H] +.

[00801] Step 1: Preparation of isopropyl 5- (1- (4- (dimethylamino) piperidin-1-yl) vinyl) -2- (1H-imidazol-2-yl) -6-methylindolizin a-7-carboxylate : ESI-MS m / z 395 [M + H] +.

[00802] Step 3: Preparation of 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -2-methyl-2- (imidazol-2-yl) -6-methylindolazine-7-carboxylate isopropyl: the yield of the two stages was 55%.
ESI-MS m / z 397 [M + H] +.

[00803] Step 4: Preparation of 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -2- (1H-imidazol-2-yl) -6-methylindolizine -7-carboxylic acid: ESI -MS m / z 355 [M + H] +.

[00804] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamino) pip eridin -1-yl) ethyl) -6-methyl-2- (1-methyl-1H-imidazol-2-yl) indolizine-7-carboxamide: The yield of the two stages was 13%. 1H NMR (MeOD, 400 MHz): 9.13 (s, 1 H), 7.55 - 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, 1 H), 3.88 - 3.85 (m, 1 H), 3.71 (s, 4 H ), 3.23 - 3.21 (m, 2 H), 2.91 - 2.81 (m, 2 H), 2.38 (s, 3 H), 2.31 (s, 3 H), 2.19 (s, 3 H), 1.61 - 1.59 (m, 3 H); ESI-MS m / z 489.3 [M + H] +.

[00805] Example 112: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinoethyl) -2 - (pyrazol-5-yl) indolizine-7-carboxamide: the same as in Example 31.

[00806] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2- (1H-pyrazol-5-yl) indolizine-7-carboxylate: Yield 31%. ESI-MS m / z 312.1 [M + H] +.

[00807] Step 2: Preparation of isopropyl 6-methyl-5- (1-morpholinovinyl) -2- (1H-pyrazol-5-yl) indolizine-7-carboxylate: ESI-MS m / z 395 [M + H ] +.

[00808] Step 3: Step 3: Preparation of isopropyl 6-methyl-5- (1-morpholinoethyl) -2- (1H-pyrazol-5-yl) indolizine-7-carboxylate: the yield of the two steps was 53 %. ESI-MS m / z 397 [M + H] +.

[00809] Step 4: Step 4: Preparation of 6-methyl-5- (1-morpholinoethyl) -2- (1H-pyrazol-5-yl) indolizine-7-carboxylic acid: ESI-MS m / z 355 [M + H] +.

[00810] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinoethyl) -2 - (1H-pyrazol-5-yl) indolizine-7-carboxamide: 14% yield. 1H NMR (MeOD, 400 MHz): 7.90 (s, 1 H), 7.62 (s, 1 H), 6.80 (s, 1 H), 6.30 (s, 1 H), 4.50 (s, 2 H), 3.89 - 3.88 (m, 4 H), 3.21 - 3.19 (m, 2 H), 2.43 - 2.42 (m, 6 H ), 2.30 - 2.26 (m, 5 H), 1.94 - 1.92 (m, 3 H); ESI-MS m / z 489 [M + H] +.

[00811] Example 113: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinylethyl) -2 - (1-ethyl-1H-pyrazole) indolizine-7-carboxamide:

[00812] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2- (1-ethyl-1H-pyrazole) indolizine-7-carboxylate: 43% yield. ESI-MS m / z 340 [M + H] +.

[00813] Step 2: Preparation of isopropyl 6-methyl-5- (1-morpholinylvinyl) -2- (1-ethyl-1H-pyrazol) indolizine-7-carboxylate: ESI-MS m / z 423 [M + H ] +.

[00814] Step 3: Preparation of 6-methyl-5- (1-morpholinylethyl) -2- (1-ethyl-1H-pyrazole) indolizine-7-carboxylate: the yield of the two steps was 40%. ESI-MS m / z 425 [M + H] +.

[00815] Step 4: Preparation of 6-methyl-5- (1-morpholinylethyl) -2- (1-ethyl-1H-pyrazole) indolizine-7-carboxylate:
ESI-MS m / z 383 [M + H] +.

[00816] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinylethyl) -2 - (1-ethyl-1H-pyrazole) indolizine-7-carboxamide: the yield of the two stages was 42%. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (s, 1H), 8.56 (s, 1H), 8.17 (s, 1H), 7.46 (s, 1H), 7 , 35 (s, 1H), 6.72 (s, 1H), 6.43 (s, 1H), 5.88 (s, 1H), 4.27 - 4.32 (m, 9H), 3, 60 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H), 2.12 (s, 3H), 1.49 (s, 2H), 1.38 (t, J = 6.8 Hz, 3H), 1.24 (s, 2H); ESI-MS m / z 539 [M + H] +.

[00817] Example 114: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinoethyl) - 2 - (4,5,6,7-tetrahydro [2,3-c] pyridin-2-yl) indolizine-7-carboxamide: the first four steps are similar to those of Example 31.

[00818] Step 1: Synthesis of ethyl 5-acetyl-6-methyl-2- (4,5,6,7-tetrahydrothieno [2,3-c] pyridin-2-yl) indolizine-7-formate yield of 53%. ESI-MS m / z 383 [M + H] +.

[00819] Step 2: Synthesis of isopropyl-6-methyl-5- (1-morpholinovinyl) -2- (4,5,6,7-tetrahydrothieno [2,3-c] pyridin-1-yl) indolizine-7 ethyl ethyl carboxylate: ESI-MS m / z 466 [M + H] +.

[00820] Step 3: Synthesis of isopropyl-6-methyl-5- (1-morpholinoethyl) -2- (4,5,6,7-tetrahydrothieno [2,3-c] pyridin-1-yl) indolizine-7 - ethyl carboxylate: 68% yield in both stages.
ESI-MS m / z 468 [M + H] +.

[00821] Step 4: Synthesis of 6-methyl-5- (1-morpholinoethyl) -2- (4,5,6,7-tetrahydrothieno [2,3-c] pyridin-2-yl) indolizin a-7 -formic: 63% yield. ESI-MS m / z 426 [M + H] +.

[00822] Step 5: Synthesis of 2- (6- (tert-butoxycarbonyl) -4,5,6,7-tetrahydrothieno [2,3-c] pyridin-2-yl) -6-methyl-5- ( 1-morpholinoethyl) indolizine-7-carboxylic: For a dry flask of three necks, of 25 ml, 6-methyl-5- (1-morpholinoethyl) -2- (4,5,6,7-tetrahydrothienoic acid [2, 3-c] pyridin-2-yl) indolizin a-7-carboxylic crude product (120 mg, 0.28 mmol), di-tert-butyl dicarbonate (123 mg, 0.56 mmol), sodium hydroxide ( 22 mg, 0.56 mmol) were added successively, dissolved in 1,4-dioxane / water (1: 1) (3 mL) and stirred for 2 hours at room temperature. After the reaction was completed, 1N diluted hydrochloric acid was added to the reaction mixture to adjust the pH = 7, and the product was extracted with ethyl acetate (130 mg, yellow solid), yield: 88%. ESI-MS m / z 526 [M + H] +.

[00823] Step 6: Preparation of 2- (7 - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) carbamoyl) -6-methyl-5- (1 - morpholinoethyl) indol-2-yl) -4,5-dihydro-thieno [2,3-c] pyridine-6 (2H) tert-butyl-6-carboxylate: the same as in Step 5, in Example 31. Yield of: 24%.
ESI-MS m / z 660 [M + H] +

[00824] Step 7: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinoethyl) -2 - (4,5,6,7-tetrahydro [2,3-c] pyridin-2-yl) indolizine-7-carboxamide: the same as in Step 6, in Example 44. Yield: 74%.

[00825] 1H NMR (MeOD, 400 MHz): 8.74 (s, 1 H), 7.33 (s, 1 H), 7.04 (s, 1 H), 6.67 (s, 1 H), 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 (s, 4 H), 3.54 - 3.51 (m, 2 H), 3.03 - 3.00 (m, 2 H), 2.69 - 2.67 (m, 2 H), 2.37 (s, 3 H), 2.30 (s, 3 H), 2.22 (s, 3 H), 1.51 - 1.49 (m, 3 H). ESI-MS m / z 560 [M + H] +.

[00826] Example 115: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinoethyl) - 2 - (4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) indolizine-7-carboxamide: the same as in Example 53.

[00827] Step 1: Synthesis of 2- (5-acetyl-7- (ethoxycarbonyl) -6-methylindolizin-1-yl) -6,7-tetrahydrothieno [3,2-c] pyridine-5 (4H) - tert-butyl format, 29% yield. ESI-MS m / z 483 [M + H] +.

[00828] Step 2: Synthesis of 2- (7- (isopropoxycarbonyl) -6-methyl-5- (1-morpholinoethyl) indolizin-1-yl) -6,7-tetrahydrothieno [3,2-c] pyridine- 5 (4H) tert-butyl carboxylate, the yield of the two stages was 72%. ESI-MS m / z 568 [M + H] +.

[00829] Step 3: Synthesis of 2- (5- (tert-butoxycarbonyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) -6-methyl-5- ( 1-morpholinoethyl) indolizine-7-carboxylic, 72% yield. ESI-MS m / z 526 [M + H] +.

[00830] Step 4: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinoethyl) -2 - (4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) indolizine-7-carboxamide: the yield of the two stages was 6%. 1H NMR (CDCl3, 400 MHz): 7.36 (s, 1H), 7.05 (s, 1H), 6.12 (s, 1H), 4.59 (s, 2H), 4.28 ( s, 2H), 3.85 (s, 1H), 3.71 (s, 4H), 3.58 - 3.55 (m, 2H), 3.23 - 3.21 (m, 2H), 3 , 17 - 3.15 (m, 2H), 2.77 (s, 2H), 2.38 (s, 3H), 2.31 (s, 3H), 2.19 (s, 3H), 1, 58 (d, J = 6.9 Hz, 3H); ESI-MS m / z 560 [M + H] +.

[00831] Example 116: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -1- (3- (dimethylamine) phenyl) - 6- methyl-5- (1-morpholinylethyl) indolizine-7-carboxamide: the same as in Example 31.

[00832] Step 1: Preparation of ethyl 5-acetyl-1- (3- (dimethylamine) phenyl) -6-methylindolizine-7-carboxylate: 25% yield. ESI-MS m / z 365 [M + H] +.

[00833] Step 2: Preparation of isopropyl 1- (3- (dimethylamine) phenyl) -6-methyl-5- (1-morpholinavinyl) indolizine-7-carboxylate: ESI-MS m / z 448 [M + H] +.

[00834] Step 3: Preparation of isopropyl 1- (3- (dimethylamine) phenyl) -6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxylate: the yield of the two steps was 42%. ESI-MS m / z 450 [M + H] +.

[00835] Step 4: Preparation of 1- (3- (dimethylamine) phenyl) -6-methyl-5- (1-morpholinylethyl) indolizine-7-carboxylic acid: ESI-MS m / z 408 [M + H] + .

[00836] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -1- (3- (dimethylamine) phenyl) - 6- methyl-5- (1-morpholinylethyl) indolizine-7-carboxamide: 27% yield. 1H NMR (400 MHz, CDCl3) δ ppm 11.47 (s, 1H), 8.41 (s, 1H), 8.24-8.26 (m, 1H), 7.57 (s, 1H) , 7.19 - 7.23 (m, 1H), 6.97 - 6.98 (d, J = 2.8 Hz, 1H), 6.61 (m, 2H), 5.85 (s, 1H ), 4.25 - 4.26 (m, 2H), 4.05 - 4.07 (m, 1H), 3.58 (m, 4H), 2.88 (s, 6H), 2.63 - 2.66 (m, 2H), 2.31 (s, 3H), 2.11 - 2.17 (m, 5H), 2.11 (s, 3H), 1.43 - 1.44 (m, 3H); ESI-MS m / z 542 [M + H] +.

[00837] Example 117: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinylethyl) -1 - (3-morpholinylphenyl) indolizine-7-carboxamide: the same as in Example 31.

[00838] Step 1: Preparation of ethyl 5-acetyl-6-methyl-1- (3-morphinolinylphenyl) indolizine-7-carboxylate: Yield 21%. ESI-MS m / z 406 [M + H] +.

[00839] Step 2: Preparation of isopropyl 6-methyl-1- (3-morphinolinylphenyl) -5- (1-morphinolinylvinyl) indolizine-7-carboxylate: ESI-MS m / z 490 [M + H] +.

[00840] Step 3: Preparation of isopropyl 6-methyl-1- (3-morphinolinylphenyl) -5- (1-morphinolinylethyl) indolizine-7-carboxylate: ESI-MS m / z 492 [M + H] +.

[00841] Step 4: Preparation of 6-methyl-1- (3-morphinolinylphenyl) -5- (1-morfinolinylethyl) indolizine-7-carboxylic acid: the yield of the two stages was 46%. ESI-MS m / z 450 [M + H] +.

[00842] Step 6: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 1- (3-morphinolinylphenyl) indolizine-7-carboxamide: 40% yield. 1H NMR (400 MHz, CDCl3) δ ppm 11.44 (s, 1 H), 8.42-8.41 (s, 1 H), 8.29 (s, 1 H), 7.54 (s , 1 H), 7.29 - 7.25 (m, 1 H), 7.07 (s, 1 H), 7.03-6.99 (m, 2 H), 6.82-6.80 (d, J = 6.0 Hz, 1 H), 5.86 (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 - 3.49 (m, 4 H), 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), 2.11 (s, 3 H), 1.45 - 1.44 ( m, 3 H); ESI-MS m / z 584 [M + H] +.

[00843] Example 118: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -1- (4- (dimethylamine) phenyl) - 6- methyl-5- (1-morpholinylethyl) indolizine-7-carboxamide: the same as in Example 31.

[00844] Step 1: Preparation of ethyl 5-acetyl-1- (4- (dimethylamino) phenyl) -6-methylindolizine-7-carboxylate: Yield 5%. ESI-MS m / z 365 [M + H] +.

[00845] Step 2: Preparation of isopropyl 1- (4- (dimethylamine) phenyl) -6-methyl-5- (1-morpholinavinyl) indolizine-7-carboxylate: ESI-MS m / z 448 [M + H] +.

[00846] Step 3: Preparation of isopropyl 1- (4- (dimethylamine) phenyl) -6-methyl-5- (1-morphinolinylethyl) indolizine-7-carboxylate: the yield of the two steps was 25%. ESI-MS m / z 450 [M + H] +.

[00847] Step 4: Preparation of 1- (4- (dimethylamine) phenyl) -6-methyl-5- (1-morpholinylethyl) indolizine-7-carboxylic acid: ESI-MS m / z 408 [M + H] + .

[00848] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -1- (4- (dimethylamine) phenyl) - 6- methyl-5- (1-morpholinylethoxy) indolizine-7-carboxamide: 38% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.45 (s, 1H), 7.59 (s, 1H), 7.41 - 7.39 (m, 2H), 6.87 - 6.84 ( m, 1H), 6.10 (s, 1H), 5.85 (s, 1H), 4.66 (s, 2H), 4.10 - 4.08 (m, 1H), 3.67 (m , 4H), 2.94 (s, 6H), 2.69 - 2.68 (m, 2H), 2.36 (s, 3H), 2.30 - 2.23 (m, 5H), 2, 20 (s, 3H), 1.52 - 1.50 (m, 3H); ESI-MS m / z 542 [M + H] +.

[00849] Example 119: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinylethyl) -1 - (4-morpholinylphenyl) indolizine-7-carboxamide: the same as in Example 31.

[00850] Step 1: Preparation of ethyl 5-acetyl-6-methyl-1- (4-morphinolinylphenyl) indolizine-7-carboxylate: Yield 19%. ESI-MS m / z 407 [M + H] +.

[00851] Step 2: Preparation of isopropyl 6-methyl-1- (4-morphinolinylphenyl) -5- (1-morphinolinylvinyl) indolizine-7-carboxylate: ESI-MS m / z 490 [M + H] +.

[00852] Step 3: Preparation of isopropyl 6-methyl-1- (4-morphinolinylphenyl) -5- (1-morphinolinylethyl) indolizine-7-carboxylate: the yield of the two steps was 46%. ESI-MS m / z 492 [M + H] +.

[00853] Step 4: Preparation of 6-methyl-1- (4-morphinolinylphenyl) -5- (1-morphinolinylethyl) indolizine-7-carboxylic acid: ESI-MS m / z 450 [M + H] +.

[00854] Step 5: Preparation of N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 1- (4-morphinolinylphenyl) indolizine-7-carboxamide: the yield of the two stages was 14%. 1H NMR (400 MHz, CDCl3) δ ppm 8.50 (s, 1H), 7.60 (s, 1H), 7.44 - 7.46 (m, 2H), 7.01 - 7.04 ( m, 2H), 6.87 (d, J = 2.8 Hz, 1H), 6.10 (s, 1H), 4.45 (s, 2H), 4.07 - 4.12 (m, 1H ), 3.84 - 3.86 (m, 4H), 3.67 (m, 4H), 3.14 - 3.17 (m, 4H), 2.68 - 2.70 (m, 2H), 2.36 (s, 3H), 2.27 - 2.31 (m, 5H), 2.23 (s, 3H), 1.50 - 1.52 (m, 3H); ESI-MS m / z 584 [M + H] +.

[00855] Example 120: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinylethyl) -1 - (3-methoxyphenyl) indolizine -7-amide: the same as in Example 31.

[00856] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2- (3-methoxyphenyl) indolizine-7-carboxylate: 14% yield. ESI-MS m / z 352 [M + H] +.

[00857] Step 2: Preparation of isopropyl 6-methyl-5- (1-morphinolinylvinyl) -1- (3-methoxyphenyl) indolizine-7-carboxylate: ESI-MS m / z 435 [M + H] +.

[00858] Step 3: Preparation of isopropyl 6-methyl-5- (1-morphinolinylethyl) -1- (3-methoxyphenyl) indolizine-7-carboxylate: the yield of the two steps was 79%. ESI-MS m / z 437 [M + H] +.

[00859] Step 4: Preparation of 6-methyl-5- (1-morphinolinylethyl) -1- (3-methoxyphenyl) indolizine-7-carboxylic acid:
ESI-MS m / z 395 [M + H] +.

[00860] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfinolinylethyl) - 1- (3-methoxyphenyl) indolizine-7-carboxamide: the yield of the two stages was 9%. 1H NMR (400 MHz, CDCl3) δ ppm 11.16 (s, 1 H), 8.41 (s, 1 H), 7.61 (s, 1 H), 7.22 - 7.20 (m , 2 H), 7.06 - 7.04 (m, 2 H), 7.00 (s, 1 H), 6.83 (s, 1 H), 6.67 - 6.65 (m, 1 H), 5.81 (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), 3.62 (s, 4 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 (s, 3 H), 1.43 - 1.41 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 551 [M + H] +.

[00861] Example 121: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinylethyl) -1 - (4-methoxyphenyl) indolizine-7-carboxamide:

[00862] Step 1: Preparation of ethyl 5-acetyl-6-methyl-2- (4-methoxyphenyl) indolizine-7-carboxylate: Yield 11%. ESI-MS m / z 352 [M + H] +.

[00863] Step 2: Preparation of isopropyl 6-methyl-5- (1-morphinolinylvinyl) -1- (4-methoxyphenyl) indolizine-7-carboxylate: ESI-MS m / z 435 [M + H] +.

[00864] Step 3: Preparation of isopropyl 6-methyl-5- (1-morphinolinylethyl) -1- (4-methoxyphenyl) indolizine-7-carboxylate: 78% yield. ESI-MS m / z 437 [M + H] +.

[00865] Step 4: Preparation of 6-methyl-5- (1-morphinolinylethyl) -1- (4-methoxyphenyl) indolizine-7-carboxylic acid:
ESI-MS m / z 395 [M + H] +.

[00866] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) 6-methyl-5- (1-morpholinylethyl) - 1- (4-methoxyphenyl) indolizine-7-carboxamide: 1H NMR (400 MHz, CDCl3) δ ppm 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 (m, 1 H), 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), 6.79-6.78 (m, 1 H), 4 , 44 - 4.42 (d, J = 5.6 Hz, 2H), 4.03 - 4.01 (d, J = 6.8 Hz, 1H), 3.72 (s, 3H), 3, 62 (s, 4H), 2.32 (s, 3H), 2.26 (s, 3H), 2.17 - 2.13 (t, J = 7.6 Hz, 2H), 1.97 - 1 , 92 (m, 2H), 1.42 - 1.44 (d, J = 6.4 Hz, 3H). ESI-MS m / z 551 [M + H] +.

[00867] Example 122: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (pyrrole-1) -yl) ethyl) indolizine-7-carboxamide: the same as in Example 30.

[00868] Step 1: Step 2: Preparation of isopropyl 2-bromo-6-methyl-5- (1- (pyrrol-1-yl) vinyl) indolizine-7-carboxylate: ESI-MS m / z 391 [M + H] +.

[00869] Step 2: Preparation of isopropyl 2-bromo-6-methyl-5- (1- (pyrrol-1-yl) ethyl) indolizine-7-carboxylate: the yield of the two steps was 59%. ESI-MS m / z 393 [M + H] +.

[00870] Step 3: Preparation of 2-bromo-6-methyl-5- (1- (pyrrol-1-yl) ethyl) indolizine-7-carboxylic acid: ESI-MS m / z 351 [M + H] + .

[00871] Step 4: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (pyrrol-1-yl) ethyl) indolizine-7-carboxamide: Yield 4%. 1H NMR (400 MHz, DMSO-d6) δ 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), 4.57 (m, 2 H), 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), 2.18 (s, 3 H), 1.78 - 1.77 (m, 4 H), 1 , 49 - 1.47 (m, 3 H); ESI-MS m / z 485 [M + H] +.

[00872] Example 123: Preparation of 2-bromo-5- (1- (4,4-difluoropiperidin-1-yl) ethyl) -N - (((4,6-dimethyl-2-oxo-1,2-di -hydro opiridin-3-yl) methyl) -6-methylindolizine-7-carboxamide: the same as in Example 30.

[00873] Step 1: Preparation of isopropyl 2-bromo-5- (1- (4,4-difluoropiperidin-1-yl) vinyl) -6-methylindolizine-7-carboxylate: ESI-MS m / z 441 [M + H] +.

[00874] Step 2: Preparation of isopropyl 2-bromo-5- (1- (4,4-difluoropiperidin-1-yl) ethyl) -6-methylindolizine-7-carboxylate: the yield of the two steps was 7% . ESI-MS m / z 443 [M + H] +.

[00875] Step 3: Preparation of 2-bromo-5- (1- (4,4-difluoropiperidin-1-yl) ethyl) -6-methylindolizine-7-carboxylic acid: ESI-MS m / z 401 [M + H] +.

[00876] Step 4: Preparation of 2-bromo-5- (1- (4,4-difluoropiperidin-1-yl) ethyl) -N - (((4,6-dimethyl-2-oxo-1,2-di -hydro opiridin-3-yl) methyl) -6-methylindolizine-7-carboxamide: the yield of the two stages was 51%. 1H NMR (MeOD, 400 MHz): 7.36 (s, 1 H), 6.59 (s, 1 H), 6.14 (s, 1 H), 4.48 (s, 2 H), 4.39 (s, 1 H), 2.96 - 2.95 (m, 2 H), 2.55 - 2.53 (m, 2 H), 2.37 (s, 3 H), 2, 30 (s, 3 H), 2.35 (s, 3 H), 2.03 - 2.02 (m, 4 H). 1.60 - 1.58 (m, 3 H); ESI-MS m / z 535 [M + H] +.

[00877] Example 124: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -2- (2-fluoro-5-methoxyphenyl) -6 -methyl-5- (1-morpholinoethyl) indolizine-7-carboxamide: the same as in Example 31.

[00878] Step 1: Preparation of ethyl 5-acetyl-2- (2-fluoro-5-methoxyphenyl) -6-methylindolizine-7-carboxylate: Yield 66%. ESI-MS m / z 370 [M + H] +.

[00879] Step 2: Preparation of isopropyl 2- (2-fluoro-5-methoxyphenyl) -6-methyl-5- (1-morphinolinylvinyl) indolizine-7-carboxylate. ESI-MS m / z 453 [M + H] +.

[00880] Step 3: Preparation of 2- (2-fluoro-5-methoxyphenyl) -6-methyl-5- (1-morpholinylethyl) indolizine-7-carboxylate isopropyl: the yield of the two steps was 65%. ESI-MS m / z 455 [M + H] +.

[00881] Step 4: Preparation of 2- (2-fluoro-5-methoxyphenyl) -6-methyl-5- (1-morpholinylethyl) indolizine-7-carboxylic acid: ESI-MS m / z 413 [M + H] +.

[00882] Step 5: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -2- (2-fluoro-5-methoxyphenyl) - 6 -methyl-5- (1-morpholinylethyl) indolizine-7-carboxamide: the yield of the two stages was 32%. 1H NMR (CDCl3, 400 MHz): 12.78 (s, 1H), 8.88 (s, 1H), 7.35 (s, 2H), 7.18 - 7.15 (m, 1H), 7.07 - 7.03 (m, 1H), 6.74-6.72 (m, 2H), 5.98 (s, 1H), 4.54 - 4.52 (m, 2H), 4, 07 - 4.02 (m, 1H), 3.83 (s, 3H), 3.69 - 3.68 (m, 4H), 2.65 - 2.64 (m, 2H), 2.39 ( s, 3H), 2.35 (s, 3H), 2.27 - 2.22 (m, 2H), 2.04 (s, 3H), 1.50 - 1.48 (m, 3H); ESI-MS m / z 547 [M + H] +.

[00883] Example 125: Preparation of 7 - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) carbamoyl) -6-methyl-5- (1-m orfolinylethyl) methyl indolizine-2-carboxylate:

[00884] Step 1: Synthesis of 7 - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) carbamoyl) -6-methyl-5- (1-m orfolinoethyl) methyl indolizine-2-carboxylate: 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- ( 1-mor folino) indolizine-7-carboxamide (170 mg, 0.34 mmol), Pd (dppf) Cl2 (17 mg), triethylamine (69 mg, 0.68 mmol) and 30 ml of methanol were added in succession in a 25 ml CO-protected single-mouthed flask, stirred to reflux overnight, and then 50 ml of ethyl acetate and 20 ml of water were added. The organic phase was separated and concentrated to provide a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to provide a product as yellow solids (13 mg, yield: 8% ). 1H NMR (DMSO, 400 MHz): 11.48 (s, 1 H), 8.77 (s, 1 H), 8.25 (s, 1 H),, 48 - 7.47 (m, 1 H), 6.85 (m, 1 H), 5.85 (s, 1 H), 4.39 - 4.37 (m, 3 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), 1.55 - 1.54 (m, 3 H) . ESI-MS m / z 481 [M + H] +.

[00885] Example 126: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (morpholin-4-carbonyl ) -5 - (1-morpholinoethyl) indolizine-7-carboxamide:

[00886] Step 1: Preparation of 7 - ((((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) carbamoyl) -6-methyl-5- (1- m orfolinoethyl) indolizine-2-carboxylic:
Methyl 7 - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) carbamoyl) -6-methyl-5- (1-mo rfolinoethyl) indolizine-2-carboxylate (50 mg (crude), 0.104 mmol), lithium hydroxide (17.5 mg, 0.417 mmol) and 20 ml of THF / 15 ml of water were added successively to a 50 ml single-necked flask , stirred to reflux overnight, 2N hydrochloric acid was added to adjust the pH to 6 to 7, and 100 ml of ethyl acetate was added to the reaction system. The organic phase was separated and evaporated to provide a crude product (50 mg), which was used directly in the next step.

[00887] Step 2: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (morpholine-4-car bonil ) -5- (1-morpholinoethyl) indolizine-7-carboxamide: 21% yield. 1H NMR (MeOD, 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, 3 H), 3.79 - 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); ESI-MS m / z 536 [M + H] +.

[00888] Example 127: Preparation of N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (4-dimethylamino piperidinylethyl) - 1-phenylindolizine-7-carboxamide: the same as in Example 31.

[00889] Step 1: Preparation of isopropyl 6-methyl-5- (4-dimethylamidopiperidinylvinyl) -1-phenylindolizine-7-carboxylate: ESI-MS m / z 446 [M + H] +.

[00890] Step 2: Preparation of isopropyl 6-methyl-5- (4-dimethylamidopiperidinylvinyl) -1-phenylindolizine-7-carboxylate: the yield of the two steps was 91%. ESI-MS m / z 320 [M + H-C7H16N2] +.

[00891] Step 3: Preparation of 6-methyl-5- (4-dimethylamidopiperidinylvinyl) -1-phenylindolizine-7-carboxylic acid:
ESI-MS m / z 406 [M + H] +.

[00892] Step 4: Preparation of N - (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (4-dimethylamino piperidinylethyl) - 1-phenylindolizine-7-carboxamide: the yield of the two stages was 27%. 1H NMR (400 MHz, MeOD) δ ppm 7.73 (s, 1 H), 7.547 (d, J = 7.2 Hz, 2 H), 7.41 (t, J = 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 H), 3, 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 (m, 6 H), 2.30 (s, 2 H), 2.26 (s, 3 H), 2.21 - 2.16 (m, 2 H), 2.04 - 2.00 (m, 2 H), 1.73 (d, J = 6.0 Hz, 3 H); ESI-MS m / z 562 [M + H] +.

[00893] Example 128: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (4-dimethyl aminopiperidinylethyl ) -1-phenylindolizine-7-carboxamide: the same as in Example 108.

[00894] Step 1: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (4-dimethyl aminopiperidinylethylene ) -1-phenylindolizine-7-carboxamide: 31% yield. 1H NMR (400 MHz, d6-DMSO) δ ppm 11.44 (s, 1 H), 8.37 (s, 1 H), 8.10 (s, 1 H), 7.60 - 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 H), 6, 11 (s, 1 H), 4.42 (d, J = 4 Hz, 2 H), 4.11 - 4.06 (m, 1 H), 3.80 (s, 3 H), 3.03 (d, J = 6.8 Hz, 2 H), 2.86 (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 (s, 3 H), 2.18 (s, 4 H), 1.47 (d, J = 3.4 Hz, 3 H); ESI-MS m / z 556 [M + H] +.

[00895] Example 129: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamine) pip eridin -1-yl) ethyl) -6-methyl-1- (1-methyl-1H-pyrazol-5-yl) indolizine-7-carboxamide:

[00896] Step 1: Preparation of 5- (1- (4- (dimethylamine) piperidin-1-yl) vinyl) -6-methyl-1- (1-methyl-1H-pyrazol-5-yl) in dolizine- Isopropyl 7-carboxylate: ESI-MS m / z 450 [M + H] +.

[00897] Step 2: Preparation of 5- (1- (4- (dimethylamine) piperidin-1-yl) ethyl) -6-methyl-1- (1-methyl-1H-pyrazol-5-yl) ind olizine- Isopropyl 7-carboxylate: the yield of the two stages was 35%. ESI-MS m / z 452 [M + H] +.

[00898] Step 3: Preparation of 5- (1- (4- (dimethylamine) piperidin-1-yl) ethyl) -6-methyl-1- (1-methyl-1H-pyrazol-5-yl) ind olizine -7-formic: ESI-MS m / z 282 [M + H-C7H16N2] +.

[00899] Step 4: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamine) pip eridin -1-yl) ethyl) -6-methyl-1- (1-methyl-1H-pyrazol-5-yl) indolizine-7-carboxamide: the yield of the two stages was 16%. 1H NMR (400 MHz, CDCl3) δ ppm 8.48 (s, 1 H), 8.27 (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), 5.85 (s, 1 H), 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 (m, 13 H), 1.99 - 1.86 (m, 5 H), 1.61 - 1.59 (m, 1 H), 1.41 - 1.39 (m, 3 H); ESI-MS m / z 544 [M + H] +.

[00900] Example 130: Preparation of 2-chloro-5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -N - (((4-methoxy-6-methyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6-methylindolizine-7-carboxamide: the same as in Example 108.

[00901] Step 1: Preparation of 2-chloro-5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -N - (((4-methoxy-6-methyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6-methylindolizine-7-carboxamide: Yield 12%. 1H NMR (DMSO-d6, 400 MHz): 11.48 (s, 1 H), 9.50 (s, 1 H), 8.25 (s, 1 H), 8.05 (s, 1 H ), 7.28 (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), 3.20 (m, 2 H), 2.77 - 2.76 (m, 8 H), 2.28 (s, 3 H), 2.21 - 2.19 (m, 7 H), 1.55 - 1.54 (m, 3 H); ESI-MS m / z 514 [M + H] +.

[00902] Example 131: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinylethyl) ) -1-phenylindolizine-7-carboxamide: the same as in Example 108.

[00903] Step 1: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinylethyl) ) -1-phenylindolizine-7-carboxamide: the yield of the two stages was 24%. 1H NMR (400 MHz, MeOD) δ ppm 7.68 (s, 1H), 7.54 (d, J = 7.6 Hz, 2H), 7.439 (t, J = 7.6 Hz, 2H), 7.22 (t, J = 7.2 Hz, 1H), 6.98 (s, 1H), 6.29 (s, 1H), 4.44 (s, 2H), 3.91 (s, 3H ), 3.88 - 3.86 (m, 1H), 3.74 (s, 4H), 3.23 - 3.18 (m, 2H), 2.37 (s, 3H), 2.32 ( s, 3H), 1.64 (d, J = 6.4 Hz, 3H), 1.31 (s, 2H); ESI-MS m / z 515 [M + H] +.

[00904] Example 132: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (1-methyl- 1 H-pyrazol-5-yl) -5- (1-morpholinylethyl) indolizine-7-carboxamide: the same as in Example 108.

[00905] Step 1: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (1-methyl- 1 H-pyrazol-5-yl) -5- (1-morpholinylethyl) indolizine-7-carboxamide: Yield 21%. 1H NMR (400 MHz, CDCl3) δ ppm 11.40 (s, 1H), 8.47 (s, 1H), 8.05 - 8.06 (d, J = 3.6 Hz, 1H), 7 , 46 (d, J = 1.2 Hz, 1H), 7.02 (d, J = 2.8 Hz, 1H), 6.08 (s, 1H), 6.38 (s, 1H), 4 , 19 - 4.20 (m, 2H), 4.05 - 4.09 (m, 1H), 3.78 (s, 3H), 3.82 (s, 3H), 3.65 (m, 4H ), 2.63 - 2.70 (m, 2H), 2.37 (s, 3H), 2.00 (m, 5H), 1.45 - 1.44 (m, 3H); ESI-MS m / z 542 [M + H] +.

[00906] Example 133: Preparation of N - (((4N - ((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl) -2- (1-methyl-1H-imidazol-5-yl) -5- (1-morpholinoethyl) indolizine-7-carboxamide: the same as in Example 108.

[00907] Step 1: Synthesis of N - ((4N - ((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- ( 1-m ethyl-1H-imidazol-5-yl) -5- (1-morpholinoethyl) indolizine-7-carboxamide, 37% yield. 1H NMR (MeOD, 400 MHz): 8.91 (s, 1 H ), 7.68 (s, 1 H), 7.58 (s, 1 H), 6.93 (s, 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), 3.79 (s, 4 H), 3.23 - 3.20 (m, 2 H), 2.75 - 2.68 (m, 2 H), 2.39 (s, 6 H), 1.76 - 1.75 (m, 3 H); ESI-MS m / z 519, 5 [M + H] +.

[00908] Example 134: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamino) pip eridin -1-yl) ethyl) -6-methyl-2- (1-methyl-1H-imidazol-5-yl) indolizine-7-carboxamide: the same as in Example 31.

[00909] Step 1: Synthesis of 5- (1- (4- (dimethylamino) piperidin-1-yl) vinyl) -6-methyl-2- (1-methyl-1H-imidazol-5-yl) i ndolizine- 7-isopropyl format: ESI-MS m / z 450 [M + H] +.

[00910] Step 2: Synthesis of 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -6-methyl-2- (1-methyl-1H-imidazol-5-yl) in dolizine- 7-isopropyl format: the yield of the two stages was 29%.
ESI-MS m / z 452 [M + H] +.

[00911] Step 3: Synthesis of 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -6-methyl-2- (1-methyl-1H-imidazol-5-yl) in dolizine -7-formic: ESI-MS m / z 410 [M + H] +.

[00912] Step 4: Synthesis of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamino) pip eridin -1-yl) ethyl) -6-methyl-2- (1-methyl-1H-imidazol-5-yl) indolizine-7-carboxamide: the yield of the two stages was 40%. 1H NMR (MeOD, 400 MHz): 8.69 (s, 1 H), 8.59 (s, 1 H), 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, 2 H), 4.17 - 4.13 (m, 1 H), 3, 98 (s, 3 H), 3.58 - 3.56 (m, 1 H), 3.30 (s, 4 H), 2.84 (s, 6 H), 2.37 (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, 2 H), 1.62 - 1.54 (m, 3 H); ESI-MS m / z 544 [M + H] +.

[00913] Example 135: Preparation of 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -N - ((4-methoxy-6-methyl-2-oxo-1,2-di- hi dropiridin-3-yl) methyl) -6-methyl-2- (1-methyl-1H-imidazol-5-yl) indolizine-7-carboxylic acid: the same as in Example 108.

[00914] Step 1: Synthesis of 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -N - ((4-methoxy-6-methyl-2-oxo-1,2-di- hi dropiridin-3-yl) methyl) -6-methyl-2- (1-methyl-1H-imidazol-5-yl) indolizine-7-carboxylic acid: Yield 32%. 1H NMR (CDCl3, 400 MHz): 8.59 (s, 1 H), 7.48 (s, 1 H), 7.42 (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 - 4.55 (m, 2 H), 4.01 - 3, 99 (m, 1 H), 3.89 (s, 3 H), 3.75 (s, 3 H), 3.37 - 3.34 (m, 1 H), 2.53 (s, 3 H ), 2.37 - 2.36 (m, 3 H), 2.35 (s, 6 H), 2.02 - 1.94 (m, 4 H), 1.63 - 1.57 (m, 2 H), 1.55 - 1.47 (m, 3 H); ESI-MS m / z 560 [M + H] +.

[00915] Example 136: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl-1H- imid azol-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: the same as in Example 83.

[00916] Step 1: Synthesis of 5- (1- (4- (tert-butoxycarbonyl) piperazin-1-yl) vinyl) -6-methyl-2- (1-methyl-1H-imidaz ol-5-yl) isopropyl indolizine-7-carboxylate: ESI-MS m / z 508 [M + H] +.

[00917] Step 2: Synthesis of 5- (1- (4- (tert-butoxycarbonyl) piperazin-1-yl) vinyl) -6-methyl-2- (1-methyl-1H-imidaz ol-5-yl) indolizine-7-isopropyl formate: the yield of the two stages was 35%. ESI-MS m / z 510 [M + H] +.

[00918] Step 3: Synthesis of isopropyl 6-methyl-2- (1-methyl-1H-imidazol-5-yl) -5- (1- (piperazin-1-yl) ethyl) indolizine-7-carboxylate : ESI-MS m / z 410 [M + H] +.

[00919] Step 4: Synthesis of 6-methyl-2- (1-methyl-1H-imidazol-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl ) and useful) isopropyl indolizine-7-carboxylate: 33% yield. ESI-MS m / z 492 [M + H] +.

[00920] Step 5: Synthesis of 6-methyl-2- (1-methyl-1H-imidazol-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1- il) and tyl) indolizine-7-carboxylic: ESI-MS m / z 450 [M + H] +.

[00921] Step 6: Synthesis of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl-1H- imid azo-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide a: the yield of the two stages was 70%. 1H MeOD NMR, 400 MHz): 8.96 (s, 1 H), 7.70 (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 - 3.34 (m, 1 H), 3.05 - 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 H). 1.87 - 1.85 (m, 3 H); ESI-MS m / z 584 [M + H] +.

[00922] Example 137: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl- 1 H-imidazol-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carb oxamide:

[00923] Step 1: Synthesis of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (1-methyl- 1 H-imidazol-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carb oxamide: 62% yield. 1H NMR (CDCl3, 400 MHz): 8.96 (s, 1 H), 7.71 (s, 1 H), 7.62 (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, 1 H), 3.30 - 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 H), 1.89 - 1, 86 (m, 3 H); ESI-MS m / z 600.5 [M + H] +.

[00924] Example 138: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinethyl) ) -2- (thiazol-5-yl) indolizine-7-carboxamide: the same as in Example 50.

[00925] Step 1: Synthesis of ethyl 5-acetyl-6-methyl-2- (thiazol-5-yl) indolizine-7-carboxylate: Yield 68%. ESI-MS m / z 329 [M + H] +.

[00926] Step 2: Synthesis of isopropyl 6-methyl-5- (1-morpholinovinyl) -2- (thiazol-5-yl) indolizine-7-carboxylate: ESI-MS m / z 412 [M + H] + .

[00927] Step 3: Synthesis of isopropyl 6-methyl-5- (1-morpholinoethyl) -2- (thiazol-5-yl) indolizine-7-carboxylate: the yield of the two steps was 47%. ESI-MS m / z 414 [M + H] +.

[00928] Step 4: Synthesis of 6-methyl-5- (1-morpholinoethyl) -2- (thiazol-5-yl) indolizine-7-carboxylic acid: ESI-MS m / z 372 [M + H] +.

[00929] Step 5: Synthesis of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morfoethyl ) -2- (thiazol-5-yl) indolizine-7-carboxamide: the yield of the two stages was 24%. 1H NMR (MeOD, 400 MHz): 8.96 (s, 1 H), 8.15 (s, 1 H), 7.56 (s, 1 H), 6.49 (s, 1 H), 4.47 (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 H), 1.83 (m, 3 H); ESI-MS m / z 522 [M + H] +.

[00930] Example 139: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamino) pip eridin -1-yl) ethyl) -6-methyl-2- (thiazol-5-yl) indolizine-7-carboxamide: the same as in Example 31.

[00931] Step 1: Synthesis of isopropyl 5- (1- (4- (dimethylamino) piperidin-1-yl) vinyl) -6-methyl-2- (thiazol-5-yl) indolizine-7-carboxylate: ESI-MS m / z 453 [M + H] +.

[00932] Step 2: Synthesis of isopropyl 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -6-methyl-2- (thiazol-5-yl) indolizine-7-carboxylate: the yield of the two stages was 44%. ESI-MS m / z 455 [M + H] +.

[00933] Step 3: Synthesis of 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -6-methyl-2- (thiazol-5-yl) indolizine-7-carboxylic acid: ESI -MS m / z 413 [M + H] +.

[00934] Step 4: Synthesis of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4- (dimethylamino)) pip eridin-1-yl) ethyl) -6-methyl-2- (thiazol-5-yl) indolizine-7-carboxamide, the yield of the two steps was: 10%. 1H NMR (MeOD, 400 MHz): 8.89 (s, 1 H), 8.05 (s, 1 H), 7.39 (s, 1 H), 6.77 (s, 1 H), 6.14 (s, 1 H), 4.47 (s, 2 H), 3.99 (s, 2 H), 2.92 (s, 1 H), 2.85 (s, 6 H), 2.38 (s, 3 H), 2.32 (s, 3 H), 2.28 - 2.25 (m, 5 H), 1.60 - 1.59 (m, 3 H). ESI-MS m / z 547 [M + H] +.

[00935] Example 140: Preparation of 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -N - ((4-methoxy-6-methyl-2-oxo) -1,2-di -hi dropiridin-3-yl) methyl) -6-methyl-2- (thiazol-5-yl) indolizine-7-carboxamide: the same as in Example 108.

[00936] Step 1: Synthesis of 5- (1- (4- (dimethylamino) piperidin-1-yl) ethyl) -N - ((4-methoxy-6-methyl-2-oxo-1,2-di- hi dropiridin-3-yl) methyl) -6-methyl-2- (thiazol-5-yl) indolizine -7-carboxamide: Yield 11%. 1H NMR (MeOD, 400 MHz): 8.89 (s, 1 H), 8.05 (s, 1 H), 7.39 (s, 1 H), 6.74 (s, 1 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 H), 3.22 (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), 1.60 - 1.59 (m, 3 H); ESI-MS m / z 563 [M + H] +.

[00937] Example 141: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (thiazol-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: the same as in Example 83.

[00938] Step 1: Synthesis of 5- (1- (4- (tert-butoxycarbonyl) piperazin-1-yl) vinyl) -6-methyl-2- (thiazol-5-yl) indolizin a-7-carboxylate isopropyl: ESI-MS m / z 511 [M + H] +.

[00939] Step 2: Synthesis of 5- (1- (4- (tert-butoxycarbonyl) piperazin-1-yl) ethyl) -6-methyl-2- (thiazol-5-yl) indolizine -7-isopropyl formate : the yield of the two stages was 34%. ESI-MS m / z 513 [M + H] +.

[00940] Step 3: Synthesis of isopropyl 6-methyl-5- (1- (piperazin-1-yl) ethyl) -2- (thiazol-5-yl) indolizine-7-carboxylate: ESI-MS m / z 413 [M + H] +.

[00941] Step 4: Synthesis of 6-methyl-2- (thiazol-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7 - isopropyl formate: the yield of the two stages was 25%. ESI-MS m / z 495 [M + H] +.

[00942] Step 5: Synthesis of 6-Methyl-2- (thiazol-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine- 7 -carboxylic: ESI-MS m / z 453 [M + H] +.

[00943] Step 6: Synthesis of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (thiazol-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: the yield of the two stages was 46%. 1H NMR (MeOD, 400 MHz): 8.92 (s, 1 H), 8.09 (s, 1 H), 7.50 (s, 1 H), 6.13 (s, 1 H), 4.47 (s, 3 H), 3.26-3.22 (m, 6 H), 2.94 (m, 4 H), 2.38 (s, 3 H), 2.34 (s, 3 H), 2.25 (s, 3 H), 1.77 - 1.76 (m, 3 H); ESI-MS m / z 587 [M + H] +.

[00944] Example 142: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (thiazol-5- yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: the same as in Example 108.

[00945] Step 1: Synthesis of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-2- (thiazol-5- yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: 38.7% yield. 1H NMR (MeOD, 400 MHz): 8.93 (s, 1H), 8.09 (s, 1H), 7.50 (s, 1H), 6.34 (s, 1H), 4.52 ( s, 2H), 3.96 (s, 3H), 3.26-3.22 (m, 6H), 2.94 (m, 4H), 2.38 (s, 3H), 2.34 (s , 3H), 1.77 - 1.76 (m, 3H); ESI-MS m / z 603 [M + H] +.

[00946] Example 143: Preparation of 2-Bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4-methoxypiperidin-1-yl) ethyl) indolizine-7-carboxamide: the same as in Example 30.

[00947] Step 1: Preparation of isopropyl 2-bromo-6-methyl-5- (1- (4-methoxypiperidin-1-yl) vinyl) indolizine-7-carboxylate: ESI-MS m / z 436 [M + H] +.

[00948] Step 2: Preparation of isopropyl 2-bromo-6-methyl-5- (1- (4-methoxypiperidin-1-yl) ethyl) indolizine-7-carboxylate: the yield of the two steps was 74%. ESI-MS m / z 438 [M + H] +.

[00949] Step 3: Preparation of 2-bromo-6-methyl-5- (1- (4-methoxypiperidin-1-yl) ethyl) indolizine-7-carboxylic acid: ESI-MS m / z 396 [M + H ] +.

[00950] Step 4: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4-methoxypiperidin-1-yl) ethyl) indolizine-7-carboxamide: the yield of the two stages was 57%. 1H NMR (400 MHz, MeOD-d4) δ ppm 7.54 (s, 1 H), 6.78 (s, 1 H), 6.13 (s, 1 H), 5.18 - 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), 2.38 - 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 ), 1.29 (s, 2 H); ESI-MS m / z 552 [M + H] +.

[00951] Example 144: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4-hydroxypi peridin-1-yl) ethyl) -6-indolizine-7-carboxamide: the same as in Example 30.

[00952] Step 1: Preparation of isopropyl 2-bromo-5- (1- (4-hydroxypiperidin-1-yl) vinyl) -6-methylindolizine-7-carboxylate: ESI-MS m / z 421 [M + H ] +.

[00953] Step 2: Preparation of isopropyl 2-bromo-5- (1- (4-hydroxypiperidin-1-yl) ethyl) -6-methylindolizine-7-carboxylate: the yield of the two steps was 41%. ESI-MS m / z 423 [M + H] +.

[00954] Step 3: Preparation of 2-bromo-5- (1- (4-hydroxypiperidin-1-yl) ethyl) -6-methylindolizine-7-carboxylic acid: ESI-MS m / z 381 [M + H] +.

[00955] Step 4: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (4-hydroxypi peridin-1-yl) ethyl) -6-indolizine-7-carboxamide, the yield of the two stages was 23%. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.45 (s, 1 H), 8.39 (s, 1 H), 8.21-8.20 (d, J = 2.4 Hz, 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 - 4.25 (m, 2 H), 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), 2.21 (s, 3 H), 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 H). ESI-MS m / z 517 [M + H] +.

[00956] Example 145: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4- (pyrrolidin-1-yl) piperidin-1-yl) ethyl) indolizine-7-carboxamide: the same as in Example 30.

[00957] Step 1: Synthesis of isopropyl 2-bromo-6-methyl-5- (1- (4- (pyrrolidin-1-yl) piperidin-1-yl) vinyl) indolizine-7-carboxylate: ESI- MS m / z 474 [M + H] +.

[00958] Step 2: Synthesis of 2-bromo-6-methyl-5- (1- (4- (pyrrolidin-1-yl) piperidin-1-yl) ethyl) indolizine-7-carboxyl isopropyl act: yield of the two stages was 69%. ESI-MS m / z 476 [M + H] +.

[00959] Step 3: Synthesis of 2-bromo-6-methyl-5- (1- (4- (pyrrolidin-1-yl) piperidin-1-yl) ethyl) indolizine-7-carboxylic acid: ESI-MS m / z 434 [M + H] +.

[00960] Step 4: Synthesis of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4- (pyrrolidin-1-yl) piperidin-1-yl) ethyl) indolizine-7-carboxamide: the yield of the two steps was 12%. 1H NMR (MeOD, 400 MHz): 8.07 (s, 1 H), 6.83 (s, 1 H), 3.68 - 3.61 (m, 4 H), 3.12 - 3, 08 (m, 5 H), 2.81 (s, 2 H), 2.57 (s, 4 H), 2.47 - 2.42 (m, 2 H), 2.39 (m, 5 H ), 2.08 (m, 5 H), 1.55 - 1.54 (m, 5 H). ESI-MS m / z 570 [M + H] +.

[00961] Example 146: Preparation of 2-bromo-5- (1- (4-cyanopiperidin-1-yl) ethyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyr din-3-yl) methyl) -6-methylindolizine-7-carboxamide: the same as in Example 30.

[00962] Step 1: Synthesis of isopropyl 2-bromo-5- (1- (4-cyanopiperidin-1-yl) vinyl) -6-methylindolizine-7-carboxylate: ESI-MS m / z 430 [M + H ] +.

[00963] Step 2: Synthesis of isopropyl 2-bromo-5- (1- (4-cyanopiperidin-1-yl) ethyl) -6-methylindolizine-7-carboxylate: the yield of the two steps was 50%. ESI-MS m / z 432 [M + H] +.

[00964] Step 3: Synthesis of 2-bromo-5- (1- (4-cyanopiperidin-1-yl) ethyl) -6-methylindolizine-7-carboxylic acid: ESI-MS m / z 392 [M + H] +.

[00965] Step 4: Synthesis of 2-bromo-5- (1- (4-cyanopiperidin-1-yl) ethyl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyr din-3-yl) methyl) -6-methylindolizine-7-carboxamide, the yield of the two stages was 7%. 1H NMR (MeOD, 400 MHz): 7.39 (s, 1 H), 6.62 (s, 1 H), 6.12 (s, 1 H), 4.45 (s, 2 H), 2.92 - 2.90 (m, 2 H), 2.37 (s, 3 H), 2.32 (s, 3 H), 2.24 (s, 3 H), 1.94 - 1, 93 (m, 2 H), 1.91 - 1.88 (m, 2 H), 1.63 - 1.61 (m, 3 H); ESI-MS m / z 526 [M + H] +.

[00966] Example 147: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (3- ( dimethyl mino) azetidin-1-yl) ethyl) -6-methylindolizine-7-carboxamide: the same as in Example 30.

[00967] Step 1: Synthesis of 2-bromo-5- (1- (3- (dimethylamino) azetidin-1-yl) vinyl) -6-methylindolizine-7-carboxyl isopropyl act: ESI-MS m / z 420 [M + H] +.

[00968] Step 2: Synthesis of 2-bromo-5- (1- (3- (dimethylamino) azetidin-1-yl)
ethyl) -6-methylindolizine-7-isopropyl carboxylate: the yield of the two stages was 8%. ESI-MS m / z 422 [M + H] +.

[00969] Step 3: Synthesis of 2-bromo-5- (1- (3- (dimethylamino) azetidin-1-yl) ethyl) -6-methylindolizine-7-carboxylic acid: ESI-MS m / z 380 [ M + H] +.

[00970] Step 4: Synthesis of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -5- (1- (3- ( dimethyl mino) azetidin-1-yl) ethyl) -6-methylindolizine-7-carboxamide, the yield of the two stages was 65%. ESI-MS m / z 514 [M + H] +.

[00971] Example 148: Preparation of 2- (3,5-dimethoxy-4- (morphinylmethyl) phenyl) -N - ((4,5-dimethyl-2-oxo-1,2-dihydropyridi n-3- il) methyl) -6-methyl-5- (1-morpholinatyl) indolizine-7-carboxamide: the same as in Example 74.

[00972] Step 1: Preparation of ethyl 5-acetyl-2- (4-formyl-3,5-dimethoxyphenyl) -6-methylindolizine-7-carboxylate: 53% yield. ESI-MS m / z 410 [M + H] +.

[00973] Step 2: Preparation of ethyl 5-acetyl-2- (3,5-dimethoxy-4- (morpholinomethyl) phenyl) -6-methylindolizine-7-carboxylate: 84% yield. ESI-MS m / z 394 [M + H-C4H9NO] +.

[00974] Step 3: Preparation of isopropyl 2- (3,5-dimethoxy-4 - ((morpholinomethyl) phenyl) -6-methyl-5- (1-morphinylvinyl) indolizine-7-carboxylate: ESI-MS m / z 564 [M + H] +.

[00975] Step 4: Preparation of isopropyl 2- (3,5-dimethoxy-4 - ((morpholinylmethyl) phenyl) -6-methyl-5- (1-morpholinoethyl) indolizin a-7-carboxylate: yield: 97 %. ESI-MS m / z 479 [M + H-C4H9NO] +.

[00976] Step 5: Preparation of 2- (3,5-dimethoxy-4 - ((morpholinylmethyl) phenyl) -6-methyl-5- (1-morpholinoethyl) indolizin a-7-carboxylic acid: ESI-MS m / z 524 [M + H] +.

[00977] Step 6: Preparation of 2- (3,5-dimethoxy-4- (morphinylmethyl) phenyl) -N - ((4,5-dimethyl-2-oxo-1,2-dihydropyridine) -3 -yl) methyl) -6-methyl-5- (1-morpholinoethyl) indolizine-7-carboxamide:
5% yield. 1H NMR (400 MHz, DMSO) δ 11.49 (s, 1H), 9.47 (s, 1H), 8.81 (s, 1H), 8.21 (s, 1H), 7.33 ( s, 1H), 7.03 (s, 2H), 5.87 (s, 1H), 4.25 (s, 2 H), 3.91 (s, 6 H), 3.89 (brs, 2 H), 3.77 - 3.50 (m, 8H), 3.36 - 3.22 (m, 2 H), 3.19 - 3.03 (m, 2 H), 2.35 - 2, 25 (m, 2H), 2.19 (s, 3H), 2.10 (s, 3H), 1.53 - 1.50 (m, 3 H); ESI-MS m / z 571 [M + H-C4H9NO] +.

[00978] Example 149: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-7- (1- mor folinopropyl) indolizine-5-carboxamide: the same as in Example 29.

[00979] Step 1: Preparation of 4-bromo-1- (2-oxobutyl) -1H-pyrrole-2-carbaldehyde: yield: 86%. ESI-MS m / z 216 [M + H-CO] +.

[00980] Step 2: Preparation of ethyl 2-bromo-6-methyl-7-propionylindolizine-5-carboxylate: yield: 46%. ESI-MS m / z 338 [M + H] +.

[00981] Step 3: Preparation of (Z) 2-bromo-6-methyl-7- (1-morpholinyl-1-propen-1-yl) indolizine-5-carboxylate or (E) -isopropyl: yield of: 75%. ESI-MS m / z 421 [M + H] +.

[00982] Step 4: Preparation of isopropyl 2-bromo-6-methyl-7- (1-morpholinylpropyl) indolizine-5-carboxylate: yield: 81%. ESI-MS m / z 423 [M + H] +.

[00983] Step 5: Preparation of 2-bromo-6-methyl-7- (1-morpholinylpropyl) indolizine-5-carboxylic acid: yield: 91%. ESI-MS m / z 381 [M + H] +.

[00984] Step 6: Preparation of 2-bromo-N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-7- (1- mor folinylpropyl) indolizine-5-carboxamide: Yield: 99%. 1H NMR (400 MHz, CDCl3) δ 10.93 (s, 1H), 8.35 (s, 1H), 7.32 (s, 1H), 6.48 (s, 1H), 5.96 ( s, 1H), 4.50 (s, 1H), 3.90 (s, 4H), 3.67 (s, 6H), 2.75 (s, 2H), 2.65 (s, 2H), 2.39 (s, 3H), 2.34 (s, 3H), 2.25 (s, 3H), 1.38 (m, 2H), 0.62 (t, J = 7.3 Hz, 3H ); ESI-MS m / z 515 [M + H] +.

[00985] Example 150: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -7- (1-methoxymethyl) -6-methyl-2 - (3,4,5-trimethoxyphenyl) indolizine-5-carboxamide: the same as in Example 1.

[00986] Step 1: Preparation of ethyl 7- (1-hydroxyethyl) -6-methyl-2- (3,4,5-trimethoxyphenyl) indolizine-5-carboxylate: Yield: 91%. ESI-MS m / z 414 [M + H] +.

[00987] Step 2: Preparation of ethyl 7- (1-methoxymethyl) -6-methyl-2- (3,4,5-trimethoxyphenyl) indolizine-5-carboxylate: Yield: 95%. ESI-MS m / z 428 [M + H] +.

[00988] Step 3: Preparation of 7- (1-methoxymethyl) -6-methyl-2- (3,4,5-trimethoxyphenyl) indolizine-5-carboxylic acid: Yield: 83%. ESI-MS m / z 400 [M + H] +.

[00989] Step 4: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -7- (1-methoxymethyl) -6-methyl-2 - (3,4,5-trimethoxyphenyl) indolizine-5-carboxamide: yield: 92%. 1H NMR (400 MHz, CDCl3) δ 11.00 (brs, 1H), 8.18 (s, 1H), 7.37 (s, 1H), 6.85 (s, 2H), 6.73 ( s, 1H), 6.07 (s, 1H), 5.13 (q, J = 6.8 Hz, 1H), 4.53 (s, 1H), 3.94 (s, 6H), 3, 87 (s, 3H), 3.23 (s, 2H), 2.80 (s, 3H), 2.46 (s, 3H), 2.33 (s, 3H), 2.30 (s, 3H) ), 1.65 (d, J = 6.8 Hz, 3H); ESI-MS m / z534 [M + H] +.

[00990] Example 151: Biological activity test

[00991] 1. Determination of the activity of a compound for the PRC2 complex (EZH2Y641F):

[00992] Detection method: Fluorescence Solved in Homogeneous Time (HTRF)

[00993] MATERIALS: Histone methyltransferase (EZH2 Y641F / EED / SUZ12 / RbAp48 / AEBP2) PRC2 complex was purchased from Cisbio; the substrate H3 (1-50) K27me1 was a product of GL Biochem; methyl donor S- (5-adenosyl) -L-methionine (SAM) dihydrochloride was purchased from Sigma-aldrich; H3K27me3 with Eu identification, Streptavidin-XL665 and the buffer required for the reaction were purchased from Cisbio.

[00994] Experimental method: PRC2 complex (EZH2 Y641F / EED / SUZ12 / RbAp48 / AEBP2), H3 substrate (1-50) me1, SAM methyl donor and a compound were added to each well. The total reaction system was 10µL. The reaction was carried out in the dark, at room temperature, for 4 h. Antibody H3K27 Me3 with identification Eu 5υ1 and 5υ1 Streptavidin-XL665 were added to each well, mixed and incubated for 1 h at room temperature, and fluorescence was measured at 620 nm and 665 nm with the multiple identification microplate assay system (PerkinElmer Envision), and the HTRF signal ratio per well (665 nm / 620 nm) was calculated. The IC50 values of the compounds were calculated using the SoftMax Pro 5.4.1 software.

[00995] 2. Determination of the activity of a compound for the PRC2 complex (wild type of EZH2):

[00996] Detection method: Enzyme linked immunosorbent assay (ELISA)

[00997] MATERIALS: The PRC2 complex histone methyltransferase (EZH2 / EED / SUZ12 / RbAp48 / AEBP2) was purchased from BPS; the substrate Biotina H3 (21-44) me0 was produced by AnaSpec; SAM was purchased from Sigma, which is a GL Biochem product; SAM methyl donor was purchased from Sigma-aldrich; the H3K27me3 antibody was purchased from BPS.

[00998] Experimental method: Avdina of a final concentration of 100 nM was used to coat the 96-well plate in 10 µL / well, placed in a humid box and shaken overnight and then 100 µL, 3% of BSA per well were added and blocked for 1 h at room temperature. PRC2 complex (EZH2 / EED / SUZ12 / RbAp48 / AEBP2), substrate H3 (21 - 44) me0, SAM methyl donor and the compound were added to each well of the blocked 96-well plate. The total reaction system was 100µL, placed in a humid box and was able to react for 1 h on the shaker, at room temperature. The plate was washed with TBS-T [20 mM Tris-HCl (pH 7.2 to 7.4, room temperature), 150 mM NaCl, 0.1% (v / v) Tween-20] for 3 times, blocked with 3% BSA for 10 min., and anti-H3K27me3 antibody was added and incubated for 1 h, in a humid box on the shaker, at room temperature. The plate was washed again with TBS-T for 3 times, and blocked with 3% BSA per well, for 10 min. The secondary antibody with the identification of horseradish peroxidase was added and reacted in a humid box at room temperature for 1 h and, finally, it was washed with TBS-T for 3 times. 2 mg / ml of OPD color development solution (100 µL / well) was added for staining, and the reaction was stopped with 2M H2SO4 (50 µL / well). The plate was read by a plate reader by a plate reader at 490 nm, and the IC50 of the compound was calculated using the SoftMax Pro 5.4.1 software.

[00999] The results are shown below:

[001000] Table 1 shows the IC 50 values of some of the compounds of the present invention.

[001001] The letter A represents IC50 ≤ 100 nm;

[001002] The letter B represents IC50 from> 100 nm to ≤1,000 nm;

[001003] The letter C represents IC50 of> 1 µM to ≤10 µM;

[001004] The letter D represents IC 50> 10 µM

[001005] Example 152: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinylethyl) ) -1- (1H-pyrazol-4-yl) indolizine-7-carboxamide: the same as in Example 31.

[001006] Step 1: Preparation of ethyl 5-acetyl-1- (1- (tert-butyloxycarbonyl) -1H-pyrazol-4-yl) -6-methylindolizine-7-carboxylate: Yield 43%. ESI-MS m / z 412 [M + H] +.

[001007] Step 2: Preparation of isopropyl 6-methyl-5- (1-morphinolinylvinyl) -1- (1H-pyrazol-4-yl) indolizine-7-carboxylate: ESI-MS m / z 395 [M + H ] +.

[001008] Step 3: Preparation of isopropyl 6-methyl-5- (1-morphinolinylethyl) -1- (1H-pyrazol-4-yl) indolizine-7-carboxylate: the yield of the two steps was 49%. ESI-MS m / z 397 [M + H] +.

[001009] Step 4: Preparation of 6-methyl-5- (1-morphinolinylethyl) -1- (1H-pyrazol-4-yl) indolizine-7-carboxylic acid: 43% yield. ESI-MS m / z 355 [M + H] +.

[001010] Step 5: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinylethyl) ) -1- (1H-pyrazol-4-yl) indolizine-7-carboxamide: Yield 50%. 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (s, 1 H), 7.86 (s, 1 H), 7.80 (s, 1 H), 7.68 (t, J = 4 , 8 Hz, 1 H), 7.62 (s, 1 H), 7.51 (d, J = 3.8 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1 H) , 6.82 (d, J = 1.4 Hz, 1 H), 5.91 (s, 1 H), 4.62 - 4.51 (m, 2 H), 4.09 - 4.03 ( m, 1 H), 3.87 (s, 3 H), 3.69 (s, 4 H), 2.85 (s, 2 H), 2.42 (s, 3 H), 2.27 - 2.23 (m, 5 H), 1.49 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 505 [M + H] +.

[001011] Example 153: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinylethyl) ) -1- (1H-pyrazol-5-yl) indolizine-7-carboxamide: the same as in Example 31.

[001012] Step 1: Preparation of ethyl 5-acetyl-6-methyl-1- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) indolizine-7-carboxylate: 82% yield. ESI-MS m / z 396 [M + H] +.

[001013] Step 2: Preparation of 6-methyl-5- (1-morphinolinylvinyl) -1- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) ind olizine-7- isopropyl carboxylate: ESI-MS m / z 479 [M + H] +.

[001014] Step 3: Preparation of 6-methyl-5- (1-morphinolinylethyl) -1- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) indo lizina-7- isopropyl carboxylate: the yield of the two stages was 44%.
ESI-MS m / z 481 [M + H] +.

[001015] Step 4: Preparation of 6-methyl-5- (1-morphinolinylethyl) -1- (1H-pyrazol-5-yl) indolizine-7-carboxylic acid:
ESI-MS m / z 355 [M + H] +.

[001016] Step 5: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1-morpholinylethyl) ) -1- (1H-pyrazol-5-yl) indolizine-7-carboxamide: the yield of the two stages was 10%. 1H NMR (400 MHz, CDCl3) δ ppm 12.60 (s, 1 H), 11.43 (s, 1 H), 8.37 (s, 1 H), 8.00 (s, 1 H) , 7.05 (s, 1 H), 6.50 (s, 1 H), 6.10 (s, 1 H), 5.87 (s, 1 H), 4.30 - 4.24 (m , 2 H), 4.05 - 4.02 (m, 1 H), 4.02 (s, 3 H), 3.63 - 3.44 (m, 4 H), 2.66 - 2.54 (m, 2 H), 2.33 - 2.11 (m, 8 H), 1.44 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 505 [M + H] +.

[001017] Example 154: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (1Hpyrazol-5- yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxylic acid: the same as in Example 31.

[001018] Step 1: Preparation of 6-methyl-1- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) -5- (1- (4- (2,2 , 2-trifluoroethyl) piperazin-1-yl) vinyl) isopropyl indolizine-7-carboxylate: ESI-MS m / z 560 [M + H] +.

[001019] Step 2: Preparation of 6-methyl-1- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) -5- (1- (4- (2,2 , Isopropyl 2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxylate: the yield of the two steps was 32%. ESI-MS m / z 562 [M + H] +.

[001020] Step 3: Preparation of 6-methyl-1- (1H-pyrazol-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) indolizine7- formic: 77% yield ESI-MS m / z 436 [M + H] +.

[001021] Step 5: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (1H-pyrazole) -5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: 25% yield. 1H- (DMSO-d6, 400 MHz) NMR: 11.46 (brs, 1 H), 8.36 (brs, 1 H), 8.02 (s, 1 H), 7.72 (s, 1 H), 7.54 (s, 1 H), 7.04 (s, 1 H), 6.50 (s, 1 H), 6.11 (s, 1 H), 4.23 (d, J = 4.0 Hz, 2 H), 4.04 (q, J = 6.8 Hz, 1 H), 3.82 (s, 3 H), 3.16-3.11 (m, 2 H) , 2.61 (brs, 6 H), 2.32 (s, 3 H), 2.19 - 2.18 (m, 5 H), 1.43 (d, J = 6.8 Hz, 3 H ); ESI-MS m / z 586 [M + H] +.

[001022] Example 155: Preparation of (S) -N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- ( 1H-pi razol-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxami da or (R) -N - (( 4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (1H-pi razol-5-yl) -5- (1- ( 4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: Compound 154 was separated by means of preparative chiral liquid chromatography to provide Compound 155 and Compound 156.

[001023] The separation conditions were: column type: OD-H; column size: 0.46 cm ID × 15 cm L; injection volume: 2 μL; mobile phase: Hep / EtOH (0.1% DEA) = 60/40 (v / v); flow rate: 0.5 ml / min .; detection conditions: UVλ = 254 nm; column temperature: 25 ° C.

[001024] Compound 155: 1H NMR (DMSO-d6, 400 MHz): 11.46 (brs, 1 H), 8.36 (brs, 1 H), 8.02 (s, 1 H), 7, 72 (s, 1 H), 7.54 (s, 1 H), 7.04 (s, 1 H), 6.50 (s, 1 H), 6.11 (s, 1 H), 4, 23 (d, J = 4.0 Hz, 2 H), 4.04 (q, J = 6.8 Hz, 1 H), 3.82 (s, 3 H), 3.16-3.11 ( m, 2 H), 2.61 (brs, 6 H), 2.32 (s, 3 H), 2.19 - 2.18 (m, 5 H), 1.43 (d, J = 6, 8 Hz, 3 H); ESI-MS m / z 586 [M + H] +; tR = 4.398 min.

[001025] Compound 156: 1H NMR (DMSO-d6, 400 MHz): 11.46 (brs, 1 H), 8.36 (brs, 1 H), 8.02 (s, 1 H), 7, 72 (s, 1 H), 7.54 (s, 1 H), 7.04 (s, 1 H), 6.50 (s, 1 H), 6.11 (s, 1 H), 4, 23 (d, J = 4.0 Hz, 2 H), 4.04 (q, J = 6.8 Hz, 1 H), 3.82 (s, 3 H), 3.16 - 3.11 ( m, 2 H), 2.61 (brs, 6 H), 2.32 (s, 3 H), 2.19 - 2.18 (m, 5 H), 1.43 (d, J = 6, 8 Hz, 3 H); ESI-MS m / z 586 [M + H] +; tR = 4.806 min.

[001026] Example 156: Preparation of 1- (6-aminopyridin-3-yl) -N - ((4-methoxy-6-methyl-2-oxo) -1,2-dihydropyridin-3-yl) me tyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: similar to Example 83.

[001027] Step 1: Preparation of ethyl 5-acetyl-1- (6-aminopyridin-3-yl) -6-methylindolizine-7-carboxylate: 67% yield. ESI-MS m / z 338 [M + H] +.

[001028] Step 2: Preparation of isopropyl 1- (6-aminopyridin-3-yl) -6-methyl-5- (1- (piperazin-1-yl) vinyl) indolizine-7-carboxylate: ESI-MS m / z 420 [M + H] +.

[001029] Step 3: Preparation of isopropyl 1- (6-aminopyridin-3-yl) -6-methyl-5- (1- (piperazin-1-yl) ethyl) indolizine-7-carboxylate: the yield of two stages was 99%. ESI-MS m / z 422 [M + H] +.

[001030] Step 4: Preparation of 1- (6-aminopyridin-3-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) ind isopropyl olizine-7-carboxylate: the yield of the two stages was 67%. ESI-MS m / z 504 [M + H] +.

[001031] Step 5: Preparation of 1- (6-aminopyridin-3-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl acid) ind olizine-7-carboxylic: the yield of the two stages was 95%. ESI-MS m / z 562 [M + H] +.

[001032] Step 6: Preparation of 1- (6-aminopyridin-3-yl) -N - ((4-methoxy-6-methyl-2-oxo) -1,2-dihydropyridin-3-yl) me tyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: 42% yield. 1H NMR (DMSO-d6, 400 MHz) δ ppm 11.43 (brs, 1 H), 8.37 (s, 1 H), 8.15 (s, 1 H), 8.06 (s, 1 H), 7.59 (d, J = 4, Hz, 1 H), 7.42 (s, 1 H), 6.88 (d, J = 1.4 Hz, 1 H), 6.53 ( d, J = 4.2 Hz, 1 H), 6.10 (s, 1 H), 5.83 (s, 2 H), 4.21 (d, J = 2.2 Hz, 2 H), 4.04 (q, J = 6.8 Hz, 1 H), 3.81 (s, 3 H), 3.16 - 3.13 (m, 2 H), 3.63 (s, 6 H) , 2.27 (s, 3 H), 2.18 (s, 5 H), 1.43 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 634 [M + Na] +.

[001033] Example 157: Preparation of 1- (6-aminopyridin-3-yl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6 - methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: similar to that of Example 156.

[001034] Step 1: Preparation of 1- (6-aminopyridin-3-yl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6 - methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: 28% yield. 1H NMR (400MHz, CDCl3) δ ppm 12.10 (brs, 1 H), 8.43 (s, 1 H), 8.22 (s, 1H), 7.58 - 7.54 (m, 2 H), 7.46 (t, J = 5.6 Hz, 1 H), 6.80 (d, J = 1.4 Hz, 1 H), 6.43 (d, J = 4.2 Hz, 1 H), 4.65 (brs, 2 H), 4.53 - 4.44 (m, 2 H), 4.05 (q, J = 6.8 Hz, 1 H), 2.94 (q , J = 9.6 Hz, 2 H), 2.68 - 2.63 (m, 8 H), 2.39 (s, 3 H), 2.35 (s, 3 H), 2.10 ( s, 3 H), 1.49 (d, J = 6.8 Hz, 3H); ESI-MS m / z 618 [M + Na] +.

[001035] Example 158: Preparation of (S) -1- (6-aminopyridin-3-yl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamid a or (R) 1- (6-aminopyridin-3 -yl) -N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4- (2,2, 2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: Compound 158 was separated by means of preparative chiral liquid chromatography to provide Compound 159 and Compound 160.

[001036] The separation conditions were: column type: OD-H; column size: 0.46 cm ID × 15 cm L; injection volume: 2 μL; mobile phase: Hep / EtOH (0.1% DEA) = 60/40 (v / v); flow rate: 0.5 ml / min .; detection conditions: UVλ = 254 nm; column temperature: 25 ° C.

[001037] Compound 159: 1H NMR (400MHz, CDCl3) δ ppm 12.10 (brs, 1 H), 8.43 (s, 1 H), 8.22 (s, 1H), 7.58 - 7 , 54 (m, 2 H), 7.46 (t, J = 5.6 Hz, 1 H), 6.80 (d, J = 1.4 Hz, 1 H), 6.43 (d, J = 4.2 Hz, 1 H), 4.65 (brs, 2 H), 4.53 - 4.44 (m, 2 H), 4.05 (q, J = 6.8 Hz, 1 H) , 2.94 (q, J = 9.6 Hz, 2 H), 2.68 - 2.63 (m, 8 H), 2.39 (s, 3 H), 2.35 (s, 3 H ), 2.10 (s, 3 H), 1.49 (d, J = 6.8 Hz, 3H); ESI-MS m / z 618 [M + Na] +; tR = 4.586 min.

[001038] Compound 160: 1H NMR (400MHz, CDCl3) δ ppm 12.10 (brs, 1 H), 8.43 (s, 1 H), 8.22 (s, 1H), 7.58 - 7 , 54 (m, 2 H), 7.46 (t, J = 5.6 Hz, 1 H), 6.80 (d, J = 1.4 Hz, 1 H), 6.43 (d, J = 4.2 Hz, 1 H), 4.65 (brs, 2 H), 4.53 - 4.44 (m, 2 H), 4.05 (q, J = 6.8 Hz, 1 H) , 2.94 (q, J = 9.6 Hz, 2 H), 2.68 - 2.63 (m, 8 H), 2.39 (s, 3 H), 2.35 (s, 3 H ), 2.10 (s, 3 H), 1.49 (d, J = 6.8 Hz, 3H); ESI-MS m / z 618 [M + Na] +; tR = 4.948 min.

[001039] Example 159: Preparation of 1- (3,5-dimethylisoxazol-4-yl) -N - ((4-methoxy-6-methyl-2-oxo) -1,2-dihydropyridin-3-yl ) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carb oxamide: similar to Example 83.

[001040] Step 1: Preparation of isopropyl 1-bromo-6-methyl-5- (1- (piperazin-1-yl) vinyl) indolizine-7-carboxylate: ESI-MS m / z 406 [M + H] +.

[001041] Step 2: Preparation of isopropyl 1-bromo-6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) vinyl) indolizine-7-carboxylate: the yield of the two stages was 99%. ESI-MS m / z 488 [M + H] +.

[001042] Step 3: Preparation of isopropyl 1-bromo-6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxylate: 91% yield. ESI-MS m / z 490 [M + H] +.

[001043] Step 4: Preparation of 1- (3,5-dimethylisoxazol-4-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) et il) isopropyl indolizine-7-carboxylate: the yield was 70%. ESI-MS m / z 507 [M + H] +.

[001044] Step 5: Preparation of 1- (3,5-dimethylisoxazol-4-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) acid et il) indolizine-7-carboxylic: ESI-MS m / z 465 [M + H] +.

[001045] Step 6: Preparation of 1- (3,5-dimethylisoxazol-4-yl) -N - ((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carbo xamide: 32% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.42 (brs, 1 H), 8.42 (s, 1 H), 8.02 (s, 1 H), 6.99 (s, 1 H), 6.83 (s, 1 H), 6.08 (s, 1 H), 6.10 (s, 1 H), 4.19 (brs, 2 H), 406 (q, J = 6.8 Hz, 1 H), 3.77 (s, 3 H), 3.16-3.13 (m, 2 H), 2.63 (brs, 6 H), 2.29 (brs, 6H), 2 , 24 - 2.21 (m, 9 H), 1.44 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 615 [M + H] +.

[001046] Example 160: Preparation of 1- (4-fluorophenyl) -N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-m ethyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: the same as in Example 159.

[001047] Step 1: Preparation of isopropyl 1- (4-fluorophenyl) -methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxylate : 56% yield. ESI-MS m / z 338 [M-C6H11F3N2 + H] +.

[001048] Step 2: Preparation of 1- (4-fluorophenyl) -methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxylic acid: 73% yield. ESI-MS m / z 464 [M + H] +.

[001049] Step 3: Preparation of 1- (4-fluorophenyl) -N - (((4-methoxy-6-methyl-2-oxo) -1,2-dihydropyridin-3-yl) methyl) -6- methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: 56% yield. 1H NMR (MeOD, 400 MHz) δ ppm 7.57 - 7.52 (m, 3 H), 7.17 - 7.10 (m, 2 H), 6.89 (d, J = 2.8 Hz, 1 H), 6.24 (s, 1 H), 4.42 (s, 2 H), 4.11 (q, J = 6.8 Hz, 1 H), 3.90 (s, 3 H), 3.04 - 3.01 (m, 2 H), 2.74 - 2.66 (m, 6 H), 2.33 - 2.30 (m, 9 H), 1.51 (d , J = 6.8 Hz, 3 H); ESI-MS m / z 614 [M + H] +.

[001050] Example 161: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (6- (methyl mino) pyridin-3-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-car boxamide: the same as in Example 159.

[001051] Step 1: Preparation of 6-methyl-1- (6- (methylamino) pyridin-3-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) isopropyl indolizine-7-carboxylate: 33% yield. ESI-MS m / z 518 [M + H] +.

[001052] Step 2: Preparation of 6-methyl-1- (6- (methylamino) pyridin-3-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl acid ) ethyl) indolizine-7-carboxylic: ESI-MS m / z 476 [M + H] +.

[001053] Step 3: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (6- (methyl mino) pyridin-3-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-car boxamide: the yield of the two stages was 34% . 1H NMR (MeOD, 400 MHz) δ ppm 8.44 (s, 1 H), 8.11 (d, J = 2.0 Hz, 1 H), 7.65 (dd, J = 8.8, 2.4 Hz, 1 H), 7.50 (s, 1 H), 6.82 (d, J = 2.8 Hz, 1 H), 6.59 (d, J = 8.8 Hz, 1 H), 6.24 (s, 1 H), 4.42 (s, 2 H), 4.09 (q, J = 6.8 Hz, 1 H), 3.90 (s, 3 H), 3.02 (q, J = 10.0 Hz, 2 H), 2.89 (s, 3 H), 2.68 - 2.66 (m, 4 H), 2.33 (s, 3 H) , 2.30 - 2.29 (m, 4 H), 1.50 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 626 [M + H] +.

[001054] Example 162: Preparation of (S) -N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- ( 6- (methylamino) pyridin-3-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-formide or (R) -N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (6- (methylamino) pyridin-3-yl) - 5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-formide: Compound 163 was separated by means of chiral preparative liquid chromatography to provide Compound 164 and Compound 165.

[001055] The separation conditions were: column type: AD-H; column size: 0.46 cm ID × 15 cm L; injection volume: 2 μL; mobile phase: Hep / EtOH (0.1% DEA) = 60/40 (v / v); flow rate: 0.5 ml / min .; detection conditions: UVλ = 254 nm; column temperature: 25 ° C.

[001056] Compound 164: 1H NMR (MeOD, 400 MHz) δ ppm 8.44 (s, 1 H), 8.11 (d, J = 2.0 Hz, 1 H), 7.65 (dd, J = 8.8, 2.4 Hz, 1 H), 7.50 (s, 1 H), 6.82 (d, J = 2.8 Hz, 1 H), 6.59 (d, J = 8.8 Hz, 1 H), 6.24 (s, 1 H), 4.42 (s, 2 H), 4.09 (q, J = 6.8 Hz, 1 H), 3.90 ( s, 3 H), 3.02 (q, J = 10.0 Hz, 2 H), 2.89 (s, 3 H), 2.68 - 2.66 (m, 4 H), 2.33 (s, 3 H), 2.30 - 2.29 (m, 4 H), 1.50 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 626 [M + H] +; tR = 2.319 min.

[001057] Compound 165: 1H NMR (MeOD, 400 MHz) δ ppm 8.44 (s, 1 H), 8.11 (d, J = 2.0 Hz, 1 H), 7.65 (dd, J = 8.8, 2.4 Hz, 1 H), 7.50 (s, 1 H), 6.82 (d, J = 2.8 Hz, 1 H), 6.59 (d, J = 8.8 Hz, 1 H), 6.24 (s, 1 H), 4.42 (s, 2 H), 4.09 (q, J = 6.8 Hz, 1 H), 3.90 ( s, 3 H), 3.02 (q, J = 10.0 Hz, 2 H), 2.89 (s, 3 H), 2.68 - 2.66 (m, 4 H), 2.33 (s, 3 H), 2.30 - 2.29 (m, 4 H), 1.50 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 626 [M + H] +; tR = 6.490 min.

[001058] Example 163: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (2- (methylpi ridin-3-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: the same as in Example 159.

[001059] Step 1: Preparation of 6-methyl-1- (2-methylpyridin-3-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) isopropyl lizine-7-carboxylate: 44% yield. ESI-MS m / z 503 [M + H] +.

[001060] Step 2: Preparation of 6-methyl-1- (2-methylpyridin-3-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) lizine-7-carboxylic acid: ESI-MS m / z 461 [M + H] +.

[001061] Step 3: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (2-methylpyridine) -3-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide a: the yield of the two stages was 35%. 1H NMR (MeOD, 400 MHz) δ ppm 8.55 (s, 1 H), 8.33 (dd, J = 4.8, 1.2 Hz, 1 H), 7.75 (dd, J = 7.6, 1.2 Hz, 1 H), 7.30 (dd, J = 7.6, 4.8 Hz, 1 H), 7.16 (s, 1 H), 6.85 (d, J = 2.4 Hz, 1 H), 6.22 (s, 1 H), 4.38 (s, 2 H), 4.13 (q, J = 6.8 Hz, 1 H), 3, 04 (q, J = 10.0 Hz, 2 H), 2.74 - 2.67 (m, 6 H), 2.49 (s, 3 H), 2.34 - 2.30 (m, 6 H), 2.29 (s, 3 H), 1.53 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 611 [M + H] +.

[001062] Example 164: Preparation of 1- (2-chloropyridin-4-yl) -N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: the same as in Example 159.

[001063] Step 1: Preparation of 1- (2-chloropyridin-4-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) ind isopropyl olizine-7-carboxylate: 35% yield. ESI-MS m / z 523 [M + H] +.

[001064] Step 2: Preparation of 1- (2-chloropyridin-4-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl acid) ind olizine-7-carboxylic: the yield was 97%. ESI-MS m / z 481 [M + H] +.

[001065] Step 3: Preparation of 1- (2-chloropyridin-4-yl) -N - (((4-methoxy-6-methyl-2-oxo) -1,2-dihydropyridin-3-yl) methyl l) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: 30% yield. 1H NMR (CDCl3, 400 MHz) δ ppm 8.49 (s, 1 H), 8.20 (d, J = 8.2 Hz, 1 H), 7.75 (s, 1 H), 7, 71 (t, J = 5.6 Hz, 1 H), 7.38 (s, 1 H), 7.32 (d, J = 5.2 Hz, 1 H), 6.93 (d, J = 4.3 Hz, 1 H), 5.87 (s, 1 H), 4.57 (t, J = 5.2 Hz, 2 H), 4.09 (q, J = 6.8 Hz, 1 H), 3.89 (s, 3 H), 2.95 (q, J = 6.8 Hz, 2 H), 2.67 - 2.61 (m, 6 H), 2.41 (s, 3 H), 2.29 - 2.28 (m, 2 H), 2.17 (s, 3 H), 1.48 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 631 [M + H] +.

[001066] Example 165: Preparation of (S) -1- (2-chloropyridin-4-yl) -N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3- yl) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carbox amide or (R) 1- (2-chloropyridin -4-yl) -N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4- ( 2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: Compound 167 was separated by means of preparative chiral liquid chromatography to provide Compound 168 and Compound 169.

[001067] The separation conditions were: column type: AD-H; column size: 0.46 cm ID × 15 cm L; injection volume: 2 μL; mobile phase: Hep / EtOH (0.1% DEA) = 60/40 (v / v); flow rate: 0.5 ml / min .; detection conditions: UVλ = 254 nm; column temperature: 25 ° C.

[001068] Compound 168: 1H NMR (CDCl3, 400 MHz) δ ppm 8.49 (s, 1 H), 8.20 (d, J = 8.2 Hz, 1 H), 7.75 (s, 1 H), 7.71 (t, J = 5.6 Hz, 1 H), 7.38 (s, 1 H), 7.32 (d, J = 5.2 Hz, 1 H), 6, 93 (d, J = 4.3 Hz, 1 H), 5.87 (s, 1 H), 4.57 (t, J = 5.2 Hz, 2 H), 4.09 (q, J = 6.8 Hz, 1 H), 3.89 (s, 3 H), 2.95 (q, J = 6.8 Hz, 2 H), 2.67 - 2.61 (m, 6 H), 2.41 (s, 3 H), 2.29 - 2.28 (m, 2 H), 2.17 (s, 3 H), 1.48 (d, J = 6.8 Hz, 3 H) ; ESI-MS m / z 631 [M + H] +; t R = 3.461 min.

[001069] Compound 169: 1H NMR (CDCl3, 400 MHz) δ ppm 8.49 (s, 1 H), 8.20 (d, J = 8.2 Hz, 1 H), 7.75 (s, 1 H), 7.71 (t, J = 5.6 Hz, 1 H), 7.38 (s, 1 H), 7.32 (d, J = 5.2 Hz, 1 H), 6, 93 (d, J = 4.3 Hz, 1 H), 5.87 (s, 1 H), 4.57 (t, J = 5.2 Hz, 2 H), 4.09 (q, J = 6.8 Hz, 1 H), 3.89 (s, 3 H), 2.95 (q, J = 6.8 Hz, 2 H), 2.67 - 2.61 (m, 6 H), 2.41 (s, 3 H), 2.29 - 2.28 (m, 2 H), 2.17 (s, 3 H), 1.48 (d, J = 6.8 Hz, 3 H) ; ESI-MS m / z 631 [M + H] +; tR = 5.255 min.

[001070] Example 166: Preparation of 1- (2- (dimethylamino) pyridin-4-yl) -N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin -3-yl ) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-c arboxamide: the same as in Example 159.

[001071] Step 1: Preparation of 1- (2- (dimethylamino) pyridin-4-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) isopropyl indolizine-7-carboxylate: the yield of the two stages was 49%. ESI-MS m / z 532 [M + H] +.

[001072] Step 2: Preparation of 1- (2- (dimethylamino) pyridin-4-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl acid ) ethyl) indolizine-7-carboxylic: 88% yield. ESI-MS m / z 490 [M + H] +.

[001073] Step 3: Preparation of 1- (2- (dimethylamino) pyridin-4-yl) -N - ((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin -3-yl ) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-c arboxamide: 24% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (s, 1 H), 8.12 (t, J = 4.4 Hz, 1 H) 8.06 (d, J = 5.2 Hz, 1 H), 7.63 (s, 1 H), 7.12 (d, J = 2.1 Hz, 1 H), 6.81 (d, J = 5.2 Hz, 1 H), 6, 73 (s, 1 H), 6.18 (s, 1 H), 4.25 (brs, 2 H), 4.07 (q, J = 6.8 Hz, 1 H), 3.85 (s , 3 H), 3.10 (q, J = 9.8 Hz, 2 H), 3.02 (s, 6 H), 2.63 - 2.51 (m, 6 H), 2.30 ( s, 3 H), 2.36 (s, 6 H), 1.48 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 640 [M + H] +.

[001074] Example 167: Preparation of (S) -1- (2- (dimethylamino) pyridin-4-yl) -N - ((4-methoxy-6-methyl-2-oxo-1,2-dihydropyr idin-3-yl) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine7-carboxamide or (R) 1- (2- (dimethylamino) pyridin-4-yl) -N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-c arboxamide: Compound 170 was separated by means of preparative chiral liquid chromatography to provide Compound 171 and Compound 172.

[001075] The separation conditions were: column type IC-H; column size: 0.46 cm ID × 15 cm L; injection volume: 2 μL; mobile phase: Hep / EtOH (0.1% DEA) = 60/40 (v / v); flow rate: 0.5 ml / min .; detection conditions: UVλ = 254 nm; column temperature: 25 ° C.

[001076] Compound 171: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (s, 1 H), 8.12 (t, J = 4.4 Hz, 1 H) 8.06 (d, J = 5.2 Hz, 1 H), 7.63 (s, 1 H), 7.12 (d, J = 2.1 Hz, 1 H), 6.81 (d, J = 5.2 Hz, 1 H), 6.73 (s, 1 H), 6.18 (s, 1 H), 4.25 (brs, 2 H), 4.07 (q, J = 6.8 Hz, 1 H) , 3.85 (s, 3 H), 3.10 (q, J = 9.8 Hz, 2 H), 3.02 (s, 6 H), 2.63 - 2.51 (m, 6 H ), 2.30 (s, 3 H), 2.36 (s, 6 H), 1.48 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 640 [M + H] +; tR = 24.811 min.

[001077] Compound 172: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (s, 1 H), 8.12 (t, J = 4.4 Hz, 1 H) 8.06 (d , J = 5.2 Hz, 1 H), 7.63 (s, 1 H), 7.12 (d, J = 2.1 Hz, 1 H), 6.81 (d, J = 5.2 Hz, 1 H), 6.73 (s, 1 H), 6.18 (s, 1 H), 4.25 (brs, 2 H), 4.07 (q, J = 6.8 Hz, 1 H), 3.85 (s, 3 H), 3.10 (q, J = 9.8 Hz, 2 H), 3.02 (s, 6 H), 2.63 - 2.51 (m, 6 H), 2.30 (s, 3 H), 2.36 (s, 6 H), 1.48 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 640 [M + H] +; t R = 30.994 min.

[001078] Example 168: Preparation of 1- (2- (2,6-dimethylpyridin-4-yl) -N - ((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3 -yl) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carb oxamide: the same as in Example 159.

[001079] Step 1: Preparation of 1- (2-dimethylpyridin-4-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) in isopropyl dolizine-7-carboxylate: 60% yield. ESI-MS m / z 517 [M + H] +.

[001080] Step 2: Preparation of 1- (2,6-dimethylpyridin-4-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) acid ethyl) indolizine-7-carboxylic: ESI-MS m / z 475 [M + H] +.

[001081] Step 3: Preparation of 1- (2,6-dimethylpyridin-4-yl) -N - ((4-methoxy-6-methyl-2-oxo) -1,2-dihydropyridin-3-yl ) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carbox amide: the yield of the two steps was 6%. 1H NMR (MeOD, 400 MHz) δ ppm 8.54 (s, 1 H), 7.75 (s, 1 H), 7.30 (s, 2 H), 7.08 (d, J = 2 , 8 Hz, 1 H), 6.26 (s, 1 H), 4.45 (brs, 2 H), 4.13 (q, J = 6.8 Hz, 1 H), 3.91 (s , 3 H), 3.02 (q, J = 9.8 Hz, 2 H), 2.78 - 2.67 (m, 6 H), 2.50 (s, 6 H), 2.36 ( s, 3 H), 2.92 - 2.30 (m, 5 H), 1.51 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 625 [M + H] +.

[001082] Example 169: Preparation of (S) -1- (2,6-dimethylpyridin-4-yl) -N - ((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin- 3 -yl) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-car boxamide or (R) 1- (2 , 6-dimethylpyridin-4-yl) -N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: Compound 173 was separated by means of preparative chiral liquid chromatography to provide Compound 174 and Compound 175.

[001083] The separation conditions were: column type IC-H; column size: 0.46 cm ID × 15 cm L; injection volume: 2 μL; mobile phase: Hep / EtOH (0.1% DEA) = 60/40 (v / v); flow rate: 0.5 ml / min .; detection conditions: UVλ = 254 nm; column temperature: 25 ° C.

[001084] Compound 174: 1H NMR (MeOD, 400 MHz) δ ppm 8.54 (s, 1 H), 7.75 (s, 1 H), 7.30 (s, 2 H), 7.08 (d, J = 2.8 Hz, 1 H), 6.26 (s, 1 H), 4.45 (brs, 2 H), 4.13 (q, J = 6.8 Hz, 1 H) , 3.91 (s, 3 H), 3.02 (q, J = 9.8 Hz, 2 H), 2.78 - 2.67 (m, 6 H), 2.50 (s, 6 H ), 2.36 (s, 3 H), 2.92 - 2.30 (m, 5 H), 1.51 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 625 [M + H] +; tR = 9.681 min.

[001085] Compound 175: 1H NMR (MeOD, 400 MHz) δ ppm 8.54 (s, 1 H), 7.75 (s, 1 H), 7.30 (s, 2 H), 7.08 (d, J = 2.8 Hz, 1 H), 6.26 (s, 1 H), 4.45 (brs, 2 H), 4.13 (q, J = 6.8 Hz, 1 H) , 3.91 (s, 3 H), 3.02 (q, J = 9.8 Hz, 2 H), 2.78 - 2.67 (m, 6 H), 2.50 (s, 6 H ), 2.36 (s, 3 H), 2.92 - 2.30 (m, 5 H), 1.51 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 625 [M + H] +; t R = 11.694 min.

[001086] Example 170: Preparation of 1- (2- (2,6-dimethylpyridin-3-yl) -N - ((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3 -yl) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carb oxamide: the same as in Example 159.

[001087] Step 1: Preparation of 1- (2-dimethylpyridin-3-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) in isopropyl dolizine-7-carboxylate: 25% yield. ESI-MS m / z 517 [M + H] +.

[001088] Step 2: Preparation of 1- (2,6-dimethylpyridin-3-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) acid ethyl) indolizine-7-carboxylic: 68% yield. ESI-MS m / z 475 [M + H] +.

[001089] Step 3: Preparation of 1- (2,6-dimethylpyridin-3-yl) -N - ((4-methoxy-6-methyl-2-oxo) -1,2-dihydropyridin-3-yl ) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carbox amide: 18% yield. 1H (CDCl3, 400 MHz) δ ppm 8.42 (s, 1 H), 7.46 (d, J = 7.6 Hz, 1 H), 7.27 - 7.26 (m, 2 H), 6.97 (d, J = 8.0 Hz, 1 H), 6.75 (s, 1 H), 5.87 (s, 1 H), 4.50 (d, J = 5.2 Hz, 1 H), 4.06 (q, J = 6.4 Hz, 1 H), 3.85 (s, 3 H), 2.95 (q, J = 8.8 Hz, 2 H), 2, 68 - 2.58 (m, 6 H), 2.52 (s, 3 H), 2.47 (s, 3 H), 2.37 - 2.31 (m, 5 H), 2.10 ( s, 3 H), 1.50 (d, J = 6.4 Hz, 3 H); ESI-MS m / z 625 [M + H] +.

[001090] Example 171: Preparation of (S) -1- (2,6-dimethylpyridin-3-yl) -N - ((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin- 3 -yl) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-car boxamide or (R) 1- (2 , 6-dimethylpyridin-3-yl) -N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carbox amide: Compound 176 was separated by means of preparative chiral liquid chromatography to provide Compound 177 and Compound 178.

[001091] The separation conditions were: column type IC-H; column size: 0.46 cm ID × 15 cm L; injection volume: 2 μL; mobile phase: EtOH (0.1% DEA) = 100; flow rate: 0.5 ml / min .; detection conditions: UVλ = 254 nm; column temperature: 25 ° C.

[001092] Compound 177: 1H NMR (CDCl3, 400 MHz) δ ppm 8.42 (s, 1 H), 7.46 (d, J = 7.6 Hz, 1 H), 7.27 - 7, 26 (m, 2 H), 6.97 (d, J = 8.0 Hz, 1 H), 6.75 (s, 1 H), 5.87 (s, 1 H), 4.50 (d , J = 5.2 Hz, 1 H), 4.06 (q, J = 6.4 Hz, 1 H), 3.85 (s, 3 H), 2.95 (q, J = 8.8 Hz, 2 H), 2.68 - 2.58 (m, 6 H), 2.52 (s, 3 H), 2.47 (s, 3 H), 2.37 - 2.31 (m, 5 H ), 2.10 (s, 3 H), 1.50 (d, J = 6.4 Hz, 3 H); ESI-MS m / z 625 [M + H] +; t R = 12,450 min.

[001093] Compound 178: 1H NMR (CDCl3, 400 MHz) δ ppm 8.42 (s, 1 H), 7.46 (d, J = 7.6 Hz, 1 H), 7.27 - 7, 26 (m, 2 H), 6.97 (d, J = 8.0 Hz, 1 H), 6.75 (s, 1 H), 5.87 (s, 1 H), 4.50 (d , J = 5.2 Hz, 1 H), 4.06 (q, J = 6.4 Hz, 1 H), 3.85 (s, 3 H), 2.95 (q, J = 8.8 Hz, 2 H), 2.68 - 2.58 (m, 6 H), 2.52 (s, 3 H), 2.47 (s, 3 H), 2.37 - 2.31 (m, 5 H), 2.10 (s, 3 H), 1.50 (d, J = 6.4 Hz, 3 H); ESI-MS m / z 625 [M + H] +; t R = 17.820 min.

[001094] Example 172: Preparation of 1- (2- (dimethylamino) pyridin-3-yl) -N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin -3-yl ) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide:

[001095] Step 1: Preparation of 1- (2-fluoropyridin-3-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) ind isopropyl olizine-7-carboxylate: the same as in Step 1, Example 160. Yield was 43%. ESI-MS m / z 339 [M-C6H11F3N2 + H] +.

[001096] Step 2: Preparation of 1- (2- (dimethylamino) pyridin-3-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) isopropyl indolizine-7-carboxylate: In a dry sealed 25 mL tube, compound 1- (2-fluoropyridin-3-yl) -6-methyl-5- (1- (4- (2,2 , Isopropyl 2-trifluoroethyl) piperazin-1-yl) ethyl) ind olizine-7-carboxylate (330 mg, 0.59 mmol), dimethylamine aqueous solution (25 ml), was added successively and dissolved in tetrahydrofuran ( 5 ml), 85 ° C, reacted for 2 days. The reaction solution was extracted with dichloromethane (200 ml), washed with water (100 ml × 2) and saturated brine (100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product. After purification by column chromatography (dichloromethane: methanol = 20: 1), 280 mg of yellow oil was provided, 81% yield. ESI-MS m / z 532 [M + H] +.

[001097] Step 3: Preparation of 1- (2- (dimethylamino) pyridin-3-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl acid ) ethyl) indolizine-7-carboxylic: same as in Step 2, Example 160. ESI-MS m / z 490 [M + H] +.

[001098] Step 4: Preparation of 1- (2- (dimethylamino) pyridin-3-yl) -N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl ) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-c arboxamide: the same as in Step 3 of Example 160. The yield of the two stages was 8%. 1H NMR (CDCl3, 400 MHz) δ ppm 8.45 (s, 1 H), 8.08 (d, J = 3.2 Hz, 1 H), 7.48 (dd, J = 7.2, 1.6 Hz, 1 H), 7.36 (s, 1 H), 7.18 (t, J = 7.2 Hz, 1 H), 6.85 (d, J = 2.8 Hz, 1 H), 6.74 (dd, J = 7.2, 2.4 Hz, 1 H), 5.87 (s, 1 H), 4.52 (d, J = 5.2 Hz, 2 H) , 4.05 (q, J = 6.4 Hz, 1 H), 3.86 (s, 3 H), 2.95 (q, J = 9.6 Hz, 2 H), 2.68 - 2 , 66 (m, 6 H), 2.64 (s, 6 H), 2.35 (s, 3 H), 2.32 - 2.29 (m, 2 H), 2.15 (s, 3 H), 1.50 (d, J = 6.4 Hz, 3 H); ESI-MS m / z 640 [M + H] +.

[001099] Example 173: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (2- (methyl mino) pyridin-4-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-car boxamide: the same as in Example 172.

[001100] Step 1: Preparation of 1- (2-fluoropyridin-4-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) ind isopropyl olizine-7-carboxylate: 65% yield. ESI-MS m / z 507 [M + H] +.

[001101] Step 2: Preparation of 6-methyl-1- (2- (methylamino) pyridin-4-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) isopropyl indolizine-7-carboxylate: 39% yield. ESI-MS m / z 518 [M + H] +.

[001102] Step 3: Preparation of 6-methyl-1- (2- (methylamino) pyridin-4-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl acid ) ethyl) indolizine-7-carboxylic: 63% yield. ESI-MS m / z 476 [M + H] +.

[001103] Step 4: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (2- (methyl mino) pyridin-4-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-car boxamide: 15% yield. 1H NMR (MeOD, 400 MHz) δ ppm 8.55 (brs, 1 H), 7.86 (d, J = 4.8 Hz, 1 H), 7.76 (s, 1 H), 7, 05 (d, J = 3.2 Hz, 1 H), 6.88 (d, J = 5.6 Hz, 1 H), 6.80 (s, 1 H), 6.25 (s, 1 H ), 4.57 (s, 3 H), 4.44 (s, 2 H), 4.14 (q, J = 6.4 Hz, 1 H), 3.95 (s, 3 H), 3 , 13 (q, J = 9.6 Hz, 2 H), 2.98 (s, 3 H), 2.68 - 2.64 (m, 6 H), 2.35 (s, 3 H), 2.34 - 2.32 (m, 6 H), 1.50 (d, J = 6.4 Hz, 3 H); ESI-MS m / z 626 [M + H] +.

[001104] Example 174: Preparation of (S) -N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- ( 2- (methylamino) pyridin-4-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-formamide or (R) -N- ((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (2- (methylamino) pyridin-4-yl) -5 - (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-formide: Compound 180 was separated by means of preparative chiral liquid chromatography to provide Compound 181 and Compound 182.

[001105] The separation conditions were: column type: AD-H; column size: 0.46 cm ID × 15 cm L; injection volume: 2 μL; mobile phase: Hep / EtOH (0.1% DEA) = 60/40 (v / v); flow rate: 0.5 ml / min .; detection conditions: UVλ = 254 nm; column temperature: 25 ° C.

[001106] Compound 181: 1H NMR (CDCl3, 400 MHz) δ ppm 8.44 (s, 1 H), 7.39 (d, J = 4.4 Hz, 1 H), 7.59 (d, J = 7.2 Hz, 2 H), 7.28 (s, 1 H), 7.19 (s, 1 H), 7.14 (t, J = 4.8 Hz, 1 H), 6, 78 (s, 1 H), 5.88 (s, 1 H), 4.50 (d, J = 4.0 Hz, 1 H), 4.07 (q, J = 6.8 Hz, 1 H ), 3.86 (s, 3 H), 2.96 (q, J = 9.6 Hz, 2 H), 2.75 - 2.66 (m, 6 H), 2.52 (s, 3 H), 2.37 - 2.31 (m, 5 H), 2.14 (s, 3 H), 1.51 (d, J = 6.4 Hz, 3 H); ESI-MS m / z 626 [M + H] +; ESI-MS m / z 626 [M + H] +; t R = 10.432 min.

[001107] Compound 182: 1H NMR (CDCl3, 400 MHz) δ ppm 8.44 (s, 1 H), 7.39 (d, J = 4.4 Hz, 1 H), 7.59 (d, J = 7.2 Hz, 2 H), 7.28 (s, 1 H), 7.19 (s, 1 H), 7.14 (t, J = 4.8 Hz, 1 H), 6, 78 (s, 1 H), 5.88 (s, 1 H), 4.50 (d, J = 4.0 Hz, 1 H), 4.07 (q, J = 6.8 Hz, 1 H ), 3.86 (s, 3 H), 2.96 (q, J = 9.6 Hz, 2 H), 2.75 - 2.66 (m, 6 H), 2.52 (s, 3 H), 2.37 - 2.31 (m, 5 H), 2.14 (s, 3 H), 1.51 (d, J = 6.4 Hz, 3 H); ESI-MS m / z 626 [M + H] +; tR = 17.440 min.

[001108] Example 175: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (1-methyl- 1 H-1,2,4-triazol-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: similar to Example 50.

[001109] Step 1: Preparation of ethyl 5-acetyl-6-methyl-1- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indolizine-7-carboxylate: 41% yield. ESI-MS m / z 372 [M + H] +.

[001110] Step 2: Preparation of ethyl 5-acetyl-6-methyl-1- (1-methyl-1H-1,2,4-triazol-5-yl) indolizine-7-carboxylate: 50% yield. ESI-MS m / z 327 [M + H] +.

[001111] Step 3: Preparation of 6-methyl-1- (1-methyl-1H-1,2,4-triazol-5-yl) -5- (1- (piperazin-1-yl) vinyl) indolizine- 7-carboxylate: ESI-MS m / z 409 [M + H] +.

[001112] Step 4: Preparation of 6-methyl-1- (1-methyl-1H-1,2,4-triazol-5-yl) -5- (1- (piperazin-1-yl) ethyl) indolizine- 7-c isopropyl arboxylate: the yield of the two stages was 50%. ESI-MS m / z 411 [M + H] +.

[001113] Step 5: Preparation of 6-methyl-1- (1-methyl-1H-1,2,4-triazol-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl ) isopropyl piperazin-1-yl) ethyl) indolizine-7-carboxylate: 19% yield. ESI-MS m / z 493 [M + H] +.

[001114] Step 6: Preparation of 6-methyl-1- (1-methyl-1H-1,2,4-triazol-5-yl) -5- (1- (4- (2,2,2- trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxylic: ESI-MS m / z 451 [M + H] +.

[001115] Step 7: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (1-methyl- 1 H-1,2,4-triazol-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: the yield of two stages was 33%. 1H NMR (CDCl3, 400 MHz) δ ppm 8.50 (s, 1 H), 8.13 (s, 1 H), 7.83 (s, 1 H), 7.42 (t, J = 4 , 8 Hz, 1 H), 6.98 (d, J = 2.8 Hz, 1 H), 5.89 (s, 1 H), 4.55 (d, J = 5.2 Hz, 2 H ), 4.09 (q, J = 6.8 Hz, 1 H), 4.03 (s, 3 H), 3.89 (s, 3 H), 2.96 (q, J = 9.6 Hz, 2 H), 2.68 - 2.64 (m, 6 H), 2.38 (s, 3 H), 2.31 - 2.29 (m, 2 H), 2.21 (s, 3 H), 1.50 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 601 [M + Na] +.

[001116] Example 176: Preparation of 1- (6-aminopyridin-3-yl) -N - ((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl) methyl) -6 - methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: the procedures are the same as in Example 108. 3- (aminomethyl hydrochloride ) -2,6-lutidine-4 (1H) -one was synthesized, as described in reference to document No. (WO2015200650).

[001117] Step 1: Preparation of 1- (6-aminopyridin-3-yl) -N - ((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl) methyl) -6 - methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: 12% yield. 1H NMR (400MHz, CDCl3) δ ppm 8.41 (s, 1 H), 8.10 (s, 1 H), 7.65 (s, 1 H), 7.56 (d, J = 4, 0 Hz, 1 H), 7.45 (s, 1 H), 6.75 (s, 1 H), 6.59 (d, J = 4.2 Hz, 1 H), 6.08 (s, 1 H), 4.43 (s, 2 H), 4.02 (q, J = 6.8 Hz, 1 H), 2.95 (q, J = 9.6 Hz, 2 H), 2, 66 (brs, 6 H), 2.47 (s, 3 H), 2.30 (brs, 5 H), 2.16 (s, 3 H), 1.46 (d, J = 6.4 Hz , 3 H); ESI-MS m / z 618 [M + Na] +.

[001118] Example 177: Preparation of 1- (6-aminopyridin-3-yl) -6-methyl-N - ((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3 - il) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: the procedure was similar to that of Example 108. Hydrochloride 3- (aminomethyl) The desired -6-methyl-4-lutidine-2 (1H) -one was synthesized, as described in reference to document No. (WO2014177982).

[001119] Step 1: Preparation of 1- (6-aminopyridin-3-yl) -6-methyl-N - ((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3 - yl) methyl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide a: 27% yield. 1H MHz NMR, DMSO-d6) δ ppm 11.46 (brs, 1 H), 8.36 (s, 1 H), 8.25 (t, J = 2.0 Hz, 2 H), 8, 14 (s, 1 H), 7.58 (d, J = 2.0 Hz, 1 H), 7.42 (s, 1 H), 6.86 (d, J = 2.4 Hz, 1 H ), 6.50 (d, J = 5.6 Hz, 1 H), 5.88 (s, 1 H), 5.81 (s, 2 H), 4.26 (d, J = 4.8 Hz, 2 H), 4.03 (q, J = 6.8 Hz, 1 H), 3.14 (q, J = 9.6 Hz, 2 H), 2.66 - 2.62 (m, 6 H), 2.25 (s, 3 H), 2.21 - 2.11 (m, 5 H), 1.46 (q, J = 8.0 Hz, 2 H), 1.42 (d , J = 6.8 Hz, 3 H), 0.89 (t, J = 8.0 Hz, 3 H); ESI-MS m / z 624 [M + H] +.

[001120] Example 178: Preparation of 1- (6-aminopyridin-3-yl) -6-methyl-N - ((6-methyl-2-oxo-4- (trifluoromethyl) -1,2-dihydro opiridin -3-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxy mida: the procedure was similar to that of Example 108. Hydrochloride of The desired 3- (aminomethyl) -6-methyl-4- (trifluoromethyl) pyridin-2 (1H) -one was synthesized, as described in WO2014177982.

[001121] Step 1: Preparation of 1- (6-aminopyridin-3-yl) -6-methyl-N - ((6-methyl-2-oxo-4- (trifluoromethyl) -1,2-dihydro opiridin -3-yl) methyl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: 37% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.37 (s, 1 H), 8.38 (s, 1 H), 8.29 (s, 1 H), 8.14 (s, 1 H), 7.57 (dd, J = 8.4, 2.0 Hz, 1 H), 7.43 (s, 1 H), 6.89 (d, J = 2.4 Hz, 1 H) , 6.52 (d, J = 8.4 Hz, 1 H), 6.28 (s, 1 H), 5.85 (s, 2 H), 4.34 (s, 2 H), 4, 05 (q, J = 6.8 Hz, 1 H), 3.17 - 3.11 (m, 2 H), 2.66 - 2.59 (m, 6 H), 2.65 - 2.20 (m, 8 H), 1.43 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 650 [M + H] +.

[001122] Example 179: Preparation of 1- (6-aminopyridin-3-yl) -N - ((5-methoxy-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4- yl) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carb oxamide: the procedure was the same as in Example 108. The desired 4- (aminomethyl) -5-methoxy-1-methyl-1H-pyrazol-3 (1H) -one hydrochloride was synthesized as described in reference to document No. (WO2015010049).

[001123] Step 1: Preparation of 1- (6-aminopyridin-3-yl) -N - ((5-methoxy-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4- yl) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carb oxamide: 19% yield. 1H NMR (400 MHz, MeOD) δ ppm 8.49 (s, 1 H), 8.08 (s, 1 H), 7.70 (dd, J = 8.4, 2.4 Hz, 1 H ), 7.55 (s, 1H), 6.85 (d, J = 2.8 Hz, 1 H), 6.67 (d, J = 8.4 Hz, 1 H), 4.58 (s , 1 H), 4.27 (s, 2 H), 4.09 (q, J = 6.8 Hz, 1 H), 4.04 (s, 3 H), 3.31 (s, 3 H ), 3.05 (q, J = 7.2 Hz, 1 H), 3.06 - 3.01 (m, 6 H), 2.67 - 2.33 (m, 5 H), 1.50 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 600 [M + H] +.

[001124] Example 180: Preparation of 1- (6-aminopyridin-3-yl) -N - ((7-isobutyl-1-methyl-3-oxo-2,3,5,6,7,8-hexa- hydro-2,7-naphth-hiridin-4-yl) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) in dolizine-7 -carboxamide: the procedure was the same as in Example 108. 4- (Aminomethyl) -7-isobutyl-1-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3 (2H) hydrochloride - the desired name was synthesized as described, with reference to document No. (WO2015110999).

[001125] Step 1: Preparation of 1- (6-aminopyridin-3-yl) -N - ((7-isobutyl-1-methyl-3-oxo-2,3,5,6,7,8-hexa- hydro-2,7-naphthyridin-4-yl) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) ind olizine-7-carboxamide : 20% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (brs, 1 H), 8.38 (s, 1 H), 8.29 (t, J = 4.8 Hz, 1 H), 8.15 (d, J = 2.4 Hz, 1 H), 7.60 (d, J = 2.4 Hz, 1 H), 7.43 (s, 1 H), 6.88 (d, J = 2.8 Hz, 1 H), 6.52 (d, J = 8.8 Hz, 1 H), 5.84 (s, 2 H), 4.26 (d, J = 4.8 Hz , 2 H), 4.04 (q, J = 6.8 Hz, 1 H), 3.21 - 3.10 (m, 6 H), 2.83 (t, J = 5.6 Hz, 2 H), 2.67 - 2.62 (m, 6 H), 2.26 (s, 3 H), 2.18 (d, J = 7.6 Hz, 4 H), 2.09 (s, 3 H), 1.86 (sept, J = 6.8 Hz, 1H), 1.43 (d, J = 6.8 Hz, 3 H), 0.87 (d, J = 6.8 Hz, 6 H); ESI-MS m / z 715 [M + Na] +.

[001126] Example 181: Preparation of 1- (6- (4-aminopiperidin-1-yl) pyridin-3-yl) -6-methyl-N - ((1-methyl-3-oxo-2,3-di -hydro genisoquinolin-4-yl) methyl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: the procedure was similar to that of Example 156. Tert-butyl (1- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl) piperidin-4-yl) carbamate The desired result was synthesized, as described in reference to document No. (WO2008090181), and the synthesis of 4- (aminomethyl) -1-methylisoquinoline-3 (2H) -one hydrochloride was synthesized, as described in document No. WO2015077193.

[001127] Step 1: Preparation of 1- (6- (4 - ((tert-butoxycarbonyl) amino) piperidin-1-yl) pyridin-3-yl) -6-methyl-5- (1- (4- ( 2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxylate isopropyl: Yield 25%. ESI-MS m / z 687 [M + H] +.

[001128] Step 4: Preparation of 1- (1- (6- (4 - ((tert-butoxycarbonyl) amino) piperidin-1-yl) pyridin-3-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxylic: 77% yield ESI-MS m / z 645 [M + H] +.

[001129] Step 3: (1- (5- (6-methyl-3-oxo-2,3-dihydroisoquinolin-4-yl) methyl) carbamoyl) -5- (1- (4- (2,2 , 2-trifluoroethyl) piperazin-1-yl) ethyl) indolizin-1-yl) pyridin-2-yl) piperidine-4-yl) tert-butyl carbate: ESI-MS m / z 815 [M + H] +.

[001130] Step 4: Preparation of 1- (6- (4-aminopiperidin-1-yl) pyridin-3-yl) -6-methyl-N - (((1-methyl-3-oxo-2,3-di -hydroi soquinolin-4-yl) methyl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: the yield of the two stages was 18 %. 1H NMR (MeOD, 400 MHz) δ ppm 8.52-8.39 (m, 4 H), 8.26 (s, 1 H), 8.14 - 8.10 (m, 1 H), 7 , 98 (s, 1 H), 7.79 - 7.75 (m, 1 H), 7.58 - 7.56 (m, 1 H), 7.25 (s, 1 H), 5.00 (s, 2 H), 4.42 - 4.38 (m, 2 H), 3.47 - 3.44 (m, 2 H), 3.41 - 3.31 (m, 4 H), 2 , 30 - 2.29 (m, 2 H), 3.24 - 3.21 (m, 2 H), 2.97 - 2.94 (m, 4 H), 2.89 - 2.87 (m , 1 H), 2.46 (s, 3 H), 2.31 - 2.25 (m, 3 H), 1.93 - 1.87 (m, 2 H), 1.84 - 1.82 (m, 3 H); ESI-MS m / z 715 [M + H] +.

[001131] Example 182: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (1- (tetrahydro-2Hpiran -4-yl) -1H-pyrazol-4-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: similar to Example 83.

[001132] Step 1: Preparation of ethyl 5-acetyl-6-methyl-1- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) indolizine-7-carboxylate: 27% yield. ESI-MS m / z 396 [M + H] +.

[001133] Step 2: Preparation of 6-methyl-5- (1- (piperazin-1-yl) vinyl) -1- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4- il) isopropyl indolizine-7-carboxylate: ESI-MS m / z 478 [M + H] +.

[001134] Step 3: Preparation of 6-methyl-5- (1- (piperazin-1-yl) ethyl) -1- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4- il) isopropyl n-dolizine-7-carboxylate: ESI-MS m / z 480 [M + H] +.

[001135] Step 4: Preparation of 6-methyl-1- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) -5- (1- (4- (2,2 , Isopropyl 2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxylate: the yield of the three stages was 37%. ESI-MS m / z 562 [M + H] +.

[001136] Step 5: Preparation of 6-methyl-1- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) -5- (1- (4- (2, 2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxylic: ESI-MS m / z 520 [M + H] +.

[001137] Step 6: Preparation of N - ((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (1- (tetrahydro-2Hpiran -4-yl) -1H-pyrazol-4-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: the yield of two stages was 43%. 1H NMR (MeOD, 400 MHz) δ ppm 8.46 (s, 1 H), 7.95 (s, 1 H), 7.76 (s, 1 H), 7.57 (s, 1 H) , 6.85 (d, J = 2.4 Hz, 1 H), 6.11 (s, 1 H), 4.46 - 4.45 (m, 3 H), 4.11 - 4.09 ( m, 3 H), 3.61 (d, J = 10.8 Hz, 2 H), 3.02 (q, J = 6.8 Hz, 2 H), 2.72 - 2.67 (m, 6 H), 2.37 (s, 3 H), 2.31 (s, 3 H), 2.28 - 2.24 (m, 5 H), 2.16 - 2.09 (m, 4 H ), 1.42 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 654 [M + H] +.

[001138] Example 183: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (1H-pyrazole) -5-yl) -5- (1- (thiazol-2-ylmethoxy) ethyl) indolizine-7-carboxamide:

[001139] Step 1: Preparation of ethyl 1-bromo-5- (1-hydroxyethyl) -6-methylindolizine-7-carboxylate: compound 5-acetyl-1-bromo-6-methylindolizine-7-carboxylate (600 mg, 1.86 mmol) and 10 mL of methanol were added in a 50 mL dry nitrogen-protected single neck flask, cooled to 0 ° C and then sodium borohydride (1,054 mg, 27.86 mmol) was added to the portion. The reaction was stirred at room temperature for 2 hours and then the mixture was extracted with ethyl acetate (50 ml) and washed with water (50 ml × 2) and saturated brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product. After purification by column chromatography (petroleum ether: EtOAc = 20: 1), yellow solids (478 mg, yield: 79%) were obtained. ESI-MS m / z 396 [M + H] +.

[001140] Step 2: Preparation of ethyl 1-bromo-6-methyl-5- (1- (thiazol-2-ylmethoxy) ethyl) indolizine-7-carboxylate: in a single neck flask with nitrogen protection, from 25mL, compound 1-bromo-5- (1-hydroxyethyl) -6-methylindolizine-7-carboxylate (478 mg, 1.47 mmol) and sodium hydride (53 mg, 2.21 mmol) were added successively, and dissolved in 3mL of DMF. The mixture was stirred for 15 minutes in an ice bath, then 2-bromomethylthiazole (312 mg, 1.476 mmol) was added and stirred at room temperature for 4 hours. The reaction was cooled with aqueous ammonia, extracted with ethyl acetate (50 ml), washed with water (50 ml × 2) and saturated brine (50 ml), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product. After purification by column chromatography (petroleum ether: EtOAc = 10: 1), yellow solids (480 mg, yield: 77%) were obtained.
ESI-MS m / z 423 [M + H] +.

[001141] Step 3: Preparation of 6-methyl-1- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) -5- (1- (thiazol-2-ylmethoxy) et il) ethyl indolizine-7-carboxylate: In a 100 ml nitrogen-protected dry mouth bottle, the compound 1-bromo-6-methyl-5- (1- (thiazol-2-ylmethoxy) ethyl) ethyl indolizine-7-carboxylate (480 mg, 1.13 mmol), 1- (tetrahydro-2H-pyran-2-yl) -5- (4,4,5,5-tetramethyl-1,3), 2-dioxoborolan-2-yl) -1H-p irazole (630 mg, 2.27 mmol), [2- (dicyclohexylphosphine) -3,6-methoxy-2 ', 4', 6'-triisopropyl -1,1'-biphenyl] [2- (2-aminethyl) benzene] palladium (45 mg, 0.057 mmol), Cs2CO3 (738 mg, 2.27 mmol) were added to 6 mL of toluene: DMF = 10: 1. The flask was exchanged for nitrogen several times, connected to a flask filled with nitrogen, and the mixture was stirred overnight, in an oil bath, at 110 ° C. The mixture was extracted with dichloromethane (100 ml) and was washed with water (50 ml × 2) and saturated brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product. After purification by column chromatography (petroleum ether: EtOAc = 10: 1), yellow-green solids (223 mg, yield: 40%) were obtained. ESI-MS m / z 495 [M + H] +.

[001142] Step 4: Preparation of 6-methyl-1- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) -5- (1- (thiazol-2-ylmethoxy) ) et il) indolizine-7-carboxylic: in a 25mL nitrogen-protected single-necked flask, 6-methyl-1- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole- Ethyl 5-yl) -5- (1- (thiazol-2-ylmethoxy) et yl) indolizine -7-carboxylate (223 mg, 0.451 mmol), 2.5 mL of THF and 2.5 mL of methanol added, and an excess sodium hydroxide, in 2.5 ml of water, were successively added to the reaction system, heated to 60 ° C and stirred to reflux overnight. The reaction solution was neutralized with hydrochloric acid diluted to pH 5, extracted with dichloromethane (50 ml). The organic phase was dried over sodium sulfate, filtered and concentrated to provide pale yellow solids (140 mg, 81% yield). ESI-MS m / z 383 [M + H] +.

[001143] Step 5: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (1H-pyrazole) -5-yl) -5- (1- (thiazol-2-ylmethoxy) ethyl) indolizine-7-carboxamide: 6-Methyl-1- (1- (tetrahydro-2H-pyran-2-yl) -1H- acid pyrazol-5-yl) -5- (1- (thiazol-2-ylmethoxy) et yl) indolizine-7-carboxylic (70 mg, 0.163 mmol), 3- (aminomethyl) -4-methoxy-6-methylpyridin hydrochloride -2 (1H) -one (37 mg, 0.196 mmol), HATU (93 mg, 0.245 mmol), TEA (49 mg, 0.489 mmol) and DMF 2 mL were added successively in a single-necked flask. with 25mL nitrogen protection and stirred at room temperature overnight. Yellow solids (1 mg, yield: 1%) were obtained by preparative purification. 1H NMR (400 MHz, CDCl3) δ 12.11 (s, 1 H), 8.20 (s, 1 H), 8.12 (s, 1 H), 8.06 (s, 1 H), 7.73 (d, J = 3.2 Hz, 1 H), 7.44 (s, 1 H), 7.32 (d, J = 2.8 Hz, 1 H), 6.99 (s, 1 H), 6.39 (s, 1 H), 5.84 (s, 1 H), 5.45 (q, J = 13.2, 6.0 Hz, 1 H), 4.67 (s , 2 H), 4.56 (s, 2 H), 3.84 (s, 3 H), 2.42 (s, 3 H), 2.16 (s, 3 H), 1.73 (d , J = 6.5 Hz, 3 H); ESI-MS m / z 533 [M + H] +.

[001144] Example 184: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (6- (methylpi ridin-3-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: the same as in Example 159.

[001145] Step 1: Preparation of 6-methyl-1- (6-methylpyridin-3-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) indolizine na- Isopropyl 7-carboxylate: 33% yield ESI-MS m / z 503 [M + H] +.

[001146] Step 2: Preparation of 6-methyl-1- (6-methylpyridin-3-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) lizine-7-carboxylic acid: 87% yield. ESI-MS m / z 461 [M + H] +.

[001147] Step 3: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (6-methylpyridine) -3-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide a: 17% yield. 1H NMR (CDCl3, 400 MHz) δ ppm 8.71 (s, 1 H), 8.46 (s, 1 H), 7.32 (dd, J = 8.0, 2.4 Hz, 1 H), 7.66 (d, J = 7.7 Hz, 1 H), 7.60 (t, J = 2.4 Hz, 1 H), 7.16 (d, J = 8.0 Hz, 1 H), 6 , 89 (s, 1 H), 5.87 (s, 1 H), 4.52 (d, J = 5.2 Hz, 2 H), 4.06 (q, J = 6.4 Hz, 1 H), 3.87 (s, 3 H), 2.95 (q, J = 9.6 Hz, 2 H), 2.68 - 2.58 (m, 6 H), 2.50 (s, 3 H), 2.37 (s, 3 H), 2.35 - 2.31 (m, 2 H), 2.22 (s, 3 H), 1.48 (d, J = 6.4 Hz , 3 H); ESI-MS m / z 611 [M + H] +.

[001148] Example 185: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -1- (2-methoxypyridin-4-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxylic acid: the same as in Example 159.

[001149] Step 1: Preparation of 1- (2-methoxypyridin-4-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) in isopropyl dolizine-7-carboxylate: the yield of the two stages was 80%. ESI-MS m / z 519 [M + H] +.

[001150] Step 2: Preparation of 1- (2-methoxypyridin-4-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) in dolizine-7-carboxylic: ESI-MS m / z 477 [M + H] +.

[001151] Step 3: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -1- (2-methoxypyridin-4-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxylic acid: the yield of the two stages was 53%. 1H NMR (CDCl3, 400 MHz) δ ppm 12.13 (brs, 1 H), 8.50 (s, 1 H), 8.06 (d, J = 5.2 Hz, 1 H), 7, 76 (s, 1 H), 7.64 (t, J = 5.2 Hz, 1 H), 7.06 (dd, J = 6.8, 5.2 Hz, 1 H), 6.95 ( d, J = 7.2 Hz, 1 H), 6.90 (s, 1 H), 5.87 (s, 1 H), 4.56 (d, J = 2.8 Hz, 2 H), 4.07 (q, J = 6.8 Hz, 1 H), 3.92 (s, 3 H), 3.89 (s, 3 H), 2.95 (q, J = 9.6 Hz, 2 H), 2.68 - 2.58 (m, 6 H), 2.38 (s, 3 H), 2.33 - 2.29 (m, 2 H), 2.18 (s, 3 H ), 1.48 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 627 [M + H] +.

[001152] Example 186: Preparation of (S) -N - ((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -1- (2-methoxypyridine) -4-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carbo xamide or (R) -N - (( 4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -1- (2-methoxypyrid in-4-yl) -6-methyl-5- (1- ( 4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carbo xamide: Compound 193 was separated by means of preparative chiral liquid chromatography to provide Compound 194 and Compound 195.

[001153] The separation conditions were: column type IC-H; column size: 0.46 cm I.D. × 15 cm L; injection volume: 2 μL; mobile phase: EtOH (0.1% DEA); flow rate: 0.5 ml / min .; detection conditions: UVλ = 254 nm; column temperature: 25 ° C.

[001154] Compound 194: 1H NMR (CDCl3, 400 MHz) δ ppm 11.48 (brs, 1 H), 8.50 (s, 1 H), 8.06 (d, J = 5.2 Hz, 1 H), 7.76 (s, 1 H), 7.64 (t, J = 5.2 Hz, 1 H), 7.06 (dd, J = 6.8, 5.2 Hz, 1 H ), 6.95 (d, J = 7.2 Hz, 1 H), 6.90 (s, 1 H), 5.87 (s, 1 H), 4.56 (d, J = 2.8 Hz, 2 H), 4.07 (q, J = 6.8 Hz, 1 H), 3.92 (s, 3 H), 3.89 (s, 3 H), 2.95 (q, J = 9.6 Hz, 2 H), 2.68 - 2.58 (m, 6 H), 2.38 (s, 3 H), 2.33 - 2.29 (m, 2 H), 2, 18 (s, 3 H), 1.48 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 627 [M + H] +; t R = 10.543 min.

[001155] Compound 195: 1H NMR (CDCl3, 400 MHz) δ ppm 12.51 (brs, 1 H), 8.50 (s, 1 H), 8.06 (d, J = 5.2 Hz, 1 H), 7.76 (s, 1 H), 7.64 (t, J = 5.2 Hz, 1 H), 7.06 (dd, J = 6.8, 5.2 Hz, 1 H ), 6.95 (d, J = 7.2 Hz, 1 H), 6.90 (s, 1 H), 5.87 (s, 1 H), 4.56 (d, J = 2.8 Hz, 2 H), 4.07 (q, J = 6.8 Hz, 1 H), 3.92 (s, 3 H), 3.89 (s, 3 H), 2.95 (q, J = 9.6 Hz, 2 H), 2.68 - 2.58 (m, 6 H), 2.38 (s, 3 H), 2.33 - 2.29 (m, 2 H), 2, 18 (s, 3 H), 1.48 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 627 [M + H] +; t R = 12.384 min.

[001156] Example 187: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (2-methylpyrimidine -5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxylic acid: the same as in Example 159.

[001157] Step 1: Preparation of 6-methyl-1- (2-methylpyrimidin-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) indolyzine- Isopropyl 7-carboxylate: 82% yield ESI-MS m / z 504 [M + H] +.

[001158] Step 2: Preparation of 6-methyl-1- (2-methylpyrimidin-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) in dolizine-7-carboxylic: 78% yield. ESI-MS m / z 462 [M + H] +.

[001159] Step 3: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (2-methylpyrimidine -5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxy: 30% yield. 1H NMR (CDCl3, 400 MHz) δ ppm 8.83 (s, 2 H), 8.51 (s, 1 H), 7.66 - 7.62 (m, 2 H), 6.92 (d , J = 2.8 Hz, 1 H), 5.89 (s, 1 H), 4.53 (d, J = 5.6 Hz, 2 H), 4.08 (q, J = 6.8 Hz, 1 H), 3.89 (s, 3 H), 2.95 (q, J = 8.8 Hz, 2 H), 2.78 - 2.23 (m, 8 H), 2.39 (s, 3 H), 2.33 - 2.29 (m, 2 H), 2.21 (s, 3 H), 1.48 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 612 [M + H] +.

[001160] Example 188: Preparation of (S) -N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- ( 2-metilpyrimidin-5-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-formamide or (R) -N - ((4 -methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (2-metylpyrimidin-5-yl) -5- (1- (4 - (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-wet form: Compound 196 was separated by means of preparative chiral liquid chromatography to provide compound 197 and compound 198.

[001161] The separation conditions were: column type IC-H; column size: 0.46 cm I.D. × 15 cm L; injection volume: 2 μL; mobile phase: EtOH (0.1% DEA); flow rate: 0.5 ml / min .; detection conditions: UVλ = 254 nm; column temperature: 25 ° C.

[001162] Compound 197: 1H NMR (CDCl3, 400 MHz) δ ppm 8.83 (s, 2 H), 8.51 (s, 1 H), 7.66 - 7.62 (m, 2 H) , 6.92 (d, J = 2.8 Hz, 1 H), 5.89 (s, 1 H), 4.53 (d, J = 5.6 Hz, 2 H), 4.08 (q , J = 6.8 Hz, 1 H), 3.89 (s, 3 H), 2.95 (q, J = 8.8 Hz, 2 H), 2.78 - 2.23 (m, 8 H), 2.39 (s, 3 H), 2.33 - 2.29 (m, 2 H), 2.21 (s, 3 H), 1.48 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 612 [M + H] +; t R = 10.921 min.

[001163] Compound 198: 1H NMR (CDCl3, 400 MHz) δ ppm 8.83 (s, 2 H), 8.51 (s, 1 H), 7.66 - 7.62 (m, 2 H) , 6.92 (d, J = 2.8 Hz, 1 H), 5.89 (s, 1 H), 4.53 (d, J = 5.6 Hz, 2 H), 4.08 (q , J = 6.8 Hz, 1 H), 3.89 (s, 3 H), 2.95 (q, J = 8.8 Hz, 2 H), 2.78 - 2.23 (m, 8 H), 2.39 (s, 3 H), 2.33 - 2.29 (m, 2 H), 2.21 (s, 3 H), 1.48 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 612 [M + H] +; t R = 12.259 min.

[001164] Example 189: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (6-methylpyrazin) -3-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: similar to that of Example 50.

[001165] Step 1: Preparation of ethyl 5-acetyl-6-methyl-1- (6-methylpyridazin-3-yl) indolizine-7-carboxylate: 48% yield. ESI-MS m / z 338 [M + H] +.

[001166] Step 2: Preparation of 6-methyl-1- (6-methylpyridazin-3-yl) -5- (1- (piperazin-1-yl) vinyl) indolizine-7-carboxyl act: ESI-MS m / z 420 [M + H] +.

[001167] Step 3: Preparation of 6-Methyl-1- (6-methylpyridazin-3-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) vinyl) i isopropyl ndolizine-7-carboxylate: ESI-MS m / z 502 [M + H] +.

[001168] Step 4: Preparation of 6-methyl-1- (6-methyl-3,4,5,6-tetrahydropyridazin-3-yl) -5- (1- (4- (2,2,2-trifluoroethyl ) isopropyl pi perazin-1-yl) ethyl) indolizine-7-carboxylate: the yield of these three stages was 55%. ESI-MS m / z 508 [M + H] +.

[001169] Step 5: Preparation of 6-methyl-1- (6-methylpyridazin-3-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) in dolizine-7-carboxylic: 68% yield. ESI-MS m / z 462 [M + H] +.

[001170] Step 6: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (6-methylpyridazin -3-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxy: 52% yield. 1H NMR (CDCl3, 400 MHz) δ ppm 8.65 (s, 1 H), 8.48 (brs, 1 H), 7.62 - 7.58 (m, 2 H), 7.25 (d , J = 8.8 Hz, 1 H), 7.11 (d, J = 2.8 Hz, 1 H), 5.83 (s, 1 H), 4.57 (d, J = 5.6 Hz, 2 H), 4.09 (q, J = 6.8 Hz, 1 H), 3.88 (s, 3 H), 2.96 (q, J = 9.6 Hz, 2 H), 2.68 - 2.63 (m, 9 H), 2.39 (s, 3 H), 2.32 - 2.29 (m, 2 H), 2.16 (s, 3 H), 1, 50 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 612 [M + H] +.

[001171] Example 190: Preparation of (S) -N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- ( 6-metilpyridazin-3-yl) -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-wet form or (R) -N - (( 4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-1- (6-methylpyridazin-3-yl) -5- (1- ( 4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-wet form: Compound 199 was separated by means of preparative chiral liquid chromatography to provide Compound 200 and Compound 201.

[001172] The separation conditions were: column type: AD-H; column size: 0.46 cm ID × 15 cm L; injection volume: 2 μL; mobile phase: Hep / EtOH (0.1% DEA) = 60/40 (v / v); flow rate: 0.5 ml / min .; detection conditions: UVλ = 254 nm; column temperature: 25 ° C.

[001173] Compound 200: 1H NMR (CDCl3, 400 MHz) δ ppm 8.65 (s, 1 H), 8.48 (brs, 1 H), 7.62 - 7.58 (m, 2 H) , 7.25 (d, J = 8.8 Hz, 1 H), 7.11 (d, J = 2.8 Hz, 1 H), 5.83 (s, 1 H), 4.57 (d , J = 5.6 Hz, 2 H), 4.09 (q, J = 6.8 Hz, 1 H), 3.88 (s, 3 H), 2.96 (q, J = 9.6 Hz, 2 H), 2.68 - 2.63 (m, 9 H), 2.39 (s, 3 H), 2.32 - 2.29 (m, 2 H), 2.16 (s, 3 H), 1.50 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 612 [M + H] +; tR = 5.077 min.

[001174] Compound 201: 1H NMR (CDCl3, 400 MHz) δ ppm 8.65 (s, 1 H), 8.48 (brs, 1 H), 7.62 - 7.58 (m, 2 H) , 7.25 (d, J = 8.8 Hz, 1 H), 7.11 (d, J = 2.8 Hz, 1 H), 5.83 (s, 1 H), 4.57 (d , J = 5.6 Hz, 2 H), 4.09 (q, J = 6.8 Hz, 1 H), 3.88 (s, 3 H), 2.96 (q, J = 9.6 Hz, 2 H), 2.68 - 2.63 (m, 9 H), 2.39 (s, 3 H), 2.32 - 2.29 (m, 2 H), 2.16 (s, 3 H), 1.50 (d, J = 6.8 Hz, 3 H); ESI-ESI-MS m / z 612 [M + H] +; t R = 8.617 min.

[001175] Example 191: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (methyl (1- (2,2,2-trifluoroethyl) piperidin-4-yl) amino) -1- (1H-pyrazol-5-yl) indolizine-7-carboxamide:

[001176] Step 1: Preparation of ethyl 1-bromo-5-chloro-6-methylindolizine-7-carboxylate: compound 4,4-dichloro-3-methyl-2-butenoate (2.0 g, 10, 2 mmol) (prepared according to: Owusu-Ansah, E .; Durow, AC; Harding, JR; Jordan, AC; O'Connell, SJ, and Willis, CL, Synthesis of dysideaproline E Using organocatalysis. Org. Biomol. Chem., 2011, 9, pages 265 to 272.), 3-bromo-1H-pyrrole-2-carbaldehyde (1.5 g, 8.5 mmol) (prepared according to: WO2012029942), potassium carbonate (2 , 5 g, 17.9 mmol) and 10 mL of DMF were added in a 100 mL single neck flask, and stirred overnight in an oil bath at 65 ° C. The mixture was extracted with ethyl acetate (100 ml) and washed with water (50 ml × 2) and saturated brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product. After purification by column chromatography (petroleum ether: EtOAc = 100: 1), white solids (1.6 g, yield: 61%) were obtained. 1H NMR (400 MHz, CDCl3) δ ppm 8.09 (s, 1 H), 7.60 (d, J = 2.9 Hz, 1 H), 6.94 (d, J = 2.9 Hz , 1 H), 4.37 (q, J = 7.1 Hz, 2 H), 2.62 (s, 3 H), 1.42 (t, J = 7.1 Hz, 3 H); ESI-MS m / z 316 [M + H] +.

[001177] Step 2: Preparation of ethyl 5-chloro-6-methyl-1- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) indolizine-7-carboxylate: In a 50 ml nitrogen-protected, single-necked dry bottle, ethyl 1-bromo-5-chloro-6-methylpyridazin-7-carboxylate (1.53 g, 4.85 mmol), 1- (tetrahydro-2H -pyran-2-yl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) -1H-p irazole (2.70 g, 9.71 mmol), Pd (dppf) Cl2 (666 mg, 0.83 mmol), K2CO3 (1.34 g, 9.71 mmol) were added in 6 mL of 1,4-dioxane and 5 drops of water. The bottle was exchanged three times for nitrogen, and the mixture was stirred in an oil bath at 110 ° C overnight. The mixture was extracted with ethyl acetate (100 ml) and washed with water (50 ml × 2) and saturated brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product. After purification by column chromatography (petroleum ether: EtOAc = 100: 1), white solids (634 mg, yield: 34%) were obtained. ESI-MS m / z 304 [M-THP + H] +.

[001178] Step 3: Preparation of 5 - ((1-tert-butoxycarbonylpiperidin-4-yl) amino) -6-methyl-1- (1- (tetrahydro-2H-pyran -2-yl) -1H-pyrazole- 5-yl) ethyl indolizine-7-carboxylate: In a 100 ml nitrogen-protected dry single-necked flask, the compound 5-chloro-6-methyl-1- (1- (tetrahydro-2H-pyran-2 -yl) -1H-pyrazol-5-yl) ethyl indolizine-7-carboxylate (634 mg, 1.64 mmol), 1-tert-butoxycarbonyl-4-aminopiperidine (1.64 g, 8.19 mmol) , Pd2 (dba) 3 (150 mg, 0.164 mmol), Xantphos (95 mg, 0.164 mmol) and Cs2CO3 (1.069 mg, 3.28 mmol) were added in 10 mL of toluene. The flask was exchanged three times for nitrogen and shaken in an oil bath, at 110 ° C, overnight. The mixture was extracted with ethyl acetate (100 ml) and washed with water (50 ml × 2) and saturated brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product. After purification by column chromatography (petroleum ether: EtOAc = 5: 1), yellow solids (443 mg, yield: 49%) were obtained. ESI-MS m / z 552 [M + H] +.

[001179] Step 4: Preparation of 5 - ((1- (tert-butoxycarbonyl) piperidin-4-yl) (methyl) amino) -6-methyl-1- (1- (tetrahydro2H-pyran-2-yl) - Ethyl 1H-pyrazol-5-yl) indolizine-7-carboxylate: In the microwave tube, compound 5 - ((1-tert-butoxycarbonylpiperidin-4-yl) amino) -6-methyl-1- (1 - Ethyl (tetrahydro-2H-pyran -2-yl) -1H-pyrazol-5-yl) indolizine-7-carboxylate (400 mg, 0.73 mmol), sodium hydride (58 mg, 1.45 mmol) were successively added to 2 ml of DMF, stirred for 30 min in an ice bath, and then methyl iodide (515 mg, 3.63 mmol) was added and transferred to room temperature and stirred overnight, the reaction was cooled with water, extracted with ethyl acetate (50 ml), washed with water (50 ml × 2) and saturated brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product. After purification by column chromatography (petroleum ether: EtOAc = 5: 1), yellow solids were obtained (154 mg, yield: 37%). ESI-MS m / z 566 [M + H] +.

[001180] Step 5: Preparation of ethyl 6-methyl-5- (methyl (piperidin-4-yl) amino) -1- (1H-pyrazol-5-yl) indolizine-7-carboxylate: compound 5- ( (1- (tert-butoxycarbonyl) piperidin-4-yl) (methyl) amino) -6-methyl-1- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) indolizine -7-ethyl carboxylate (154 mg, 0.272 mmol), 2 ml dichloromethane and 0.5 ml trifluoroacetic acid were added successively to a 50 ml neck bottle and stirred at room temperature for 1 hour. The saturated aqueous solution of sodium hydrogen carbonate was added and extracted with dichloromethane (50 ml), washed with water (25 ml × 2) and brine (25 ml). The organic phase was dried over anhydrous sodium sulfate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product, yellow solid (121 mg, 99% yield). ESI-MS m / z 382 [M + H] +.

[001181] Step 6: Preparation of 6-methyl-5- (methyl (1- (2,2,2-trifluoroethyl) piperidin-4-yl) amino) -1- (1H-pyrazol-5-yl) i ndolizine -7-ethyl carboxylate: in a 50ml single-necked dry flask, compound 6-methyl-5- (methyl (piperidin-4-yl) amino) -1- (1H-pyrazol-5-yl) indolizine- Ethyl 7-carboxylate (121 mg, 0.317 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (110 mg, 0.476 mmol) and triethylamine (48 mg, 0.476 mmol) were added and dissolved in 2 mL of tetrahydrofuran and stirred at room temperature overnight. The reaction was cooled with water and extracted with dichloromethane (50 ml), washed with water (50 ml × 2) and saturated brine (50 ml), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product, yellow solids (103 mg, 70% yield). ESI-MS m / z 464 [M + H] +.

[001182] Step 7: Preparation of 6-methyl-5- (methyl (1- (2,2,2-trifluoroethyl) piperidin-4-yl) amino) -1- (1H-pyrazol-5-yl) i ndolizine-7-formic: The compound 6-methyl-5- (methyl (1- (2,2,2-trifluoroethyl) piperidin-4-yl) amino) -1- (1H-pyrazol-5-yl) i ndolizine-7-carboxylic acid (103 mg, 0.222 mmol), 2.5 ml of tetrahydrofuran and 2.5 ml of methanol were added successively to a 25 ml nitrogen-protected single neck bottle. 50 mg of sodium hydroxide dissolved in 2.5 ml of water were added to the reaction system, and the mixture was heated to 60 ° C and stirred under reflux for 5 hours. The reaction solution was neutralized with dilute hydrochloric acid to pH 5, concentrated by means of filtration and then purified by means of reverse phase chromatography to provide yellow solids (25 mg, yield: 23%). ESI-MS m / z 436 [M + H] +.

[001183] Step 8: Preparation of N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (methyl (1- (2,2,2-trifluoroethyl) piperidin-4-yl) amino) -1- (1H-pyrazol-5-yl) indolizine-7-carboxy: in a microwave tube, 6-methyl-5 acid - (methyl (1- (2,2,2-trifluoroethyl) piperidin-4-yl) amino) -1- (1H-pyrazol-5-yl) indolizine-7-carboxylic (25 mg, 0.058 mmol), hydrochloride 3- (aminomethyl) -4-methoxy-6-methylpyridin-2 (1H) -one (15 mg, 0.069 mmol), HATU (33 mg, 0.086 mmol), TEA (18 mg, 0.172 mmol) and DMF of 2 ml were added and stirred at room temperature overnight. yellow solids (10 mg, yield: 29%) were obtained by preparative purification. 1H NMR (400 MHz, CDCl3) δ ppm 8.07 (s, 1 H), 7.45 (s, 1 H), 6.93 (s, 1 H), 6.37 (s, 1 H) , 5.84 (s, 1 H), 4.65 - 4.44 (m, 2 H), 3.85 (s, 3 H), 3.21 - 3.07 (m, 2 H), 3 .00 - 2.85 (m, 7 H), 2.37 (s, 3 H), 2.29 - 2.18 (m, 2 H), 2.16 (s, 3 H), 2.07 - 1.95 (m, 4 H); ESI-MS m / z 586 [M + H] +.

[001184] Example 192: Preparation of 1- (2- (dimethylamino) pyridin-4-yl) -5- (ethyl (1- (2,2,2-trifluoroethyl) piperidin-4-yl) amino) -N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methylindolizine-7-carboxamide: similar to that of Example 191.

[001185] Step 1: Preparation of ethyl 5-chloro-1- (2- (dimethylamino) pyridin-4-yl) -6-methylindolizine-7-carboxylate: 44% yield. ESI-MS m / z 358 [M + H] +.

[001186] Step 2: Preparation of 5 - ((1- (tert-butoxy) piperidin-4-yl) amino) -1- (2- (dimethylamino) pyridin-4-yl) -6-methyl indolizine-7- ethyl carboxylate: 41% yield. ESI-MS m / z 522 [M + H] +.

[001187] Step 3: Preparation of ethyl 1- (2- (dimethylamino) pyridin-4-yl) -6-methyl-5- (piperidin-4-ylamino) indolizine-7-carboxylate: 97% yield. ESI-MS m / z 422 [M + H] +.

[001188] Step 4: Preparation of 1- (2- (dimethylamino) pyridin-4-yl) -6-methyl-5 - ((1- (2,2,2-trifluoroethyl) piperidin-4-yl) to min ) indolizine-7-carboxylate: 59% yield. ESI-MS m / z 504 [M + H] +.

[001189] Step 5: Preparation of 1- (2- (dimethylamino) pyridin-4-yl) -5- (ethyl (1- (2,2,2-trifluoroethyl) piperidin-4-yl) amino) -6 ethyl-methylindolizine-7-carboxylate: Yield 22%. ESI-MS m / z 532 [M + H] +

[001190] Step 6: Preparation of 1- (2- (dimethylamino) pyridin-4-yl) -5- (ethyl (1- (2,2,2-trifluoroethyl) piperidin-4-yl) amino acid) - 6-methylindolizine-7-carboxylic: Yield 79%. ESI-MS m / z 504 [M + H] +.

[001191] Step 7: Preparation of 1- (2- (dimethylamino) pyridin-4-yl) -5- (ethyl (1- (2,2,2-trifluoroethyl) piperidin-4-yl) amino) -N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methylindolizine-7-carboxamide: 26% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.02 (s, 1 H), 7.81 (s, 1 H), 7.76 (s, 1 H), 7.75 (s, 1 H) , 6.94 (s, 1 H), 6.70 (s, 1 H), 6.59 (s, 1 H), 5.83 (s, 1 H), 4.56 (s, 2 H) , 3.86 (s, 3 H), 3.29 - 3.10 (m, 3 H), 3.09 - 2.82 (m, 12 H), 2.35 (s, 3 H), 2 , 12 (s, 3 H), 0.98 (brs, 3 H); ESI-MS m / z 654 [M + H] +.

[001192] Example 193: Preparation of 1- (2- (dimethylamino) pyridin-4-yl) -5- (ethyl (1- (2,2,2-trifluoroethyl) piperidin-4-yl) amino) -N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methylimidazo [1,5-a] pyridine-7-carboxamide.

[001193] Step 1: Preparation of ethyl 5-chloro-6-methylimidazo [1,5-a] pyridine-7-carboxylate: 4,4-dichloro-3-methyl-2-butenoate (1.53 g, 7.82 mmol), 1H-imidazole-5-carbaldehyde (500 mg, 5.21 mmol), potassium carbonate (2.16 g, 15.62 mmol) and 15 mL of DMF were added in a flask of single neck, 100 mL, and stirred in a 60 ° C oil bath overnight. The mixture was extracted with ethyl acetate (100 ml) and washed with water (50 ml × 2) and saturated brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product. After purification by column chromatography (petroleum ether: EtOAc = 4: 1), yellow solids (648 mg, yield: 52%) were obtained. ESI-MS m / z 239 [M + H] +.

[001194] Step 2: Preparation of ethyl 1-bromo-5-chloro-6-methylimidazo [1,5-a] pyridine-7-carboxylate: In a 50 mL, 5-chlorine-6 single-neck flask Ethyl-methylimidazo [1,5-a] pyridine-7-carboxylate (442 mg, 1.86 mmol) was dissolved in 25 mL of acetonitrile, transferred to an ice bath and stirred for 10 min., and NBS (330 mg, 1.86 mmol) was added three times, and stirred for 1 hour in an ice bath. Acetonitrile was dried by rotary evaporator, and the residue was extracted with methylene chloride (30 ml), washed with water (30 ml × 2) and brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product. After purification by column chromatography (petroleum ether: EtOAc = 20: 1), yellow solids (552 mg, yield: 90%) were obtained. ESI-MS m / z 317 [M + H] +.

[001195] Step 3: Preparation of ethyl 5-chloro-1- (2- (dimethylamino) pyridin-4-yl) -6-methylimidazo [1,5-a] pyridine-7-carbo xylate: in a vial 50 ml nitrogen-protected single neck, ethyl 1-bromo-5-chloro-6-methylimidazo [1,5-a] pyridine-7-carboxylate (504 mg, 1.59 mmol), N, N-dimethyl -4- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) pyridine-2-amine (396 mg, 1.59 mmol), Pd (dppf) Cl2 (58 mg, 0.08 mmol), Cs2CO3 (1.04 g, 3.19 mmol) were added in 6 mL of toluene: DMF = 3: 1. The flask was exchanged three times for nitrogen, and the mixture was stirred in a 100 ℃ oil bath overnight. The mixture was extracted with ethyl acetate (100 ml) and washed with water (50 ml × 2) and saturated brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product. After purifying by column chromatography (petroleum ether: EtOAc = 5: 1), white solids (217 mg, yield: 38%) were obtained. ESI-MS m / z 359 [M + H] +.

[001196] Step 4: preparation of 5 - ((1- (tert-butoxycarbonyl) piperidin-4-yl) amino) -1- (2- (dimethylamino) pyridin-4-yl) -6-methylimidazo [1, 5 -a] ethyl pyridine-7-carboxylate: in a microwave tube,
Ethyl 5-chloro-1- (2- (dimethylamino) pyridin-4-yl) -6-methylimidazo [1,5-a] pyridine-7-carbo xylate (217 mg, 0.606 mmol), 1-tert-butoxycarbonyl -4-aminopiperidine (364 mg, 1.82 mmol), Pd (OAc) 2 (21 mg, 0.091 mmol), Ru-fos (43 mg, 0.091 mmol), Cs2CO3 (395 mg, 1.21 mmol) in 4 ml of toluene. The tube was exchanged three times for nitrogen and shaken in a 130 ℃ oil bath for 2 days. The mixture was extracted with ethyl acetate (100 ml) and washed with water (50 ml × 2) and saturated brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product. After purification by column chromatography (petroleum ether: EtOAc = 1: 1), they were obtained (251 mg, yield: 79%).
ESI-MS m / z 523 [M + H] +.

[001197] Step 5: Preparation of 5 - ((1- (tert-butoxycarbonyl) piperidin-4-yl) (ethyl) amino) -1- (2- (dimethylamino) pyridi n-4-yl) -6-methylimidazo Ethyl [1,5-a] pyridine-7-carboxylate: 5 - ((1- (tert-butoxycarbonyl) piperidin-4-yl) amino) -1- (2- (dimethylamino) pyridin-4-yl) - Ethyl 6-methylimidazo [1,5-a] pyridine-7-carboxylate (251 mg, 0.481 mmol), sodium hydride (39 mg, 0.962 mmol) were dissolved in 2 mL of DMF, stirred for 30 min. in an ice bath, then ethyl iodide (3.75 g, 24.04 mmol) was added, stirred for 3 hours in an ice bath, then transferred to room temperature and stirred overnight. The reaction was cooled with water and extracted with ethyl acetate (50 ml), washed with water (50 ml × 2) and saturated brine (50 ml), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product. After purification by column chromatography (petroleum ether: EtOAc = 5: 1), yellow solids (169 mg, yield: 64%) were obtained. ESI-MS m / z 551 [M + H] +.

[001198] Step 6: Preparation of 1- (2- (dimethylamino) pyridin-4-yl) -5- (ethyl (piperidin-4-yl) amino) -6-methylimidazo [1,5-a] pyridine-7 -format: In a 50 ml dry single-necked flask, 5 - ((1- (tert-butoxycarbonyl) piperidin-4-yl) (ethyl) amino) -1- (2- (dimethylamino) pyridi n-4 -yl) -6-methylimidazo [1,5-a] pyridine-7-carboxylate (169 mg, 0.307 mmol), 2 ml of dichloromethane and 0.5 ml of fluoroacetic acid were added successively and stirred at temperature room for 1 hour. The saturated aqueous solution of sodium hydrogen carbonate was added and extracted with dichloromethane (50 ml), washed with water (25 ml × 2) and brine (25 ml). The organic phase was dried over anhydrous sodium sulfate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product, yellow solid (148 mg, 91% yield). ESI-MS m / z 451 [M + H] +.

[001199] Step 7: Preparation of 1- (2- (dimethylamino) pyridin-4-yl) -5- (ethyl (1- (2,2,2-trifluoroethyl) piperidin-4-yl) amino) -6 -methylimidazo [1,5-a] pyridine-7-carboxylate ethyl: in a 50 ml single-necked dry flask, 1- (2- (dimethylamino) pyridin-4-yl) -5- (ethyl (piperidin- Ethyl 4-yl) amino) -6-methylimidazo [1,5-a] pyridine-7-carboxylate (169 mg, 0.375 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (131 mg, 0.563 mmol) and triethylamine (57 mg, 0.563 mmol) were added and dissolved in 2 ml of THF and stirred overnight at room temperature. The reaction was cooled with water and extracted with dichloromethane (50 ml), washed with water (50 ml × 2) and saturated brine (50 ml), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a crude product, yellow solid (148 mg, 74% yield). ESI-MS m / z 533 [M + H] +.

[001200] Step 8: Preparation of 1- (2- (dimethylamino) pyridin-4-yl) -5- (ethyl (1- (2,2,2-trifluoroethyl) piperidin-4-yl) amino acid) - 6-methylimidazo [1,5-a] pyridine-7-carboxylic: Compound 1- (2- (dimethylamino) pyridin-4-yl) -5- (ethyl (1- (2,2,2-trifluoroethyl) piperidin -4-yl) amin o) -6-methylimidazo [1,5-a] pyridine-7-carboxylate (148 mg, 0.278 mmol), 2.5 ml of tetrahydrofuran and 2.5 ml of methanol were added successively to a 25 ml nitrogen-protected single neck bottle. 50 mg of sodium hydroxide dissolved in 2.5 ml of water were added to the reaction system, and the mixture was heated to 60 ° C and stirred under reflux for 5 hours. The reaction solution was neutralized with dilute hydrochloric acid to pH 5, filtered and concentrated, and then purified by reverse phase chromatography to provide yellow solids (66 mg, yield: 47%). ESI-MS m / z 505 [M + H] +.

[001201] Step 9: Preparation of 1- (2- (dimethylamino) pyridin-4-yl) -5- (ethyl (1- (2,2,2-trifluoroethyl) piperidin-4-yl) amine) -N - (((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methylimidazo [1,5-a] pyridine -7-formamide: Acid 1- ( 2- (dimethylamino) pyridin-4-yl) -5- (ethyl (1- (2,2,2-trifluoroethyl) piperidin-4-yl) amin o) -6-methylimidazo [1,5-a] pyridine- 7-carboxylic (66 mg, 0.131 mmol), 3- (aminomethyl) -4-methoxy-6-methylpyridin-2 (1H) -one hydrochloride (32 mg, 0.157 mmol), HATU (75 mg, 0.196 mmol), TEA (40 mg, 0.393 mmol) and 1.5 mL DMF were added successively in a microwave tube and stirred at room temperature overnight. yellow solids (25 mg, yield: 29%) were obtained by means of preparative purification. 1H NMR (400 MHz, CDCl3) δ ppm 12.70 (s, 1 H), 8.26 (s, 1 H), 8.05 (s, 1 H), 8.03 (s, 1 H) , 7.82 (s, 1 H), 7.04 (s, 1 H), 6.89 (d, J = 5.2 Hz, 1 H), 5.83 (s, 1 H), 4, 64 - 4.51 (m, 2 H), 3.86 (s, 3 H), 3.34 - 3.18 (m, 2 H), 3.17 - 3.09 (m, 2 H), 3.07 (s, 6 H), 2.90 (q, J = 9.4 Hz, 2 H), 2.40 - 2.26 (m, 5 H), 2.17 (s, 3 H) , 0.99 (t, J = 7.1 Hz, 3 H); ESI-MS m / z 655 [M + H] +.

[001202] Example 194: Preparation of 1- (2-ethylpyridin-4-yl) -N - ((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) - 6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: the same as in Example 159.

[001203] Step 1: Preparation of 1- (2-ethylpyridin-4-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indoli isopropyl zine-7-carboxylate: the yield of the two stages was 31%. ESI-MS m / z 517 [M + H] +.

[001204] Step 2: Preparation of 1- (2-ethylpyridin-4-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl acid) indolyzine-7-carboxylic: 93% yield. ESI-MS m / z 475 [M + H] +.

[001205] Step 3: Preparation of 1- (2-ethylpyridin-4-yl) -N - ((4-methoxy-6-methyl-2-oxo) -1,2-dihydropyridin-3-yl) methyl ) - 6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide: 44% yield. 1H NMR (CDCl3, 400 MHz) δ ppm 8.46 (s, 1 H), 8.34 (d, J = 5.2 Hz, 1 H), 7.92 (t, J = 4.8 Hz , 1 H), 7.76 (s, 1 H), 7.23 - 7.20 (m, 2 H), 6.93 (d, J = 2.8 Hz, 1 H), 5.83 (s, 1 H), 4.57 (d, J = 5.6 Hz, 2 H), 4.07 (q, J = 6.8 Hz, 1 H), 3.87 (s, 3 H), 2, 95 (q, J = 6.8 Hz, 3 H), 2.78 - 2.05 (m, 8 H), 2.41 (s, 3 H), 2.31 - 2.19 (m, 2 H), 2.11 (s, 3 H), 1.48 (d, J = 6.8 Hz, 3 H), 1.18 (t, J = 7.6 Hz, 3 H); ESI-MS m / z 625 [M + H] +.

[001206] Example 195: Preparation of 1- (2-isopropylpyridin-3-yl) -N - (((4-methoxy-6-methyl-2-oxo) -1,2-dihydropyridin-3-yl) methyl ) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxamide a: similar to Example 50.

[001207] Step 1: Preparation of ethyl 5-acetyl-1- (2-isopropylpyridin-4-yl) -6-methylindolizine-7-carboxylate: 54% yield. ESI-MS m / z 365 [M + H] +.

[001208] Step 2: Preparation of isopropyl 1- (2-isopropylpyridin-4-yl) -6-methyl-5- (1- (piperazin-1-yl) vinyl) indolizine-7-carboxylate: ESI-MS m / z 447 [M + H] +.

[001209] Step 3: Preparation of 1- (2-isopropylpyridin-4-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) vinyl) indolizine -7-isopropyl carboxylate: the yield of the two stages was 39%. ESI-MS m / z 529 [M + H] +.

[001210] Step 4: Preparation of 1- (2-isopropylpyridin-4-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) i isopropyl ndolizine-7-carboxylate: ESI-MS m / z 531 [M + H] +.

[001211] Step 5: Preparation of 1- (2-isopropylpyridin-4-yl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl acid) i-ndolizine-7-carboxylic: ESI-MS m / z 489 [M + H] +.

[001212] Step 6: Preparation of 1- (2-isopropylpyridin-4-yl) -N - ((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carbox amide: the yield of the three stages was 34%. 1H NMR (CDCl3, 400 MHz) δ ppm 8.47 (s, 1 H), 8.39 (d, J = 6.0 Hz, 1 H), 7.83 (t, J = 4.2 Hz , 1 H), 7.75 (s, 1 H), 7.24 (d, J = 4.4 Hz, 1 H), 6.95 (d, J = 3.2 Hz, 1 H), 5 , 84 (s, 1 H), 4.56 (d, J = 5.6 Hz, 2 H), 4.07 (q, J = 6.8 Hz, 1 H), 3.86 (s, 3 H), 3.01 - 2.90 (m, 3 H), 2.70 - 2.61 (m, 6 H), 2.41 (s, 3 H), 2.28 - 2.10 (m , 2 H), 2.12 (s, 3 H), 1.48 (d, J = 6.8 Hz, 3 H), 1.21 (d, J = 7.2 Hz, 6 H); ESI-MS m / z 639 [M + H] +.

[001213] Example 196: Preparation of 1- (2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-4-yl) -N - (((4-methoxy-6-methyl-2- oxo) -1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine- 7-carboxamide: similar to Example 50.

[001214] Step 1: Preparation of 4- (5-acetyl-7- (ethoxycarbonyl) -6-methylindolizin-1-yl) -2,3-dihydro-1H-pyrrolo [2,3- b] pyridine- 1-carboxylate: 30% yield. ESI-MS m / z 464 [M + H] +.

[001215] Step 2: Preparation of 4- (7- (isopropoxycarbonyl) -6-methyl-5- (1- (piperazin-1-yl) vinyl) indolizin-1-yl) -2,3-d i-hydro -1H-pyrrolo [2,3-b] pyridine-1-carboxylate: ESI-MS m / z 546 [M + H] +.

[001216] Step 3: Preparation of 4- (7- (isopropoxycarbonyl) -6-methyl-5 - (((4- (2,2,2-trifluoroethyl) piperazin-1-yl) vinyl) i ndolizin-1-yl ) Tert-butyl -2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-1-carboxylate: ESI-MS m / z 628 [M + H] +.

[001217] Step 4: Preparation of 4- (7- (isopropoxycarbonyl) -6-methyl-5 - (((4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizin-1-yl) -2,3-dihydro-1H-pyrrolo [2,3-b] pyridine-1-carboxylate tert-butyl: the yield of the three stages was 27%. ESI-MS m / z 630 [M + H] +.

[001218] Step 5: Preparation of 1- (1- (tert-butoxycarbonyl) -2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-4-yl) -6-methyl-5 - (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine-7-carboxylic:
68% yield. ESI-MS m / z 588 [M + H] +.

[001219] Step 6: Preparation of 4- (7 - ((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) carbamoyl) -6-methyl -5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizin-1-yl) -2,3-dihydro-1H-pyrol [2,3-b] pyridine Tert-butyl -1-carboxylate: Yield 26%. ESI-MS m / z 738 [M + H] +.

[001220] Step 7: Preparation of 1- (2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-4-yl) -N - (((4-methoxy-6-methyl-2- oxo) -1,2-dihydropyridin-3-yl) methyl) -6-methyl-5- (1- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethyl) indolizine- 7-carboxamide: 95% yield. 1H NMR (CDCl3, 400 MHz) δ ppm 8.45 (s, 1 H), 7.83 (t, J = 4.8 Hz, 1 H), 7.68 (d, J = 5.6 Hz , 1 H), 7.54 (s, 1 H), 6.82 (d, J = 2.8 Hz, 1 H), 6.64 (d, J = 5.6 Hz, 1 H), 5 , 90 (s, 1 H), 5.55-5.30 (m, 2 H), 4.55 (ddd, J = 18.0, 13.6, 6.8 Hz, 2 H), 4, 08 (q, J = 6.8 Hz, 1 H), 3.88 (s, 3 H), 3.50 (t, J = 8.4 Hz, 2 H), 3.08 (t, J = 8.0 Hz, 2 H), 2.94 (q, J = 8.4 Hz, 2 H), 2.80 - 2.60 (m, 6 H), 2.40 (s, 3 H), 2.38 - 2.36 (m, 2 H), 2.28 (s, 3 H), 1.49 (d, J = 6.8 Hz, 3 H); ESI-MS m / z 638 [M + H] +.

[001221] All of the literature mentioned in this application is incorporated into this document as a reference, as if each were individually incorporated as a reference. Additionally, it should be understood that, after reading the above teachings, those skilled in the art can make various changes and modifications to the present invention. These equivalents are also within the scope defined by the attached claims.

Claims (10)

Compound of Formula I, or a pharmaceutically acceptable salt, an enantiomer, a diastereomer, a tautomer, a solvate, a polymorph or a prodrug thereof,

CHARACTERIZED by the fact that X1 is CR4 or N;
X2 is CR5 or N;
X3 is CR6 or N; and at most one of X1, X2, X3 is N;
R4 is selected from H, a halogen, substituted or unsubstituted C1-C6 alkyl;
R5 or R6 is selected from H, a halogen, -COOH, -CN, substituted or unsubstituted 5-8 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl, substituted or unsubstituted 5-8 membered aryl substituted fused to the substituted or unsubstituted 5- to 8-membered heterocyclic group, substituted or unsubstituted 5- to 8-membered heterocyclic fused to the substituted or unsubstituted 5- to 8-membered heterocyclic group, fused substituted or unsubstituted 5- to 8-membered heterocyclic group substituted or unsubstituted 5-8 membered carbocyclic group, substituted or unsubstituted 5-8 membered heteroaryl fused to substituted or unsubstituted 5-8 membered carbocyclic group, substituted or unsaturated saturated or unsaturated carbocyclic group substituted, substituted or unsubstituted 4- to 8-membered saturated or unsaturated heterocyclic group, substituted or unsubstituted C1-C6 alkylcarbonyl, -C (O) O- (substituted C1-C6 alkyl or unsubstituted), -C (O) (NRaRb), (CH2) mNRaRb substituted or unsubstituted, substituted or unsubstituted C1-C6 alkyl, boronic acid group, substituted or unsubstituted C2-C8 alkenyl, substituted or C2-C8 alkynyl not replaced; wherein the heteroaryl or heterocyclic group contains 1 to 3 heteroatoms selected from N, O, S, P; m is an integer from 0 to 5; and said "substituted" means that it has one or more (for example, 1, 2, 3 or 4) substituents selected from group A;
where Ra, Rb are each independently selected from H, a halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5- to 8-membered carbocyclic ring, substituted or 5- to 8-membered heterocyclic ring unsubstituted, or Ra and Rb are attached to N to form a substituted or unsubstituted 4- to 8-membered heterocyclic ring; wherein said heterocyclic ring contains 1 to 3 heteroatoms selected from N, O, S or P; R1 is selected from

R2 is selected from H, a halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted aryl;
R3 is selected from

and when R1 is

then, R3 is

wherein, R7 is selected from H, substituted or unsubstituted C1-C6 alkyl;
R8 and R9 are each independently selected from H, a substituted or unsubstituted C1-C6 alkyl;
Y is selected from

wherein, R12 and R13 are each independently selected from H, substituted or unsubstituted C1-C4 alkyl;
R14 and R15 are each independently selected from H, a halogen, -NH2, -NO2, -CF3, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, (CH2) substituted nNRcRd or unsubstituted, or R14 and R15 are combined to form a substituted or unsubstituted 5- to 6-membered saturated heterocyclic ring, or R14 and R15 are joined to form a substituted or unsubstituted 5- to 6-membered aromatic ring; n is an integer from 0 to 4;
R16 is H, a substituted or unsubstituted C1-C4 alkyl;
R17 and R19 are each independently selected from H, a substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, - (CH2) nNRcRd; n is an integer from 0 to 4;
R18 is selected from H, a halogen, -NH2, -NO2, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, (CH2) nNRc Rd substituted or unsubstituted; where n is an integer from 0 to 4;
R20 and R21 are each independently selected from H, a substituted or unsubstituted C1-C4 alkyl;
R22 is selected from H, a substituted or unsubstituted C1-C4 alkyl;

or substituted or unsubstituted C1-C4 alkoxy;
wherein Rc, Rd are each independently selected from H, a substituted or unsubstituted C1-C4 alkyl;
Z is selected from N or CH;
R10 and R11 are each independently selected from: H, -OH, a substituted or unsubstituted C1-C6 alkyl, -ORe, substituted or unsubstituted 4- to 8-membered heterocyclic group, 4 to 8 carbocyclic group substituted or unsubstituted members, 5- to 8-membered substituted or unsubstituted aryl, -NRf Rg; wherein said heterocyclic ring contains 1 to 3 heteroatoms selected from N, O, S or P; and said "substituted" means that it has one or more (for example, 1, 2, 3 or 4) substituents selected from group B;
where Re is selected from H, a substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsaturated 4- or 8-membered carbocyclic ring unsubstituted, substituted or unsubstituted saturated or unsaturated 4- to 8-membered heterocyclic ring, substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, - (CH2) p (5- to 5-membered aryl 8-member substituted or unsubstituted), - (CH2) p (5- to 8-membered substituted or unsubstituted heteroaryl); wherein the heterocyclic or heteroaryl group comprises 1 to 3 heteroatoms selected from N, O, S or P; p is an integer from 0 to 3; and said "substituted" refers to one or more (for example, 1, 2, 3 or 4) among the following substituents: halogen, C1-C4 alkyl, C1-C4 alkoxy, -NO2, -NRsRt;
wherein Rf and Rg are each independently selected from: H, a substituted or unsubstituted C1-C6 alkyl, where the substituent is -OH, C1-C4 alkoxy or -NRsRt;
substituents from group A are selected from the group consisting of H, = O, -CN, -COOH, -NRsRt, a halogen, substituted or unsubstituted C1-C6 alkoxycarbonyl, substituted or unsubstituted C1-C6 alkyl, heterocyclic group 4- to 8-membered substituted or unsubstituted, substituted or unsubstituted C1-C4 alkoxy; wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, S or P;
substituents from group B are selected from the group consisting of H, -OH, a halogen, substituted or unsubstituted C1-C6 alkyl, -NRsRt, -NO2, substituted or unsubstituted C1-C6 alkoxycarbonyl, substituted C1-C6 alkylsulfonyl or unsubstituted, substituted or unsubstituted C1-C6 alkylcarbonyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted 4- to 6-membered heterocyclic ring, substituted or unsubstituted C5-C8 heteroaryl, Boc, benzyl; wherein said heteroaryl comprises 1 to 3 heteroatoms selected from N, O, S or P;
furthermore, in the substituents of group A and group B and in Ra, Rb, substitution means having one or more (for example, 1, 2, 3 or 4) substitutions selected from group C: H, a halogen, -OH, -CN, C1-C4 alkyl, C1-C4 alkoxy, -NRsRt, 5-8 membered aryl, 4-8 membered heterocyclic group, Boc, C1-C4 acyl; and said substitution is one or more (for example, 1, 2, 3 or 4) substituents;
and, in R7, R8, R9, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, Rc, Rd, the “substituted” means having one or more (for example, 1, 2, 3 or 4) substituents selected from the group D: H, a halogen, C1-C4 alkyl, C1-C4 haloalkyl, nitro, -OH, amino;
Rs and Rt are each independently selected from the group consisting of: H, a C1-C4 alkyl, C1-C4 haloalkyl. Compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, CHARACTERIZED by the fact that R10 is a substituted or unsubstituted C1-C4 alkoxy, C1 alkyl -C4 substituted or unsubstituted. Compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, CHARACTERIZED by the fact that R11 is selected from the group consisting of -OH,

-ORe, -NRfRg,

where Re is selected from the group consisting of substituted or unsubstituted C1-C4 alkyl, allyl, isobutenyl, propargyl, cyclohexane, cyclohexenyl group,

where, Re1 is selected from the group consisting of H, a halogen, C1-C4 alkoxy; and the number of Re1 is 1 to 3; Re2 is selected from -NO2, -NH2, -N (CH3) 2; Re3 is selected from H, a halogen, -NRsRt, substituted or unsubstituted C1-C4 alkyl (preferably methyl);
Rf is H, a substituted or unsubstituted C1-C4 alkyl;
Rg is a C1-C4 alkoxy or C1-C4 alkyl substituted by -NsRt;
Rh is selected from H, a halogen;
Ri is selected from H, a substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkylcarbonyl, substituted or unsubstituted C1-C4 alkoxycarbonyl, substituted or unsubstituted C1-C4 alkylsulfonyl, trifluoromethyl C1-C2 alkyl , difluoromethyl C1-C2 alkyl, -NRsRt, and

wherein Rh1 is selected from -OH, -CN, a C1-C4 alkyl;
Rj is selected from the group consisting of: -OH, a halogen, C1-C4 alkoxy, -NRsRt,

wherein R1 is selected from a C1-C4 alkoxy (preferably a methoxy);
R j 'is selected from H or a halogen;
and when Rj is a halogen, then Rj 'is a halogen;
Rk is selected from the group consisting of H, -OH, a C1-C4 alkoxy,
R1 is selected from the group consisting of H, -NRsRt, preferably H or dimethylamino;
Rm is selected from the group consisting of: H, -NRsRt, preferably H or dimethylamino;
Rn is selected from the group consisting of trifluoromethyl C1-C4 alkyl, preferably CF3CH2-. Compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, CHARACTERIZED by the fact that R5 or R6 are each independently selected, from the group consisting of H, substituted or unsubstituted C1-C4 alkyl, -CN, halogen, C1-C4 alkylcarbonyl, R51 (C1-C4 alkoxy) carbonyl, R52C (O) -, -COOH, -C (O) ( NRaRb),

R57 (C1-C3) alkylalkynyl; where R51 is selected from the group consisting of dimethylamino,

and wherein Rb is selected from the group consisting of H, a C1-C4 alkyl, Boc, C1-C4 acyl;
R52 is selected from

Ra is selected from H, a substituted or unsubstituted C1-C4 alkyl;
Rb is selected from H, a substituted or unsubstituted C1-C4 alkyl,

cyclopentyl, Rb "(C1-C4) alkyl; where X is heteroatom selected from N, O or S;
R55 is 1 to 3 substituents selected from the group consisting of H, R551C1-C4 alkyl, halogen, -CN, -NH2, (C1-C4 alkyl) NH-, (R551 C1-C4 alkyl) O-, dimethylamino, -CH2 (Me) 2,

R551 (C1-C6) alkyl OC (O) -, -COOH, -C (O) (NRaRb); where R551 is H, -OH, a C1-C4 alkoxy, amino, dimethylamino, methylamino, diethylamino, methylethylamino, ethylamino,

wherein R541 is selected from H, a C1-C4 alkyl;
R57 is selected from a (C1-C4) alkyl,

dimethylamino;
Rb is selected from the group consisting of -OH, a C1-C3 alkoxy, dimethylamino,

Compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, CHARACTERIZED by the fact that the compound of Formula I has the structure of Formula Ia below:

wherein said R1, R2, R3, R4, R5, R6 are as described above. Compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, CHARACTERIZED by the fact that the compound is selected from the group consisting of

Preparation method for the compound of Formula I, as defined in claim 1, wherein the compound of Formula I has the structure shown in Formula I-1 and the method is CHARACTERIZED in that it comprises the steps:

• (1) in the presence of a reducing agent, reduce compound d to form the compound e, while the reducing agent is selected from the group consisting of sodium borohydride, lithium borohydride, potassium borohydride, or combinations thereof;
• (2) in the presence of a base, react the compound and with a corresponding hydrocarbonylation reagent to form compound f, the base is selected from the group consisting of sodium hydride, potassium t-butoxide, sodium hydroxide, potassium hydroxide, n-butyl lithium, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, potassium carbonate, cesium carbonate, sodium carbonate, or combinations thereof; and the alkylating agent is selected from the group consisting of halogenated hydrocarbons, methanesulfonate, p-toluenesulfonate, trifluoroacetate, triflate, or combinations thereof;
• (3) hydrolyze compound f to form compound g;
• (4) condensing compound g with an amine compound to form compound I-1,

wherein R2, R3, R7, R8, R9, R10, T1, Re, Rf, X1, X2, X3 and Y are as defined above, and Rk is a straight or branched C1-C4 alkyl;
and / or
a method of preparation for the Formula I compound as defined in claim 1, wherein the Formula I compound has the structure shown in Formula I-2 and the method comprises the steps:

• (i) in an inert solvent, in the presence of a reducing agent, react compound d with compound f to form compound i;
• (ii) hydrolyze compound i to form compound j;
• (iii) condensing compound g with the amine compound to form compound I-2;

wherein R2, R3, R7, R8, R9, R10, Re, Rf, Rk, X1, X2, X3 and Y are as described above;
and / or
a method of preparation for the Formula I compound as defined in claim 1, wherein the Formula I compound has the structure shown in Formula I-3 and the method comprises the steps:

(a) in an inert solvent, in the presence of a reducing agent, reduce compound k to form compound l;
(b) in the presence of an alkylating agent, reacting compound 1 to form compound m, and said alkylating agent is selected from the group consisting of X-R10 ', HSO4-R10', HO-R10 ', R10'-O-R10 ', or combinations thereof;
where X is halogen; R10 'is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or unsaturated 4- to 8-membered heterocyclic group, 4-carbocyclic group substituted or unsubstituted saturated or unsaturated 8-member, substituted or unsubstituted, saturated or unsaturated 5- to 8-membered aryl wherein said heterocyclic ring comprises 1 to 3 heteroatoms selected from N, O, S, P; and said "substituted" means having one or more (for example, 1, 2, 3 or 4) substituents selected from group B as defined in claim 1;
(c) hydrolyzing compound m to form compound n;
(d) condensing compound n with the amine compound to form compound I-3;
wherein R2, R3, R7, R8, R9, R10, Re, Rf, Rk, X1, X2, X3 and Y are as described above. Pharmaceutical composition, CHARACTERIZED by the fact that it comprises:

• (1) a compound as defined in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof;
• (2) pharmaceutically acceptable carriers.

Use of the compound of Formula I as defined in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, CHARACTERIZED by the fact that the use is selected from the group consisting of :

• (a) preparing a drug to prevent or treat a disease associated with the EZH2 mutation, activity or expression;
• (b) non-therapeutic inhibition of the activity of EZH2 and its mutants in vitro; and / or
• (c) non-therapeutic inhibition of tumor cell proliferation in vitro.

Use, according to claim 9, CHARACTERIZED by the fact that the disease associated with the EZH2 mutation, activity or expression is selected from the group consisting of tumor or autoimmune disease.