CN111320621B

CN111320621B - Indolizine compound and preparation method and application thereof

Info

Publication number: CN111320621B
Application number: CN201811531971.3A
Authority: CN
Inventors: 许�永; 向秋萍; 张岩; 张�成; 邹龄娇; 王超; 王蕊
Original assignee: Guangzhou Institute of Biomedicine and Health of CAS
Current assignee: Guangzhou Institute of Biomedicine and Health of CAS
Priority date: 2018-12-14
Filing date: 2018-12-14
Publication date: 2022-10-04
Anticipated expiration: 2038-12-14
Also published as: CN111320621A

Abstract

The invention provides an indolizine compound and a preparation method and application thereof, wherein the indolizine compound has a structure shown as a formula I or a formula II; the indolizine compound provided by the invention can be effectively combined with the CBP/EP300 bromodomain, the inhibition rate can generally reach more than 90%, and the indolizine compound has good effect and good selectivity on other bromodomain family proteins; the indolizine compound provided by the invention has a stable structure, and the synthesis method is simpler.

Description

Indolizine compound and preparation method and application thereof

Technical Field

The invention relates to the technical field of chemical medicines, in particular to an indolizine compound and a preparation method and application thereof.

Background

Bromodomains are a class of evolutionarily conserved modules that mediate protein-protein interactions. The bromodomain is a reader of histone acetylation, can specifically recognize acetylated lysine residues of histone, thereby influencing the transcription and translation of target genes, and the complex dysfunction of the protein is related to the occurrence of various diseases, so that the bromodomain protein becomes a novel target. Inhibitors of bromodomain proteins have important biological implications, for example, a number of compounds have been reported to be effective in the treatment of cancer, inflammatory and autoimmune diseases, sepsis, viral infections, and the like.

Bromodomain proteins were first discovered in Drosophila genes, from which they were found in many nucleoproteins, such as Histone Acetyltransferases (HATs), ATP-dependent chromatin remodeling complexes, methyltransferases and transcriptional coactivators, among others. The 61 bromodomains encoded by the human proteome are currently present in 46 different nuclear and cytoplasmic proteins. The bromodomain protein family can be divided into 8 subfamilies according to their functions. Among them is histone acetyltransferase, which includes: CBP, EP300, P/CAF and GCN5, etc. CBP is a homologous protein to EP 300.

CBP/EP300 is a multifunctional transcriptional co-activator of the cAMP response element binding protein CREB, which is involved in a variety of physiological processes: cell cycle regulation, cell differentiation, apoptosis, and the like. The CBP/EP300 protein plays a role of a bridge between a transcription factor and a target DNA through HAT of the CBP/EP300 protein; can inhibit cell replication and make cells stay in G1 phase; the CBP/EP300 protein has the function of a cancer suppressor and is also involved in a plurality of cancer suppressor information conduction paths. CBP/EP300 is involved in various diseases such as prostate cancer and inflammatory therapy (lung inflammation and asthma), in addition to recurrent acute lymphoblastic leukemia, RTS and neurodegenerative diseases. Targeting the CBP/EP300 protein is helpful to provide a new treatment strategy for diseases such as cancer, neurodegenerative diseases and inflammation.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide an indolizine compound, a preparation method and application thereof, wherein the compound can effectively inhibit a CBP/EP300 bromodomain receptor and can be further developed into a medicament for treating cancers, inflammatory diseases, autoimmune diseases, septicemia and virus infection.

In order to achieve the purpose, the invention adopts the following technical scheme:

in a first aspect, the present invention provides an indolizine compound having a structure represented by formula I or formula II:

wherein R is ₁ Selected from hydrogen, C ₁ ～C ₁₀ Alkyl radical, C ₁ ～C ₁₀ Cycloalkyl, substituted C ₁ ～C ₁₀ Cycloalkyl radical, C ₁ ～C ₁₀ Any one of cycloalkenyl, pyridyl, substituted pyridyl, pyrazinyl, substituted pyrazinyl, pyrimidinyl, morpholinyl, substituted pyrimidinyl, pyridazinyl, substituted pyridazinyl, piperidinyl, substituted piperidinyl, furanyl, substituted furanyl, thienyl, substituted thienyl, pyrrolyl, substituted pyrrolyl, imidazolyl, substituted imidazolyl, pyrazolyl, substituted pyrazolyl, quinolinyl, isoquinolinyl, or benzenesulfonyl; r is ₂ Any one selected from hydrogen, halogen atom, hydroxyl, aldehyde group, carboxyl, hydroxymethyl, carbomethoxy, trifluoromethyl, amido, 2-methoxy tetrahydropyranyl, alkoxycarbonyl or 2, 2-dimethyl ethyl propionate; r is ₃ Selected from hydrogen, halogen atoms, C ₁ ～C ₁₀ Alkyl or C ₁ ～C ₁₀ Any one of cycloalkyl groups; r is ₄ Selected from the group consisting of hydrogen, amino, methoxy, phenolic hydroxy, N-methylamino, dimethylcarbamato, C ₁ ～C ₁₀ Any one of alkyl, boc protected amino, boc protected methylamino, boc protected aminomethyl, 2-dimethylpropionate methyl ester, benzyl alcohol group or cyclopropyl methanol group; r is ₅ Selected from hydrogen, halogen atoms, C ₁ ～C ₁₀ Any one of an alkyl group, an amino group, or a Boc-protected amino group; r is ₆ Selected from hydrogen, C ₁ ～C ₁₀ Alkyl radical, C ₁ ～C ₁₀ Any one of cycloalkyl, amino, boc-protected amino or methylamino; r ₇ Selected from hydrogen, C ₁ ～C ₁₀ Alkyl or C ₁ ～C ₁₀ Any one of cycloalkyl groups.

The indolizine compound provided by the invention has good selectivity on CBP/EP300, can effectively combine with proteins with bromodomains, effectively inhibits CBP/EP300 bromodomain receptors, has an inhibition rate generally reaching over 90%, and has good effect.

As a preferred embodiment, R is ₁ Is selected from any one of furyl, 1-methyl-1H-pyrazolyl, 1-cyclopropyl-1H-pyrazolyl, 1- (difluoromethyl) -1H-pyrazole, phenyl or substituted phenyl.

Preferably, said R is ₂ Selected from any one of hydroxymethyl, carboxyl or carbomethoxy.

Preferably, said R is ₃ Selected from any one of fluorine atom, chlorine atom or methyl.

Preferably, said R is ₄ Is selected from any one of amino, methoxy, phenolic hydroxyl, N-methylamino, dimethyl carbamate, methyl or ethyl.

Preferably, said R is ₅ Is an amino group.

Preferably, said R is ₆ Is methyl or ethyl.

Preferably, said R is ₇ Is methyl or cyclopropyl.

In the compounds of the invention, when any variable (e.g. R) ₁ 、R ₂ Etc.) occur more than one time in any constituent, then the definition of each occurrence is independent of the definitions of each other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. The line drawn from a substituent into the ring system indicates that the indicated bond can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that such a bond is only attached to any suitable carbon atom of the adjacent ring. It is to be understood that substituents and substitution patterns on the compounds of the present invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by those skilled in the art and from readily available starting materials. If the substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stabilized。

The terms "alkyl" and "alkylene" as used herein are intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C ₁ ～C ₁₀ "in alkyl" C ₁ ～C ₁₀ The definition of "includes groups having 1, 2, 3,4, 5, 6, 7, 8, 9, 10 carbon atoms in a linear or branched arrangement. For example, "C ₁ ～C ₁₀ "alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. "cycloalkyl" refers to a cyclic aliphatic hydrocarbon group having a specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, naphthyl, methyl-cyclopropyl, 2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, and the like. The alkoxycarbonyl group in the present invention means a straight-chain or branched-chain alkyloxycarbonyl group, and may be, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, tert-butoxycarbonyl, or the like.

The term "substituted" as used herein means that the group may be substituted with any group, for example, the substituted phenyl group may be substituted with one, two or three substituents selected from halogen, alkoxy, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, cyano, aldehyde, carboxyl, nitro, amino, methylsulfonyl, phenyldiazenyl or heterocyclic group, for example, morpholinyl, piperidinyl, quinolinyl, furanyl, tetrahydrofuranyl, pyridinyl, etc.; c ₁ ～C ₁₀ Alkyl or C ₁ ～C ₁₀ Cycloalkyl groups may likewise be substituted.

The invention includes free forms of the compounds of formula I and formula II, as well as pharmaceutically acceptable salts and stereoisomers thereof. Some specific exemplary compounds herein are protonated salts of amine-based compounds. The term "free form" refers to the amine compound in a non-salt form. Included pharmaceutically acceptable salts include not only exemplary salts of the particular compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of formula I and formula II. The free form of a particular salt of the compound may be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a dilute aqueous solution of a suitable base, such as a dilute aqueous NaOH solution, a dilute aqueous potassium carbonate solution, dilute aqueous ammonia, and a dilute aqueous sodium bicarbonate solution. The free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.

Pharmaceutically acceptable salts of the invention can be synthesized from compounds of the invention containing a basic or acidic moiety by conventional chemical methods. In general, salts of the basic compounds are prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric amount or excess of the inorganic or organic acid in the form of the desired salt in an appropriate solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with suitable inorganic or organic bases.

Thus, pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts of the compounds of the present invention formed by the reaction of a basic compound of the present invention and an inorganic or organic acid. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as those prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.

If the compounds of the invention are acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared by pharmaceutically acceptable non-toxic bases including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, diethylaminoethanol, dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

Since acidic moieties such as carboxyl groups deprotonated in a compound under physiological conditions may be anionic and such charge may then be balanced out by a protonated or alkylated basic moiety such as a quaternary nitrogen atom bearing a cation internally, it should be noted that the compounds of the present invention are potential internal salts or zwitterions.

In a second aspect, the present invention provides a method for preparing an indolizine compound as described in the first aspect, wherein when the indolizine compound has a structure as shown in formula I, the preparation method is as follows:

route one is specifically as follows:

wherein R is ₁ And R as described in claim 1 ₁ Have the same range;

when the indolizine compound has a structure shown as a formula II, the preparation method comprises any one of a route II, a route III, a route IV, a route V or a route VI;

wherein, the route two is specifically as follows:

route three is specifically shown below:

route four is specifically shown below:

route five is specifically shown below:

route six is specifically shown below:

wherein R is ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ 、R ₇ And R as described in claim 1 ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ 、R ₇ Having the same range, X is Cl or Br.

The compounds shown in the formulas II-1, II-2, II-3, II-4 and II-5 obtained by the preparation method belong to compounds with the structures shown in the formula II, and the synthetic routes respectively correspond to a route II, a route III, a route IV, a route V and a route VI.

Preferably, in the first route, the compound 12 is prepared by reacting the compound 11 with ammonium chloride under the conditions of acetic acid and ethanol as solvents and iron as a catalyst.

Preferably, compound 13 is prepared from compound 12 and borate in the presence of potassium carbonate, pd (dppf) Cl ₂ In the presence of dimethylformamide, wherein the structure of the borate is

Preferably, compound 15 is obtained by reacting compound 14 with 1-chloropropan-2-one in acetone.

Preferably, compound 16 is obtained by reacting compound 15 with methyl propiolate in dichloromethane and triethylamine.

Preferably, compound 17 is obtained from the reaction of compound 16 in methanol in the presence of sodium hydroxide.

Preferably, the compound shown in the formula I is prepared by reacting a compound 13 with a compound 17 in toluene in the presence of 2-chloro-1-methylpyridine iodine and tri-n-butylamine at the temperature of 80-100 ℃ for 10-20 h.

Preferably, in scheme two, compound 19 is prepared by reacting compound 18 with N-bromosuccinimide in sulfuric acid overnight.

Preferably, compound 20 is prepared by reacting compound 19 with ammonium chloride in the presence of acetic acid and ethanol as solvents and iron as a catalyst.

Preferably, compound 21 is prepared from compound 20 and a borate in the presence of potassium carbonate, pd (dppf) Cl ₂ In the presence of dimethylformamide, wherein the structure of the borate is

Preferably, in the second route, the compound shown in the formula II-1 is prepared by reacting the compound 21 with the compound 17 in toluene in the presence of 2-chloro-1-methylpyridine iodine, tri-n-butylamine and arylamine at the temperature of 80-100 ℃ for 10-20 h.

Preferably, compound 23 is prepared by reacting compound 22 with N-bromosuccinimide in sulfuric acid overnight in scheme three.

Preferably, compound 24 is prepared by reacting compound 23 with sodium borohydride in ethanol.

Preferably, compound 25 is prepared by reacting compound 24 with 3, 4-dihydro-2H-pyran in the presence of pyridinium p-toluenesulfonate in dichloromethane.

Preferably, compound 26 is prepared by reacting compound 25 with ammonium chloride in the presence of acetic acid and ethanol as solvents and iron as a catalyst.

Preferably, compound 27 is prepared from compound 26 with a borate in the presence of potassium carbonate, pd (dppf) Cl ₂ In the presence of dimethylformamide, wherein the structure of the borate is

Preferably, the compound 28 is prepared by reacting the compound 27 with the compound 17 in toluene in the presence of 2-chloro-1-methylpyridine iodine and tri-n-butylamine at the temperature of 80-100 ℃ for 10-20 h.

Preferably, in the third route, the compound shown in the formula II-2 is prepared by reacting the compound 28 in ethanol and in the presence of pyridinium p-toluenesulfonate at the temperature of 60-90 ℃ for 1-3 h.

Preferably, in scheme four, compound 30 is prepared by reacting compound 29 with 1-chloropropan-2-one in acetone.

Preferably, compound 31 is obtained by reacting compound 30 with methyl propiolate in dichloromethane and triethylamine.

Preferably, compound 32 is obtained by reacting compound 31 in methanol in the presence of sodium hydroxide.

Preferably, the compound 33 is prepared by reacting the compound 32 with the compound 27 in toluene in the presence of 2-chloro-1-methylpyridine iodine and tri-n-butylamine at the temperature of between 80 and 100 ℃ for 10 to 20 hours, wherein R in the compound 27 ₃ And R ₇ Are all methyl.

Preferably, in the fourth route, the compound shown in the formula II-3 is prepared by reacting the compound 33 in ethanol and in the presence of pyridinium p-toluenesulfonate at 60-90 ℃ for 1-3 h. Further, the compound represented by the formula II prepared from the compound 33 may have a structure corresponding to the structure represented by the formula II, in which Boc protection is further removed by trifluoroacetic acid if the compound has an amino group protected with Boc.

Preferably, in the fifth route, the compound 35 is prepared by reacting the compound 34 with benzyl alcohol or cyclopropylmethanol in the presence of sodium hydride at 0-65 ℃ in dimethylformamide for 2-6 h.

Preferably, compound 36 is prepared from compound 35 and

prepared by reacting in acetone overnight, wherein X is Cl or Br.

Preferably, compound 37 is obtained by reacting compound 36 with methyl propiolate in dichloromethane and triethylamine.

Preferably, compound 38 is obtained by reacting compound 37 in methanol in the presence of sodium hydroxide.

Preferably, the compound 39 is prepared by reacting the compound 38 with the compound 27 in toluene in the presence of 2-chloro-1-methylpyridine iodine and tri-n-butylamine at the temperature of 80-100 ℃ for 10-20 h, wherein R in the compound 27 is ₃ Is F with R ₇ Is methyl or R ₃ Is methyl with R ₇ Is cyclopropyl.

Preferably, in the fifth route, the compound shown in the formula II-4 is prepared by directly reacting a compound 39 in ethanol at 60-90 ℃ for 1-3 h in the presence of pyridinium p-toluenesulfonate; or the compound 39 is reduced by palladium carbon to obtain a compound 40, and then the compound 40 is reacted in ethanol at 60-90 ℃ for 1-3 h in the presence of pyridinium p-toluenesulfonate to obtain the palladium-containing palladium catalyst.

Preferably, in the sixth scheme, the compound 41 is prepared by the reflux reaction of the compound 40' with pivaloyl chloride or dimethylcarbamoyl chloride in acetonitrile and in the presence of potassium carbonate for 4-6 h.

Preferably, in the sixth route, the compound shown in the formula II-5 is prepared by reacting the compound 41 in ethanol and in the presence of pyridinium p-toluenesulfonate at the temperature of 60-90 ℃ for 1-3 h.

In the reaction route of the present invention, the molar ratio of the raw materials, the reaction temperature, the reaction time, the solvent, etc. in each step of the reaction can be appropriately selected by those skilled in the art according to the actual conditions and actual needs of the reaction.

In a third aspect, the present invention provides the use of an indolizine compound as described in the first aspect for the preparation of CBP/EP300 bromodomain receptor inhibitors.

Preferably, the CBP/EP300 bromodomain receptor inhibitor is used for the preparation of a medicament for the treatment of cancer, cell proliferative disorders, inflammatory and autoimmune diseases, sepsis, viral infections or neurodegenerative disorders.

Preferably, the CBP/EP300 bromodomain receptor inhibitor is used for the preparation of a medicament for the treatment of cancer.

Preferably, the CBP/EP300 bromodomain receptor inhibitor is used for the preparation of a medicament for the treatment of prostate cancer.

The indolizine compound provided by the invention is further used for preparing a CBP/EP300 bromodomain receptor inhibitor, and has a particularly remarkable curative effect on prostatic cancer.

In a fourth aspect, the present invention provides a pharmaceutical composition comprising the indolizine compound of the first aspect.

In a fifth aspect, the present invention provides a use of the pharmaceutical composition according to the fourth aspect for the preparation of a medicament for the treatment, prevention or amelioration of cancer, cell proliferative disorders, inflammation, autoimmune diseases, sepsis, viral infections or neurodegenerative disorders.

Preferably, the cancer is prostate cancer.

<xnotran> CBP/EP300 , , , , , , , , , , , , , , , T / , , , , , , , , , , , B , B , B , , , , , , , , , , , , , , , , , , , , T , , , , B , , , , , , , , , , , , , , , , </xnotran> <xnotran> , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , B , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , T- , , , , , , , , , , , , , , , </xnotran> Skin cancer, small round cell tumor, small cell cancer, soft tissue sarcoma, somatostatin tumor, spinal cord tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, small intestine cancer, squamous cell carcinoma, gastric cancer, T-cell lymphoma, testicular cancer, thyroid cancer, transitional cell cancer, laryngeal cancer, umbilical-urinary duct cancer, genitourinary cancer, uterine cancer, verrucous cancer, visual pathway glioma, vulval cancer, or vaginal cancer, and the like.

CBP/EP300 bromodomain receptor inhibitors, including benign soft tissue tumors, brain and spinal cord tumors, eyelid and orbital tumors, granulomas, lipomas, meningiomas, multiple endocrine tumors, nasal polyps, pituitary tumors, prolactinoma, seborrheic keratoma, gastric polyps, thyroid nodules, hepatic hemangiomas, vocal cord nodules, polyps, cysts, tibetan hair disease, cutaneous fibromas, pilaris cysts, or pyogenic granulomas.

The inflammatory diseases which can be treated by the CBP/EP300 bromodomain receptor inhibitor comprise inflammatory pelvic diseases, urethritis, skin sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, pancreatitis, psoriasis, allergy, crohn's disease, intestinal syndrome, ulcerative colitis, tissue transplant rejection, organ transplant rejection, asthma, allergic rhinitis, chronic obstructive pulmonary disease, autoimmune diseases, autoimmune alopecia, anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenia, goodpasture's syndrome, atherosclerosis, addison's disease, parkinson's disease, alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, chronic thrombocytopenia purpura, myasthenia gravis, hashimoto's thyroiditis, allergic dermatitis, degenerative arthritis, inflammatory-barren syndrome, mycosis or mycosis.

The virus infection which can be treated by the medicament prepared by the CBP/EP300 bromodomain receptor inhibitor and the pharmaceutical composition comprises human papilloma virus, herpes virus, barr virus, human immunodeficiency virus, hepatitis B virus or hepatitis C virus infection and the like.

The medicines prepared by the CBP/EP300 bromodomain receptor inhibitor and the nervous degenerative diseases which can be treated by the medicine composition comprise Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, bovine spongiform encephalopathy, creutzfeldt-Jakob disease, huntington's disease, cerebellar atrophy, multiple sclerosis, parkinson's disease, primary lateral sclerosis or spinal muscular atrophy and the like.

The medicaments prepared from the CBP/EP300 bromodomain receptor inhibitors, as well as the pharmaceutical compositions, may be adapted for various routes of administration, typical but non-limiting examples being: oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal, by lumbar puncture, transurethral, transdermal or parenteral (including intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intrathecal, surgical implantation), and the like. The pharmaceutical compositions of the present invention may be in liquid, semi-liquid or solid form, formulated in a manner suitable for the route of administration employed. The compositions of the present invention may be administered as follows: oral, parenteral, intraperitoneal, intravenous, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, liposomal, and the like. Pharmaceutical compositions for oral administration may be solid, gel or liquid. Examples of solid formulations include, but are not limited to, tablets, capsules, granules, and bulk powders. These formulations may optionally contain binders, diluents, disintegrants, lubricants, glidants, sweeteners, flavoring agents and the like. Examples of binders include, but are not limited to, microcrystalline cellulose, glucose solutions, acacia mucilage, gelatin solutions, sucrose and starch pastes; examples of lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate, stearic acid; examples of diluents include, but are not limited to, lactose, sucrose, starch, mannitol, dicalcium phosphate; examples of glidants include, but are not limited to, silicon dioxide; examples of disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, and carboxymethylcellulose. The pharmaceutical compositions of the present invention are administered parenterally, typically by injection, including subcutaneous, intramuscular, or intravenous injection. Injectables can be prepared in any conventional form, such as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or emulsions. Examples of pharmaceutically acceptable carriers that may be used in the injections of the present invention include, but are not limited to, aqueous carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffers, antioxidants, suspending and dispersing agents, emulsifying agents, chelating agents, and other pharmaceutically acceptable materials. Examples of aqueous carriers include sodium chloride injection, ringer's injection, isotonic glucose injection, sterile water injection, dextrose and lactated ringer's injection; examples of non-aqueous carriers include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil; examples of antimicrobial agents include m-cresol, benzyl alcohol, chlorobutanol, benzalkonium chloride, and the like; examples of isotonic agents include sodium chloride and glucose; buffers include phosphate and citrate.

The pharmaceutical compositions of the present invention may also be prepared as sterile lyophilized powder injections by dissolving the compound in a sodium phosphate buffer solution containing glucose or other suitable excipients, followed by sterile filtration of the solution under standard conditions known to those skilled in the art, followed by lyophilization to provide the desired formulation.

Compared with the prior art, the invention has the following beneficial effects:

the indolizine compound provided by the invention can be effectively combined with the CBP/EP300 bromodomain, the inhibition rate can generally reach more than 90%, and the indolizine compound has good effect and good selectivity on other bromodomain family proteins; the indolizine compound provided by the invention has a stable structure, and the synthesis method is simpler.

Detailed Description

The technical solution of the present invention is further described below by way of specific embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention. The compounds obtained in each example are numbered in the following examples of the invention.

The structures of the compounds of examples 1-92 and comparative examples 1 and 2 are shown in table 1.

TABLE 1

EXAMPLE 1 Synthesis of 3-acetyl-N- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-methoxyindolizine-1-carboxamide

Step 1, synthesis of 3-bromo-2-fluoroaniline

Mixing Fe powder (2.5g, 45.5mmol) and NH ₄ A reaction mixture of Cl (48.6mg, 0.91mmol) in AcOH (1.2 mL) and water (2 mL) was heated at 80 ℃ for 5 min. 1-bromo-2-fluoro-3-nitrobenzene (11) (2.0 g,9.1 mmol) was dissolved in ethanol (15 mL) and added to the reaction mixture. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through a celite pad. The filtrate was concentrated, and the residue was extracted with an ethyl acetate solvent. The organic phase was washed with saturated brine and anhydrous Na ₂ SO ₄ Drying and concentration gave 3-bromo-2-fluoroaniline as a brown oil (1.6 g, 93%). ¹ H NMR(500MHz,DMSO-d ₆ )δ6.80(t,J＝8.1Hz,1H),6.77–6.70(m,2H),5.41(s,2H).

Step 2, synthesis of 2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) aniline

(1-methyl-1H-pyrazol-4-yl) boronic acid (636mg, 5.1mmol), 3-bromo-2-fluoroaniline (800mg, 4.2mmol), K ₂ CO ₃ (1.7g, 12.6 mmol) was dissolved in DMF (30 mL), and water (3 mL) and PdCl were added to the reaction system ₂ (dppf) (171mg, 0.21mmol) and the reaction was heated overnight at 110 ℃ under nitrogen. After the reaction was completed, the reaction system was cooled to room temperature and filtered through a celite pad. The filtrate was diluted with water (50 mL) and extracted with ethyl acetate (3X 30 mL). The organic phase was washed with brine and anhydrous Na ₂ SO ₄ Dried and concentrated to give 2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) aniline as a yellow solid (600mg, 75%). ¹ H NMR(400MHz,DMSO-d ₆ )δ8.03(s,1H),7.79(s,1H),6.84(t,J＝7.6Hz,1H),6.78(t,J＝6.4Hz,1H),6.60(t,J＝8.0Hz,1H),5.10(s,2H),3.88(s,3H).

Step 3, synthesis of 4-methoxy-1- (2-oxopropyl) pyridine-1-chloride

Pyridine derivative (2.0g, 18.3mmol) was added to an acetone solution (1.7g, 21.9mmol) of 1-chloroprop-2-one. The reaction was stirred at 60 ℃ overnight. After the reaction was completed, it was cooled to room temperature, and the resulting precipitate was filtered, washed with ethyl acetate or acetone, and recrystallized from ethanol to obtain the corresponding pure pyridinium salt (2.0 g, 93%).

Step 4, synthesis of 3-acetyl-7-methoxy indolizine-1-carboxylic acid methyl ester

Triethylamine (2.3g, 22.95mmol) was added dropwise to a solution of 4-methoxy-1- (2-oxopropyl) pyridine-1-chloride (3.08g, 15.27mmol) and methyl propiolate (1.50g, 18.36mmol) in dichloromethane. The reaction was stirred at room temperature for 6 hours and then concentrated in vacuo. The crude residue was washed with EtOH (Et removal) ₃ N · HBr), the solid obtained after filtration was purified by column chromatography to give pure methyl 3-acetyl-7-methoxyindolizine-1-carboxylate (1.65g, 44% yield) as a yellow solid. ¹ H NMR(400MHz,CDCl ₃ )δ9.72(d,J＝7.6Hz,1H),7.89(s,1H),7.67(d,J＝2.4Hz,1H),6.69(dd,J＝8.0,2.8Hz,1H),3.94(s,3H),3.91(s,3H),2.53(s,3H).

Step 5, synthesis of 3-acetyl-7-methoxyindolizine-1-carboxylic acid

To a solution of methyl 3-acetyl-7-methoxyindolizine-1-carboxylate (4.0 g, 15.67mmol) in methanol (50 mL) was added NaOH (6.37g, 156.7 mmol). The reaction was stirred at 80 ℃ for 2 hours. After the reaction was complete, the solution was concentrated and acidified with 6N HCl to pH =1. The solid was filtered, washed with water, and dried to give 3-acetyl-7-methoxyindolizine-1-carboxylic acid (3.2g, 87% yield) as a yellow solid. The product was used in the next step without further purification. H NMR (500MHz, DMSO-d) ₆ )δ12.45(s,1H),9.64(d,J＝7.8Hz,1H),8.03(s,1H),7.61(s,1H),6.92(d,J＝7.7Hz,1H),3.91(s,3H),2.50(s,3H).

Step 6, synthesis of 3-acetyl-N- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-methoxyindolizine-1-carboxamide

2-fluoro-3- (1-methyl-1H-pyrazol-4-yl)Aniline (300mg, 1.57mmol), 3-acetyl-7-methoxyindolizine-1-carboxylic acid (332.5mg, 1.43mmol), 3-chloro-1-iodo-2-methylpyridin-1-ium (876.8mg, 3.43mmol) and n-Bu ₃ N (1.27g, 6.86mmol) was dissolved in toluene. The reaction was stirred at 90 ℃ overnight under nitrogen. It was concentrated and re-dissolved in EtOAc. With saturated NH ₄ Cl solution, saturated NaHCO ₃ The organic phase was extracted with solution, 1N HCl and brine. The combined organic phases are washed with Na ₂ SO ₄ Dried and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography to give the desired product (173mg, 30% yield) as a white solid. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.73(s,1H),9.65(d,J＝5.0Hz,1H),8.56(s,1H),8.16(s,1H),7.91(s,1H),7.87(s,1H),7.54(d,J＝5.0Hz,1H),7.51(d,J＝10.0Hz,1H),7.20(t,J＝10.0Hz,1H),6.92(d,J＝5.0Hz,1H),3.91(s,3H),3.89(s,3H),2.53(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.22,162.24,158.40,141.28,137.21,129.52,129.45,129.39,126.53,124.75,123.95,123.48,120.93,120.63,120.52,115.19,108.93,105.89,97.49,55.57,38.6

EXAMPLE 2 Synthesis of 3-acetyl-N- (2-fluoro-3- (1-methyl-1H-pyrazol-5-yl) phenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 1. ¹ H NMR(500MHz,CDCl ₃ )δ9.75(d,J＝7.5Hz,1H),8.55–8.47(m,1H),7.91(d,J＝2.5Hz,1H),7.87(d,J＝3.0Hz,1H),7.71(s,1H),7.57(d,J＝1.5Hz,1H),7.28(d,J＝8.0Hz,1H),7.10–7.04(m,1H),6.74(dd,J＝7.5,2.5Hz,1H),6.36(d,J＝1.5Hz,1H),3.96(s,3H),3.85(s,3H),2.58(s,3H). ¹³ C NMR(125MHz,CDCl ₃ )δ186.80,162.65,159.70,150.79,148.85,142.30,138.85,137.00,130.43,127.58,125.57,124.76,122.81,122.18,121.99,118.66,109.80,107.63,106.15,97.77,55.94,37.51,27.06.

EXAMPLE 3 Synthesis of 3-acetyl-N- (2-fluoro-3- (furan-2-yl) phenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 1. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.81(s,1H),9.65(d,J＝5.0Hz,1H),8.56(s,1H),7.86(s,2H),7.63(t,J＝5.0Hz,2H),7.29(t,J＝10.0Hz,1H),6.95–6.89(m,2H),6.68(s,1H),3.89(s,3H),2.53(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.23,162.24,158.46,152.08,147.01,143.21,141.31,129.54,126.68,125.33,124.76,124.26,121.62,120.96,118.64,112.24,110.15,108.95,105.74,97.49,55.58,26.57.

EXAMPLE 4 Synthesis of 3-acetyl-N- (2-fluoro-3- (furan-3-yl) phenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 1. ¹ H NMR(400MHz,CDCl ₃ )δ9.76(d,J＝7.6Hz,1H),8.31(td,J＝7.6,1.6Hz,1H),7.98–7.82(m,3H),7.72(s,1H),7.52(s,1H),7.24–7.17(m,1H),6.79(s,1H),6.73(dd,J＝7.6,2.8Hz,1H),3.95(s,3H),2.60(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.22,162.25,158.42,143.86,141.29,141.25,141.15,129.52,126.54,124.91,124.75,124.16,124.05,120.94,119.94,119.54,109.33,108.93,105.82,97.49,55.57,26.57.

EXAMPLE 5 Synthesis of 3-acetyl-N- (2-fluoro-3- (5-methylfuran-2-yl) phenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.77(s,1H),9.65(d,J＝7.6Hz,1H),8.56(s,1H),7.86(t,J＝2.8Hz,1H),7.58(dd,J＝14.8,7.2Hz,2H),7.26(t,J＝8.0Hz,1H),6.93(dd,J＝7.6,2.8Hz,1H),6.79(t,J＝3.2,1H),6.32–6.24(m,1H),3.89(s,3H),2.53(s,3H),2.38(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.24,162.24,158.46,152.10,151.81,149.82,145.42,141.31,129.54,126.62,124.72,124.16,121.18,120.97,118.85,111.23,108.95,108.46,105.78,97.49,55.58,26.57,13.28.

EXAMPLE 6 Synthesis of 3-acetyl-N- (2-fluoro-3- (5-formylfuran-2-yl) phenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.90(s,1H),9.68(s,1H),9.66(d,J＝7.6Hz,1H),8.57(s,1H),7.86(d,J＝2.8Hz,1H),7.80–7.73(m,2H),7.71(d,J＝4.0Hz,1H),7.39(t,J＝8.0Hz,1H),7.18(t,J＝6.8Hz,1H),6.94(dd,J＝7.6,2.8Hz,1H),3.89(s,3H),2.54(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.25,178.10,162.22,158.51,151.53,141.34,131.42,129.56,128.59,127.56,124.73,122.75,121.00,112.50,108.98,105.58,97.47,55.59,26.58.

EXAMPLE 7 Synthesis of 3-acetyl-N- (3- (cyclopent-1-en-1-yl) -2-fluorophenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.70(s,1H),9.65(d,J＝8.0Hz,1H),8.56(s,1H),7.86(d,J＝2.8Hz,1H),7.57(t,J＝7.6Hz,1H),7.23(t,J＝6.4Hz,1H),7.17(t,J＝8.0Hz,1H),6.92(dd,J＝8.0,2.8Hz,1H),6.35(d,J＝2.0Hz,1H),3.89(s,3H),2.79–2.66(m,2H),2.62–2.58(m,2H),2.52(s,3H),2.02–1.87(m,2H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.24,162.26,158.41,141.29,136.51,131.08,131.01,129.53,126.32,125.01,124.76,123.61,120.94,108.93,105.89,97.51,55.58,34.27,33.32,26.58,22.27.

EXAMPLE 8 Synthesis of 3-acetyl-N- (2-fluoro-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -3-yl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 1. ¹ H NMR(400MHz,CDCl ₃ )δ9.75(d,J＝8.0Hz,1H),8.32–8.22(m,1H),7.91(d,J＝2.8Hz,1H),7.83(d,J＝3.6Hz,1H),7.68(s,1H),7.11(t,J＝8.4Hz,1H),6.97(td,J＝7.6,1.6Hz,1H),6.72(dd,J＝7.6,2.4Hz,1H),5.95(s,1H),3.95(s,3H),2.58(s,3H),2.44–2.33(m,2H),2.28–2.15(m,2H),1.84–1.68(m,2H),1.73–1.67(m,2H). ¹³ C NMR(125MHz,CDCl ₃ )δ186.65,162.52,159.41,142.08,133.24,131.38,130.23,128.55,126.88,124.07,123.71,122.15,121.75,119.98,109.61,106.60,97.70,55.84,28.85,26.93,25.80,23.04,22.05.

EXAMPLE 9 Synthesis of 3-acetyl-N- (3, 6-dihydro-2H-pyran-4-yl) -2-fluorophenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 1. ¹ H NMR(400MHz,CDCl ₃ )δ9.75(d,J＝7.6Hz,1H),8.30(t,6.8Hz,1H),7.91(d,J＝2.8Hz,1H),7.83(d,J＝3.2Hz,1H),7.69(s,1H),7.14(t,J＝8.0Hz,1H),7.00(td,J＝8.0,1.6Hz,1H),6.73(dd,J＝7.6,2.4Hz,1H),6.05(s,1H),4.34(dd,J＝5.6,2.8Hz,2H),3.95(s,3H),3.93(d,J＝5.6Hz,2H),2.58(s,3H),2.53(s,2H). ¹³ C NMR(125MHz,CDCl ₃ )δ186.74,162.60,159.54,151.22,149.28,142.19,130.79,130.33,128.99,127.18,126.85,124.38,123.11,122.19,121.86,120.80,109.71,106.49,97.76,65.78,64.49,55.91,28.71,27.02.

EXAMPLE 10 Synthesis of 3-acetyl-N- (3- (1-benzyl-1H-pyrazol-4-yl) -2-fluorophenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 1. ¹ H NMR(400MHz,CDCl ₃ )δ9.74(d,J＝8.0Hz,1H),8.25(t,J＝8.0Hz,1H),7.93(s,1H),7.91(d,J＝2.4Hz,1H),7.86(d,J＝3.2Hz,1H),7.78(d,J＝2.0Hz,1H),7.69(s,1H),7.41–7.32(m,3H),7.30–7.26(m,2H),7.16(t,J＝8.0Hz,1H),6.72(dd,J＝7.6,2.8Hz,1H),5.37(s,2H),3.94(s,3H),2.58(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.23,162.22,158.42,152.80,150.83,141.29,137.73,137.26,129.53,129.02,128.50,127.64,127.60,126.51,124.74,123.96,123.48,120.94,120.44,115.46,108.93,105.88,97.50,55.58,54.96,26.57.

EXAMPLE 11 Synthesis of 3-acetyl-N- (2-fluoro- [1,1' -biphenyl ] -3-yl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.80(s,1H),9.66(d,J＝8.0Hz,1H),8.57(s,1H),7.87(d,J＝2.4Hz,1H),7.75–7.68(m,1H),7.58(d,J＝7.6Hz,2H),7.51(t,J＝7.2Hz,2H),7.43(t,J＝7.2Hz,1H),7.38–7.27(m,2H),6.93(dd,J＝7.6,2.8Hz,1H),3.89(s,3H),2.53(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.30,162.32,158.48,141.34,135.11,129.57,128.80,128.63,127.91,126.63,126.53,125.73,124.80,124.15,120.98,108.99,105.87,97.52,55.62,26.63.

EXAMPLE 12 Synthesis of 3-acetyl-N- (2-fluoro-3- (pyridin-3-yl) phenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 1. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.82(s,1H),9.65(d,J＝5.0Hz,1H),8.79(s,1H),8.63(d,J＝5.0Hz,1H),8.56(s,1H),8.00(d,J＝5.0Hz,1H),7.87(s,1H),7.78(t,J＝5.0Hz,1H),7.58–7.50(m,1H),7.43–7.40(m,1H),7.38–7.33(m,1H),6.93(d,J＝5.0Hz,1H),3.89(s,3H),2.53(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.28,162.27,158.49,141.33,141.31,136.07,133.72,129.90,129.57,127.02,126.48,126.36,124.79,124.45,120.98,108.99,105.74,97.50,55.61,43.48,26.61.

EXAMPLE 13 Synthesis of 3-acetyl-N- (2-fluoro-3- (pyrimidin-5-yl) phenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.87(s,1H),9.65(d,J＝8.0Hz,1H),9.25(s,1H),9.06(s,2H),8.56(s,1H),7.84(m,2H),7.51(t,J＝6.8Hz,1H),7.39(t,J＝7.8Hz,1H),6.93(dd,J＝7.7,2.7Hz,1H),3.89(s,3H),2.53(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.27,162.25,158.50,157.56,156.25,156.22,141.34,129.57,129.05,127.21,126.77,126.30,124.80,124.66,122.23,120.98,108.98,105.66,97.49,55.60,26.60.

EXAMPLE 14 Synthesis of 3-acetyl-N- (2-fluoro-3 '- (methylsulfonyl) - [1,1' -biphenyl ] -3-yl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 1. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.83(s,1H),9.66(d,J＝10.0Hz,1H),8.57(s,1H),8.11(s,1H),8.00(d,J＝5.0Hz,1H),7.95(d,J＝10.0Hz,1H),7.87(s,1H),7.81(t,J＝5.0Hz,2H),7.45(t,J＝10.0Hz,1H),7.36(t,J＝10.0Hz,1H),6.93(d,J＝10.0Hz,1H),3.90(s,3H),3.29(s,3H),2.53(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.32,162.23,158.59,141.41,137.51,137.47,129.90,129.84,129.59,124.83,121.02,114.57,109.34,109.12,109.01,108.68,108.48,105.54,97.48,55.62,38.70,26.60.

EXAMPLE 15 Synthesis of 3-acetyl-N- (2-fluoro-3- (isoquinolin-4-yl) phenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.85(s,1H),9.65(d,J＝8.0Hz,1H),9.42(s,1H),8.55(s,1H),8.51(s,1H),8.26(d,J＝8.0Hz,1H),7.95–7.84(m,2H),7.82–7.79(m,1H),7.76(dd,J＝10.8,4.0Hz,1H),7.67(d,J＝8.6Hz,1H),7.46–7.38(m,1H),7.38–7.31(m,1H),6.96–6.88(m,1H),3.90(s,3H),2.51(s,3H).

EXAMPLE 16 Synthesis of 3-acetyl-N- (2-fluoro-3- (1-trityl-1H-pyrazol-4-yl) phenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 1. ¹ H NMR(400MHz,CDCl ₃ )δ9.75(d,J＝7.6Hz,1H),8.24(t,J＝8.8Hz,1H),8.05(s,1H),7.91(d,J＝2.7Hz,1H),7.82(d,J＝2.8Hz,1H),7.80(d,J＝1.2Hz,1H),7.69(s,1H),7.38–7.30(m,9H),7.24–7.17(m,8H),6.73(dd,J＝7.6,2.8Hz,1H),3.94(s,3H),2.59(s,3H).

EXAMPLE 17 Synthesis of 3-acetyl-N- (3- (1-cyclopropyl-1H-pyrazol-4-yl) -2-fluorophenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 1. ¹ H NMR(400MHz,CDCl ₃ )δ9.75(d,J＝8.0Hz,1H),8.25(t,J＝8.0Hz,1H),7.92(d,J＝2.4Hz,1H),7.88(d,J＝3.2Hz,1H),7.85(s,2H),7.70(s,1H),7.24(d,J＝1.6Hz,1H),7.16(dd,J＝10.8,5.2Hz,1H),6.72(dd,J＝7.6,2.8Hz,1H),3.95(s,3H),3.66(tt,J＝7.2,3.6Hz,1H),2.59(s,3H),1.21–1.12(m,2H),1.07–1.02(m,2H). ¹³ C NMR(125MHz,CDCl ₃ )δ186.73,162.58,159.54,150.56,148.63,142.22,138.02,130.32,128.58,127.45,124.69,122.15,121.90,121.86,120.26,119.59,115.85,109.73,106.49,97.77,55.92,33.04,27.04,6.68.

EXAMPLE 18 Synthesis of 3-acetyl-N- (2-fluoro-3- (1H-pyrazol-4-yl) phenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ13.11(s,1H),9.74(s,1H),9.66(d,J＝7.6Hz,1H),8.58(s,1H),8.19(s,1H),7.99(s,1H),7.87(d,J＝2.8Hz,1H),7.60–7.49(m,2H),7.20(t,J＝8.0Hz,1H),6.92(dd,J＝7.6,2.8Hz,1H),3.89(s,3H),2.53(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.29,162.30,158.44,152.88,150.91,141.32,129.56,126.59,126.49,124.80,123.99,123.84,123.77,120.96,120.93,120.83,114.60,108.98,105.93,97.52,55.61,48.58,26.62.

EXAMPLE 19 Synthesis of 3-acetyl-N- (3- (1- (difluoromethyl) -1H-pyrazol-4-yl) -2-fluorophenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 1. ¹ H NMR(400MHz,DMSO)δ9.81(s,1H),9.66(d,J＝7.6Hz,1H),8.68(s,1H),8.56(s,1H),8.31(s,1H),8.10–7.72(m,2H),7.70–7.57(m,2H),7.27(t,J＝8.0Hz,1H),6.93(dd,J＝7.6,2.0Hz,1H),3.89(s,3H),2.53(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.28,162.26,158.48,153.18,151.20,141.33,141.08,129.57,127.32,126.66,125.29,124.80,124.26,120.97,118.95,117.73(s),112.24,110.26,109.01,108.29,105.80,97.48,55.61,26.62.

Example 20-acetyl-N- (2-fluoro-5-formyl-3- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-methoxyindolizine-1-carboxamide

Step 1, synthesis of 3-bromo-4-fluoro-5-nitrobenzaldehyde

1, 4-difluoro-2-nitrobenzene (10g, 59.13mmol) was dissolved in concentrated H at 0 deg.C ₂ SO ₄ NBS (12.62g, 70.96mmol) was added thereto in three portions over 15 minutes (50 mL), and the reaction was stirred at 60 ℃ overnight. After the reaction was complete, the reaction was poured into ice water, followed by extraction with 50mL x 5 with dichloromethane. The combined organic phases were dried over sodium sulfate. The crude product was purified by column chromatography to give the desired product (6 g,41% yield). ¹ H NMR(400MHz,CDCl ₃ )δ9.99(s,1H),8.51(dd,J＝6.4,2.0Hz,1H),8.39(dd,J＝5.6,2.0Hz,1H).

Step 2, synthesis of 3-amino-5-bromo-4-fluorobenzaldehyde

The synthesis was as in step 1 of example 1. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.78(s,1H),7.34(d,J＝3.0Hz,1H),7.24(d,J＝7.5Hz,1H),5.89(s,2H).

Step 3, synthesis of 3-amino-4-fluoro-5- (1-methyl-1H-pyrazol-4-yl) benzaldehyde

The synthesis was as in step 2 of example 1. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.82(s,1H),8.16(s,1H),7.90(s,1H),7.43(d,J＝5.0Hz,1H),7.11(d,J＝7.0Hz,1H),5.59(s,2H),3.90(s,3H).

Step 4, synthesis of 3-acetyl-N- (2-fluoro-5-formyl-3- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in step 6 of example 1. H NMR (400MHz, DMSO-d) ₆ )δ10.01(s,1H),9.94(s,1H),9.65(d,J＝7.6Hz,1H),8.59(s,1H),8.29(s,1H),8.16(d,J＝5.6Hz,1H),8.11(d,J＝5.2Hz,1H),8.02(s,1H),7.87(s,1H),6.94(d,J＝6.0Hz,1H),3.93(s,3H),3.90(s,3H),2.54(s,3H). ¹³ CNMR(125MHz,DMSO-d ₆ )δ191.73,186.31,162.29,158.61,141.42,137.40,132.54,129.94,129.61,127.81,127.70,125.09,124.82,123.20,121.66,121.05,114.21,109.05,105.48,97.47,55.64,38.71,26.60.

EXAMPLE 21 Synthesis of 3-acetyl-N- (2, 5-difluoro-3- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 20. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.80(s,1H),9.65(d,J＝7.6Hz,1H),8.58(s,1H),8.22(s,1H),7.98(s,1H),7.85(d,J＝2.4Hz,1H),7.57–7.47(dd,J＝7.2,3.6Hz,1H),7.42(dd,J＝9.2,5.2Hz,1H),6.93(dd,J＝7.6,2.4Hz,1H),3.91(s,3H),3.90(s,3H),2.53(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.25,162.26,158.46,149.04,148.85,141.32,139.74,136.21,130.89,129.55,126.44,124.77,124.42,123.67,120.97,119.11,108.95,105.75,104.89,97.50,55.59,36.62,26.59.

EXAMPLE 22 Synthesis of 3-acetyl-N- (5-chloro-2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 20. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.80(s,1H),9.64(d,J＝7.7Hz,1H),8.56(s,1H),8.24(s,1H),7.98(s,1H),7.85(d,J＝2.4Hz,1H),7.70(d,J＝3.8Hz,1H),7.64–7.55(m,1H),6.92(dd,J＝7.6,2.5Hz,1H),3.91(s,3H),3.90(s,3H),2.53(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.33,162.23,158.62,141.42,137.50,129.96,129.62,128.05,127.94,127.86,124.82,122.21,122.07,121.04,114.11,109.05,105.47,97.49,55.64,38.70,26.59.

EXAMPLE 23 Synthesis of 3-acetyl-N- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (trifluoromethyl) phenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 20. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.94(s,1H),9.66(d,J＝7.6Hz,1H),8.58(s,1H),8.33(s,1H),8.06(s,1H),8.01(d,J＝4.8Hz,1H),7.89(d,J＝4.8Hz,1H),7.86(d,J＝2.8Hz,1H),6.94(dd,J＝7.6,2.8Hz,1H),3.92(s,3H),3.91(s,3H),2.54(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.31,162.32,158.66,141.43,137.59,130.16,130.10,129.60,127.80,124.84,121.92,121.06,119.66,119.34,113.97,109.05,105.36,97.46,55.65,38.70,26.58.

EXAMPLE 24 Synthesis of methyl 3- (3-acetyl-7-methoxyindolizine-1-carboxamido) -4-fluoro-5- (1-methyl-1H-pyrazol-4-yl) benzoate

The synthesis was as in example 20. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.87(s,1H),9.65(d,J＝7.5Hz,1H),8.57(s,1H),8.29(s,1H),8.22(d,J＝5.0Hz,1H),8.05(d,J＝4.3Hz,1H),7.96(s,1H),7.87(s,1H),6.93(d,J＝5.0Hz,1H),3.92(s,3H),3.91(s,3H),3.90(s,3H),2.53(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.28,165.35,162.22,158.60,141.40,137.32,129.84,129.58,125.77,124.83,123.92,121.03,114.28,109.04,105.51,97.48,55.64,52.30,38.66,28.94,26.58.

EXAMPLE 25 Synthesis of 3-acetyl-N- (5-carbamoyl-2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 20. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.95(s,1H),9.66(d,J＝5.0Hz,1H),8.57(s,1H),8.28(s,1H),8.10(d,J＝5.0Hz,1H),8.06(d,J＝5.0Hz,1H),8.04(s,1H),7.85(d,J＝5.0Hz,1H),6.94(d,J＝5.0Hz,1H),5.75(s,2H),3.92(s,3H),3.90(s,3H),2.54(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.37,162.29,158.71,141.47,137.60,130.20,129.67,127.94,127.03,126.39,124.87,122.53,121.11,118.06,113.48,109.11,105.26,97.49,55.66,38.75,26.61.

EXAMPLE 26 Synthesis of 3-acetyl-N- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) -7-methoxyindolizine-1-carboxamide

Step 1, synthesis of 3-bromo-4-fluoro-5-nitrobenzaldehyde

The synthesis was as in example 20, step 1. ¹ H NMR(400MHz,CDCl ₃ )δ9.99(s,1H),8.51(dd,J＝6.4,2.0Hz,1H),8.39(dd,J＝5.6,2.0Hz,1H).

Step 2 Synthesis of (3-bromo-4-fluoro-5-nitrophenyl) methanol

3-bromo-4-fluoro-5-nitrobenzaldehyde (100mg, 0.4mmol) was dissolved in ethanol (10 mL), and NaBH was added to the reaction at 0 deg.C ₄ (23.5mg, 0.6 mmol), and after completion of the sample addition, the reaction was stirred at room temperature for 2 hours. After the reaction was completed, ethanol was removed by a rotary evaporator, and the resulting product was extracted with ethyl acetate. Purification by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate (10). ¹ H NMR(400MHz,CDCl ₃ )δ7.99(d,J＝6.0Hz,1H),7.88(d,J＝5.2Hz,1H),4.76(s,2H).

Step 3, synthesis of 2- ((3-bromo-4-fluoro-5-nitrobenzyl) oxy) tetrahydro-2H-pyran

(3-bromo-4-fluoro-5-nitrophenyl) methanol (80mg, 0.32mmol), DHP (32.3mg, 0.38mmol) and PPTS (8.4 mg, 0.032mmol) were weighed, dissolved with dichloroethane, and stirred at 50 ℃ for 5 hours. After the reaction was completed, the resulting solution was poured into water and extracted with dichloromethane. The organic layer was washed with brine and Na ₂ SO ₄ And (5) drying. The resulting crude material was purified by column chromatography to give the product (yellow oil, 60mg, yield 57%). ¹ H NMR(400MHz,CDCl ₃ )δ7.98(d,J＝6.0Hz,1H),7.85(d,J＝3.6,Hz,1H),4.78(d,J＝12.8Hz,1H),4.72–4.71(m,1H),4.51(d,J＝12.8Hz,1H),3.90–3.81(m,1H),3.61–3.52(m,1H),1.87-1.81(m,1H),1.79–1.73(m,1H),1.73–1.64(m,2H),1.65–1.59(m,2H).

Step 4, synthesis of 3-bromo-2-fluoro-5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) aniline

The synthesis was as in step 1 of example 1. ¹ H NMR(400MHz,CDCl ₃ )δ6.88(s,1H),6.71(s,1H),4.94(s,1H),4.61(t,J＝8.0Hz,1H),4.33(d,J＝4.0Hz,1H),4.11(s,1H),1.72–1.68(m,2H),1.61–1.57(m,4H).

Step 5, synthesis of 2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) aniline

The synthesis was as in step 2 of example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.04(s,1H),7.78(s,1H),6.74(d,J＝4.4Hz,1H),6.62(d,J＝7.6Hz,1H),5.15(s,2H),4.65(s,1H),4.52(d,J＝11.6Hz,1H),4.29(d,J＝11.6Hz,1H),3.88(s,3H),3.81(d,J＝8.0Hz,1H),3.47(d,J＝10.8Hz,1H),1.73–1.64(m,2H),1.50–1.48(m,4H).

Step 6, synthesis of 3-acetyl-N- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in step 6 of example 1. ¹ H NMR(400MHz,CDCl ₃ )δ9.76(d,J＝7.6Hz,1H),8.26(dd,J＝6.8,1.6Hz,1H),7.91(d,J＝2.4Hz,1H),7.88(s,1H),7.86(d,J＝3.6Hz,1H),7.77(d,J＝1.6Hz,1H),7.70(s,1H),7.30(dd,J＝7.2,2.0Hz,1H),6.73(dd,J＝7.6,2.8Hz,1H),4.80(d,J＝11.6Hz,1H),4.75(t,J＝4.0Hz,1H),4.52(d,J＝12.0Hz,1H),3.98(s,3H),3.96(s,3H),3.93–3.92(m,1H),3.60–3.55(m,1H),2.59(s,3H),1.90–1.88(m,1H),1.82–1.72(m,1H),1.72–1.61(m,2H),1.58–1.54(m,2H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.24,162.23,158.44,141.29,137.22,134.11,131.44,129.54,128.61,126.32,124.79,123.07,122.72,120.95,120.31,115.15,108.96,105.87,97.49,97.40,67.61,61.42,55.60,38.63,30.16,26.58,24.98,19.08(s).

EXAMPLE 27 Synthesis of 3-acetyl-N- (2-chloro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 26. ¹ H NMR(400MHz,CDCl ₃ )δ9.77(d,J＝7.6Hz,1H),8.42(s,1H),8.30(s,1H),7.91(s,1H),7.80(s,1H),7.73(d,J＝4.8Hz,2H),7.25(s,1H),6.74(d,J＝7.6Hz,1H),4.82(d,J＝12.4Hz,1H),4.76(s,1H),4.55(d,J＝12.0Hz,1H),3.99(s,3H),3.96(s,3H),3.94–3.87(m,1H),3.60–3.56(m,1H),2.60(s,3H),1.91–1.73(m,2H),1.62–1.57(m,4H).

EXAMPLE 28 Synthesis of 3-acetyl-7-methoxy-N- (2-methyl-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) indolizine-1-carboxamide

The synthesis was as in example 26. ¹ H NMR(400MHz,CDCl ₃ )δ9.75(d,J＝6.8Hz,1H),7.92(s,1H),7.70(s,1H),7.62(s,1H),7.59(s,1H),7.51(s,1H),7.45(s,1H),7.21(s,1H),6.72(d,J＝5.2Hz,1H),4.79(d,J＝12.0Hz,1H),4.73(s,1H),4.50(d,J＝11.6Hz,1H),3.97(s,3H),3.91(s,3H),3.54(s,1H),2.58(s,3H),2.36(s,3H),1.82–1.71(m,2H),1.60–1.53(m,4H).

EXAMPLE 29 Synthesis of 3-acetyl-N- (2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-methoxyindolizine-1-carboxamide

3-acetyl-N- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) -7-methoxyindolizine-1-carboxamide (150mg, 0.29mmol) and PPTS (1.17mg, 0.0015 mmol) were dissolved in ethanol (10 mL), stirred at 80 ℃ for 2 hours, and after completion of the reaction, it was concentrated and redissolved in EtOAc. The organic phase was extracted with water and brine. The combined organic phases were washed with Na ₂ SO ₄ Dried and concentrated under reduced pressure. The crude product obtained was purified by silica gel chromatography to give the desired product. White solid (150 mg, yield 65%). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.73(s,1H),9.65(d,J＝7.6Hz,1H),8.57(s,1H),8.15(s,1H),7.89–7.87(m,2H),7.51(d,J＝7.2Hz,1H),7.45(d,J＝5.6Hz,1H),6.93(dd,J＝7.6,2.8Hz,1H),5.29(t,J＝5.2Hz,1H),4.52(d,J＝4.8Hz,2H),3.91(s,3H),3.89(s,3H),2.53(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.25,162.22,158.40,138.24,137.09,129.52,129.35,126.16,124.84,121.89,121.23,120.93,119.94,115.40,108.94,105.95,97.49,62.32,55.60,39.19,39.02,38.62,26.58.

EXAMPLE 30 Synthesis of 3-acetyl-N- (2-chloro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 29. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.71–9.60(m,2H),8.55(s,1H),8.16(s,1H),7.86(d,J＝2.4Hz,1H),7.81(s,1H),7.49(s,1H),7.37(s,1H),6.93(dd,J＝8.0,2.8Hz,1H),4.54(s,2H),3.91(s,3H),3.89(s,3H),2.53(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.27,162.31,158.39,141.45,141.26,138.20,135.67,131.65,130.21,129.56,127.99,125.47,124.51,123.77,120.99,118.99,108.96,106.01,97.49,62.09,55.59,38.60,26.62.

EXAMPLE 31 Synthesis of 3-acetyl-N- (5- (hydroxymethyl) -2-methyl-3- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 29. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.65(t,J＝3.6Hz,2H),8.51(s,1H),7.92(s,1H),7.87(d,J＝2.4Hz,1H),7.61(s,1H),7.20(d,J＝8.0Hz,2H),6.90(dd,J＝7.6,2.4Hz,1H),4.50(s,2H),3.90(s,3H),3.87(s,3H),2.52(s,3H),2.25(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.08,162.40,158.16,141.13,139.78,138.07,136.80,132.86,129.62,129.44,124.51,123.30,121.32,120.80,108.84,106.50,97.53,62.50,55.54,38.49,26.57,15.83.

EXAMPLE 32 Synthesis of 3-acetyl-N- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 26. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.80(s,1H),9.69(d,J＝7.2Hz,1H),8.58(s,1H),8.29(s,1H),8.17(s,1H),7.91(s,1H),7.50(t,J＝6.4Hz,2H),7.09(dd,J＝7.2,1.6Hz,1H),4.72(d,J＝2.8Hz,1H),4.69(d,J＝12.0Hz,1H),4.46(d,J＝12.0Hz,1H),3.91(s,3H),3.88–3.77(m,1H),3.56–3.47(m,1H),2.56(s,3H),2.43(s,3H),1.82–1.61(m,2H),1.61–1.47(m,4H).

EXAMPLE 33 Synthesis of 3-acetyl-7-ethyl-N- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) indolizine-1-carboxamide

The synthesis was as in example 26. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.82(s,1H),9.70(d,J＝7.2Hz,1H),8.59(s,1H),8.30(s,1H),8.18(s,1H),7.91(s,1H),7.50(d,J＝6.4Hz,2H),7.13(d,J＝6.0Hz,1H),4.73–4.67(m,2H),4.45(d,J＝2.8Hz,1H),3.91(s,3H),3.87–3.76(m,1H),3.52–3.49(m,1H),2.74(q,J＝7.6Hz,2H),2.56(s,3H),1.79–1.67(m,2H),1.56–1.49(m,4H),1.23(d,J＝7.6Hz,3H).

EXAMPLE 34 Synthesis of tert-butyl (3-acetyl-1- ((2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) carbamoyl) indolizin-7-yl) carbamate

The synthesis was as in example 26. ¹ H NMR(400MHz,CDCl ₃ )δ9.78(d,J＝7.6Hz,1H),8.40(d,J＝2.0Hz,1H),8.27(d,J＝7.2Hz,1H),7.87(d,J＝4.4Hz,2H),7.76(s,1H),7.74(s,1H),7.40(d,J＝6.4Hz,1H),7.29(d,J＝9.8Hz,1H),7.09–6.96(m,1H),4.79–4.75(m,2H),4.54–4.49(m,1H),3.97(s,3H),3.94–3.92(m,1H),3.59–3.56(m,1H),2.59(s,3H),1.89–1.83(m,2H),1.82–1.68(m,4H),1.54(s,9H).

Example 35 Synthesis of tert-butyl (3-acetyl-1- ((2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) carbamoyl) indolizin-7-yl) (methyl) carbamate

The synthesis was as in example 26. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.83(s,1H),9.68(d,J＝7.6Hz,1H),8.60(s,1H),8.33(d,J＝2.4Hz,1H),8.18(s,1H),7.91(s,1H),7.50(s,1H),7.48(s,1H),7.34(dd,J＝8.0,2.8Hz,1H),4.72(t,J＝3.6Hz,1H),4.69(d,J＝12.0Hz,1H),4.47(d,J＝12.0Hz,1H),3.91(s,3H),3.86–3.79(m,1H),3.54–3.46(m,1H),3.30(s,3H),2.56(s,3H),1.81–1.63(m,2H),1.60–1.43(m,4H),1.46(s,9H).

EXAMPLE 36 Synthesis of tert-butyl (3-acetyl-1- ((2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) carbamoyl) indolizin-6-yl) carbamate

The synthesis was as in example 26. ¹ H NMR(400MHz,DMSO-d ₆ )δ12.26(s,1H),10.34(s,1H),9.58(d,J＝6.8Hz,1H),8.65(s,1H),8.19(d,J＝5.2Hz,2H),7.93(s,1H),7.59(d,J＝4.8Hz,1H),7.37(d,J＝5.2Hz,1H),7.20(t,J＝7.2Hz,1H),4.80–4.72(m,J＝3.8Hz,1H),4.70(d,J＝12.0Hz,1H),4.48(d,J＝12.0Hz,1H),3.90(s,3H),3.87–3.77(m,1H),3.55–3.46(m,1H),2.60(s,3H),1.81–1.61(m,2H),1.61–1.46(m,4H),1.44(s,9H).

EXAMPLE 37 Synthesis of 3-acetyl-7- (cyclopropylmethoxy) -N- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) indolizine-1-carboxamide

The synthesis was as in example 26. ¹ H NMR(400MHz,CDCl ₃ )δ9.75(d,J＝7.6Hz,1H),8.33–8.18(m,1H),7.88(s,1H),7.85(d,J＝2.4Hz,2H),7.77(d,J＝1.6Hz,1H),7.69(s,1H),7.36–7.28(m,1H),6.77(dd,J＝8.0,2.8Hz,1H),4.80(d,J＝12.0Hz,1H),4.77–4.70(m,1H),4.52(d,J＝11.6Hz,1H),3.98(s,3H),3.94–3.90(m,1H),3.60–3.50(m,1H),1.88–1.72(m,2H),1.60–1.49(m,4H),0.89–0.83(m,1H),0.69(q,J＝7.2Hz,2H),0.39(q,J＝5.6Hz,2H).

EXAMPLE 38 Synthesis of 3-acetyl-7- (benzyloxy) -N- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) indolizine-1-carboxamide

The synthesis was as in example 26. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.77(s,1H),9.68(d,J＝7.6Hz,1H),8.57(s,1H),8.18(s,1H),7.99(d,J＝2.8Hz,1H),7.91(s,1H),7.50(dd,J＝7.2,3.6Hz,4H),7.43–7.35(m,3H),7.00(dd,J＝7.6,2.8Hz,1H),5.24(s,2H),4.72(s,1H),4.69(d,J＝11.6Hz,1H),4.46(d,J＝12.0Hz,1H),3.91(s,3H),3.85–3.80(m,1H),3.52–3.49(m,1H),2.53(s,3H),1.77–1.68(m,2H),1.57–1.49(m,4H).

EXAMPLE 39 Synthesis of 7- (benzyloxy) -N- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) -3-propionylindolizine-1-carboxamide

The synthesis was as in example 26. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.77(s,1H),9.71(d,J＝7.6Hz,1H),8.60(s,1H),8.18(s,1H),7.99(d,J＝2.4Hz,1H),7.91(s,1H),7.50(dd,J＝6.8,4.8Hz,3H),7.47–7.32(m,4H),7.01(dd,J＝7.6,2.4Hz,1H),5.24(s,2H),4.72(s,1H),4.69(d,J＝12.0Hz,1H),4.46(d,J＝12.0Hz,1H),3.91(s,3H),3.88–3.78(m,1H),3.52–3.49(m,1H),2.93(q,J＝7.4Hz,2H),1.81–1.63(m,2H),1.62–1.49(m,4H),1.19(t,J＝7.4Hz,3H).

EXAMPLE 40 Synthesis of 7- (benzyloxy) -N1- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) -N3-methylindolizine-1, 3-dicarboxamide

The synthesis was as in example 26. ¹ H NMR(400MHz,CDCl ₃ )δ9.52(d,J＝7.6Hz,1H),8.24(d,J＝7.2Hz,1H),7.92(d,J＝2.0Hz,1H),7.84(s,1H),7.81(d,J＝3.2Hz,1H),7.70(s,1H),7.47–7.45(m,3H),7.44–7.38(m,3H),7.36(d,J＝7.2Hz,1H),6.68(dd,J＝7.6Hz,2.4Hz,1H),6.26(s,1H),5.14(s,2H),4.78(d,J＝11.6Hz,1H),4.73(d,J＝3.2Hz,1H),4.50(d,J＝11.6Hz,1H),3.95(s,3H),3.93–3.91(m,1H),3.58–3.55(s,1H),3.02(d,J＝4.7Hz,3H),1.92–1.77(m,2H),1.60–1.50(m,4H).

EXAMPLE 41 Synthesis of 7- (benzyloxy) -N- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) -3-isobutyrylindolizine-1-carboxamide

The synthesis was as in example 26. ¹ H NMR(400MHz,CDCl ₃ )δ9.85(d,J＝7.6Hz,1H),8.28(d,J＝6.8Hz,1H),8.06(d,J＝2.8Hz,1H),7.89(s,1H),7.86(d,J＝4.4Hz,1H),7.78(d,J＝2.0Hz,1H),7.76(s,1H),7.48(d,J＝7.2Hz,2H),7.45–7.36(m,4H),7.34–7.28(m,1H),6.81(dd,J＝7.6,2.4Hz,1H),5.20(s,2H),4.81(d,J＝12.0Hz,1H),4.75–4.56(m,1H),4.53(d,J＝11.6Hz,1H),3.98(s,3H),3.97–3.62(m,1H),3.63–3.52(m,1H),3.47(dt,J＝13.6,6.6Hz,1H),1.30(d,J＝6.8Hz,6H).

EXAMPLE 42 Synthesis of 7- (benzyloxy) -N- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) -3-pivaloyl indolizine-1-carboxamide

The synthesis was as in example 26. ¹ H NMR(400MHz,CDCl ₃ )δ9.88(d,J＝7.6Hz,1H),8.22(d,J＝4.8Hz,1H),8.03(s,1H),7.87(s,1H),7.85(s,1H),7.78(s,1H),7.46(d,J＝7.6Hz,2H),7.39–7.33(m,4H),7.30(d,J＝7.2Hz,1H),6.77(d,J＝7.2Hz,1H),5.18(s,2H),4.80(d,J＝12.0Hz,1H),4.74–4.68(m,1H),4.52(d,J＝11.6Hz,1H),3.97(s,3H),3.93–3.84(m,1H),3.60–3.50(m,1H),1.67–1.62(m,2H),1.57–1.53(m,4H),1.48(s,9H).

EXAMPLE 43 Synthesis of 7- (benzyloxy) -3- (cyclopropanecarbonyl) -N- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) indolizine-1-carboxamide

The synthesis was as in example 26. ¹ H NMR(400MHz,CDCl ₃ )δ9.79(d,J＝8.0Hz,1H),8.28(d,J＝1.6Hz,1H),8.05(d,J＝2.8Hz,1H),7.92(s,2H),7.87(s,1H),7.77(s,1H),7.47(d,J＝6.8Hz,2H),7.42(d,J＝7.2Hz,1H),7.39(d,J＝1.2Hz,2H),7.30(d,J＝1.6Hz,1H),6.77(dd,J＝8.0,2.8Hz,1H),5.19(s,2H),4.80(d,J＝12.0Hz,1H),4.77–4.71(m,1H),4.52(d,J＝12.0Hz,1H),3.97(s,3H),3.95–3.89(m,1H),3.59–3.55(m,1H),2.56(td,J＝7.6,4.4Hz,1H),1.70–1.65(m,2H),1.60–1.53(m,4H),1.25–1.22(m,2H),0.89–0.84(m,2H).

EXAMPLE 44 Synthesis of 3-acetyl-7- (benzyloxy) -6-fluoro-N- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) indolizine-1-carboxamide

The synthesis was as in example 26. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.83(s,1H),9.81(d,J＝7.2Hz,1H),8.58(s,1H),8.18(s,1H),8.14(d,J＝8.8Hz,1H),7.91(s,1H),7.54–7.43(m,4H),7.41(dt,J＝14.0,6.8Hz,3H),5.34(s,2H),4.72(s,1H),4.69(d,J＝12.0Hz,1H),4.46(d,J＝12.0Hz,1H),3.91(s,3H),3.86–3.80(m,1H),3.56–3.44(m,1H),2.54(s,3H),1.78–1.68(m,2H),1.56–1.45(m,4H).

EXAMPLE 45 Synthesis of 3-acetyl-7- (benzyloxy) -N- (3- (1-cyclopropyl-1H-pyrazol-4-yl) -2-fluoro-5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) indolizine-1-carboxamide

The synthesis was as in example 26. ¹ H NMR(400MHz,CDCl ₃ )δ9.77(d,J＝7.6Hz,1H),8.30–8.24(m,1H),8.05(d,J＝2.4Hz,1H),7.89(d,J＝8.4Hz,1H),7.86(s,2H),7.72(s,1H),7.47(d,J＝6.8Hz,2H),7.43–7.37(m,3H),7.29(d,J＝8.8Hz,1H),6.80(dd,J＝7.6,2.8Hz,1H),6.57(d,J＝8.8Hz,1H),5.19(s,2H),4.80(d,J＝12.0Hz,1H),4.76–4.72(m,1H),4.52(d,J＝12.0Hz,1H),3.94–3.90(m,1H),3.68–3.60(m,1H),3.61–3.55(m,1H),2.59(s,3H),1.91–1.77(m,2H),1.56–1.50(m,4H),1.05–1.01(m,2H),0.87–0.84(m,2H).

EXAMPLE 46 Synthesis of tert-butyl (3-acetyl-1- ((2-fluoro-3- (furan-3-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) carbamoyl) indolizin-7-yl) carbamic acid

The synthesis was as in example 26. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.01(s,1H),9.75(s,1H),9.64(d,J＝7.6Hz,1H),8.79(d,J＝1.9Hz,1H),8.54(s,1H),8.16(s,1H),7.83(s,1H),7.59(d,J＝5.2Hz,1H),7.51(d,J＝6.2Hz,1H),7.21(dd,J＝7.7,2.3Hz,1H),7.04(s,1H),4.73(d,J＝3.4Hz,1H),4.71(d,J＝11.9Hz,1H),4.49(d,J＝11.9Hz,1H),3.84(dd,J＝15.4,7.3Hz,1H),3.55–3.47(m,1H),2.52(s,3H),1.76–1.64(m,2H),1.56–1.52(m,4H).

EXAMPLE 47 Synthesis of 3-acetyl-N- (2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-methylindolizine-1-carboxamide

The synthesis was as in example 29. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.76(s,1H),9.69(s,1H),8.58(s,1H),8.29(s,1H),8.15(s,1H),7.89(s,1H),7.50(s,1H),7.46(s,1H),7.09(s,1H),4.52(s,2H),3.91(s,3H),2.56(s,3H),2.43(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.74,162.01,139.10,138.25,138.10,137.13,129.41,127.96,127.45,125.46,124.27,121.80,121.32,119.98,119.88,117.92,117.82,115.39,106.70,62.35,38.62,26.84,21.02.

EXAMPLE 48 Synthesis of 3-acetyl-7-ethyl-N- (2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) indolizine-1-carboxamide

The synthesis was as in example 29. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.78(s,1H),9.71(d,J＝6.4Hz,1H),8.60(s,1H),8.31(s,1H),8.15(s,1H),7.89(s,1H),7.50(s,1H),7.44(s,1H),7.13(d,J＝5.2Hz,1H),5.29(s,1H),4.52(s,2H),3.91(s,3H),2.74(q,J＝7.6Hz,2H),2.56(s,3H),1.24(d,J＝7.6Hz,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.78,162.07,143.86,139.19,138.26,137.10,129.41,127.65,126.09,124.28,121.84,121.34,121.28,116.81,116.45,115.39,62.34,38.62,27.81,26.86,14.13.

Example 49 Synthesis of tert-butyl (3-acetyl-1- ((2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) carbamoyl) indolizin-7-yl) carbamate

The synthesis was as in example 29. ¹ H NMR(500MHz,DMSO-d ₆ )δ10.02(s,1H),9.68(s,1H),9.64(d,J＝6.0Hz,1H),8.81(s,1H),8.55(s,1H),8.16(s,1H),7.89(s,1H),7.51(d,J＝5.6Hz,1H),7.44(d,J＝5.2Hz,1H),7.19(dd,J＝6.0,2.0Hz,1H),5.30(t,J＝4.4Hz,1H),4.52(d,J＝4.4Hz,2H),3.91(s,3H),2.52(s,3H),1.50(s,9H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.11,162.01,152.33,140.39,138.88,138.30,137.15,129.47,128.68,126.34,124.87,121.75,121.09,120.91,115.42,108.77,106.32,103.82,80.13,59.72,38.64,27.98,26.64.

EXAMPLE 50 Synthesis of (3-acetyl-1- ((2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) carbamoyl) indolizin-7-yl) (methyl) tert-butylcarbamate

The synthesis was as in example 29. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.80(s,1H),9.68(d,J＝7.6Hz,1H),8.61(s,1H),8.33(s,1H),8.15(s,1H),7.89(s,1H),7.48(d,J＝6.5Hz,1H),7.45(d,J＝6.5Hz,1H),7.34(d,J＝7.5Hz,1H),5.30(t,J＝5.0Hz,1H),4.52(d,J＝5.0Hz,2H),3.91(s,3H),3.30(s,3H),2.56(s,3H),1.46(s,9H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.78,162.03,153.00,142.16,139.32,138.34,137.17,129.47,127.74,124.63,121.92,121.37,115.39,113.56,110.88,107.22,81.11,62.35,54.89,38.67,36.05,27.80,26.83.

EXAMPLE 51 Synthesis of tert-butyl ((3-acetyl-1- ((2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) carbamoyl) indolizin-7-yl) methyl) carbamate

The synthesis was as in example 29. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.81(s,1H),9.73(d,J＝7.2Hz,1H),8.61(s,1H),8.35(s,1H),8.16(s,1H),7.89(s,1H),7.58(t,J＝6.0Hz,1H),7.49(d,J＝6.4Hz,1H),7.46(d,J＝6.0Hz,1H),7.11(d,J＝5.6Hz,1H),5.30(t,J＝6.0Hz,1H),4.52(d,J＝5.6Hz,2H),4.23(d,J＝5.6Hz,2H),3.91(s,3H),2.57(s,3H),1.39(s,9H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ187.00,161.99,155.86,140.13,138.88,138.31,137.17,129.47,127.78,126.19,124.35,121.91,121.56,121.36,120.06,116.01,115.42,115.23,107.39,78.19,62.37,43.10,38.67,28.21,26.97.

EXAMPLE 52 Synthesis of tert-butyl (3-acetyl-1- ((2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) carbamoyl) indolizin-6-yl) carbamate

The synthesis was as in example 29. ¹ H NMR(400MHz,DMSO-d ₆ )δ12.25(s,1H),10.33(s,1H),9.58(d,J＝6.8Hz,1H),8.64(s,1H),8.19(d,J＝10.4Hz,2H),7.91(s,1H),7.55(d,J＝6.0Hz,1H),7.32(d,J＝6.0Hz,1H),7.20(t,J＝7.6Hz,1H),4.53(s,2H),3.90(s,3H),2.60(s,3H),1.44(s,9H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ187.34,164.37,152.79,138.62,137.19,131.58,130.53,129.56,126.03,122.97,122.12,121.98,116.04,115.21,112.86,108.23,79.90,62.20,38.66,28.00,27.41.

EXAMPLE 53 Synthesis of 3-acetyl-7- (cyclopropylmethoxy) -N- (2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) indolizine-1-carboxamide

The synthesis was as in example 29. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.73(s,1H),9.65(d,J＝7.6Hz,1H),8.57(s,1H),8.15(s,1H),7.89(s,1H),7.83(d,J＝2.4Hz,1H),7.50(d,J＝6.4Hz,1H),7.44(d,J＝6.4Hz,1H),6.94(dd,J＝7.6,2.8Hz,1H),4.51(s,2H),3.95(d,J＝6.8Hz,2H),3.91(s,3H),2.52(s,3H),1.28–1.23(m,1H),0.60(d,J＝7.2Hz,2H),0.39(d,J＝4.8Hz,2H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.29,162.28,157.79,141.38,138.27,137.16,129.61,129.47,124.81,121.85,121.24,120.96,119.95,115.45,109.29,105.88,98.04,72.74,62.40,56.06,38.69,26.62,18.55,9.74,3.17.

EXAMPLE 54 Synthesis of 3-acetyl-7- (benzyloxy) -N- (2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) indolizine-1-carboxamide

The synthesis was as in example 29. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.73(s,1H),9.68(d,J＝7.2Hz,1H),8.58(s,1H),8.16(s,1H),8.00(s,1H),7.89(s,1H),7.50–7.38(m,6H),7.11(d,J＝7.2Hz,1H),7.01(d,J＝5.6Hz,1H),5.24(s,2H),4.52(s,2H),3.91(s,3H),2.53(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.30,162.20,157.42,141.16,137.13,135.83,129.63,129.36,128.47,128.12,128.00,127.84,125.47,124.79,121.88,120.99,115.40,109.20,106.04,98.67,69.70,62.35,38.63,26.60,20.72.

Example 55 Synthesis of 3-acetyl-1- ((2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) carbamoyl) indolizin-7-yldimethylcarbamate

The synthesis was as in example 29. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.83(s,1H),9.78(d,J＝8.0Hz,1H),8.65(s,1H),8.22(d,J＝2.4Hz,1H),8.16(s,1H),7.89(s,1H),7.49(d,J＝6.8Hz,1H),7.46(d,J＝6.4Hz,1H),7.13(dd,J＝7.6,2.4Hz,1H),5.28(t,J＝5.6Hz,1H),4.52(d,J＝5.6Hz,2H),3.91(s,3H),3.08(s,3H),2.95(s,3H),2.58(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.99,161.87,152.90,149.92,138.34,137.15,129.43,129.27,126.01,124.67,121.87,121.65,121.43,115.37,112.03,109.67,107.50,62.34,39.36,39.19,39.02,38.64,36.40,36.20,26.86.

EXAMPLE 56 Synthesis of 3-acetyl-1- ((2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) carbamoyl) indolizin-7-yl pivalate

The synthesis was as in example 29. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.87(s,1H),9.80(d,J＝7.6Hz,1H),8.66(s,1H),8.19(d,J＝2.4Hz,1H),8.14(s,1H),7.88(s,1H),7.47(dd,J＝11.2,6.8Hz,2H),7.10(dd,J＝7.6,2.4Hz,1H),5.30(t,J＝5.6Hz,1H),4.51(s,2H),3.90(s,3H),2.58(s,3H),1.33(s,9H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ187.28,175.90,161.90,149.24,139.50,138.35,137.16,129.59,129.50,129.45,126.03,125.93,124.68,121.91,121.51,120.10,119.99,115.41,111.90,110.32,107.82,62.37,26.97,26.64.

EXAMPLE 57 Synthesis of 3-acetyl-N- (2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-hydroxyindolizine-1-carboxamide

The synthesis was as in example 29. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.92(s,1H),9.67–9.63(m,2H),8.52(s,1H),8.15(s,1H),7.89(s,1H),7.78(s,1H),7.48(d,J＝7.2Hz,1H),7.44(d,J＝6.0Hz,1H),6.83–6.81(m,1H),4.51(s,2H),3.91(s,3H),2.51(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ185.63,162.22,157.38,141.99,138.23,137.11,130.05,129.40,127.99,126.55,125.47,125.10,121.89,121.15,120.59,115.43,109.10,104.97,100.63,62.36,38.63,26.45.

EXAMPLE 58 Synthesis of N- (2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-hydroxy-3-propionylindolizine-1-carboxamide

The synthesis was as in example 29. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.91(s,1H),9.69(d,J＝7.2Hz,1H),9.62(s,1H),8.55(s,1H),8.15(s,1H),7.89(s,1H),7.78(d,J＝2.4Hz,1H),7.48(d,J＝7.2Hz,1H),7.44(d,J＝5.6Hz,1H),6.82(dd,J＝7.2,2.0Hz,1H),4.51(s,2H),3.91(s,3H),2.89(q,J＝7.6Hz,2H),1.18(t,J＝7.2Hz,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ189.18,162.21,157.29,151.58,141.93,138.24,137.11,130.03,129.37,126.31,124.29,121.83,121.10,119.95,115.42,109.04,104.88,100.62,62.35,39.19,39.02,38.61,31.24,9.60.

Example 59 Synthesis of N1- (2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-hydroxy-N3-methylindolizine-1, 3-dicarboxamide

The synthesis was as in example 29. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.52(s,1H),9.46(d,J＝7.6Hz,1H),9.29(s,1H),8.13(s,2H),7.98(s,1H),7.87(s,1H),7.63(s,1H),7.60(s,1H),7.40(s,1H),6.67(d,J＝6.2Hz,1H),4.50(s,2H),3.90(s,3H),2.79(d,J＝2.8Hz,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ162.63,161.78,155.13,151.05,149.10 139.72,138.24,137.14,129.36,128.98,126.88,120.73,120.50,119.64,117.42,115.53,108.00,102.97,99.75,62.44,38.63,25.55.

EXAMPLE 60 Synthesis of N- (2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-hydroxy-3-isobutyryl indolizine-1-carboxamide

The synthesis was as in example 29. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.93(s,1H),9.72(d,J＝7.6Hz,1H),9.63(s,1H),8.61(s,1H),8.16(s,1H),7.89(s,1H),7.79(d,J＝2.4Hz,1H),7.49(d,J＝5.2Hz,1H),7.44(d,J＝6.4Hz,1H),6.82(dd,J＝7.6,2.8Hz,1H),4.51(s,2H),3.91(s,3H),3.51–3.43(m,1H),1.20(s,3H),1.18(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ192.59,162.20,157.40,151.57,149.61,142.20,138.25,137.08,130.20,129.38,127.95,126.30,125.45,124.18,121.82,121.10,119.90,119.35,115.41,109.07,104.99,100.67,62.35,38.61,35.32,19.88.

EXAMPLE 61 Synthesis of N- (2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-hydroxy-3-pivaloyl indolizine-1-carboxamide

The synthesis was as in example 29. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.86(s,1H),9.87–9.74(m,2H),8.61(s,1H),8.18(s,1H),7.90(s,1H),7.84(d,J＝2.4Hz,1H),7.46(d,J＝5.2Hz,1H),7.42(d,J＝6.4Hz,1H),6.78(dd,J＝7.6,2.8Hz,1H),4.52(s,2H),3.90(s,3H),1.42(s,9H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ194.95,162.28,157.12,151.94,149.98,141.21,138.19,137.10,130.63,129.41,123.78,122.46,121.32,108.87,100.56,62.31,51.81,43.17,39.19,39.02,38.60,28.82.

EXAMPLE 62 Synthesis of 3- (cyclopropanecarbonyl) -N- (2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-hydroxyindolizine-1-carboxamide

The synthesis was as in example 29. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.94(s,1H),9.68(d,J＝7.2Hz,1H),9.64(s,1H),8.74(s,1H),8.16(s,1H),7.89(s,1H),7.78(s,1H),7.50(d,J＝6.0Hz,1H),7.44(d,J＝5.2Hz,1H),6.80(d,J＝6.0Hz,1H),4.51(s,2H),3.91(s,3H),2.67–2.64(m,1H),1.12–1.02(m,2H),0.98–0.96(m,2H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ187.21,162.24,157.33,151.51,149.55,141.94,138.23,137.08,130.10,129.34,127.96,126.36,125.46,124.44,121.70,120.98,119.88,115.42,109.03,105.27,100.55,62.37,38.62,16.98,9.27.

EXAMPLE 63 Synthesis of 3-acetyl-6-fluoro-N- (2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-hydroxyindolizine-1-carboxamide

The synthesis was as in example 29. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.73(s,1H),9.79(d,J＝7.2Hz,1H),9.71(s,1H),8.54(s,1H),8.16(s,1H),7.96(d,J＝8.8Hz,1H),7.89(s,1H),7.45(d,J＝6.4Hz,2H),4.51(s,2H),3.91(s,3H),3.44(d,J＝7.6Hz,1H),2.51(s,3H). ¹³ C NMR(125MHz,DMSO)δ186.16,162.10,151.75,149.78,148.08,145.53,138.73,138.32,137.19,129.47,126.20,124.49,122.01,121.37,120.81,120.01,119.96,116.94,116.63,115.44,105.69,101.90,62.39,38.69,26.46.

EXAMPLE 64 Synthesis of 3-acetyl-N- (3- (1-cyclopropyl-1H-pyrazol-4-yl) -2-fluoro-5- (hydroxymethyl) phenyl) -7-hydroxyindolizine-1-carboxamide

The synthesis was as in example 29. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.88(s,1H),9.66(d,J＝7.6Hz,1H),9.59(s,1H),8.51(s,1H),8.22(s,1H),7.87(s,1H),7.78(d,J＝2.4Hz,1H),7.50(d,J＝6.8Hz,1H),7.45(d,J＝6.8Hz,1H),6.82(dd,J＝7.6,2.8Hz,1H),5.25(t,J＝5.6Hz,1H),4.51(d,J＝5.6Hz,2H),3.81(tt,J＝7.6,4.0Hz,1H),2.5(s,3H),1.15–1.05(m,2H),1.00–0.96(m,2H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ185.63,162.21,157.39,151.66,149.70,141.99,138.26,137.17,130.05,128.43,126.36,125.10,121.94,121.24,120.59,119.83,119.72,115.33,109.11,104.96,100.63,62.37,54.85,32.84,26.45,6.23.

EXAMPLE 65 Synthesis of 3-acetyl-1- ((3- (1-cyclopropyl-1H-pyrazol-4-yl) -2-fluoro-5- (hydroxymethyl) phenyl) carbamoyl) indolizin-7-yldimethylcarbamate

The synthesis was as in example 29. ¹ H NMR(400MHz,CDCl ₃ )δ9.75(d,J＝7.6Hz,1H),8.26(d,J＝2.4Hz,1H),8.19(dd,J＝7.2,2.0Hz,1H),8.02(d,J＝3.2Hz,1H),7.84(s,2H),7.77(s,1H),7.27(d,J＝2.0Hz,1H),6.88(dd,J＝7.6,2.8Hz,1H),4.66(d,J＝5.2Hz,2H),3.65(tt,J＝7.2,3.6Hz,1H),3.10(s,3H),3.03(s,3H),2.57(s,3H),1.18(td,J＝7.4,4.9Hz,2H),1.06(td,J＝7.5,5.3Hz,2H). ¹³ C NMR(125MHz,CDCl ₃ )δ187.32,162.05,153.93,150.55,150.04,148.10,140.53,138.05,137.59,129.88,128.54,127.06,122.71,122.17,120.54,120.05,118.84,115.92,111.96,110.81,108.07,64.92,36.97,36.70,33.02,27.24,6.67.

EXAMPLE 66 Synthesis of tert-butyl (3-acetyl-1- ((2-fluoro-3- (furan-3-yl) -5- (hydroxymethyl) phenyl) carbamoyl) indolizin-7-yl) carbamate

The synthesis was as in example 29. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.00(s,1H),9.67(d,J＝17.0Hz,1H),9.63(t,J＝9.9Hz,1H),8.80(d,J＝1.9Hz,1H),8.55(s,1H),8.12(d,J＝14.8Hz,1H),7.82(s,1H),7.60(d,J＝7.0Hz,1H),7.20(dd,J＝7.7,2.3Hz,1H),7.11(d,J＝7.9Hz,1H),7.01(s,1H),4.54(s,2H),2.52(s,3H),1.50(s,9H).

EXAMPLE 67 Synthesis of 3-acetyl-7-amino-N- (2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) indolizine-1-carboxamide

To a stirred dichloromethane/trifluoroacetic acid (1/2) (10 mL) mixture was added tert-butyl (3-acetyl-1- ((2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) carbamoyl) indolizin-7-yl) carbamate (80mg, 0.15mmol). The mixture was stirred at room temperature for 30 minutes. Reduced pressureRemoving the solvent and subjecting the obtained residue to NaHCO ₃ And dichloromethane (3X 20 mL). The combined organic phases were washed with Na ₂ SO ₄ Dried and concentrated under reduced pressure. The crude desired product obtained was purified by silica gel chromatography (30% yield). ¹ H NMR(400MHz,DMSO-d ₆ ) ¹ H NMR(400MHz,DMSO-d ₆ )δ9.48(d,J＝7.5Hz,1H),9.44(s,1H),8.39(s,1H),8.14(s,1H),7.88(s,1H),7.52(d,J＝5.9Hz,1H),7.47(d,J＝2.0Hz,1H),7.40(d,J＝5.7Hz,1H),6.60(dd,J＝7.5,2.2Hz,1H),6.37(s,2H),5.25(t,J＝5.3Hz,1H),4.50(d,J＝4.8Hz,2H),3.91(s,3H),2.43(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ184.40,162.34,149.04,142.76,137.23,129.65,129.40,127.41,125.45,123.87,120.77,120.07,114.84,107.51,103.08,96.33,69.38,38.70,26.20.MS(APCI),m/z forC ₂₂ H ₂₀ FN ₅ O ₃ ,([M+H] ⁺ ),calcd:421.43,found 422.2.

EXAMPLE 68 Synthesis of 3-acetyl-N- (2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) -7- (methylamino) indolizine-1-carboxamide

The synthesis was as in example 67. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.50(s,1H),9.45(d,J＝7.6Hz,1H),8.42(s,1H),8.15(s,1H),7.89(s,1H),7.51(d,J＝5.2Hz,1H),7.41(d,J＝6.8Hz,1H),7.28(d,J＝2.4Hz,1H),6.95(d,J＝4.8Hz,1H),6.63(dd,J＝7.6,2.4Hz,1H),5.28(t,J＝5.6Hz,1H),4.51(d,J＝5.6Hz,2H),3.91(s,3H),2.77(d,J＝4.8Hz,3H),2.45(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ184.63,162.47,151.44,148.83,142.78,138.21,137.15,129.43,128.78,126.61,125.20,121.67,120.81,120.07,119.87,115.48,107.19,103.71,92.41,62.41,38.65,28.96,26.26.

EXAMPLE 69 Synthesis of 3-acetyl-7- (aminomethyl) -N- (2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) indolizine-1-carboxamide

The synthesis was as in example 67. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.93(s,1H),9.80(d,J＝7.2Hz,1H),8.70(s,1H),8.64(s,1H),8.42(s,2H),8.15(s,1H),7.89(s,1H),7.50(d,J＝7.2Hz,1H),7.47(d,J＝6.4Hz,1H),7.29(d,J＝7.2Hz,1H),5.32(s,1H),4.52(s,2H),4.19(s,2H),3.91(s,3H),2.60(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ187.46,161.83,138.36,138.13,137.18,133.28,129.41,127.86,124.41,121.95,121.87,121.48,119.05,115.97,115.41,108.26,62.32,41.61,40.02,39.86,38.67,27.10.

EXAMPLE 70 Synthesis of 3-acetyl-6-amino-N- (2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) indolizine-1-carboxamide

The synthesis was as in example 67. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.11(s,1H),9.25(d,J＝6.4Hz,1H),8.44(s,1H),8.17(s,1H),7.90(s,1H),7.50(d,J＝5.6Hz,1H),7.37(d,J＝5.6Hz,1H),7.04(s,2H),6.97(t,J＝7.2Hz,1H),6.55(d,J＝7.6Hz,1H),5.30(t,J＝5.6Hz,1H),4.52(d,J＝6.0Hz,2H),3.91(s,3H),2.56(s,3H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ186.62,163.83,140.80,138.44,137.17,129.78,129.55,125.18,122.49,122.05,121.62,117.11,116.33,115.31,109.28,106.26,62.28,38.66,27.29.MS(APCI),m/z for C ₂₂ H ₂₀ FN ₅ O ₃ ,[M–H] ^– ,calcd:421.43；found,420.5

EXAMPLE 71 Synthesis of 3-acetyl-7-amino-N- (2-fluoro-3- (furan-3-yl) -5- (hydroxymethyl) phenyl) indolizine-1-carboxamide

The synthesis was as in example 67. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.55–9.41(m,2H),8.39(s,1H),8.12(s,1H),7.82(s,1H),7.60(d,J＝5.6Hz,1H),7.47(d,J＝2.2Hz,1H),7.42(d,J＝5.1Hz,1H),7.00(s,1H),6.60(dd,J＝7.5,2.4Hz,1H),6.38(s,2H),5.29(s,1H),4.52(s,2H),2.43(s,3H).

EXAMPLE 72 Synthesis of 7-amino-N- (2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) -3-propionylindolizine-1-carboxamide

The synthesis was as in example 67. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.56–9.43(m,2H),9.43(s,1H),8.42(s,1H),8.14(s,1H),7.88(s,1H),7.53(t,J＝10.6Hz,1H),7.47(d,J＝2.2Hz,1H),7.40(d,J＝5.6Hz,1H),6.60(dd,J＝7.5,2.4Hz,1H),6.35(s,2H),5.32(s,1H),4.50(s,2H),3.91(s,3H),2.82(q,J＝7.4Hz,2H),1.17(t,J＝7.5Hz,3H).

EXAMPLE 73 Synthesis of 3-acetyl-N- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) -7-hydroxyindolizine-1-carboxamide

The compound 3-acetyl-7- (benzyloxy) -N- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) indolizine-1-carboxamide (230mg, 0.39mmol) was dissolved in methanol (20 mL), and Pd-C (230 mg) was added. The reaction mixture was stirred at room temperature under hydrogen blanket overnight. After completion of the reaction, the reaction mixture was filtered through silica gel, and the resulting crude product was purified by silica gel chromatography to obtain the desired product (60mg, 31%). ¹ H NMR(400MHz,DMSO-d ₆ )δ10.92(s,1H),9.66(d,J＝7.2Hz,2H),8.51(s,1H),8.17(s,1H),7.91(s,1H),7.78(d,J＝2.8Hz,1H),7.48(dd,J＝6.4,4.4Hz,2H),6.82(dd,J＝7.6,2.4Hz,1H),4.72(d,J＝3.8Hz,1H),4.68(d,J＝11.6Hz,1H),4.46(d,J＝12.0Hz,1H),3.91(s,3H),3.86–3.80(m,1H),3.53–3.49(m,1H),2.50(s,3H),1.77–1.60(m,2H),1.36–1.22(m,4H).

EXAMPLE 74 Synthesis of N- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) -7-hydroxy-3-propionoindolizine-1-carboxamide

The synthesis was as in example 73. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.91(s,1H),9.69(d,J＝7.6Hz,1H),9.65(s,1H),8.54(s,1H),8.17(s,1H),7.91(s,1H),7.78(d,J＝2.4Hz,1H),7.48(t,J＝6.8Hz,2H),6.82(dd,J＝7.6,2.8Hz,1H),4.72(d,J＝3.6Hz,1H),4.68(d,J＝12.0Hz,1H),4.46(d,J＝12.0Hz,1H),3.91(s,3H),3.85–3.80(m,1H),3.53–3.49(m,1H),2.89(q,J＝7.6Hz,2H),1.77–1.68(m,2H),1.56–1.49(m,4H),1.18(t,J＝7.6Hz,3H).

Example Synthesis of 75 N1- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) -7-hydroxy-N3-methylindolizine-1, 3-dicarboxamide

The synthesis was as in example 73. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.53(s,1H),9.46(d,J＝8.0Hz,1H),9.33(s,1H),8.15(s,2H),7.98(s,1H),7.89(s,1H),7.63(d,J＝2.4Hz,1H),7.61(d,J＝5.6Hz,1H),7.42(d,J＝5.2Hz,1H),6.67(dd,J＝7.6,2.4Hz,1H),4.72(d,J＝3.6Hz,1H),4.67(d,J＝11.6Hz,1H),4.45(d,J＝11.6Hz,1H),3.91(s,3H),3.86–3.78(m,1H),3.55–3.45(m,1H),3.01(s,1H),2.79(d,J＝4.4Hz,3H),1.77–1.68(m,2H),1.57–1.49(m,4H).

EXAMPLE 76 Synthesis of N- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) -7-hydroxy-3-isobutyrylindolizine-1-carboxamide

The synthesis was as in example 73. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.93(s,1H),9.72(d,J＝7.6Hz,1H),9.66(s,1H),8.60(s,1H),8.18(s,1H),7.91(s,1H),7.79(d,J＝2.5Hz,1H),7.49(t,J＝6.8Hz,2H),6.82(dd,J＝7.6,2.7Hz,1H),4.73(t,J＝2.8Hz,1H),4.68(d,J＝11.9Hz,1H),4.46(d,J＝11.9Hz,1H),3.91(s,3H),3.87–3.78(m,1H),3.48–3.42(m,2H),1.81–1.63(m,2H),1.60–1.43(m,4H),1.20(s,3H),1.18(s,3H).

EXAMPLE 77 Synthesis of N- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) -7-hydroxy-3-pivaloyl indolizine-1-carboxamide

The synthesis was as in example 73. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.86(s,1H),9.85(s,1H),9.79(d,J＝7.6Hz,1H),8.61(s,1H),8.19(s,1H),7.92(s,1H),7.84(d,J＝2.8Hz,1H),7.50(d,J＝4.8Hz,1H),7.43(d,J＝6.8Hz,1H),6.78(dd,J＝7.6,2.8Hz,1H),4.73(t,J＝2.8Hz,1H),4.69(d,J＝12.0Hz,1H),4.46(d,J＝12.0Hz,1H),3.91(s,2H),3.87–3.79(m,1H),3.55–3.46(m,1H),1.81–1.63(m,2H),1.61–1.45(m,4H),1.42(s,9H).

EXAMPLE 78 Synthesis of 3- (cyclopropanecarbonyl) -N- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) -7-hydroxyindolizine-1-carboxamide

The synthesis was as in example 73. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.93(s,1H),9.75–9.62(m,2H),8.72(s,1H),8.17(s,1H),7.91(s,1H),7.78(d,J＝2.0Hz,1H),7.52(d,J＝6.8Hz,1H),7.47(d,J＝5.6Hz,1H),6.80(dd,J＝7.6,2.4Hz,1H),4.74–4.71(m,1H),4.69(d,J＝12.0Hz,1H),4.46(d,J＝12.0Hz,1H),3.91(s,3H),3.88–3.78(m,1H),3.54–3.49(m,1H),2.68–2.64(m,1H),1.77–1.71(m,2H),1.56–1.51(m,4H),1.01–0.94(m,2H),0.87–0.83(m,2H).

EXAMPLE 79 Synthesis of 3-acetyl-6-fluoro-N- (2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) -7-hydroxyindolizine-1-carboxamide

The synthesis was as in example 73. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.74(s,1H),9.79(d,J＝7.2Hz,1H),9.74(s,1H),8.53(s,1H),8.18(s,1H),7.96(d,J＝9.2Hz,1H),7.91(s,1H),7.48(t,J＝6.0Hz,2H),4.73(s,1H),4.46(d,J＝12.0Hz,1H),4.46(d,J＝12.0Hz,1H),3.91(s,3H),3.82–3.75(m,1H),3.57–3.46(m,1H),1.76–1.65(m,2H),1.56–1.45(m,4H).

EXAMPLE 80 Synthesis of 3-acetyl-N- (3- (1-cyclopropyl-1H-pyrazol-4-yl) -2-fluoro-5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) -7-hydroxyindolizine-1-carboxamide

The synthesis was as in example 73. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.91(s,1H),9.66(s,1H),9.65(s,1H),8.51(s,1H),8.25(s,1H),7.89(s,1H),7.78(d,J＝2.4Hz,1H),7.50(t,J＝5.6Hz,2H),6.82(dd,J＝7.6,2.4Hz,1H),4.72(d,J＝3.6Hz,1H),4.68(d,J＝12.0Hz,1H),4.46(d,J＝12.0Hz,1H),3.88–3.82(m,1H),3.80–3.78(m,1H),3.50–3.47(m,1H),2.50(s,3H),1.77–1.64(m,2H),1.60–1.44(m,4H),1.13–1.08(m,2H),1.01–0.95(m,2H).

Example 81 Synthesis of 3-acetyl-1- ((3- (1-cyclopropyl-1H-pyrazol-4-yl) -2-fluoro-5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) carbamoyl) indolizin-7-yldimethylcarbamate

A mixture of 3-acetyl-N- (3- (1-cyclopropyl-1H-pyrazol-4-yl) -2-fluoro-5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) was weighed of phenyl) -7-hydroxyindolizine-1-carboxamide (QP 264) (880mg, 1.64mmol) and K ₂ CO ₃ (339mg, 2.46mmol) with CH ₃ CN (10 mL) and Me was added dropwise slowly at 0 ℃ ₂ NCOCl (0.23mL, 2.46mmol), refluxed for 5 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in H ₂ O (20 mL) and extracted with EtOAc (3X 20 mL). The organic phase was extracted with water and brine. The combined organic phases were washed with Na ₂ SO ₄ Dried and concentrated under reduced pressure. The crude product obtained is purified by silica gel chromatography to obtainPure carbamate (890 mg, 90% yield). ¹ H NMR(400MHz,CDCl ₃ )δ9.88(d,J＝7.6Hz,1H),8.29(dd,J＝8.0,2.0Hz,2H),7.90(d,J＝4.0Hz,1H),7.86(s,2H),7.77(s,1H),7.28(dd,J＝7.2,2.0Hz,1H),7.00(dd,J＝7.6,2.4Hz,1H),4.78(d,J＝12.0Hz,1H),4.76–4.72(m,1H),4.51(d,J＝12.0Hz,1H),4.00–3.89(m,1H),3.72–3.64(m,1H),3.61–3.56(m,1H),3.12(s,3H),3.04(s,3H),2.62(s,3H),1.91–1.75(m,2H),1.58–1.52(m,4H),1.21–1.62(m,2H),1.11–1.04(m,2H).

EXAMPLE 82 Synthesis of 3-acetyl-1- ((2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) carbamoyl) pivalic acid-7-yl pivalate

The synthesis was as in example 81. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.91(s,1H),9.80(d,J＝7.6Hz,1H),8.65(s,1H),8.18(d,J＝2.4Hz,1H),8.16(s,1H),7.90(s,1H),7.49(t,J＝6.1Hz,2H),7.11(dd,J＝7.6,2.6Hz,1H),4.71(d,J＝3.9Hz,1H),4.68(d,J＝11.9Hz,1H),4.46(d,J＝11.9Hz,1H),3.90(s,3H),3.85–3.78(m,1H),3.56–3.45(m,1H),2.58(s,3H),1.33(s,9H).

EXAMPLE 83 Synthesis of 3-acetyl-1- ((2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) carbamoyl) indolizin-7-yldimethylcarbamate

The synthesis was as in example 81. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.32(d,J＝7.6Hz,1H),9.23(s,1H),8.21(s,1H),8.15(s,1H),7.89(s,1H),7.54(d,J＝5.6Hz,1H),7.39(d,J＝5.6Hz,1H),7.05(s,1H),6.27(d,J＝5.6Hz,1H),4.71(s,1H),4.66(d,J＝12.0Hz,1H),4.44(d,J＝12.0Hz,1H),3.90(s,3H),3.89–3.75(m,1H),3.73–3.65(m,1H),2.68(s,3H),2.36(s,3H),1.73–1.60(m,2H),1.57–1.48(m,4H).

Example 84-acetyl-6-fluoro-1- ((2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- ((pivaloyloxy) methyl) phenyl) (pivaloyl) carbamoyl) indolizin-7-yl pivalate

The synthesis was as in example 81. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.84(d,J＝6.4Hz,1H),8.20–8.12(m,2H),7.87(s,1H),7.69(d,J＝5.2Hz,1H),7.53(s,1H),7.10(d,J＝5.4Hz,1H),5.00(s,2H),3.88(s,3H),2.34(s,3H),1.36(s,9H),1.35(s,9H),0.98(s,9H).

Example 85-acetyl-6-fluoro-1- ((2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -5- ((pivaloyloxy) methyl) phenyl) carbamoyl) indolizin-7-yl pivalate

The synthesis was as in example 81. ¹ H NMR(400MHz,CDCl ₃ )δ10.02(d,J＝6.3Hz,1H),8.39(d,J＝7.8Hz,1H),8.29(d,J＝5.1Hz,1H),7.91(d,J＝3.7Hz,1H),7.86(s,1H),7.76(s,2H),7.26–7.24(m,1H),5.30(s,1H),5.11(s,2H),3.98(s,3H),2.64(s,3H),1.40(s,9H),1.25(s,9H).

EXAMPLE 86 Synthesis of 3- (3-acetyl-7-methoxyindolizine-1-carboxamido) -4-fluoro-5- (1-methyl-1H-pyrazol-4-yl) benzoic acid

To a solution of methyl 3- (3-acetyl-7-methoxyindolizine-1-carboxamido) -4-fluoro-5- (1-methyl-1H-pyrazol-4-yl) benzoate (180mg, 0.39mmol) in methanol (10 mL) was added NaOH (155mg, 3.9mmol). The mixture was stirred at 80 ℃ for 2 hours. The solution was concentrated and acidified with 6N HCl to pH =1. The solid product was filtered, washed with water and dried to give the desired product acid (140mg, 80% yield) as a yellow solid. The product was used in the next step without further purification. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.89(s,1H),9.67(d,J＝6.0Hz,1H),8.59(s,1H),8.29(s,1H),8.19(s,1H),8.05(s,1H),7.97(s,1H),7.89(s,1H),6.95(d,J＝5.2Hz,1H),3.92(s,6H),2.54(s,3H).

EXAMPLE 87 Synthesis of tert-butyl 3- (3-acetyl-7-methoxyindolizine-1-carboxamido) -4-fluoro-5- (1-methyl-1H-pyrazol-4-yl) benzoate

The synthesis was as in example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.91(s,1H),9.66(d,J＝7.6Hz,1H),8.55(s,1H),8.27(s,1H),8.08–8.00(m,1H),8.00(d,J＝6.6Hz,1H),7.95(s,1H),7.85(d,J＝2.8Hz,1H),6.94(dd,J＝7.6,2.8Hz,1H),3.92(s,3H),3.90(s,3H),2.53(s,3H),1.58(s,9H).

EXAMPLE 88 Synthesis of 3-acetyl-N- (3-bromo-1-methyl-1H-indazol-6-yl) -7-methoxyindolizine-1-carboxamide

The synthesis was as in example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.96(s,1H),9.65(d,J＝7.6Hz,1H),8.55(s,1H),8.17(s,1H),7.94(d,J＝2.4Hz,1H),7.81(d,J＝8.8Hz,1H),7.70(d,J＝9.2Hz,1H),6.92(dd,J＝7.6,2.8Hz,1H),4.04(s,3H),3.93(s,3H),2.54(s,3H).

Example 89-acetyl-7-methoxy-N- (1-methyl-3- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-6-yl) indolizine-1-carboxamide

The synthesis was as in example 1.

Example 90N- ([ 1,1' -Biphenyl ] -3-yl) -3-acetyl-7-methoxyindolizine-1-carboxamide

The synthesis was as in example 1. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.92(s,1H),9.66(d,J＝7.7Hz,1H),8.56(s,1H),8.11(s,1H),7.92(d,J＝2.7Hz,1H),7.81(d,J＝8.6Hz,1H),7.67(d,J＝7.3Hz,2H),7.49(dd,J＝14.4,6.7Hz,2H),7.45–7.40(m,1H),7.37(t,J＝8.0Hz,2H),6.93(dd,J＝7.7,2.8Hz,1H),3.92(s,3H),2.55(s,3H).

Example 91 Ethyl 3- (3-acetyl-7-methoxyindolizine-1-carboxamido) -4-fluoro-5- (1-methyl-1H-pyrazol-4-yl) benzoate

The synthesis was as in example 20. ¹ H NMR(400MHz,DMSO-d6)δ8.81(d,J＝3.1Hz,1H),8.27(dd,J＝10.0,2.9Hz,1H),7.97(s,1H),7.77(dd,J＝10.0,3.1Hz,1H),7.47(dd,J＝10.8,9.0Hz,2H),7.20(dd,J＝14.9,2.9Hz,1H),7.14(d,J＝3.0Hz,1H),4.30(q,J＝11.8Hz,2H),3.94(s,3H),3.81(s,3H),2.56(s,3H),1.30(t,J＝11.8Hz,3H).

Example 92N ¹ - (2-fluoro-5- (hydroxymethyl) -3- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-hydroxyindolizine-1, 3-dicarboxamide

The synthesis was as in example 29. ¹ H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.81(d,J＝3.1Hz,1H),8.18(s,2H),8.12(s,1H),7.92(dd,J＝10.0,3.1Hz,1H),7.72(dd,J＝10.0,2.9Hz,1H),7.41(d,J＝3.1Hz,1H),7.27(d,J＝15.1Hz,1H),6.90(d,J＝2.9Hz,1H),6.44(dd,J＝15.0,3.0Hz,1H),5.27(s,1H),4.61(s,2H),3.94(s,3H).

The indolizine compounds prepared in examples 1-92 and the compound in comparative example 1 are SGC-CBP30, and the structure is

The compound of comparative example 2 is CPI-637 having the structure

In vitro activity experiments were performed: the inhibiting ability of the compound on CBP/EP300 protein is verified by using AlphaScreen detection technology.

In vitro activity test materials include: a target protein CBP; assay buffer (10X) MOPS (500 mm), CHAPS (0.5 mm), naF (500 mm), BSA (1 mg/mL), pH7.4; in the kit, the donor microbead is 50 mu g/mL, and the acceptor microbead is 50 mu g/mL; CBP ligand, short peptide H4KAc4-botin (SGRG { Lys-Ac } GG { Lys-Ac } GLG { Lys-Ac } GGA { Lys-Ac } RHR { Lys (biotin) }) 50nM; in a 150. Mu.L reaction: CBP 15. Mu.L, assay buffer: 15 μ L, deionized water: 15 μ L, small molecule compound: 15 μ L, donor beads: 15 μ L, receptor beads: 15 mu L of the solution; positive inhibitors: SGC-CBP30.

The in vitro activity experiment method comprises the steps of adding protein and short peptide into a reaction solution, incubating for 1.5h at 20 ℃, adding donor and acceptor microbeads, and incubating for 1h in a dark place. Transferring to 384-pore plates, transferring 40 mu L of liquid in each pore, and performing detection by a PE Envison2104 multifunctional plate reader, wherein the excitation wavelength is as follows: 680nM, emission wavelength 520-620nM detection reading.

Comparative examples 1 and 2 were verified using the AlphaScreen detection technique, and the results are shown in table 2:

TABLE 2

Note: the above activity data are for the bromodomain family of CBP/EP300 proteins, where NA indicates "no effect".

Most of the compounds in the table showed stronger activity than the positive control SGC-CBP30, some of the compounds were as active as the positive control CPI-637, and the comparative positive compounds had the advantage of stable structure and easy preparation. And most of the examples have good selectivity to CBP/EP 300. Table 2 molecular level activity data indicate that these compounds can bind efficiently to proteins with bromodomains.

The applicant states that the present invention is illustrated by the above examples, but the present invention is not limited to the above process steps, i.e. it is not meant to be dependent on the above process steps to implement the present invention. It will be apparent to those skilled in the art that any modification of the present invention, equivalent substitutions of selected materials and additions of auxiliary components, selection of specific modes and the like, which are within the scope and disclosure of the present invention, are contemplated by the present invention.

Claims

1. An indolizine compound, which is characterized by having a structure shown in formula I:

wherein R is ₁ Any one selected from hydrogen, cyclopropyl, 1-cyclopentenyl, 1-cyclohexenyl, pyridyl, pyrimidyl, furyl, substituted furyl, phenyl, 1-methyl-1H-pyrazolyl, and benzenesulfonic acid; the substituted group is selected from methyl and aldehyde group.

2. The method for producing an indolizine compound according to claim 1, wherein the method comprises the following steps:

route one is specifically as follows:

wherein R is ₁ And R as described in claim 1 ₁ With the same range.

3. The method of claim 2, wherein in scheme one, compound 12 is prepared by reacting compound 11 with ammonium chloride in the presence of acetic acid and ethanol as solvents and iron as a catalyst.

4. The method of claim 2, wherein compound 13 is formed from compound 12 and a borate in the presence of potassium carbonate, pd (dppf) Cl ₂ In the presence of dimethylformamide, wherein the structure of the borate is

5. The process according to claim 2, wherein compound 15 is obtained by reacting compound 14 with 1-chloropropan-2-one in acetone.

6. The method according to claim 2, wherein the compound 16 is obtained by reacting the compound 15 with methyl propiolate in dichloromethane and triethylamine.

7. The process according to claim 2, wherein compound 17 is obtained by reacting compound 16 in methanol in the presence of sodium hydroxide.

8. The preparation method of claim 2, wherein the compound shown in formula I is prepared by reacting compound 13 with compound 17 in toluene in the presence of 2-chloro-1-methylpyridine iodide and tri-n-butylamine at 80-100 ℃ for 10-20 h.

9. An indolizine compound, characterized in that the indolizine compound has a structure as shown in formula II:

R ₂ any one of hydrogen, halogen atom, aldehyde group, carboxyl group, hydroxymethyl group, trifluoromethyl group and amido group;

R ₃ selected from hydrogen, fluorine atoms, methyl groups;

R ₄ any one selected from hydrogen, amino, methoxy, phenolic hydroxyl, methylamino, dimethylamino carbamate, ethyl, boc protected amino, boc protected methylamino, 2-dimethylpropionate, benzyl alcohol group or cyclopropyl methanol group;

R ₅ any one selected from hydrogen, halogen atom, amino group or Boc protected amino group;

R ₆ any one selected from hydrogen, methyl, ethyl, amino or methylamino;

R ₇ selected from methyl.

10. A process for the preparation of indolizines according to claim 9, comprising any of route two, route three, route four, route five or route six;

wherein, the route two is specifically as follows:

route three is specifically shown below:

route four is specifically shown below:

route five is specifically shown below:

route six is specifically shown below:

wherein X is Cl or Br;

in the fifth route, the compound shown in the formula II-4 is prepared by directly reacting a compound 39 in ethanol at 60-90 ℃ for 1-3 h in the presence of pyridinium p-toluenesulfonate; or the compound 39 is reduced by palladium carbon to obtain a compound 40, and then the compound 40 is reacted in ethanol and under the existence of pyridinium p-toluenesulfonate at the temperature of 60-90 ℃ for 1-3 h to prepare the catalyst, wherein R is ₄ Is benzyl alcohol group;

in the sixth route, the compound 41 is prepared by reflux reaction of the compound 40' with pivaloyl chloride or dimethylcarbamoyl chloride in acetonitrile and in the presence of potassium carbonate for 4-6 h.

11. The method of claim 10, wherein in scheme two, compound 19 is prepared by reacting compound 18 with N-bromosuccinimide in sulfuric acid overnight.

12. The method of claim 10, wherein compound 20 is prepared by reacting compound 19 with ammonium chloride in the presence of acetic acid and ethanol as a solvent and iron as a catalyst.

13. The method of claim 10, wherein compound 21 is prepared from compound 20 and borate in the presence of potassium carbonate, pd (dppf) Cl ₂ In the presence of dimethylformamide, of the boric acid compoundHas the structure of

14. The preparation method of claim 10, wherein in the second route, the compound shown in formula II-1 is prepared by reacting compound 21 with compound 17 in toluene in the presence of 2-chloro-1-methylpyridine iodide, tri-n-butylamine and arylamine at 80-100 ℃ for 10-20 h;

the structure of compound 17 is as follows:

15. the method of claim 10, wherein in scheme three, compound 23 is prepared by reacting compound 22 with N-bromosuccinimide in sulfuric acid overnight.

16. The method of claim 10, wherein compound 24 is prepared by reacting compound 23 with sodium borohydride in ethanol.

17. The method of claim 10, wherein compound 25 is prepared by reacting compound 24 with 3, 4-dihydro-2H-pyran in the presence of pyridinium p-toluenesulfonate in methylene chloride.

18. The method of claim 10, wherein compound 26 is prepared by reacting compound 25 with ammonium chloride in the presence of acetic acid and ethanol as a solvent and iron as a catalyst.

19. The method of claim 10, wherein compound 27 is prepared from compound 26 and a borate in the presence of potassium carbonate, pd (dppf) Cl ₂ In the presence of dimethyl formamideObtained by reaction in amide, wherein the structure of the borate is

20. The preparation method of claim 10, wherein the compound 28 is prepared by reacting the compound 27 with the compound 17 in toluene in the presence of 2-chloro-1-methylpyridine iodide and tri-n-butylamine at 80-100 ℃ for 10-20 h;

compound 17 has the structure:

21. the process according to claim 10, wherein in scheme III, the compound represented by formula II-2 is prepared by reacting compound 28 in ethanol in the presence of pyridinium p-toluenesulfonate at 60-90 ℃ for 1-3 h.

22. The process according to claim 10, wherein in scheme IV compound 30 is obtained by reacting compound 29 with 1-chloropropan-2-one in acetone.

23. The method according to claim 10, wherein the compound 31 is obtained by reacting the compound 30 with methyl propiolate in dichloromethane and triethylamine.

24. The method according to claim 10, wherein compound 32 is obtained by reacting compound 31 in methanol in the presence of sodium hydroxide.

25. The preparation method of claim 10, wherein the compound 33 is prepared by reacting the compound 32 with the compound 27 in toluene in the presence of 2-chloro-1-methylpyridine iodide and tri-n-butylamine at 80-100 ℃ for 10-20 h.

26. The method according to claim 10, wherein the compound represented by formula II-3 is prepared by reacting compound 33 in ethanol in the presence of pyridinium p-toluenesulfonate at 60 to 90 ℃ for 1 to 3 hours in scheme iv.

27. The method of claim 10, wherein in scheme five, compound 35 is prepared by reacting compound 34 with benzyl alcohol or cyclopropylmethanol in the presence of sodium hydride at a temperature of 0-65 ℃ for 2-6 h in dimethylformamide.

28. The method of claim 10, wherein compound 36 is prepared from compound 35 and

prepared by reacting in acetone overnight, wherein X is Cl or Br.

29. The method according to claim 10, wherein the compound 37 is obtained by reacting compound 36 with methyl propiolate in dichloromethane and triethylamine.

30. The method according to claim 10, wherein compound 38 is obtained by reacting compound 37 in methanol in the presence of sodium hydroxide.

31. The preparation method of claim 10, wherein the compound 39 is prepared by reacting the compound 38 with the compound 27 in toluene in the presence of 2-chloro-1-methylpyridine iodide and tri-n-butylamine at 80-100 ℃ for 10-20 h.

32. The method according to claim 10, wherein in the sixth route, the compound represented by formula II-5 is prepared by reacting compound 41 in ethanol in the presence of pyridinium p-toluenesulfonate at 60 to 90 ℃ for 1 to 3 hours.

33. An indolizine compound, which is characterized in that the indolizine compound is any one of the following structural compounds:

34. a process for the preparation of indolizines according to claim 33, wherein the process is represented by scheme two as described in claim 10;

wherein R is ₂ Selected from methoxycarbonyl or tert-butoxycarbonyl.

35. Use of an indolizine compound as claimed in claim 1, 9 or 33 for the preparation of CBP/EP300 bromodomain receptor inhibitors.

36. The use according to claim 35, wherein the CBP/EP300 bromodomain receptor inhibitor is used for the preparation of a medicament for the treatment of cancer, cell proliferative disorders, inflammatory and autoimmune diseases, sepsis, viral infections or neurodegenerative disorders.

37. The use according to claim 36, wherein the CBP/EP300 bromodomain receptor inhibitor is for the manufacture of a medicament for the treatment of prostate cancer.

38. A pharmaceutical composition comprising an indolizine compound of claim 1, 9 or 33.