HK1217326B - Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b - Google Patents

Description

Glyoxylamide-substituted pyrrole amide derivatives and their use as medicaments for the treatment of hepatitis B

Background

Hepatitis B Virus (HBV) is an enveloped, partially double-stranded DNA (dsDNA) virus of the Hepadnaviridae family (Hepadnaviridae). Its genome comprises 4 overlapping reading frames: pre-core/core gene; a polymerase gene; l, M and the S gene, which encode 3 envelope proteins; and an X gene.

After infection, the partially double-stranded DNA genome (loose circle DNA; rcDNA) is converted into covalently closed circular DNA (cccDNA) in the host cell nucleus and the viral mRNA is transcribed. Once encapsidated, the pregenomic RNA (pgRNA), which also encodes the core protein and Pol, serves as a template for reverse transcription, which regenerates the partially double-stranded dsDNA genome (rcDNA) in the nucleocapsid.

HBV causes epidemics in parts of asia and africa, and it is endemic in china. HBV has infected approximately 20 million people worldwide, of which approximately 3.5 million develop into chronic infectious diseases. The virus causes the disease hepatitis b and chronic infectious diseases are associated with a strongly increased risk of developing cirrhosis and hepatocellular carcinoma.

Transmission of hepatitis b virus results from exposure to infectious blood or body fluids, while viral DNA is detected in saliva, tears, and urine of chronic carriers with high titers of DNA in serum.

There is an effective and well-tolerated vaccine, but direct therapeutic options are currently limited to interferon and the following antiviral drugs; tenofovir, lamivudine, adefovir, entecavir and telbivudine.

In addition, heteroaryl dihydropyrimidines (HAPs) have been identified as a class of HBV inhibitors in tissue culture and animal models (Weber et al, Antiviral Res. 54: 69-78).

WO 2013/006394, published in 1/10/2013, relates to a subclass of sulfamoyl-arylamides that are effective against HBV. WO 2013/096744, published on day 26/6/2013, relates to active compounds against HBV.

In addition, WO 2014/033170 and WO 2014/033176, published 3/6/2014, relate to additional active compounds against HBV.

Among the problems with these direct HBV antivirals may be toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability, low solubility and difficulty in synthesis.

There is a need for additional HBV inhibitors that can overcome at least one of these disadvantages or that have additional advantages such as increased efficacy or an increased safety window.

Description of the invention

The present invention relates to a compound of formula (IA)

Or one stereoisomer or tautomeric form thereof, wherein:

each X independently represents CR⁷；

R¹、R²And R³Independently selected from the group consisting of: hydrogen, fluorine, chlorine, bromine, -CHF₂、-CH₂F、-CF₃、-CN、C₁-C₃Alkyl or C₃-C₄A cycloalkyl group;

R⁴is hydrogen, C₁-C₃Alkyl or C₃-C₄A cycloalkyl group;

R⁵is hydrogen;

R⁶selected from the group consisting of: c₁-C₆An alkyl group and optionally a 3-7 membered saturated ring comprising one or more heteroatoms each independently selected from the group consisting of: o, S and N, C₁-C₆Alkyl or 3-7 membered saturated ring is optionally substituted with one or more substituents selected from the group consisting of: fluorine, C₃-C₄Cycloalkyl, -OR⁸Oxo, -CN, -C (═ O) -OR⁸、-C(＝O)-N(R⁸)₂Or C optionally substituted by one or more fluorine₁-C₃An alkyl group;

each R⁷Independently represent hydrogen, C₃-C₄Cycloalkyl, -CN, fluoro, chloro, bromo or C optionally substituted by one or more fluoro₁-C₃An alkyl group;

R⁸represents hydrogen or C₁-C₃An alkyl group;

or a pharmaceutically acceptable salt or solvate thereof.

The invention further relates to a pharmaceutical composition comprising a compound of formula (IA) and a pharmaceutically acceptable carrier.

The invention also relates to the use of a compound of formula (IA) as a medicament, preferably for use in the prevention or treatment of HBV infection in a mammal.

In a further aspect, the present invention relates to a combination of a compound of formula (IA) and another HBV inhibitor.

Definition of

The term "C" as a group or part of a group_1-3Alkyl "means having the formula C_nH_2n+1Wherein n is a number in the range of 1 to 3. In case of C_1-3Alkyl is attached to another group, then it refers to formula C_nH_2n。C_1-3The alkyl group comprises from 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms. C_1-3Alkyl includes all linear or branched alkyl groups having between 1 and 3 carbon atoms and thus includes groups such as, for example, methyl, ethyl, n-propyl and isopropyl.

C as a group or part of a group_1-4Alkyl defines a straight or branched chain saturated hydrocarbon radical having from 1 to 4 carbon atoms, e.g. for C_1-3Alkyl, butyl, and the like.

C as a group or part of a group_1-6Alkyl defines a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbon atoms, e.g. for C_1-4Alkyl and pentyl, hexyl, 2-methylbutyl and the like.

As used herein, the term "3-7 membered saturated ring" means a saturated cyclic hydrocarbon having 3, 4, 5, 6 or 7 carbon atoms, and is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Such saturated rings optionally contain one or more heteroatoms such that at least one carbon atom is replaced by a heteroatom selected from N, O and S, in particular from N and O. Examples include oxetane, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, thiacyclopentane 1, 1-dioxide and pyrrolidinyl. Preferred are saturated cyclic hydrocarbons having 3 or 4 carbon atoms and 1 oxygen atom. Examples include oxetane and tetrahydrofuranyl.

It should be noted that different isomers of different heterocycles can exist in the definitions as used throughout this description. For example, the pyrrolyl group may be

1H-pyrrolyl or 2H-pyrrolyl.

The terms halo and halogen are typically fluoro, chloro, bromo or iodo. Preferred halogens are fluorine and chlorine.

It should also be noted that the residue position on any molecular moiety used in the definition may be any position on such moiety, as long as it is chemically stable. For example, pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; the pentyl group includes 1-pentyl, 2-pentyl and 3-pentyl.

The positions indicated on the phenyl (e.g., ortho, meta, and/or para) are indicated relative to the bond linking the phenyl to the main structure. With respect to R¹Any position is indicated with respect to the nitrogen (×) attached to the main structure:

when any variable (e.g. halogen or C)_1-3Alkyl) is present more than once in any component, each definition is independent.

For therapeutic use, salts of the compounds of formula (IA) are those in which the counterion is pharmaceutically or physiologically acceptable. However, salts with non-pharmaceutically acceptable counterions may also find use, for example in the preparation or purification of pharmaceutically acceptable compounds of formula (IA). All salts, whether pharmaceutically acceptable or not, are included within the scope of the invention.

The pharmaceutically acceptable or physiologically tolerable addition salt forms which the compounds of the invention are capable of forming can be conveniently prepared using suitable acids such as, for example, inorganic acids, e.g., hydrohalic acids, e.g., hydrochloric or hydrobromic acid; sulfuric acid; hemisulfuric acid, nitric acid; phosphoric acid and the like; or organic acids such as, for example, acetic acid, aspartic acid, dodecylsulfuric acid, heptanoic acid, hexanoic acid, nicotinic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, and the like.

Conversely, said acid addition salt forms can be converted into the free base form by treatment with a suitable base.

The term "salt" also includes hydrates and solvent addition forms which the compounds of the present invention are capable of forming. Examples of such forms are, for example, hydrates, alcoholates and the like.

The compounds of the invention may also exist in their tautomeric form. For example, the tautomeric form of an amide (-C (═ O) -NH-) group is iminoalcohol (-C (OH) ═ N-). Tautomeric forms, although not explicitly indicated in the structural formulae represented herein, are intended to be included within the scope of the present invention.

The term "stereochemically isomeric forms of the compounds of the present invention" as used hereinbefore defines all the possible compounds consisting of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of the present invention may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. The mixture may comprise all diastereomers and/or enantiomers of the basic molecular structure of the compound. All stereochemically isomeric forms of the compounds of the present invention, in pure form or in admixture with each other, are intended to be embraced within the scope of the present invention.

Pure stereoisomeric forms of the compounds and intermediates mentioned herein are defined as isomers of other enantiomeric or diastereomeric forms which do not have substantially the same basic molecular structure as the compounds or intermediates. In particular, the term 'stereoisomerically pure' relates to a compound or intermediate having a stereoisomeric excess of at least 80% (i.e. a minimum of 90% of one isomer and 10% of the other possible isomers) to 100% (i.e. 100% of one isomer and no other isomers), more particularly a compound or intermediate having a stereoisomeric excess of 90% to 100%, even more particularly having a stereoisomeric excess of 94% to 100% and most particularly having a stereoisomeric excess of 97% to 100%. The terms 'enantiomerically pure' and 'diastereomerically pure' should be understood in a similar manner, but in the discussion concerning the enantiomeric excess and the diastereomeric excess, respectively, in a mixture.

Pure stereoisomeric forms of the compounds and intermediates of the invention may be obtained by the application of procedures known in the art. For example, enantiomers can be separated from each other by selective crystallization of their diastereomeric salts with optically active acids or bases. Examples of these are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. The pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a particular stereoisomer is desired, the compound will be synthesized by stereospecific methods of preparation. These processes will advantageously use enantiomerically pure starting materials.

The diastereomeric forms of formula (IA) may be obtained separately by conventional methods. Suitable physical separation methods which may advantageously be employed are, for example, selective crystallization and chromatography (e.g. column chromatography).

The present invention is also intended to include all isotopes of atoms occurring on the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

Detailed description of the invention

Whenever used hereinafter, the term "compound of formula (IA)",

or "compounds of the invention" or similar terms are intended to include compounds having the general formula (IA), (I), (IA), (Ib), salts, stereoisomeric forms and racemic mixtures or any subgroup thereof.

In a first aspect, the present invention provides a compound of formula (IA)

Or one stereoisomer or tautomeric form thereof, wherein:

each X independently represents CR⁷；

R¹、R²And R³Independently selected from the group consisting of: hydrogen, fluorine, chlorine, bromine, -CHF₂、-CH₂F、-CF₃、-CN、C₁-C₃Alkyl or C₃-C₄A cycloalkyl group;

R⁴is hydrogen, C₁-C₃Alkyl or C₃-C₄A cycloalkyl group;

R⁵is hydrogen;

R⁶selected from the group consisting of: c₁-C₆An alkyl group and optionally a 3-7 membered saturated ring comprising one or more heteroatoms each independently selected from the group consisting of: o, S and N, C₁-C₆Alkyl or 3-7 membered saturated ring is optionally substituted with one or more substituents selected from the group consisting of: fluorine, C₃-C₄Cycloalkyl, -OR⁸Oxo, -CN, -C (═ O) -OR⁸、-C(＝O)-N(R⁸)₂Or C optionally substituted by one or more fluorine₁-C₃An alkyl group;

each R⁷Independently represent hydrogen, C₃-C₄Cycloalkyl, -CN, fluoro, chloro, bromo or C optionally substituted by one or more fluoro₁-C₃An alkyl group;

R⁸represents hydrogen or C₁-C₃An alkyl group;

or a pharmaceutically acceptable salt or solvate thereof.

In one aspect, the invention relates to compounds of formula (I)

Or one stereoisomer or tautomeric form thereof, wherein:

each X independently represents CR⁷；

R²Is hydrogen or fluorine;

R¹and R³Independently selected from the group consisting of: hydrogen, fluorine, chlorine, bromine, -CHF₂、-CH₂F、-CF₃-CN and methyl;

R⁴is hydrogen or methyl;

R⁵is hydrogen;

R⁶selected from the group consisting of: c₁-C₆An alkyl group and optionally a 3-7 membered saturated ring comprising one or more heteroatoms each independently selected from the group consisting of: o, S and N, C₁-C₆Alkyl or 3-7 membered saturated ring is optionally substituted with one or more substituents selected from the group consisting of: fluorine, C₁-C₃Alkyl, -CN, -C (═ O) -OR⁸or-C (═ O) -N (R)⁸)₂；

R⁷Represents hydrogen or methyl;

R⁸represents hydrogen or C₁-C₃An alkyl group;

or a pharmaceutically acceptable salt or solvate thereof.

In a further aspect, the present invention provides a compound of formula (Ia) or (Ib)

Or one stereoisomer or tautomeric form thereof, wherein:

each X independently represents CR⁷；

R²Is hydrogen or fluorine;

R¹and R³Independently selected from the group consisting of: hydrogen, fluorine, chlorine, bromine, -CHF₂、-CH₂F、-CF₃-CN and methyl;

R⁴is hydrogen or methyl;

R⁵is hydrogen;

R⁶selected from the group consisting of: c₁-C₆An alkyl group and optionally a 3-7 membered saturated ring comprising one or more heteroatoms each independently selected from the group consisting of: o, S and N, C₁-C₆Alkyl or 3-7 membered saturated ring is optionally substituted with one or more substituents selected from the group consisting of: fluorine, C₁-C₃Alkyl, -CN, -C (═ O) -OR⁸or-C (═ O) -N (R)⁸)₂；

R⁷Represents hydrogen or methyl;

R⁸represents hydrogen or C₁-C₃An alkyl group;

or a pharmaceutically acceptable salt or solvate thereof.

In a first embodiment, compounds of formula (IA), (I), (IA) and (Ib) are disclosed, wherein R is¹Selected from hydrogen, fluorine, chlorine, -CHF₂、-CN、-CF₃Or a methyl group. In another embodiment, R¹Selected from hydrogen, fluorine, chlorine, CHF₂、-CN、-CF₃Or methyl and R¹And R³Is fluorine or hydrogen. In yet another embodiment, R¹And R³Is fluorine, and the other R¹Or R³Selected from hydrogen, fluorine, chlorine, -CHF₂、-CN、-CF₃Or a methyl group.

In yet another embodiment, compounds of the invention are disclosed, wherein R is⁴Is methyl.

In a further embodiment, compounds of the invention are disclosed, wherein R is⁶Comprising a 3-7 membered saturated ring optionally comprising one oxygen, the 3-7 membered saturated ring being optionally substituted with methyl. In a further embodiment, R⁶Is a 4 or 5 membered saturated ring containing one oxygen, the 4 or 5 membered saturated ring being optionally substituted by methyl.

In another embodimentIn the examples, R⁶Is a branched chain C optionally substituted with one or more substituents selected from the group consisting of₁-C₆Alkyl, the group consisting of: fluorine, -CN, -C (═ O) -OR⁸or-C (═ O) -N (R)⁸)₂. In a further embodiment, R⁶Is a branched chain C₁-C₆An alkyl group.

Another embodiment of the invention relates to those compounds of formula (IA) or any subgroup thereof, as mentioned in any other embodiment, wherein one or more of the following restrictions apply:

(a)R⁴is methyl and R⁶Is selected from the group consisting of: c optionally substituted by one or more fluorine₁-C₆An alkyl group;

(b)R²is hydrogen or fluorine.

(c)R¹And R³Independently selected from the group consisting of: hydrogen, fluorine, chlorine, -CN and methyl.

(d) At least one R⁷Is chlorine or methyl.

(e)R²Is hydrogen or fluorine and R¹And R³Independently selected from the group consisting of: hydrogen, fluorine, chlorine and-CN.

(f)R⁶Comprising a 3-7 membered saturated ring optionally containing one oxygen, more precisely R⁶Is a 4 or 5 membered saturated ring optionally comprising an oxygen, the 4 or 5 membered saturated ring being optionally substituted with one or more substituents selected from: c optionally substituted by one or more fluorine₁-C₃Alkyl or fluoro.

(g)R⁶Comprising a branch C optionally substituted by one or more fluorine₃-C₆Alkyl, or wherein R⁶Comprising C₃-C₆Cycloalkyl, wherein the C₃-C₆Cycloalkyl substituted by one or more fluorine or by C₁-C₄Alkyl substitution of the C₁-C₄Alkyl being substituted by one or more fluoro, or wherein R⁶Comprising optionally substituted by one or more fluorine and/or by C₁-C₃Alkyl substituted C₃-C₆Cycloalkyl radical, C₁-C₃Alkyl is optionally substituted with one or more fluoro.

(h)R⁴Is methyl; r⁶Selected from the group consisting of: c optionally substituted by one or more fluorine₁-C₆Alkyl and R²Is fluorine.

Further combinations of any of these embodiments are also contemplated as being within the scope of the invention.

Preferred compounds according to the invention are compounds having the formula (IA), (I), (IA), (Ib) as represented in the synthetic part of the compounds or stereoisomers or tautomeric forms thereof and their activities are shown in table 1.

In a further aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound of formula (IA) as specified herein and a pharmaceutically acceptable carrier. In this context, a prophylactically effective amount is an amount sufficient to prevent HBV infection in a subject at risk of being infected. In this context, a therapeutically effective amount is an amount sufficient to stabilize HBV infection, reduce HBV infection, or eradicate HBV infection in an infected subject. In yet a further aspect, the present invention relates to a process for the preparation of a pharmaceutical composition as specified herein, which process comprises bringing into intimate admixture a pharmaceutically acceptable carrier and a therapeutically or prophylactically effective amount of a compound of formula (IA) as specified herein.

Thus, the compounds of the present invention, or any subgroup thereof, may be formulated in different pharmaceutical forms for administration purposes. As suitable compositions, all compositions usually used for systemic administration can be cited. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. It is desirable that these pharmaceutical compositions are in unit dosage forms suitable, in particular, for administration orally, rectally, transdermally, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations (e.g., suspensions, syrups, elixirs, emulsions and solutions); or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules represent the most advantageous oral unit dosage form in which case solid pharmaceutical carriers are employed. For parenteral compositions, the carrier will typically comprise sterile water, at least in large part, but may also comprise other ingredients, for example to aid solubility. Injectable solutions, for example, may be prepared in which the carrier comprises a physiological saline solution, a glucose solution, or a mixture of physiological saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In compositions suitable for transdermal administration, the carrier may optionally include penetration enhancers and/or suitable wetting agents, optionally in combination with small proportions of suitable additives of any nature, which do not introduce significant deleterious effects on the skin. The compounds of the present invention may also be administered via oral inhalation or insufflation in the form of a solution, suspension or dry powder using any delivery system known in the art.

It is particularly advantageous to formulate the above pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, as well as divided multiple dosage forms thereof.

The compounds of formula (IA) are active as inhibitors of the HBV replication cycle and can be used for the treatment and prevention of HBV infection or HBV-related diseases. The latter include progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, end-stage liver disease, and hepatocellular carcinoma.

Due to their antiviral properties, in particular their anti-HBV properties, the compounds of formula (IA) or any subgroup thereof are useful in the inhibition of the HBV replication cycle, in particular in the treatment of warm-blooded animals, especially humans, infected with HBV and for the prevention of HBV infection. Furthermore the present invention relates to a method of treating a warm-blooded animal, especially a human, infected with or at risk of infection with HBV which comprises administering a therapeutically effective amount of a compound of formula (IA).

The compound of formula (IA) as specified herein may thus be used as a medicament, in particular as a medicament for the treatment or prevention of HBV infection. The use or method of treatment as a medicament comprises systemically administering to an HBV infected subject or a subject susceptible to HBV infection an amount effective against a condition associated with HBV infection or an amount effective to prevent HBV infection.

The invention also relates to the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of HBV infection.

In general, it is contemplated that the antiviral effective daily amount will be from about 0.01mg/kg to about 50mg/kg body weight, or from about 0.01mg/kg to about 30mg/kg body weight. The desired dose may suitably be administered as two, three, four or more sub-doses at appropriate intervals throughout the day. The sub-doses may be formulated in unit dosage forms, for example containing from about 1mg to about 500mg, or from about 1mg to about 300mg, or from about 1mg to about 100mg, or from about 2mg to about 50mg of the active ingredient per unit dosage form.

The present invention also relates to the combination of a compound of formula (IA) or any subgroup thereof as specified herein with other anti-HBV agents. The term "combination" may relate to a product or kit comprising (a) a compound of formula (IA) as specified above, and (b) at least one other compound capable of treating HBV infection (referred to herein as an anti-HBV agent), as a combined preparation for simultaneous, separate or sequential use in the treatment of HBV infection. In one embodiment, the present invention relates to the combination of a compound of formula (IA) or any subgroup thereof with at least one anti-HBV agent. In a particular embodiment, the present invention relates to the combination of a compound of formula (IA) or any subgroup thereof with at least two anti-HBV agents. In a particular embodiment, the present invention relates to the combination of a compound of formula (IA) or any subgroup thereof with at least three anti-HBV agents. In a particular embodiment, the present invention relates to the combination of a compound of formula (IA) or any subgroup thereof with at least four anti-HBV agents.

an example of an immunomodulatory agent is interferon- α (IFN- α), pegylated interferon- α, or a stimulator of the innate immune system, such as a Toll-like receptor 7 and/or 8 agonist.

the combination of previously known anti-HBV agents, such as interferon- α (IFN- α), pegylated interferon- α, 3TC, adefovir, or combinations thereof, with a compound of formula (IA) or any subgroup thereof may be used as a medicament in a combination therapy.

General synthesis:

in this general synthesis section by R^1，2，3、R⁶Or R⁷The substituents represented are intended to include any R suitable for conversion to according to the invention without undue burden to one of ordinary skill in the art^1，2，3、R⁶Or R⁷Any substituent or reactive species of a substituent.

Scheme 1

Scheme 1A

The synthesis of compounds having general formula (I) can be performed as outlined in scheme 1. Each R^xIndependently represents lower alkyl, preferably C₁-C₃Alkyl and even more preferably methyl or ethyl. Carboxylic acids having general formula (a) can be coupled with anilines having general formula (b) using a peptide coupling reagent (like for example HATU) in the presence of an organic amine base (like TEA or DIPEA). The resulting compounds of the general formula (c) can be reacted with oxalyl chloride monoalkyl esters of the general formula (d) in Lewis acids, such as for example AlCl₃) To provide a compound having the general formula (f). Alternatively, the compound having the general formula (f) may be obtained by: the order of the above reaction steps is reversed, in particular by reacting a carboxylic acid of the general formula (a) with an oxalyl chloride monoalkyl ester of the general formula (d) in a Lewis acid (such as for example AlCl)₃) To provide a compound having general formula (e), followed by coupling of (e) with an aniline having general formula (b) using a peptide coupling reagent (like for example HATU) in the presence of an organic amine base (like TEA or DIPEA). Reacting a compound having the general formula (f) with an amine having the general formula (g) in a suitable solvent, such as for example EtOH, provides a compound having the general formula (I). Alternatively, the compound having the general formula (I) may be obtained from the compound having the general formula (f) in a two-step procedurethe procedure involves hydrolysis of the ester moiety of the compound of general formula (f) with an inorganic base of general formula (h), like for example NaOH, followed by coupling of the resulting α -keto-acid of general formula (I) with an amine of general formula (g) using a peptide coupling reagent like for example HATU in the presence of an organic amine base like TEA or DIPEA, similarly, the synthesis of the compound of general formula IA is described in scheme 1A as described for the synthesis of the compound of general formula (I) in scheme 1.

Scheme 2

Scheme 2A

The synthesis of compounds having general formula (I) can also be performed as outlined in scheme 2. Each R^xIndependently represents lower alkyl, preferably C₁-C₃Alkyl and even more preferably methyl or ethyl. The carboxylic acid esters of the general formula (j) can be reacted with oxalyl chloride monoalkyl esters of the general formula (d) in Lewis acids, such as for example AlCl₃) to provide the corresponding α -keto-acid of general formula (m) by hydrolysis of (k) with an inorganic base of general formula (h), like NaOH, the compound of general formula (n) may be obtained by coupling (m) with an amine of general formula (g) using a peptide coupling reagent like e.g. HATU in the presence of an organic amine base like e.g. TEA or DIPEA alternatively the compound of general formula (n) may be obtained from a carboxylic ester of general formula (j) in a two-step one-pot procedure comprising reacting (j) with oxalyl chloride followed by treatment of the intermediate of general formula (o) with an amine of general formula (g) the compound of general formula (n) may be hydrolyzed with an inorganic base of general formula (h), like e.g. NaOHCoupling with an aniline having the general formula (b) to provide a compound having the general formula (I). Similarly, compounds having general formula IA can be synthesized from aniline (bA) and compounds having general formula (p) as described in scheme 2A, as described for the synthesis of compounds having general formula (I) from compounds having general formula (p) and aniline (b).

Alternatively, intermediates having general formula (cA) and compounds having general formula (IA) can be synthesized as depicted in scheme 3A. In this case, the compound having the general formula (j) or (n) is reacted with the aniline having the general formula (bA) under the influence of a base like lithium bis (trimethylsilyl) amide (LiHMDS), to give the compounds having the general formulae (cA) and (IA), respectively.

Scheme 3A

General procedure LCMS method

High Performance Liquid Chromatography (HPLC) measurements were performed using LC pumps, Diode Arrays (DADs) or UV detectors and columns as specified in the corresponding methods. Additional detectors were included if necessary (see method table below).

The flow from the column is brought to a Mass Spectrometer (MS) equipped with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set tuning parameters (e.g. scan range, residence time, etc.) in order to obtain ions of nominal monoisotopic Molecular Weight (MW) that allow identification of compounds. Data acquisition is performed using appropriate software.

By which the retention time (R) is determined_t) And an ion describing compound. The reported molecular ion corresponds to [ M + H ] if not specified differently in the data sheet]⁺(protonated molecules) and/or [ M-H]^-(deprotonated molecules). In the case where the compound is not directly ionizable, the type of adduct (i.e., [ M + NH ]) is specified₄]⁺、[M+HCOO]^-Etc.). All results obtained have experimental uncertainties that are generally associated with the method used.

Hereinafter, "SQD" means a single quadrupole detector, "MSD" mass selective detector, "RT" room temperature, "BEH" bridged ethylsiloxane/silica hybrid, "DAD" diode array detector, "HSS" high intensity silica, "Q-Tof" quadrupole time-of-flight mass spectrometer, "CLND" chemiluminescent nitrogen detector, "ELSD" evaporative light scanning detector.

LCMS method

(flow rate in mL/min; column temperature (T) in ℃ C.; run time in minutes).

Synthesis of examples

Compound 1: (R) -4- (2- (sec-butylamino) -2-oxoacetyl) -N- (4-fluoro-3-methylphenyl) -1-methyl 1H-pyrrole-2-carboxamides

1-methyl-1H-pyrrole-2-carboxylic acid (2.0g, 16mmol), 4-fluoro-3-methylaniline (2.0g, 16mmol) and N, N-diisopropylethylamine (DIPEA, 6.2g, 48mmol) were dissolved in 30mL DMF and in N, N-diisopropylethylamine²Cool down on ice. 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HATU, 6.69g, 17.6mmol) was added, the ice bath was removed, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with 200mL EtOAc and treated with 1N HCl, NaHCO₃Solutions and saltsThe water is washed. Subjecting the organic layer to Na₂SO₄Dry, filter and concentrate under reduced pressure. The residue was crystallized from a mixture of 30mL MeOH with 15mL water. The crystals were filtered off and dried in vacuo to afford N- (4-fluoro-3-methylphenyl) -1-methyl-1H-pyrrole-2-carboxamide (3.22g) as grey needles (mp ═ 111.3 ℃). LC method B; rt: 0.99 min.m/z: 233.2(M + H)⁺Accurate quality: 232.1.¹H NMR(400MHz，DMSO-d₆)δppm 2.22(s，3H)，3.87(s，3H)，6.08(dd，J＝4.0，2.6Hz，1H)，6.95-7.03(m，2H)，7.07(t，J＝9.1Hz，1H)，7.44-7.54(m，1H)，7.62(dd，J＝7.3，2.4Hz，1H)，9.69(s，1H)。

n- (4-fluoro-3-methylphenyl) -1-methyl-1H-pyrrole-2-carboxamide (2.0g, 8.6mmol) was dissolved in 30mL of dichloromethane and in N²Cool down on ice. A solution of ethyloxalyl chloride (2.94g, 21.5mmol) in 5ml of dichloromethane was added dropwise and the mixture was stirred at 0 ℃ for 30 min. Aluminum (III) chloride (3.44g, 25.8mmol) was added in portions and the reaction mixture was stirred at 0 ℃ for 3 hours. The reaction mixture was poured into 100ml of vigorously stirred ice-water and extracted with EtOAc (2 ×). The combined organic layers were washed with NaHCO₃The solution was washed with brine, and then Na₂SO₄Dry, filter and concentrate under reduced pressure. The residue was crystallized from 40ml EtOH, the crystals were filtered off and dried in vacuo to afford ethyl 2- (5- (4-fluoro-3-methylphenylcarbamoyl) -1-methyl-1H-pyrrol-3-yl) -2-oxoacetate (1.29g) (mp ═ 126.3 ℃) as a white solid. LC method B; rt: 1.04 min.m/z: 333.1(M + H)⁺Accurate quality: 332.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.33(t，J＝7.2Hz，3H)，2.23(d，J＝1.8Hz，3H)，3.95(s，3H)，4.35(q，J＝7.0Hz，2H)，7.10(t，J＝9.2Hz，1H)，7.48-7.55(m，1H)，7.58(d，J＝1.8Hz，1H)，7.65(dd，J＝7.0，2.4Hz，1H)，8.01(d，J＝1.5Hz，1H)，10.07(s，1H)。

ethyl 2- (5- (4-fluoro-3-methylphenylcarbamoyl) -1-methyl-1H-pyrrol-3-yl) -2-oxoacetate (300mg, 0.9mmol) and (R) - (-) -2-aminoButane (196mg, 2.7mmol) was mixed in 5ml EtOH and stirred in a closed vessel at room temperature for 7 days. The reaction mixture was concentrated under reduced pressure and then purified by preparative HPLC (stationary phase: RP Vydac Denali C18-10 μm, 200g, 5cm), mobile phase: 0.25% NH₄HCO₃Aqueous solution, CH₃CN) purification. The product fractions were concentrated, dissolved in MeOH and concentrated again to give (R) -4- (2- (sec-butylamino) -2-oxoacetyl) -N- (4-fluoro-3-methylphenyl) -1-methyl-1H-pyrrole-2-carboxamide (compound 1, 238mg) as a white powder (mp ═ 136.5 ℃). LC method B; rt: 1.07 min.m/z: 358.1(M-H)^-Accurate quality: 359.1.¹H NMR(400MHz，DMSO-d₆)δppm 0.84(t，J＝7.4Hz，3H)，1.12(d，J＝6.6Hz，3H)，1.39-1.61(m，2H)，2.23(d，J＝1.5Hz，3H)，3.72-3.88(m，1H)，3.95(s，3H)，7.09(t，J＝9.2Hz，1H)，7.47-7.58(m，1H)，7.64(d，J＝1.8Hz，1H)，7.66(dd，J＝7.2，2.5Hz，1H)，8.13(s，1H)，8.38-8.53(m，1H)，10.04(s，1H)。

compound 2: n- (4-fluoro-3-methylphenyl) -4- (2- (isopropylamino) -2-oxoacetyl) -1-methyl- 1H-pyrrole-2-carboxamides

Compound 2 was prepared in analogy to compound 1 by reacting ethyl 2- (5- (4-fluoro-3-methylphenylcarbamoyl) -1-methyl-1H-pyrrol-3-yl) -2-oxoacetate with 10 equivalents of isopropylamine in a closed vessel at room temperature overnight with stirring in EtOH. The reaction mixture was concentrated under reduced pressure and then purified by preparative HPLC (stationary phase: RPVydac Denali C18-10 μm, 200g, 5cm), mobile phase: 0.25% NH₄HCO₃Aqueous solution, CH₃CN) purification. The product fractions were concentrated, dissolved in MeOH and concentrated again to give N- (4-fluoro-3-methylphenyl) -4- (2- (isopropylamino) -2-oxoacetyl) -1-methyl-1H-pyrrole-2-carboxamide (compound 2, 229mg) as a foam. LC method A;Rt：1.84min.m/z：344.1(M-H)^-accurate quality: 345.2.¹H NMR(400MHz，DMSO-d₆)δppm 1.15(d，J＝6.6Hz，6H)，2.23(d，J＝1.8Hz，3H)，3.95(s，3H)，3.96-4.07(m，1H)，7.09(t，J＝9.2Hz，1H)，7.49-7.57(m，1H)，7.63(d，J＝1.8Hz，1H)，7.66(dd，J＝7.2，2.5Hz，1H)，8.14(d，J＝1.5Hz，1H)，8.52(d，J＝8.1Hz，1H)，10.04(s，1H)。

compound 3: 4- (2- (tert-butylamino) -2-oxoacetyl) -N- (4-fluoro-3-methylphenyl) -1-methyl- 1H-pyrrole-2-carboxamides

Ethyl 2- (5- (4-fluoro-3-methylphenylcarbamoyl) -1-methyl-1H-pyrrol-3-yl) -2-oxoacetate (980mg, 2.9mmol) was dissolved in 20ml EtOH. Aqueous 1N NaOH (8.8mL, 8.8mmol) was added dropwise. The reaction mixture was stirred at room temperature for 5min and then cooled on ice. 1N HCl was added until pH 2. The reaction mixture was diluted by the addition of water (50mL) causing a white precipitate to form. The solid material was filtered off, washed with water and dried in vacuo to afford 2- (5- (4-fluoro-3-methylphenylcarbamoyl) -1-methyl-1H-pyrrol-3-yl) -2-oxoacetic acid (530mg) as white crystals (mp ═ 180.8 ℃). LC method B; rt: 0.61min. m/z: 303.1(M-H)^-Accurate quality: 304.1.¹H NMR(400MHz，DMSO-d₆)δppm 2.23(d，J＝1.8Hz，3H)，3.95(s，3H)，7.09(t，J＝9.2Hz，1H)，7.49-7.55(m，1H)，7.57(d，J＝1.8Hz，1H)，7.65(dd，J＝7.0，2.4Hz，1H)，7.97(d，J＝1.5Hz，1H)，10.06(s，1H)，14.05(br.s.，1H)。

2- (5- (4-fluoro-3-methylphenylcarbamoyl) -1-methyl-1H-pyrrol-3-yl) -2-oxoacetic acid (530mg, 1.74mmol)), tert-butylamine (127mg, 1.74mmol) and N, N-diisopropylethylamine (DIPEA, 675mg, 5.2mmol) were dissolved in 10mL DMF and in N₂Cool down on ice. Addition of 2- (7-aza-1H-benzotriazol)Oxazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HATU, 728mg, 1.92mmol), the ice bath was removed and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with EtOAc (100mL) and washed with 1N HCl, NaHCO₃Solution and brine washes. Subjecting the organic layer to Na₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of 10mL MeOH with 5mL water. The crystals were filtered off and dried in vacuo to afford 4- (2- (tert-butylamino) -2-oxoacetyl) -N- (4-fluoro-3-methylphenyl) -1-methyl-1H-pyrrole-2-carboxamide (compound 3, 517mg) as a white powder. LC method B; rt: 1.12min. m/z: 358.2(M-H)^-Accurate quality: 359.2.¹H NMR(400MHz，DMSO-d₆)δppm1.36(s，9H)，2.23(d，J＝1.8Hz，3H)，3.95(s，3H)，7.09(t，J＝9.2Hz，1H)，7.50-7.56(m，1H)，7.61(d，J＝1.8Hz，1H)，7.66(dd，J＝7.0，2.2Hz，1H)，7.95(s，1H)，8.10(d，J＝1.5Hz，1H)，10.05(s，1H)。

compound 4: n- (4-fluoro-3-methylphenyl) -1-methyl-4- (2- (3-methyloxetan-3-ylamino) - 2-oxoacetyl) -1H-pyrrole-2-carboxamide

2- (5- (4-fluoro-3-methylphenylcarbamoyl) -1-methyl-1H-pyrrol-3-yl) -2-oxoacetic acid (410mg, 1.35mmol), 3-methyl-3-oxetane hydrochloride (183mg, 1.48mmol) and N, N-diisopropylethylamine (DIPEA, 870mg, 6.74mmol) were dissolved in 10mL of DMF and in N, N-diisopropylethylamine (DIPEA, 870mg, 6.74mmol)₂Cool down on ice. 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HATU, 563mg, 1.48mmol) was added, the ice bath was removed and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with 100mL EtOAc and washed with 1N HCl, NaHCO₃Solution and brine washes. The organic layer was evaporated under reduced pressure. The residue was purified by preparative HPLC (stationary phase: Uptisphere C18 ODB-10 μm, 200g,5cm), mobile phase: 0.25% NH₄HCO₃Aqueous, MeOH). The product fractions were concentrated, dissolved in MeOH and concentrated again. The residue was crystallized from a mixture of 10mL MeOH with 5mL water. The crystals were filtered off and dried in vacuo to afford N- (4-fluoro-3-methylphenyl) -1-methyl-4- (2- (3-methyloxetan-3-ylamino) -2-oxoacetyl) -1H-pyrrole-2-carboxamide (compound 4, 183mg) as a white powder (mp ═ 145.1 ℃). LC method A; rt: 1.63min. m/z: 372.0(M-H)^-Accurate quality: 373.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.58(s，3H)，2.23(d，J＝1.8Hz，3H)，3.95(s，3H)，4.35(d，J＝6.8Hz，2H)，4.72(d，J＝6.4Hz，2H)，7.09(t，J＝9.2Hz，1H)，7.48-7.58(m，1H)，7.65(d，J＝1.8Hz，1H)，7.67(d，J＝2.4Hz，1H)，8.17(d，J＝1.3Hz，1H)，9.26(s，1H)，10.05(s，1H)。

compound 5: (R) -N- (4-fluoro-3-methylphenyl) -1-methyl-4- (2-oxo-2- (1, 1, 1-trifluoropropane-2-) Aminoamino) acetyl) -1H-pyrrole-2-carboxamide

2- (5- (4-fluoro-3-methylphenylcarbamoyl) -1-methyl-1H-pyrrol-3-yl) -2-oxoacetic acid (300mg, 0.95mmol), (R) -1, 1, 1-trifluoro-2-propylamine (118mg, 1.04mmol) and N, N-diisopropylethylamine (DIPEA, 367mg, 2.84mmol) in N₂Then dissolved in 5mL of DMF. 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HATU, 396mg, 1.04mmol) was added and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with 100mL EtOAc and washed with 1N HCl, NaHCO₃The solution and brine were washed. The organic layer was evaporated under reduced pressure. The residue was crystallized from a mixture of 10mL MeOH with 5mL water. The crystals were filtered off and dried in vacuo to afford (R) -N- (4-fluoro-3-methylphenyl) -1-methyl-4- (2-oxo-2- (1, 1, 1-trifluoropropan-2-ylamino) acetyl as a white powderYl) -1H-pyrrole-2-carboxamide (compound 5, 182mg) (mp ═ 156.9 ℃). LC method B; rt: 1.10min. m/z: 398.2(M-H)^-Accurate quality: 399.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.35(d，J＝7.0Hz，3H)，2.23(d，J＝1.8Hz，3H)，3.95(s，3H)，4.59-4.79(m，1H)，7.09(t，J＝9.1Hz，1H)，7.45-7.58(m，1H)，7.60-7.71(m，2H)，8.10(d，J＝1.3Hz，1H)，9.32(d，J＝9.0Hz，1H)，10.07(s，1H)。

compound 6: (S) -N- (4-fluoro-3-methylphenyl) -1-methyl-4- (2-oxo-2- (tetrahydrofuran-3-ylamino) Yl) acetyl) -1H-pyrrole-2-carboxamide

In N₂Next, 2- (5- (4-fluoro-3-methylphenylcarbamoyl) -1-methyl-1H-pyrrol-3-yl) -2-oxoacetic acid (300mg, 0.95mmol), (S) -tetrahydrofuran-3-amine hydrochloride (128mg, 1.04mmol) and N, N-diisopropylethylamine (DIPEA, 611mg, 4.73mmol) were dissolved in 5mL of DMF. 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HATU, 396mg, 1.04mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with 100mL EtOAc and washed with 1N HCl, NaHCO₃Solution and brine washes. The organic layer was evaporated under reduced pressure. The residue was crystallized from a mixture of 10mL MeOH with 5mL water. The crystals were filtered off and dried in vacuo to afford a white powder(S) -N- (4-fluoro-3-methylphenyl) -1-methyl-4- (2-oxo-2- (tetrahydrofuran-3-ylamino) acetyl) -1H-pyrrole-2-carboxamide (compound 6, 248mg) (mp ═ 155.7 ℃). LC method B; rt: 0.90 min.m/z: 372.2(M-H)^-Accurate quality: 373.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.86-1.99(m，1H)，2.07-2.18(m，1H)，2.23(d，J＝1.8Hz，3H)，3.57(dd，J＝8.9，4.5Hz，1H)，3.71(td，J＝8.1，5.7Hz，1H)，3.78-3.87(m，2H)，3.95(s，3H)，4.30-4.42(m，1H)，7.09(t，J＝9.2Hz，1H)，7.49-7.56(m，1H)，7.62(d，J＝1.8Hz，1H)，7.66(dd，J＝7.2，2.3Hz，1H)，8.11(d，J＝1.3Hz，1H)，8.88(d，J＝6.8Hz，1H)，10.05(s，1H)。

compound 7: methyl 2- (2- (5- (4-fluoro-3-methylphenylcarbamoyl) -1-methyl-1H-pyrrol-3-yl) -2- Oxoacetamido) -2-methylpropionate

2- (5- (4-fluoro-3-methylphenylcarbamoyl) -1-methyl-1H-pyrrol-3-yl) -2-oxoacetic acid (800mg, 2.58mmol), 2-dimethylglycine methyl ester hydrochloride (435mg, 2.83mmol) and N, N-diisopropylethylamine (DIPEA, 1.67mg, 12.9mmol) were dissolved in 15mL of DMF and in N, N-diisopropylethylamine (DIPEA, 1.67mg, 12.9mmol)₂Cool down on ice. 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HATU, 1078mg, 2.83mmol) was added, the ice bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with 150mL EtOAc and washed with 1N HCl, NaHCO₃Solution and brine washes. The organic layer was evaporated under reduced pressure. The residue was crystallized from a mixture of 20mL MeOH and 5mL water. The crystals were filtered off and dried in vacuo to afford methyl 2- (2- (5- (4-fluoro-3-methylphenylcarbamoyl) -1-methyl-1H-pyrrol-3-yl) -2-oxoacetamido) -2-methylpropionate (compound 7, 905mg) as a white powder (mp ═ 161.0 ℃). LC method B; rt: 1.04 min.m/z: 402.2(M-H)^-Accurate quality: 403.2.¹H NMR(400MHz，DMSO-d₆)δppm 1.46(s，6H)，2.23(d，J＝1.8Hz，3H)，3.64(s，3H)，3.95(s，3H)，7.09(t，J＝9.2Hz，1H)，7.49-7.57(m，1H)，7.62(d，J＝1.8Hz，1H)，7.66(dd，J＝7.2，2.3Hz，1H)，8.07(d，J＝1.3Hz，1H)，8.93(s，1H)，10.07(s，1H)。

compound 8: 4- { [ (2-amino-1, 1-dimethyl-2-oxoethyl) amino](oxo) acetyl } -N- (4-fluoro- 3-methylphenyl) -1-methyl-1H-pyrrole-2-carboxamide

Compound 8(300mg, 0.74mmol) was dissolved in 7M NH in MeOH (15mL)₃And stirred at room temperature for 2 days. Volatiles were removed under reduced pressure and the residue was partitioned to 7M NH in MeOH (50mL)₃Neutralized and stirred for an additional 2 days. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC followed by trituration with diisopropyl ether to give compound 8(96mg) as an off-white powder. LC method B; rt: 0.86 min.m/z: 387.2(M-H)^-Accurate quality: 388.2. differential scanning calorimetry: from 30 ℃ to 300 ℃ at 10 ℃/min: peak: 237.0 ℃.¹H NMR(400MHz，DMSO-d₆)δppm 1.52(s，6H)，2.23(d，J＝1.8Hz，3H)，3.95(s，3H)，7.09(t，J＝9.2Hz，1H)，7.17(br.s.，1H)，7.43(br.s.，1H)，7.50-7.57(m，1H)，7.63-7.70(m，2H)，8.25(d，J＝1.3Hz，1H)，8.55(s，1H)，10.06(s，1H)。

Compound 9: 4- [ { [ (1R) -2-cyano-1-methylethyl]Amino } (oxo) acetyl]-N- (4-fluoro-3-methyl) Phenyl) -1-methyl-1H-pyrrole-2-carboxamide

Compound 9(430mg) was prepared similarly as described for compound 5, using (3R) -3-aminobutyronitrile instead of (R) -1, 1, 1-trifluoro-2-propylamine. LC method B; rt: 0.95 min.m/z: 369.1(M-H)^-Accurate quality: 370.1.¹H NMR(400MHz，DMSO-d₆) δ ppm 1.23(d, J ═ 6.6Hz, 3H), 2.23(d, J ═ 1.8Hz, 3H), 2.70-2.85(m, 2H), 3.95(s, 3H), 4.12-4.28(m, 1H), 7.09(t, J ═ 9.2Hz, 1H), 7.49-7.57(m, 1H), 7.66(d, J ═ 1.8Hz, 1H), 7.67(d, J ═ 2.2Hz, 1H), 8.17(d, J ═ 1.3Hz, 1H), 8.94(d, J ═ 8.4Hz, 1H), 10.06(s, 1H). Differential scanning calorimetry: from 30 ℃ to 300 ℃ at 10 ℃/min: peak: 138.3 ℃.

Compound 10: 4- (2- (tert-butylamino) -2-oxoacetyl) -N- (3, 4-difluorophenyl) -1-methyl-1H- Pyrrole-2-carboxamides

1-methyl-1H-pyrrole-2-carboxylic acid (2.0g, 16mmol) was dissolved in 50mL of dichloromethane and in N₂Cool down on ice. A solution of ethyloxalyl chloride (5.45g, 40mmol) in 10ml of dichloromethane was added dropwise and the mixture was stirred at 0 ℃ for 10min. Aluminum (III) chloride (6.39g, 48mmol) was added in portions and the reaction mixture was stirred at 0 ℃ for 2 hours. The reaction mixture was poured into 200ml of vigorously stirred ice water, causing a white solid to precipitate. The precipitate was filtered off, washed with water, isopropanol and diisopropyl ether and dried in vacuo to afford 4- (2-ethoxy-2-oxoacetyl) -1-methyl-1H-pyrrole-2-carboxylic acid (1.44g) as a white powder. LC method B; rt: 0.38 min.m/z: 224.0(M-H)^-Accurate quality: 225.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.31(t，J＝7.0Hz，3H)，3.92(s，3H)，4.33(q，J＝7.1Hz，2H)，7.25(d，J＝1.5Hz，1H)，8.01(s，1H)，12.86(br.s.，1H)。

to a solution of 4- (2-ethoxy-2-oxoacetyl) -1-methyl-1H-pyrrole-2-carboxylic acid (750mg, 3.30mmol) and triethylamine (917 μ L, 6.59mmol) in DMF (7.5mL) was added 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HATU, 1504mg, 3.96mmol) and the mixture was stirred at room temperature for 10min. 3, 4-difluoroaniline (851mg, 6.59mmol) was added and the mixture was stirred for 2 hours. The mixture was poured into 100ml of water and the precipitate was filtered off and washed with water. The wet powder was dissolved in dichloromethane over Na₂SO₄Dried, filtered and concentrated under reduced pressure to give ethyl 2- (5) as a brown powder- (3, 4-difluorophenylcarbamoyl) -1-methyl-1H-pyrrol-3-yl) -2-oxoacetate (947 mg). LC method B; rt: 1.04 min.m/z: 335.1(M-H)^-Accurate quality: 336.3.

a solution of ethyl 2- (5- (3, 4-difluorophenylcarbamoyl) -1-methyl-1H-pyrrol-3-yl) -2-oxoacetate (937mg, 2.79mmol) in 30mL EtOH was treated with a 1N NaOH solution (8.36mL, 8.36mmol) and the reaction mixture was heated to 60 ℃ for 10min. The reaction mixture was cooled to room temperature and neutralized by addition of triethylamine hydrochloride (1.53g, 11.14 mmol). The mixture was evaporated under reduced pressure and the dry residue co-evaporated twice with toluene (50mL) to remove remaining traces of water. The crude reaction product, 2- (5- (3, 4-difluorophenylcarbamoyl) -1-methyl-1H-pyrrol-3-yl) -2-oxoacetic acid (LC method B; Rt: 0.59min. M/z: 307.1(M-H)^-Accurate quality: 308.2) was taken up in dry DMF (20mL) and split into two equal portions (10mL each) for the synthesis of compounds 10 and 11.

For the synthesis of compound 10, a solution of crude 2- (5- (3, 4-difluorophenylcarbamoyl) -1-methyl-1H-pyrrol-3-yl) -2-oxoacetic acid (ca. 1.4mmol) in 10mL DMF was mixed with triethylamine (582 μ L, 4.2mmol) and 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HATU, 637mg, 1.67mmol) and stirred at room temperature for 10min. Tert-butylamine (204mg, 2.79mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture is poured into 100ml of water, and the precipitate is filtered off and washed with water. The powder was purified by silica gel column chromatography using a solvent gradient (from 0% to 100% EtOAc in heptane) as the mobile phase to provide 4- (2- (tert-butylamino) -2-oxoacetyl) -N- (3, 4-difluorophenyl) -1-methyl-1H-pyrrole-2-carboxamide (compound 10, 220mg) as a white powder (mp ═ 170.7 ℃). LC method B; rt: 1.12min. m/z: 362.2(M-H)^-Accurate quality: 363.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.37(s，9H)，3.95(s，3H)，7.40(dt，J＝10.6，9.2Hz，1H)，7.48-7.54(m，1H)，7.64(d，J＝1.8Hz，1H)，7.88(ddd，J＝13.4，7.6，2.5Hz，1H)，7.96(br.s，1H)，8.13(d，J＝1.7Hz，1H)，10.26(s，1H)。

compound 11: n- (3, 4-difluorophenyl) -1-methyl-4- (2- (3-methyloxetan-3-ylamino) -2- Oxoacetyl) -1H-pyrrole-2-carboxamides

A solution of crude 2- (5- (3, 4-difluorophenylcarbamoyl) -1-methyl-1H-pyrrol-3-yl) -2-oxoacetic acid (approximately 1.4 mmol; as described in the procedure for the synthesis of compound 10) in 10mL DMF was mixed with triethylamine (776 μ L, 5.58mmol) and 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HATU, 637mg, 1.67mmol) and stirred at room temperature for 10min. 3-methyl-3-oxetane (243mg, 2.79mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture is poured into 100ml of water, and the precipitate is filtered off and washed with water. The solid residue was recrystallized from a mixture of 10mL MeOH and 5mL water, filtered off and dried in vacuo to afford N- (3, 4-difluorophenyl) -1-methyl-4- (2- (3-methyloxetan-3-ylamino) -2-oxoacetyl) -1H-pyrrole-2-carboxamide (compound 11, 221mg) as a beige powder (mp ═ 180.7 ℃). LC method B; rt: 0.92 min.m/z: 376.2(M-H)^-Accurate quality: 377.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.58(s，3H)，3.96(s，3H)，4.35(d，J＝6.6Hz，2H)，4.72(d，J＝6.4Hz，2H)，7.36-7.45(m，1H)，7.48-7.56(m，1H)，7.68(d，J＝1.5Hz，1H)，7.89(ddd，J＝13.4，7.5，2.4Hz，1H)，8.20(br.d，J＝1.1Hz，1H)，9.27(br.s，1H)，10.26(br.s，1H)。

compound 12: 4- (2- (tert-butylamino) -2-oxoacetyl) -1-methyl-N- (3- (trifluoromethyl) benzene 1H-pyrrole-2-carboxamides

4- (2-ethoxy-2-oxoacetyl) -1-methyl-1H-pyrrole-2-carboxylic acid (750mg, 3.30mmol) and triethylamine (917. mu.L, 6.59mmol) were combined in 7.5mL DMF. 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HATU, 1504mg, 3.96mmol) was added and the mixture was stirred for 10min. 3-trifluoromethylaniline (1062mg, 6.59mmol) was added and the mixture was stirred at room temperature for 2 hours and then heated to 40 ℃ for 30 min. The mixture is poured into 100ml of water, and the precipitate is filtered off and washed with water. The powder was dried in vacuo to give ethyl 2- (1-methyl-5- (3- (trifluoromethyl) phenylcarbamoyl) -1H-pyrrol-3-yl) -2-oxoacetate (650mg) as a beige powder. LC method B; rt: 1.12min. m/z: 367.1(M-H)^-Accurate quality: 368.1.

a solution of ethyl 2- (1-methyl-5- (3- (trifluoromethyl) phenylcarbamoyl) -1H-pyrrol-3-yl) -2-oxoacetate (650mg, 1.76mmol) in 30mL EtOH was treated with a 1N NaOH solution (5.3mL, 5.3mmol) and the reaction mixture was stirred at room temperature for 20min. The reaction mixture was neutralized by the addition of triethylamine hydrochloride (1.22g, 8.82 mmol). The mixture was evaporated under reduced pressure and the dry residue co-evaporated twice with toluene (50mL) to remove remaining traces of water. The crude reaction product 2- (1-methyl-5- (3- (trifluoromethyl) phenylcarbamoyl) -1H-pyrrol-3-yl) -2-oxoacetic acid (LC method B; Rt: 0.68min. M/z: 339.1(M-H)^-Accurate quality: 340.1) were taken up in 10mL dry DMF and split into two equal portions (5mL each) for the synthesis of compounds 12 and 13.

For the synthesis of compound 12, a solution of crude 2- (1-methyl-5- (3- (trifluoromethyl) phenylcarbamoyl) -1H-pyrrol-3-yl) -2-oxoacetic acid (approximately 0.88mmol) in 5mL DMF was mixed with triethylamine (490 μ L, 3.53mmol) and 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HATU, 1006mg, 2.64mmol) and stirred at room temperature for 10min. Tert-butylamine (193mg, 2.65mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture is poured into 100ml of water, and the precipitate is filtered off and washed with water. The powder was purified by silica gel column chromatography using a solvent gradient (from 0% to 100% EtOAc in heptane) as the mobile phase to provide 4- (2- (tert-butylamino) -2-oxoacetyl) -1-methyl-N- (3- (trifluoromethyl) phenyl) -1H-pyrrole-2-carboxamide (compound 12, 321mg) as an amorphous white powder. LC method B; rt: 1.19min. m/z: 394.2(M-H)^-Accurate quality: 395.2.¹H NMR(360MHz，DMSO-d₆)δppm 1.38(s，9H)，3.98(s，3H)，7.43(d，J＝7.7Hz，1H)，7.58(br.t，J＝8.1，8.1Hz，1H)，7.72(d，J＝1.8Hz，1H)，7.99-8.04(m，2H)，8.16(d，J＝1.1Hz，1H)，8.21-8.26(m，1H)，10.39(s，1H)。

compound 13: 1-methyl-4- (2- (3-methyloxetan-3-ylamino) -2-oxoacetyl) -N- (3- (trifluoromethyl) phenyl) -1H-pyrrole-2-carboxamide

A solution of crude 2- (1-methyl-5- (3- (trifluoromethyl) phenylcarbamoyl) -1H-pyrrol-3-yl) -2-oxoacetic acid (approximately 0.88 mmol; as described in the procedure for the synthesis of compound 12) in 5mL DMF was mixed with triethylamine (490. mu.L, 2.65mmol) and 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HATU, 1005mg, 2.65mmol) and stirred at room temperature for 10min. 3-methyl-3-oxetane (230mg, 2.65mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture is poured into 100ml of water, and the precipitate is filtered off and washed with water. The solid residue was dried in vacuo to afford 1-methyl-4- (2- (3-methyloxetan-3-ylamino) -2-oxoacetyl) -N- (3- (trifluoromethyl) phenyl) -1H-pyrrole-2-carboxamide (compound 13, 316mg) as an amorphous white powder. LC method B; rt: 1.01 min.m/z: 408.2(M-H)^-Accurate quality: 409.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.58(s，3H)，3.97(s，3H)，4.35(d，J＝6.6Hz，2H)，4.72(d，J＝6.4Hz，2H)，7.43(d，J＝7.7Hz，1H)，7.58(br.t，J＝7.9，7.9Hz，1H)，7.74(d，J＝1.8Hz，1H)，7.98-8.04(m，1H)，8.18-8.24(m，2H)，9.28(s，1H)，10.36(s，1H)。

compound 14: 4- (2- (tert-butylamino) -2-oxoacetyl) -N- (3-chloro-4, 5-difluorophenyl) -1-methyl 1H-pyrrole-2-carboxamides

Oxalyl chloride (2mL, 23.3mmol) was slowly added to a stirred solution of methyl 1-methyl-1H-pyrrole-2-carboxylate (2g, 14.4mmol) in 10mL dichloroethane at room temperature. The mixture was then heated to 38 ℃ for 2 hours. The solvent was removed under reduced pressure, and the residue was dissolved in 25mL of acetonitrile and added in portions to a stirred solution of tert-butylamine (3.05mL, 28.7mmol) and DIPEA (4.95mL, 28.7mmol) in 25mL of acetonitrile. After stirring overnight, the volatiles were removed by evaporation under reduced pressure. Mixing the residue with water, extracting with 2-methyltetrahydrofuran, and purifying with Na₂SO₄Dried, filtered and evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography using a solvent mixture (heptane and dichloromethane) as the mobile phase. The product fractions were combined and evaporated, and finally co-evaporated with MeOH under reduced pressure:

1) elution with a 60: 40 mixture of heptane: DCM provided methyl 5- (2- (tert-butylamino) -2-oxoacetyl) -1-methyl-1H-pyrrole-2-carboxylate (820mg) as a first fraction.¹H NMR(360MHz，DMSO-d₆)δppm 1.34(s，9H)，3.82(s，3H)，4.17(s，3H)，6.91(d，J＝4.4Hz，1H)，6.99(d，J＝4.4Hz，1H)，8.35(s，1H)。

2) Mixing with heptane and DCM at a ratio of 50: 50The compound was eluted to give methyl 4- (2- (tert-butylamino) -2-oxoacetyl) -1-methyl-1H-pyrrole-2-carboxylate (830mg) as a second fraction.¹H NMR(360MHz，DMSO-d₆)δppm 1.35(s，9H)，3.78(s，3H)，3.93(s，3H)，7.32(d，J＝1.8Hz，1H)，8.02(s，1H)，8.13(d，J＝1.8Hz，1H)。

Methyl 4- (2- (tert-butylamino) -2-oxoacetyl) -1-methyl-1H-pyrrole-2-carboxylate (780mg, 2.9mmol) was dissolved in 10mL MeOH and added to a stirred solution of 1N NaOH (6.44mL, 6.44 mmol). After stirring overnight at room temperature, 1N HCl (7mL) was added slowly. Precipitation was completed by the addition of 30mL of water, and after stirring for 5min, the solid was filtered off, washed with water and dried in vacuo to afford 4- (2- (tert-butylamino) -2-oxoacetyl) -1-methyl-1H-pyrrole-2-carboxylic acid (700mg) as a white powder. LC method B; rt: 0.49 min.m/z: 251.1(M-H)^-Accurate quality: 252.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.35(s，9H)，3.91(s，3H)，7.25(d，J＝1.8Hz，1H)，7.96(s，1H)，8.06(d，J＝1.5Hz，1H)，12.78(br.s.，5H)。

in N₂Next, 4- (2- (tert-butylamino) -2-oxoacetyl) -1-methyl-1H-pyrrole-2-carboxylic acid (250mg, 1mmol), 3-chloro-4, 5-difluoroaniline (162mg, 1mmol), and N, N-diisopropylethylamine (DIPEA, 384mg, 3mmol) were dissolved in 5mL of DMF. 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HATU, 414mg, 1.09mmol) was added and the mixture was stirred at 50 ℃ for 2 days. The reaction mixture was diluted with 100mL EtOAc and washed with 1N HCl, NaHCO₃Solution and brine washes. The organic layer was evaporated under reduced pressure and the residue was crystallized from a mixture of 10mL MeOH and 4mL water. The crystals were filtered off and dried in vacuo to afford 4- (2- (tert-butylamino) -2-oxoacetyl) -N- (3-chloro-4, 5-difluorophenyl) -1-methyl-1H-pyrrole-2-carboxamide (compound 14, 249mg) as an amorphous beige powder. LC method B; rt: 1.25min. m/z: 396.2(M-H)^-Accurate quality: 397.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.36(s，9H)，3.95(s，3H)，7.66(d，J＝1.8Hz，1H)，7.79-7.88(m，2H)，7.97(s，1H)，8.15(d，J＝1.3Hz，1H)，10.33(s，1H)。

compound 15: 4- (2- (tert-butylamino) -2-oxoacetyl) -N- (3-cyano-4-fluorophenyl) -1-methyl- 1H-pyrrole-2-carboxamides

In N₂Next, 4- (2- (tert-butylamino) -2-oxoacetyl) -1-methyl-1H-pyrrole-2-carboxylic acid (250mg, 1mmol), 3-cyano-4-fluoroaniline (134mg, 1mmol), and N, N-diisopropylethylamine (DIPEA, 384mg, 3mmol) were dissolved in 5mL of DMF. 2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HATU, 414mg, 1.09mmol) was added and the mixture was stirred at 50 ℃ overnight. The reaction mixture was diluted with 100mL EtOAc and washed with 1N HCl, NaHCO₃Solution and brine washes. The organic layer was evaporated under reduced pressure and the residue was crystallized from a mixture of 10mL MeOH and 5mL water. The crystals were filtered off and dried in vacuo to afford 4- (2- (tert-butylamino) -2-oxoacetyl) -N- (3-cyano-4-fluorophenyl) -1-methyl-1H-pyrrole-2-carboxamide (compound 15, 292mg) as an amorphous beige powder. LC method B; rt: 1.08 min.m/z: 369.2(M-H)^-Accurate quality: 370.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.37(s，9H)，3.96(s，3H)，7.52(t，J＝9.1Hz，1H)，7.67(d，J＝2.0Hz，1H)，7.97(s，1H)，8.03(ddd，J＝9.2，5.0，2.8Hz，1H)，8.14(d，J＝1.3Hz，1H)，8.23(dd，J＝5.8，2.8Hz，1H)，10.39(s，1H)。

compound 16: n- (3-cyano-4-fluorophenyl) -1-methyl-4- { [ (3-methyloxetan-3-yl) amino] (oxo) acetyl } -1H-pyrrole-2-carboxamide

Oxalyl chloride (7.41mL, 0.086mol) was slowly added to a stirred solution of methyl 1-methylpyrrole-2-carboxylate (6g, 0.0431mol) in dichloroethane (30 mL). The reaction mixture was stirred in an open vessel for 1 minute, then in a closed vessel for 3 hours at T-int ═ 38 ℃ (oil bath ═ 45 ℃) and at room temperature for 18 hours. Methyl 4- (2-chloro-2-oxo-acetyl) -1-methyl-pyrrole-2-carboxylate (1.45g) was filtered off, washed with dichloroethane (2 ×), and used as such. In N₂Methyl 4- (2-chloro-2-oxo-acetyl) -1-methyl-pyrrole-2-carboxylate (1.45g, 6.32mmol) was added in portions to a stirred solution of 3-methyloxetan-3-amine (1.1g, 12.6mmol) and DIPEA (2.2mL, 12.6mmol) in acetonitrile (50mL) under an atmosphere. The reaction mixture was stirred at room temperature for 1 hour. The volatile material was evaporated. The residue is taken up in H₂O (15mL), filtered off and washed with H₂O (3x) is washed and dried at 50 ℃ to give methyl 1-methyl-4- [2- [ (3-methyloxetan-3-yl) amino]-2-oxo-acetyl]Pyrrole-2-carboxylate (839 mg). LC method A; rt: 1.29min. m/z: 278.9(M-H)^-Accurate quality: .280.1.¹H NMR(400MHz，DMSO-d₆) δ ppm 1.56(s, 3H), 3.78(s, 3H), 3.93(s, 3H), 4.34(d, J ═ 6.6Hz, 2H), 4.70(d, J ═ 6.4Hz, 2H), 7.37(d, J ═ 2.0Hz, 1H), 8.20(d, J ═ 1.3Hz, 1H), 9.25(s, 1H). Adding NaOH (1M in H)₂O, 6.6mL) was added to methyl 1-methyl-4- [2- [ (3-methyloxetan-3-yl) amino]-2-oxo-acetyl]Pyrrole-2-carboxylate (939mg, 2.99mmol) in a stirred mixture of MeOH (10 mL). The reaction mixture was stirred at room temperature for 5 hours. HCl 1N (7mL) was added slowly and precipitation occurred. After stirring for 10 minutes, the mixture is left to stand for 16 hours, filtered off and washed with H₂O-MeOH 3/1(2X) and drying in vacuo at 50 deg.C gave 1-methyl-4- [2- [ (3-methyloxetan-3-yl) amino]-2-oxo-acetyl]Pyrrole-2-carboxylic acid (0.66 g).¹H NMR(400MHz，DMSO-d₆)δppm1.56(s，3H)，3.92(s，3H)，4.34(d，J＝6.6Hz，2H)，4.70(d，J＝6.4Hz，2H)，7.31(d，J＝1.8Hz1H), 8.15(d, J ═ 1.5Hz, 1H), 9.22(s, 1H), 12.80(br.s., 1H). In N₂Triethylamine (0.504mL, 3.63mmol) was added to 1-methyl-4- [2- [ (3-methyloxetan-3-yl) amino under atmosphere]-2-oxo-acetyl]Pyrrole-2-carboxylic acid (0.322g, 1.21mmol) and CH₃CN (dried over molecular sieves, 7.5 mL). To the resulting solution was added 5-amino-2-fluorobenzonitrile (0.187g, 1.33mmol), followed by HATU (0.483g, 1.27 mmol). The reaction mixture was stirred at 50 ℃ for 18 hours. The reaction mixture was allowed to reach room temperature and slowly poured into stirred H₂O (25 mL). After stirring for 10 minutes, the product is filtered off and washed with H₂O (3 ×) wash and dry in vacuo at 50 ℃ to give compound 16(291 mg). LC method A; rt: 1.55 min.m/z: 383.0(M-H)^-Accurate quality: 384.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.58(s，3H)，3.96(s，3H)，4.35(d，J＝6.6Hz，2H)，4.72(d，J＝6.4Hz，2H)，7.53(dd，J＝9.1Hz，1H)，7.71(d，J＝1.8Hz，1H)，8.04(ddd，J＝9.2，4.8，2.6Hz，1H)，8.20-8.26(m，2H)，9.28(s，1H)，10.40(s，1H)。

compound 17: n- (3-chloro-4, 5-difluorophenyl) -1-methyl-4- { [ (3-methyloxetan-3-yl) amino Base of](oxo) acetyl } -1H-pyrrole-2-carboxamide

Compound 17(251mg) was prepared similarly as described for compound 16, using 3-chloro-4, 5-difluoro-aniline instead of 5-amino-2-fluorobenzonitrile. LC method B; rt: 1.06 min.m/z: 410.2(M-H)^-Accurate quality: 411.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.58(s，3H)，3.95(s，3H)，4.35(d，J＝6.6Hz，2H)，4.72(d，J＝6.4Hz，2H)，7.70(d，J＝1.5Hz，1H)，7.79-7.88(m，2H)，8.22(d，J＝1.3Hz，1H)，9.28(s，1H)，10.34(s，1H)。

compound 18: n- (3-chloro-4, 5-di)Fluorophenyl) -1-methyl-4- (oxo { [ (1R) -2, 2, 2-trifluoro-1-methyl Ethyl radical]Amino } acetyl) -1H-pyrrole-2-carboxamide

Ethyl 2-chloro-2-oxo-acetate (12.3g, 89.8mmol) was dissolved in CH₂Cl₂(70mL) and the mixture was cooled on ice/under N2. Adding AlCl₃(14.4g, 108 mmol). Methyl 1-methylpyrrole-2-carboxylate (5g, 35.9mmol) in CH was added dropwise over 15min₂Cl₂(30mL) while cooling on ice. The mixture was stirred at 0 ℃ for 2 hours. The mixture was poured into ice water (300mL) and stirred for 10 minutes. The organic layer was separated. The aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with water and dried (Na)₂SO₄) And concentrated in vacuo to give an oil which was triturated from diisopropyl ether (100mL) to give methyl 4- (2-ethoxy-2-oxo-acetyl) -1-methyl-pyrrole-2-carboxylate (6.1g) containing 2- (5-methoxycarbonyl-1-methyl-pyrrol-3-yl) -2-oxo-acetic acid as a white powder.¹H NMR(400MHz，DMSO-d₆) δ ppm 1.31(t, J ═ 7.2Hz, 3H), 3.79(s, 3H), 3.94(s, 3H), 4.33(q, J ═ 7.2Hz, 2H), 7.30(d, J ═ 2.0Hz, 1H), 8.06(d, J ═ 1.8Hz, 1H). LC method B; rt: 0.84 min.m/z: 240.2(M + H)⁺Accurate quality: 239.1. methyl 4- (2-ethoxy-2-oxo-acetyl) -1-methyl-pyrrole-2-carboxylate (6.1g) was suspended in EtOH (40mL) and the mixture was cooled on ice. NaOH (1M, 24.5mL) and H were added₂O (30mL), and the mixture was stirred at 0 ℃ for 30 minutes. 1N HCl was added until pH 1. Brine (50mL) was added and the aqueous layer was extracted with EtOAc (5 ×). The combined organic layers were washed with brine, over Na₂SO₄Dried and evaporated to dryness to give a white powder (5.45 g). The powder was recrystallized from acetonitrile (50mL) to provide 2- (5-methoxycarbonyl-1-methyl-pyrrol-3-yl) -2 as a white powder-oxo-acetic acid (2.48 g). LC method A; rt: 0.69 min.m/z: 210.0(M-H)^-Accurate quality: 211.0. 2- (5-methoxycarbonyl-1-methyl-pyrrol-3-yl) -2-oxo-acetic acid (2.48g, 11.6mmol), (2R) -1, 1, 1-trifluoropropan-2-amine (1.3g, 11.6mmol) and DIPEA (4.5g, 34.8mmol) were mixed in DMF (30mL) and the mixture was cooled on an ice bath. HATU (4.9g, 12.8mmol) was added and after 45 minutes the mixture was stirred at room temperature. After 4 hours, the reaction mixture was filtered off, the precipitate was washed with EtOAc and dried in vacuo to give methyl 1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methylethyl as a white powder]Amino group]Acetyl group]Pyrrole-2-carboxylate (1.4 g).¹H NMR(400MHz，DMSO-d₆) δ ppm 1.34(d, J ═ 7.0Hz, 3H), 3.78(s, 3H), 3.93(s, 3H), 4.51-4.85(m, 1H), 7.35(d, J ═ 1.8Hz, 1H), 8.10-8.15(1H), 9.32(d, J ═ 8.8Hz, 1H). LC method B; rt: 0.93 min.m/z: 305.1(M-H)^-Accurate quality: 306.1. the filtrate was mixed with 200mL EtOAc and treated with 1N HCl, NaHCO₃And washed with brine and evaporated to dryness to give a white powder (2.3 g). Reacting methyl 1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxylate (3.7g) was combined with MeOH (35 mL). To the resulting suspension was added NaOH (1M, 34.9mL) and the reaction mixture was heated under reflux. After 1 hour, the mixture was cooled on ice and concentrated HCl was added until pH 1-2 a white precipitate formed, which was isolated by filtration, washed with water and dried in vacuo at 50 ℃ to give 1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl ] as an off-white powder]Amino group]Acetyl group]Pyrrole-2-carboxylic acid (2.94 g).¹H NMR(400MHz，DMSO-d₆) δ ppm 1.34(d, J ═ 7.0Hz, 3H), 3.92(s, 3H), 4.51-4.86(m, 1H), 7.29(d, J ═ 2.0Hz, 1H), 8.07(d, J ═ 1.3Hz, 1H), 9.29(d, J ═ 9.0Hz, 1H), 12.83(br.s., 1H). LC method B; rt: 0.49 min.m/z: 291.1(M-H)^-Accurate quality: 292.1. 1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methylethyl]Amino group]Acetyl group]Pyrrole-2-carboxylic acid (300mg, 1.03mmol), 3-chloro-4, 5-difluoro-anilineThe hydrochloride salt (205mg, 1.03mmol), HATU (429mg, 1.13mmol) and DIPEA (663mg, 5.1mmol) were mixed in DMF (8mL) and stirred at room temperature for 15 minutes and then at 50 ℃ -60 ℃. After 2 hours 15 minutes at 50 ℃ -60 ℃, 1 additional equivalent of 3-chloro-4, 5-difluoro-aniline hydrochloride is added and the mixture is stirred over the weekend at 50 ℃. EtOAc (100mL) is added and the mixture is washed with 1N HCl, NaHCO₃And a brine wash. After concentration in vacuo, the residue obtained was purified by preparative HPLC (stationary phase: Uptisphere C18 ODB-10 μm), mobile phase: 0.25% aqueous NH4HCO3, CH3CN) to give compound 18(253 mg). LC method B; rt: 1.20min. m/z: 436.1(M-H)^-Accurate quality: 437.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.36(d，J＝7.0Hz，3H)，3.95(s，3H)，4.58-4.81(m，1H)，7.68(d，J＝1.8Hz，1H)，7.75-7.89(m，2H)，8.14(d，J＝1.5Hz，1H)，9.33(br.s.，1H)，10.30(br.s.，1H)。

compound 19: 4- [ (tert-butylamino) (oxo) acetyl]-N- (3-cyano-4-fluorophenyl) -1, 3, 5-trimethyl 1H-pyrrole-2-carboxamides

Ethyl 1, 3, 5-trimethylpyrrole-2-carboxylate (2g, 11.0mmol) was dissolved in CH₂Cl₂(30mL) and cooled on ice. Ethyl 2-chloro-2-oxo-acetate (3.8g, 27.6mmol) was added dropwise to CH₂Cl₂(10mL) followed by partial addition of AlCl₃(4.4g, 33.1 mmol). The mixture was further stirred at 0 ℃. After 2.5h, the mixture was poured into ice water (150mL) and extracted with EtOAc (2X). The combined organic layers were washed with water and brine and dried (Na)₂SO₄) And evaporated to dryness to give ethyl 4- (2-ethoxy-2-oxo-acetyl) -1, 3, 5-trimethyl-pyrrole-2-carboxylate (4.6g) as an oil. LC method B; rt: 1.06 min.m/z: 282.1(M + H)⁺Accurate quality:281.1. crude ethyl 4- (2-ethoxy-2-oxo-acetyl) -1, 3, 5-trimethyl-pyrrole-2-carboxylate (4.6g) was taken up in EtOH (30mL), NaOH (33.1mL, 1M) was added, and the mixture was stirred at room temperature for 10min. The mixture was cooled on ice and 1N HCl was added until pH 1. Water (30mL) was added and the precipitate was filtered off and dried in vacuo to give 2- (5-ethoxycarbonyl-1, 2, 4-trimethyl-pyrrol-3-yl) -2-oxo-acetic acid (1.97g) as a white powder. LC method B; rt: 0.47 min.m/z: 252.2(M-H)^-Accurate quality: 253.1.¹H NMR(400MHz，DMSO-d₆) δ ppm 1.30(t, J ═ 7.2Hz, 3H), 2.39(s, 3H), 2.42(s, 3H), 3.73(s, 3H), 4.27(q, J ═ 7.0Hz, 2H). 2- (5-ethoxycarbonyl-1, 2, 4-trimethyl-pyrrol-3-yl) -2-oxo-acetic acid (930mg, 3.5mmol), 2-methylpropan-2-amine (258mg, 3.5mmol) and DIPEA (1.4g, 10.6mmol) were combined in DMF (15 mL). HATU (1.47g, 3.9mmol) was added at 0 ℃. After 10 minutes, the ice bath was removed and the mixture was stirred at room temperature. After 3h, EtOAc (150mL) was added and the reaction was quenched with 1N HCl, NaHCO₃And a brine wash. Through Na₂SO₄After drying, the mixture was concentrated to dryness to give crude ethyl 4- [2- (tert-butylamino) -2-oxo-acetyl]-1, 3, 5-trimethyl-pyrrole-2-carboxylate (1.52 g). Crude ethyl 4- [2- (tert-butylamino) -2-oxo-acetyl]-1, 3, 5-trimethyl-pyrrole-2-carboxylate was dissolved in EtOH (20mL), NaOH (1M, 10.6mL) was added and the mixture was stirred at room temperature overnight. Upon cooling on ice, 1M HCl was added until pH 1 and the white precipitate formed was collected by filtration and dried in vacuo to give 4- [2- (tert-butylamino) -2-oxo-acetyl]-1, 3, 5-trimethyl-pyrrole-2-carboxylic acid (760 mg). LC method B; rt: 0.45 min.m/z: 279.1(M-H)^-Accurate quality: 280.1.¹H NMR(400MHz，DMSO-d₆) δ ppm 1.33(s, 9H), 2.39(s, 3H), 2.39(s, 3H), 3.74(s, 3H), 8.18(s, 1H). Reacting 4- [2- (tert-butylamino) -2-oxo-acetyl]-1, 3, 5-trimethyl-pyrrole-2-carboxylic acid (250mg, 0.89mmol), 5-amino-2-fluoro-benzonitrile (121mg, 0.89mmol), HATU (373mg, 0.98mmol) and DIPEA (346mg, 2.68mmol) in DMF (8mL) and stirred in a closed vessel at room temperature for 3 hours and at 50 deg.C-60 deg.C for a further 3 hours. 5 equivalents of 5-amino-2-fluoro-benzonitrile were added and the mixture was stirred at 50 ℃ to 60 ℃ for 2 days. More HATU (100mg) was added and the mixture was further stirred overnight. The reaction was quenched with a small amount of MeOH, EtOAc was added and the mixture was quenched with 1N HCl, NaHCO₃And brine, and concentrated in vacuo to give an oil (450mg) which was purified by preparative HPLC (stationary phase: RP Vydac Denali C18-10 μm, 200g, 5cm), mobile phase: 0.25% NH₄HCO₃Aqueous solution, CH3CN) to give compound 19(150mg) as an off-white powder. LC method A; rt: 1.76 min.m/z: 397.0(M-H)^-Accurate quality: 398.2.¹H NMR(400MHz，DMSO-d₆) δ ppm 1.34(s, 9H), 2.27(s, 3H), 2.42(s, 3H), 3.59(s, 3H), 7.53(t, J ═ 9.1Hz, 1H), 7.98(ddd, J ═ 9.2, 4.8, 2.9Hz, 1H), 8.16-8.26(m, 2H), 10.49(s, 1H). Differential scanning calorimetry: from 30 ℃ to 300 ℃ at 10 ℃/min: peak: 188.7 ℃.

Compound 20: 4- [ (tert-butylamino) (oxo) acetyl]-N- (3, 4-difluorophenyl) -1, 3, 5-trimethyl- 1H-pyrrole-2-carboxamides

Compound 20(126mg) was prepared in analogy to the synthesis described for compound 19, using 3, 4-difluoroaniline instead of 5-amino-2-fluoro-benzonitrile. LC method A; rt: 1.84min. m/z: 390.0(M-H)^-Accurate quality: 391.2.¹H NMR(400MHz，DMSO-d₆)δppm 1.34(s，9H)，2.26(s，3H)，2.42(s，3H)，3.58(s，3H)，7.35-7.50(m，2H)，7.80-7.93(m，1H)，8.21(s，1H)，10.37(s，1H)。

compound 21: 4- [ (tert-butylamino) (oxo) acetyl]-N- (3, 4-difluorophenyl) -1, 3-dimethyl- 1H-pyrrole-2-carboxamides

In N₂Ethyl 1, 3-dimethylpyrrole-2-carboxylate (2g, 11.72mmol) was dissolved in CH under an atmosphere₂Cl₂(40 mL). The mixture was cooled to 0 ℃ and dissolved in CH added dropwise₂Cl₂Ethyl 2-chloro-2-oxo-acetate (1.5mL) in (10 mL). At 0 deg.C, adding AlCl₃(3.1g, 23.4mmol) was added in portions to the reaction mixture. The mixture was stirred at 0 ℃ for 1 hour. The mixture was poured into ice water (150 mL). The organic layer was separated and the aqueous layer was washed with CH₂Cl₂And (4) extracting. The organic fractions were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give crude ethyl 4- (2-ethoxy-2-oxo-acetyl) -1, 3-dimethyl-pyrrole-2-carboxylate. Crude ethyl 4- (2-ethoxy-2-oxo-acetyl) -1, 3-dimethyl-pyrrole-2-carboxylate was dissolved in EtOH (20mL) and NaOH (23.4mL, 1M) was added. The mixture was stirred at room temperature for 10 minutes. The mixture was cooled on an ice bath and HCl (1M in H) was added dropwise₂O, 23.4mL, 1M). A precipitate formed. Water (20mL) was added and the precipitate was filtered off, washed with water and diisopropyl ether and dried in vacuo to give 2- (5-ethoxycarbonyl-1, 4-dimethyl-pyrrol-3-yl) -2-oxo-acetic acid as a white solid (1.8 g).¹H NMR(400MHz，DMSO-d₆) δ ppm 1.31(t, J ═ 7.1Hz, 3H), 2.52(s, 3H), 3.87(s, 3H), 4.27(q, J ═ 7.1Hz, 2H), 7.91(s, 1H), 14.01(br.s., 1H). 2- (5-ethoxycarbonyl-1, 4-dimethyl-pyrrol-3-yl) -2-oxo-acetic acid (1.8g, 7.524mmol), 2-methylpropan-2-amine (877 μ L, 8.3mmol), huinine base (3.9mL, 22.6mmol) were combined in DMF (30 mL). HATU (3.15g, 8.3mmol) was added in portions at 0 ℃. After 30min, the ice bath was removed and the mixture was stirred at 5 ℃ for 1 hour. The mixture was poured into EtOAc (200mL) and saturated NaHCO with 1N HCl solution₃The solution and brine washes. The organic layer was dried (MgSO₄) Filtered and concentrated in vacuo to give an oil which was purified by column chromatography on silica gel using CH₂Cl₂And (5) eluting for purification. The product fractions were collected and concentrated in vacuo to give ethyl 4- [2- (tert-butylamino) -2-oxo-acetyl]1, 3-dimethyl-pyrrole-2-carboxylate (1.8g), which solidifies on standing. LC method B; rt: 1.16min. m/z: 293.1(M-H)^-Accurate quality: 294.2.

reacting ethyl 4- [2- (tert-butylamino) -2-oxo-acetyl]-1, 3-dimethyl-pyrrole-2-carboxylate (1.8g, 6.1mmol) was dissolved in 1, 4-dioxane (22.5mL, 264.1mmol) and lithium hydroxide monohydrate (513mg, 12.2mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was dissolved in water and washed with HCl (1M in H)₂O) (11.7mL, 1M, 11.7mmol) was neutralized. The precipitate was filtered off, washed with water and dried in vacuo to give 4- [2- (tert-butylamino) -2-oxo-acetyl as a white solid]-1, 3-dimethyl-pyrrole-2-carboxylic acid (1.3 g). Reacting 4- [2- (tert-butylamino) -2-oxo-acetyl]-1, 3-dimethyl-pyrrole-2-carboxylic acid (600mg, 2.253mmol), 3, 4-difluoroaniline (0.281mL, 2.82mmol) and DIPEA (1.17mL, 6.76mmol) were dissolved in DMF (3.67mL, 47.3mmol), HATU (1070mg, 2.8mmol) was added and the mixture was stirred at 50 ℃ for 32 h. The mixture was poured into ice water (100mL) and extracted with EtOAc. The organic layer was separated, washed with brine and dried (MgSO)₄) Filtered and concentrated in vacuo. The product was purified by silica gel column chromatography using a gradient elution from heptane to EtOAc (100-0 to 50-50). The product fractions were collected and concentrated in vacuo. The product was crystallized from 2-propanol/water, filtered and dried in vacuo to give compound 21(490g) as a solid. LC method B; rt: 1.13min. m/z: 376.2(M-H)^-Accurate quality: 377.2.¹H NMR(400MHz，DMSO-d₆)δppm 1.35(s，9H)2.38(s，3H)3.76(s，3H)7.37-7.48(m，2H)7.82-7.90(m，1H)7.96(s，1H)8.03(s，1H)10.38(s，1H)。

compound 22: 4- [ (tert-butylamino) amineRadical) (oxo) acetyl]-N- (3-cyano-4-fluorophenyl) -1, 3-dimethyl ester 1H-pyrrole-2-carboxamides

Compound 22 was prepared similarly as described for compound 21, using 5-amino-2-fluoro-benzonitrile instead of 3, 4-difluoroaniline. LC method B; rt: 1.07 min.m/z: 383.2(M-H)^-Accurate quality: 384.2.¹H NMR(400MHz，DMSO-d₆)δppm 1.36(s，9H)2.39(s，3H)3.77(s，3H)7.54(t，J＝9.0Hz，1H)7.94-8.00(m，2H)8.04(s，1H)8.17-8.22(m，1H)10.50(s，1H)。

compound 23: 4- [ (tert-butylamino) (oxo) acetyl]-3-chloro-N- (3-cyano-4-fluorophenyl) -1-methyl 1H-pyrrole-2-carboxamides

Sodium hydride (1.37g, 34.3mmol) was added in portions to a mixture of methyl 3-chloro-1H-pyrrole-2-carboxylate (4.8g, 28.6mmol) and iodomethane (2.1g, 34.3mmol) in DMF (50mL, 645.7mmol) cooled with an ice bath over a period of 10 minutes. The reaction mixture was allowed to cool to room temperature and stirred for 1 hour. The reaction mixture was acidified with 1M HCl (8mL) and evaporated to dryness. Dissolving the residue in CH₂Cl₂(25mL) and washed with water (25 mL). The product was purified by silica gel chromatography using a gradient of eluent from heptane to EtOAc (100-0 to 50-50). The product fractions were combined and concentrated in vacuo to give methyl 3-chloro-1-methyl-pyrrole-2-carboxylate (4.2 g). In N₂Methyl 3-chloro-1-methyl-pyrrole-2-carboxylate (2g, 11.5mmol) was dissolved in CH under an atmosphere₂Cl₂(40 mL). The mixture was cooled to 0 ℃ and dissolved in CH added dropwise₂Cl₂(10mL) Ethyl 2-chloro-2-oxo-acetate (2.6mL, 23.0 mmol)). At 0 deg.C, adding AlCl₃(6.15g, 46.1mmol) was added portionwise to the reaction mixture. The mixture was stirred at 0 ℃ for 1 hour. The mixture was poured into ice water (150 mL). The organic layer was separated and the aqueous layer was washed with CH₂Cl₂And (4) extracting. The organic fractions were combined and dried (MgSO)₄) Filtered and concentrated in vacuo to give crude methyl 3-chloro-4- (2-ethoxy-2-oxo-acetyl) -1-methyl-pyrrole-2-carboxylate as an oil. The crude methyl 3-chloro-4- (2-ethoxy-2-oxo-acetyl) -1-methyl-pyrrole-2-carboxylate was dissolved in EtOH (30mL) and NaOH (34.6mL, 1M, 34.6mmol) was added. The mixture was stirred at room temperature for 10 minutes. The mixture was cooled in an ice bath and HCl (1M in H) was added dropwise₂O) to a pH of about 4. A precipitate formed. Water (20mL) was added and the product was filtered off, washed with water and diisopropyl ether and dried in vacuo to give 2- (4-chloro-5-methoxycarbonyl-1-methyl-pyrrol-3-yl) -2-oxo-acetic acid as a white solid (1.93 g). 2- (4-chloro-5-methoxycarbonyl-1-methyl-pyrrol-3-yl) -2-oxo-acetic acid (1g, 4.07mmol), 2-methylpropan-2-amine (0.48mL, 4.48mmol), and huinine base (2.11mL, 12.2mmol) were combined in DMF (16 mL). HATU (1.70g, 4.48mmol) was added in portions at 0 ℃. After 10 minutes, the ice bath was removed and the mixture was stirred for 1 hour. The mixture was poured into ice water (150 mL). The mixture was extracted with EtOAc, and the organic layer was separated, dried (MgSO)₄) Filtered and concentrated in vacuo to give an oil. The product was chromatographed on silica gel with CH₂Cl₂And (5) eluting for purification. The product fractions were collected and concentrated in vacuo to yield methyl 4- [2- (tert-butylamino) -2-oxo-acetyl]-3-chloro-1-methyl-pyrrole-2-carboxylate (800mg), which solidifies on standing. LC method C; rt: 1.92 min.m/z: 299.0(M-H) -accurate Mass: 300.1. reacting methyl 4- [2- (tert-butylamino) -2-oxo-acetyl]-3-chloro-1-methyl-pyrrole-2-carboxylate (100mg, 0.333mmol) was dissolved in dry tetrahydrofuran (1 mL). 5-amino-2-fluorobenzonitrile (58.3mg, 0.416mmol) was added thereto, and the mixture was cooled in an ice-water bath and purged with nitrogen. Over a period of 2 minutes, the temperature was,bis (trimethylsilyl) aminolithium (1M in toluene, 0.67mL, 1M, 0.67mmol) was added dropwise with cooling. The resulting mixture was stirred for 1 hour while continuing to cool, and then the mixture was stirred at room temperature for another 16 hours. The mixture is treated with saturated NH₄The Cl solution was quenched. The organic layer was separated and dried (MgSO)₄) And concentrated in vacuo. The product was purified by silica gel column chromatography using a gradient eluent from heptane to EtOAc (100-0- > 50-50). The product fractions were collected and concentrated in vacuo. The product was triturated in diisopropyl ether, filtered, and dried in vacuo to give compound 23(37mg) as a solid. LC method B; rt: 1.11min. m/z: 403.2(M-H) -accurate Mass: 404.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.36(s，9H)3.82(s，3H)7.56(t，J＝9.13Hz，1H)7.93-8.02(m，1H)8.11(s，1H)8.14(s，1H)8.20(dd，J＝5.8，2.8Hz，1H)10.70(s，1H)。

compound 24: 3-chloro-N- (3-cyano-4-fluoro-phenyl) -1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-tris Fluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxamides

2- (4-chloro-5-methoxycarbonyl-1-methyl-pyrrol-3-yl) -2-oxo-acetic acid (1g, 4.071mmol), (R) -1, 1, 1-trifluoro-2-propylamine (582mg, 4.89mmol), Huning base (2.11mL, 12.21mmol) were combined in DMF (16 mL). HATU (2012mg, 5.29mmol) was added in portions at 5 ℃. The mixture was stirred at room temperature for 16 hours. The mixture was poured into EtOAc (200mL) and treated with 1N HCl solution, saturated NaHCO₃The solution and brine were washed. The organic layer was dried (MgSO₄) Filtered and concentrated in vacuo. The product was purified by silica gel column chromatography using a gradient eluent (heptane to EtOAc; 100-0- > 50-50). The product fractions were collected and concentrated in vacuo to yield methyl 3-chloro-1-methyl-4- [ 2-oxo-2- [ [ (1R) as a fluffy solid) -2, 2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxylate (657 mg). Methyl 3-chloro-1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxylate (657mg, 1.928mmol) was dissolved in 1, 4-dioxane (7.1mL) and water (1.6mL, 87.4 mmol). Lithium hydroxide monohydrate (162mg, 3.86mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was dissolved in water and washed with HCl (1M in H)₂In O) (3.86mL, 1M, 3.86 mmol). Subjecting the mixture to CH₂Cl₂Extracting and separating the organic layer, drying (MgSO)₄) Filtered and concentrated in vacuo. The residue was co-evaporated with diisopropyl ether to give 3-chloro-1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl ] as a white solid]Amino group]Acetyl group]Pyrrole-2-carboxylic acid (450 mg). Reacting 3-chloro-1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]-pyrrole-2-carboxylic acid (450mg, 1.38mmol), 5-amino-2-fluorobenzonitrile (242mg, 1.72mmol), DIPEA (0.71mL, 4.13mmol) were dissolved in DMF (10 mL). HATU (655mg, 1.72mmol) was added and the mixture was stirred at 50 ℃ for 32 h. The mixture was poured into ice water (100mL) and the precipitated product was filtered off and dried in vacuo. The product is separated from CH₃Crystallization in CN, filtration and drying in vacuo yielded compound 24 as a fluffy white solid (246 mg).¹H NMR(400MHz，DMSO-d₆) δ ppm 1.35(d, J ═ 7.04Hz, 3H)3.82(s, 3H)4.63-4.72(m, 1H)7.56(t, J ═ 9.13Hz, 1H)7.98(ddd, J ═ 9.24, 4.84, 2.64Hz, 1H)8.15(s, 1H)8.21(dd, J ═ 5.83, 2.75Hz, 1H)9.39(d, J ═ 8.80Hz, 1H)10.74(s, 1H). LC method C; rt: 1.97 min.m/z: 443.2(M-H) -accurate mass: 444.1.

compound 64: n- (3-cyano-4-fluoro-phenyl) -1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1- Methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxamides

Reacting methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxylic acid (1700mg, 5.82mmol)) was dispersed in DMF (5 mL). DIPEA (3.0mL, 17.45mmol) was then added and the mixture was stirred for 20min. HATU (2433mg, 6.4mmol) and 5-amino-2-fluorobenzonitrile (1584mg, 11.6mmol) were then added sequentially. The reaction mixture was stirred at room temperature for 2 hours. The mixture was then injected directly onto a silica stub. The mixture was purified by silica gel column chromatography using a gradient eluent from heptane to EtOAc (100: 0 to 0: 100) to yield compound 64(2.1g) as a bright white powder. LC method C; rt: 1.94 min.m/z: 409.0(M-H) -accurate mass: 410.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.30-1.41(m，3H)，3.94-4.01(m，3H)，4.60-4.79(m，1H)，7.48-7.59(m，1H)，7.67-7.73(m，1H)，7.99-8.08(m，1H)，8.11-8.17(m，1H)，8.20-8.27(m，1H)，9.23-9.45(m，1H)，10.43(br.s.，1H)

compound 25: 5-bromo-N- (3-cyano-4-fluoro-phenyl) -1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-tris Fluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxamides

Compound 26: 3-bromo-N- (3-cyano-4-fluoro-phenyl) -1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-tris Fluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxamides

Compound 27: 3, 5-dibromo-N- (3-cyano-4-fluoro-phenyl) -1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxamides

A mixture of compound 64(2.1g, 4.99mmol) in acetonitrile (80mL) and DMF (15mL) was cooled to 0 ℃. NBS (888mg, 4.99mmol) was added to this mixture in portions while stirring. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo, and the crude product was purified using silica gel column chromatography (gradient eluent: EtOAc-heptane 0: 100 to 100: 0) and by preparative HPLC (stationary phase: Uptisphere C18 ODB-10 μm, 200g, 5cm, mobile phase: 0.25% NH₄HCO₃Aqueous solution, CH₃CN) further purification. The collected fractions were concentrated in vacuo and co-evaporated twice with ACN/MeOH (2X20mL/20 mL). Compound 25(714mg), 26(225mg) and 27(117mg) were produced as bright white powders. Compound 64(14.2mg) was also recovered. Compound 25:¹H NMR(400MHz，DMSO-d₆) δ ppm 1.35(d, J ═ 7.0Hz, 3H), 3.95(s, 3H), 4.58-4.82(m, 1H), 7.54(t, J ═ 9.1Hz, 1H), 7.81(s, 1H), 7.98-8.05(m, 1H), 8.20(dd, J ═ 5.8, 2.8Hz, 1H), 9.23-9.58(m, 1H), 10.58(br.s., 1H). LC method B; rt: 1.13min. m/z: 487.0(M-H) -accurate mass: 488.0. compound 26:¹H NMR(400MHz，DMSO-d₆) δ ppm 1.35(d, J ═ 7.0Hz, 3H), 3.81(s, 3H), 4.60-4.76(m, 1H), 7.57(t, J ═ 9.1Hz, 1H), 7.95-8.02(m, 1H), 8.17(s, 1H), 8.21(dd, J ═ 5.7, 2.6Hz, 1H), 9.31-9.44(m, 1H), 10.81(br.s., 1H). LC method B; rt: 1.08 min.m/z: 489.0(M-H) -accurate mass: 490.0. compound 27:¹H NMR(400MHz，DMSO-d₆) δ ppm 1.35(d, J ═ 7.0Hz, 3H), 3.74(s, 3H), 4.59-4.80(m, 1H), 7.57(t, J ═ 9.1Hz, 1H), 7.91-8.01(m, 1H), 8.20(dd, J ═ 5.7, 2.6Hz, 1H), 9.50(d, J ═ 6.4Hz, 1H), 10.96(br.s., 1H). LC method B; rt: 1.06 min.m/z: 566.9(M-H) -accurate mass: 567.9.

compound 28: n- (3-cyano-4-fluoro-phenyl) -1, 5-dimethyl-4- [ 2-oxo-2- [ [ (2 [ (2-))1R) -2, 2, 2-tris Fluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxamides

Compound 25(50mg, 0.1mmol), tetramethyltin (0.03mL, 0.2mmol) in DMF (0.49mL, 6.29mmol) was purged with nitrogen for 5 minutes. Tetrakis (triphenylphosphine) palladium (0) (11.8mg, 0.01mmol) was added and the reaction mixture was irradiated by microwave irradiation at 140 ℃ for 30 min. The reaction mixture was concentrated and the obtained residue was purified by silica gel column chromatography (gradient from 0% to 100% EtOAc in heptane). Concentration of the product fractions yielded compound 28(104mg) as a white powder. LC method B; rt: 1.09 min.m/z: 423.1(M-H) -accurate mass: 424.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.34(d，J＝7.0Hz，3H)，2.58(s，3H)，3.85(s，3H)，4.64-4.77(m，1H)，7.52(t，J＝9.1Hz，1H)，7.65(s，1H)，8.02(ddd，J＝9.2，4.9，2.6Hz，1H)，8.21(dd，J＝5.9，2.6Hz，1H)，9.31(d，J＝8.8Hz，1H)，10.46(br.s.，1H)

compound 29: 5-bromo-3-chloro-N- (3-cyano-4-fluoro-phenyl) -1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxamides

Methyl 3-chloro-1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxylate (1.9g, 5.577mmol) was suspended in acetonitrile (100mL) and DMF (19 mL). NBS (1489mg, 8.37mmol) was added and the mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo. The product was partitioned between water and EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and concentrated in vacuo. The product was taken up in heptane using a gradient eluentTo EtOAc (100-0 to 50-50) was purified by silica gel chromatography. The product fractions were collected and concentrated in vacuo to yield methyl 5-bromo-3-chloro-1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl ] as a light yellow solid]Amino group]Acetyl group]Pyrrole-2-carboxylate (1.75 g). Reacting methyl 5-bromo-3-chloro-1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxylate (1g, 2.383mmol) was dissolved in 1, 4-dioxane (9mL) and water (2 mL). Lithium hydroxide monohydrate (200mg, 4.77mmol) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the residue was dissolved in water. Addition of HCl (1M in H)₂O) (4.767mL, 1M, 4.767mmol) and a precipitate formed. After stirring for 5min, the product was filtered off and dried in vacuo to yield 5-bromo-3-chloro-1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl as a white solid]Amino group]Acetyl group]Pyrrole-2-carboxylic acid (856 mg). Adding Et₃N (0.88mL, 6.33mmol) was added to 5-bromo-3-chloro-1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl in DMF (4.6mL, 58.9mmol)]Amino group]Acetyl group]Pyrrole-2-carboxylic acid (856mg, 2.111mmol), HATU (1003mg, 2.64mmol), 5-amino-2-fluorobenzonitrile (385mg, 2.74mmol) and the reaction mixture was stirred at 65 ℃ for 4 h. The mixture was cooled to room temperature and poured into ice water. The mixture was extracted with EtOAc and the organic layer was separated and dried (MgSO)₄) Filtered and concentrated in vacuo. Purification was carried out by preparative HPLC (stationary phase: Uptisphere C18 ODB-10 μm, 200g, 5cm, mobile phase: 0.25% NH)₄HCO₃Aqueous solution, CH₃CN) to yield compound 29(203 mg). LC method B; rt: 1.06 min.m/z: 520.9(M-H) -accurate mass: 522.0.¹H NMR(400MHz，DMSO-d₆)δppm 1.34(d，J＝7.0Hz，3H)3.76(s，3H)4.62-4.74(m，1H)7.56(t，J＝9.1Hz，1H)7.97(ddd，J＝9.2，4.8，2.9Hz，1H)8.20(dd，J＝5.7，2.6Hz，1H)9.32-9.65(m，1H)10.30-11.17(m，1H)。

compound 30: 3-chloro-N- (3-cyano-4-fluoro-phenyl) -1, 5-dimethyl-4- [ 2-oxo-2- [ [ (1R) -2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxamides

A microwave vial was charged with methyl 5-bromo-3-chloro-1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl ] dissolved in DMF (1.5mL)]Amino group]Acetyl group]Pyrrole-2-carboxylate (200mg, 0.477mmol) and tetramethyltin (139.0. mu.L, 1.291g/mL, 0.95 mmol). The mixture is mixed with N₂Purge 5 minutes. Tetrakis (triphenylphosphine) palladium (0) (55.1mg, 0.048mmol) was added and the vial was capped. The mixture was irradiated at 140 ℃ for 30 minutes. The mixture was concentrated in vacuo. The product was purified by silica gel chromatography using a gradient of eluent from heptane to EtOAc (100-0 to 50-50). The product fractions were collected and concentrated in vacuo to yield methyl 3-chloro-1, 5-dimethyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl ] as a white solid]Amino group]Acetyl group]Pyrrole-2-carboxylate (94 mg). Methyl 3-chloro-1, 5-dimethyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxylate (94mg, 0.265mmol) was dissolved in 1, 4-dioxane (1mL) and water (0.22mL, 12.0 mmol). Lithium hydroxide monohydrate (22.2mg, 0.53mmol) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and then dissolved in water. Addition of HCl (1M in H)₂O) (0.53mL, 1M, 0.53mmol), and the mixture was stirred at room temperature for 5 minutes. The mixture was extracted with Me-THF, and the organic layer was dried (MgSO)₄) Filtered and concentrated in vacuo to give 3-chloro-1, 5-dimethyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl ] as a solid]Amino group]Acetyl group]Pyrrole-2-carboxylic acid (85 mg). Reacting 3-chloro-1, 5-dimethyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxylic acid (85mg, 0.249mmol), 5-amino-2-fluorobenzonitrile (43.8mg, 0.31mmol) and DIPEA (0.129mL, 0.75g/mL, 0.748mmol) were dissolved in DMF (1.8 mL). HATU (118.6mg, 0.31mmol) was added and the mixture was mixedThe mixture was stirred at 50 ℃ for 16 hours. The mixture was concentrated in vacuo. The residue was partitioned between water and EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and concentrated in vacuo. Purification was by preparative HPLC (stationary phase: RP Xbridge Prep C18OBD-10 μm, 30X150mm, mobile phase: 0.25% NH)₄HCO₃Aqueous solution, CH₃CN) to yield 3-chloro-N- (3-cyano-4-fluoro-phenyl) -1, 5-dimethyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl ] as a white solid]Amino group]Acetyl group]Pyrrole-2-carboxamide (40 mg). LC method B; rt: 1.03 min.m/z: 457.0(M-H) -accurate mass: 458.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.32(d，J＝7.0Hz，3H)2.47(s，3H)3.66(s，3H)4.62-4.74(m，1H)7.55(t，J＝9.1Hz，1H)7.95-8.02(m，1H)8.21(dd，J＝5.8，2.5Hz，1H)9.37(d，J＝8.8Hz，1H)10.75(s，1H)。

compound 31: 3-chloro-N- (3-cyano-4-fluoro-phenyl) -5-cyclopropyl-1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxamides

Charging a microwave vial with methyl 5-bromo-3-chloro-1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxylate (150mg, 0.36mmol), Potassium Cyclopropyltrifluoroborate (79.4mg, 0.54mmol), Cs₂CO₃(349mg, 1.07mmol), DME (4mL), and water (0.4 mL). The mixture is mixed with N₂Purge 5 minutes. Tetrakis (triphenylphosphine) palladium (0) (82.6mg, 0.072mmol) was added and the vial was capped. The mixture was stirred at 110 ℃ for 16 hours. The mixture was cooled and the residue was taken up in saturated NH₄The Cl solution and Me-THF were partitioned. The organic layer was separated and dried (MgSO)₄) And concentrated in vacuo. The product was purified by silica gel chromatography (10g, liquid phase) using a gradient eluent from heptane to EtOAc (100-0 to 50-50). Collecting the productFractions and concentrated in vacuo to yield methyl 3-chloro-5-cyclopropyl-1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl ] as a solid]Amino group]Acetyl group]Pyrrole-2-carboxylate (114 mg). 3-chloro-N- (3-cyano-4-fluoro-phenyl) -5-cyclopropyl-1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxamide (22mg) was synthesized analogously as described for compound 30 using methyl 3-chloro-5-cyclopropyl-1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxylate instead of methyl 3-chloro-1, 5-dimethyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxylate. LC method C; rt: 1.99min. m/z: 483.0(M-H) -accurate mass: 484.0.¹H NMR(400MHz，DMSO-d₆)δppm 0.47-0.57(m，2H)0.94-1.05(m，2H)1.30-1.38(m，3H)1.77-1.86(m，1H)3.77(s，3H)4.61-4.73(m，1H)7.54(t，J＝9.1Hz，1H)7.92-7.99(m，1H)8.20(dd，J＝5.7，2.6Hz，1H)9.32(d，J＝9.0Hz，1H)10.75(br.s.，1H)

compound 32: 4- [2- (tert-butylamino) -2-oxo-acetyl]-3-chloro-N- (3-cyano-4-fluoro-phenyl) - 1, 5-dimethyl-pyrrole-2-carboxamide

Compound 32(81mg) was synthesized analogously as described for compound 30, using methyl 5-bromo-4- [2- (tert-butylamino) -2-oxo-acetyl]-3-chloro-1-methyl-pyrrole-2-carboxylate instead of methyl 5-bromo-3-chloro-1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxylate. LC method B; rt: 1.03 min.m/z: 417.1(M-H) -accurate mass: 418.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.34(s，9H)2.46(s，3H)3.65(s，3H)7.55(t，J＝9.1Hz，1H)7.94-8.04(m，1H)8.21(dd，J＝5.7，2.6Hz，1H)8.27(s，1H)10.70(s，1H)。

compound 33: 4- [2- (tert-butyl) sAmino) -2-oxo-acetyl]-3-chloro-N- (3-cyano-4-fluoro-phenyl) - 1-methyl-5- (trifluoromethyl) pyrrole-2-carboxamide

Compound 50(100mg, 0.207mmol) was dissolved in DMF (2 mL). 4-methylmorpholine (45.5. mu.L, 0.413mmol), copper (I) iodide (19.7mg, 0.103mmol) and methyl fluorosulfonyl (difluoro) acetate (78.1. mu.L, 0.62mmol) were added. The resulting mixture was stirred at 70 ℃ for 16 hours. The mixture was cooled and water was added. Saturated ammonium chloride solution (10mL) was added to the reaction mixture. This was then extracted with EtOAc (3 × 15 mL). The combined extracts were dried (MgSO)₄) Filtered and concentrated in vacuo. The residue obtained is purified using silica column chromatography (gradient eluent: ethyl acetate: heptane from 0% to 100%). The product fractions were collected and concentrated in vacuo to yield compound 33(60mg) as a white fluffy solid. LC method C; rt: 2.16min. m/z: 471.1(M-H) -accurate mass: 472.1.¹H NMR(400MHz，DMSO-d₆) δ ppm 1.33(s, 9H)3.84(s, 3H)7.59(t, J ═ 9.13Hz, 1H)7.93-8.02(m, 1H)8.21(dd, J ═ 5.72, 2.64Hz, 1H)8.37(s, 1H)11.15(s, 1H). Differential scanning calorimetry: from 30 ℃ to 300 ℃ at 10 ℃/min: peak: 195.7 deg.C.

Compound 34: 4- [2- (tert-butylamino) -2-oxo-acetyl]-N- (3-cyano-4-fluoro-phenyl) -3-fluoro- 1-methyl-pyrrole-2-carboxamides

Sodium hydride (5.3g, 138.7mmpol, 60%) was added in portions to ethyl 3-fluoro-1H-pyrrole-2-carboxylate (18.2g, 115.6mmol) and methyl iodide (19.7g, 138.7mmol) in DMF (150mL) under nitrogen in an ice bath and stirred at room temperature overnight. The reaction mixture was acidified with 1M HCl andand concentrated. The residue obtained was dissolved in water/EtOAc. Subjecting the organic layer to Na₂SO₄Dried, filtered and concentrated. The residue was dissolved in CH₃CN (150mL), washed with heptane and concentrated at 60 ℃ and 40mbar yielding a brown liquid which was subjected to silica gel column chromatography using a gradient from 10% to 25% EtOAc in heptane. The product fractions were concentrated to give ethyl 3-fluoro-1-methyl-pyrrole-2-carboxylate (10.7g) as a clear oil. More ethyl 3-fluoro-1-methyl-pyrrole-2-carboxylate (1.7g) was recovered from the evaporated solvent. Ethyl 3-fluoro-1-methyl-pyrrole-2-carboxylate (1.96g, 11.5mmol), ethyl 2-chloro-2-oxo-acetate (1.99mL, 17.46mmol) were dissolved in DCM (100mL) and cooled in an ice bath. Adding AlCl₃(3.06g, 22.9mmol), and the solution was stirred at 0 ℃ for 1 hour. The reaction mixture was stirred at room temperature for a further 1 hour. 1 equivalent of AlCl is additionally added₃And stirred for 1 hour. The reaction mixture was cooled in an ice bath and quenched with ice water. The mixture was acidified with HCl 1M. The organic layer was dried over magnesium sulfate, filtered and concentrated to give ethyl 4- (2-ethoxy-2-oxo-acetyl) -3-fluoro-1-methyl-pyrrole-2-carboxylate (3.29 g). The residue was dissolved in EtOH (20mL), NaOH (1M in H) was added₂O) (11.5mL, 1M, 11.5mmol), and the reaction mixture was stirred for 10min. The reaction mixture was washed with HCl (1M in H)₂In O) (11.5mL, 1M, 11.5mmol), neutralized, partially concentrated and extracted with EtOAc/water. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using a gradient from 10% to 100% EtOAc in heptane. The fractions were concentrated to give 2- (5-ethoxycarbonyl-4-fluoro-1-methyl-pyrrol-3-yl) -2-oxo-acetic acid (1.2g) as a white powder. LC method C; rt: 0.89 min.m/z: 242.0(M-H) -accurate mass: 243.1. adding Et₃N (1.02mL, 7.35mmol) was added to a solution of 2- (5-ethoxycarbonyl-4-fluoro-1-methyl-pyrrol-3-yl) -2-oxo-acetic acid (596mg, 2.45mmol), 2-methylpropan-2-amine (223.9mg, 3.06mmol), and HATU (1164mg, 3.061mmol) in DMF (3mL) and stirred at 65 ℃ for 30 min. Using from 10% to 100% EtOAc in heptaneThe gradient was subjected to silica gel column chromatography. The product fractions were concentrated to give ethyl 4- [2- (tert-butylamino) -2-oxo-acetyl as a clear oil]-3-fluoro-1-methyl-pyrrole-2-carboxylate (714mg), which was allowed to stand to cure. LC method C; rt: 1.98min. m/z: 299.1(M + H) + exact mass: 298.1. reacting ethyl 4- [2- (tert-butylamino) -2-oxo-acetyl]A mixture of-3-fluoro-1-methyl-pyrrole-2-carboxylate (204mg, 0.684mmol), LiOH (49.1mg, 2.05mmol), water (10mL,) and THF (20mL) was stirred overnight. HCl (1M, 2.1mL) was added and the THF was distilled off. The white precipitate formed was filtered off and dried under vacuum at 50 ℃ overnight to give 4- [2- (tert-butylamino) -2-oxo-acetyl as a white powder]-3-fluoro-1-methyl-pyrrole-2-carboxylic acid (121 mg). LC method C; rt: 1.03 min.m/z: 269.3(M-H) -accurate mass: 270.1.¹H NMR(400MHz，DMSO-d₆) δ ppm 1.34(s, 9H), 3.86(s, 3H), 7.97(d, J ═ 4.4Hz, 1H), 8.05(s, 1H), 13.05(br.s, 1H). Adding Et₃N (0.18mL, 1.29mmol) was added to 4- [2- (tert-butylamino) -2-oxo-acetyl-dissolved in DMF (0.9mL)]-3-fluoro-1-methyl-pyrrole-2-carboxylic acid (115.9mg, 0.43mmol), HATU (203.8mg, 0.54mmol), 5-amino-2-fluoro-benzonitrile (116.76mg, 0.86mmol) and heating at 65 ℃ for 4 hours. The reaction mixture was subjected directly to silica gel chromatography using a gradient from 10% up to 100% EtOAc in heptane. The product fractions were concentrated to yield compound 34(171mg) as white crystals, which were dried under vacuum at 50 ℃ overnight. LC method C; rt: 2.03 min.m/z: 387.1(M-H) -accurate mass: 388.1. differential scanning calorimetry: from 30 ℃ to 300 ℃ at 10 ℃/min: peak: 179.2 ℃.¹H NMR(360MHz，DMSO-d₆)δppm 1.35(s，9H)，3.85(s，3H)，7.54(t，J＝9.1Hz，1H)，7.93-7.99(m，1H)，8.04(d，J＝4.4Hz，1H)，8.12(s，1H)，8.18(dd，J＝5.7，2.7Hz，1H)，10.37(s，1H)。

Compound 35: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ (3, 3-difluoro-1-methyl-cyclobutyl) amino]-2- Oxo-acetyl]-3-fluoro-1-methyl-pyrrole-2-carboxamide

Compound 35 was prepared similarly as described for compound 34, using 4- [2- [ (3, 3-difluoro-1-methyl-cyclobutyl) amino]-2-oxo-acetyl]-3-fluoro-1-methyl-pyrrole-2-carboxylic acid instead of 4- [2- (tert-butylamino) -2-oxo-acetyl]-3-fluoro-1-methyl-pyrrole-2-carboxylic acid. Compound 35(345mg) was crystallized by adding water to MeOH solution. 4- [2- [ (3, 3-difluoro-1-methyl-cyclobutyl) amino group]-2-oxo-acetyl]-3-fluoro-1-methyl-pyrrole-2-carboxylic acid is e.g. for 4- [2- (tert-butylamino) -2-oxo-acetyl]-3-fluoro-1-methyl-pyrrole-2-carboxylic acid was prepared similarly as described using 3, 3-difluoro-1-methylcyclobutylamine hydrochloride (available from tokyo pharmacotharstone drug development limited (Pharmablock), PBN20121019) instead of 2-methylpropan-2-amine. LC method C; rt: 1.99min. m/z: 435.4(M-H) -accurate Mass: 436.1. differential scanning calorimetry: from 30 ℃ to 300 ℃ at 10 ℃/min: peak: 195.0 ℃.¹H NMR(400MHz，DMSO-d₆)δppm 1.50(s，3H)，2.61-2.73(m，2H)，2.96-3.10(m，2H)，3.85(s，3H)，7.54(t，J＝9.1Hz，1H)，7.97(ddd，J＝9.2，4.9，2.6Hz，1H)，8.10(d，J＝4.4Hz，1H)，8.18(dd，J＝5.7，2.6Hz，1H)，9.19(s，1H)，10.34(s，1H)。

Compound 36: 4- [2- (tert-butylamino) -2-oxo-acetyl]-N- (3-cyano-4-fluoro-phenyl) -3-fluoro- 1, 5-dimethyl-pyrrole-2-carboxamide

Reacting ethyl 4- [2- (tert-butylamino) -2-oxo-acetyl]-3-fluoro-1-methyl-pyrrole-2-carboxylate (510mg, 1.71mmol), NBS (456.4mg, 2.56mmol), DMF (2mL), ACN (2mL, 0.786g/mL, 38.29mmol) was stirred overnight. An additional 1.5 equivalents of NBS was added and the mixture was stirred for an additional 30 minutes. The solution was chromatographed through a column of silica gel using a gradient from 10% up to 100% EtOAc in heptaneThe purification is directly carried out by a chromatography method. The product fractions were concentrated to give ethyl 5-bromo-4- [2- (tert-butylamino) -2-oxo-acetyl as a clear oil]-3-fluoro-1-methyl-pyrrole-2-carboxylate (255 mg).¹H NMR(360MHz，DMSO-d₆) δ ppm 1.28(t, J ═ 7.1Hz, 3H), 1.32(s, 9H), 3.88(s, 3H), 4.29(q, J ═ 7.3Hz, 2H), 8.37(s, 1H). Tetrakis (triphenylphosphine) palladium (0) (65.9mg, 0.057mmol) was added to ethyl 5-bromo-4- [2- (tert-butylamino) -2-oxo-acetyl dissolved in DMF (3mL)]-3-fluoro-1-methyl-pyrrole-2-carboxylate (215mg, 0.57mmol) and tetramethyltin (214.6mg, 1.14mmol) and heating the reaction mixture by microwave radiation at 140 ℃ for 90 minutes. The reaction mixture was filtered and concentrated. The residue obtained was purified by silica gel column chromatography using a gradient from 10% to 100% EtOAc in heptane. The product fractions were concentrated to give ethyl 4- [2- (tert-butylamino) -2-oxo-acetyl as a colorless resin]-3-fluoro-1, 5-dimethyl-pyrrole-2-carboxylate (149 mg).¹H NMR(400MHz，DMSO-d₆) δ ppm 1.27(t, J ═ 7.0Hz, 3H), 1.32(s, 9H), 2.48(s, 3H), 3.77(s, 3H), 4.26(q, J ═ 7.1Hz, 2H), 8.23(s, 1H). Reacting ethyl 4- [2- (tert-butylamino) -2-oxo-acetyl]A mixture of-3-fluoro-1, 5-dimethyl-pyrrole-2-carboxylate (146mg, 0.467mmol), LiOH (33.5mg, 1.4mmol), THF (5mL, 61.44mmol), water (5mL, 276.98mmol) was stirred overnight. Addition of HCl (1M in H)₂In O (1.4mL, 1M, 1.40mmol)) and THF was distilled off. The white precipitate formed was filtered and dried in vacuo at 50 ℃ to yield 4- [2- (tert-butylamino) -2-oxo-acetyl as a white powder]-3-fluoro-1, 5-dimethyl-pyrrole-2-carboxylic acid (95 mg). LC method C; rt: 0.93 min.m/z: 283.1(M-H) -accurate mass: 284.1.¹H NMR(360MHz，DMSO-d₆) δ ppm 1.31(s, 9H), 2.48(s, 3H), 3.77(s, 3H), 8.24(s, 1H), 12.92(br.s, 1H). Adding Et₃N (0.14mL, 0.97mmol) was added to 4- [2- (tert-butylamino) -2-oxo-acetyl]-3-fluoro-1, 5-dimethyl-pyrrole-2-carboxylic acid (92mg, 0.32mmol), HATU (153.8mg, 0.41mmol) and 5-amino-2-fluoro-benzonitrile (88.1mg, 0.65mmol) in DMF (1mL) and the mixture was stirred at 40 ℃ overnight. The reaction mixture was directly purified by silica gel chromatography using a gradient from 10% to 100% EtOAc in heptane. The product fractions were concentrated. The residue was dissolved in methanol (10 mL). The product was crystallized upon addition of water. The white crystals were filtered off and dried under vacuum at 50 ℃ overnight to give compound 36(68 mg). LC method C; rt: 1.99min. m/z: 401.1(M-H)^-Accurate quality: 402.2. differential scanning calorimetry: from 30 ℃ to 300 ℃ at 10 ℃/min: peak: 153.4 ℃.¹H NMR(400MHz，DMSO-d₆)δppm 1.33(s，9H)，2.50(s，3H)，3.71(s，3H)，7.52(t，J＝9.1Hz，1H)，7.93-7.99(m，1H)，8.16(dd，J＝5.9，2.6Hz，1H)，8.25(s，1H)，10.36(s，1H)。

Compound 37: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ (3, 3-difluoro-1-methyl-cyclobutyl) amino]-2- Oxo-acetyl]-3-fluoro-1, 5-dimethyl-pyrrole-2-carboxamide

NBS (230.0mg, 1.29mmol) was added to a solution of compound 35(282mg, 0.646mmol) in ACN (1mL) and DMF (1mL) and stirred for 1 h. The reaction mixture was purified by silica gel column chromatography using a gradient from 10% to 100% EtOAc in heptane. The product fractions were concentrated and the residue crystallized from methanol (20mL) after addition of water. The white powder, crude 5-bromo-N- (3-cyano-4-fluoro-phenyl) -4- [2- [ (3, 3-difluoro-1-methyl-cyclobutyl) amino]-2-oxo-acetyl]-3-fluoro-1-methyl-pyrrole-2-carboxamide (154mg) was filtered off and dried in vacuo at 50 ℃. LC method C; rt: 1.96min. m/z: 513.0(M-H)^-Accurate quality: 514.0. nitrogen was bubbled through crude 5-bromo-N- (3-cyano-4-fluoro-phenyl) -4- [2- [ (3, 3-difluoro-1-methyl-cyclobutyl) amino]-2-oxo-acetyl]-a solution of 3-fluoro-1-methyl-pyrrole-2-carboxamide (154mg), tetramethyltin (112.5mg, 0.60mmol) in DMF (2 mL). Tetrakis (triphenylphosphine) palladium (0) (34.5mg, 0.030mmol) was added and the reaction mixture was passed throughThe microwave irradiation was heated at 140 ℃ for 90 minutes. The solution was purified by silica gel column chromatography using a gradient from 10% up to 100% EtOAc in heptane. The product fractions were concentrated. The residue was dissolved in methanol (10mL) and the product crystallized upon addition of water. The white powder was dried in vacuo at 50 ℃ to give compound 37(64 mg). LC method C; rt: 1.92 min.m/z: 449.1(M-H) -accurate mass: 450.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.50(s，3H)，2.51(s，3H)，2.62-2.74(m，2H)，2.90-3.03(m，2H)，3.71(s，3H)，7.53(t，J＝9.1Hz，1H)，7.96(ddd，J＝9.2，4.9，2.6Hz，1H)，8.16(dd，J＝5.7，2.6Hz，1H)，9.14(s，1H)，10.40(s，1H)。

compound 38: 3-chloro-N- (3-cyano-4-fluoro-phenyl) -1-methyl-4- [ 2-oxo-2- [ [ (1R) -1- (trifluoro) Methyl) propyl group]Amino group]Acetyl group]Pyrrole-2-carboxamides

Compound 38(91mg) was synthesized analogously as described for compound 40 using (R) -1, 1, 1-trifluoro-2-butylamine instead of 3, 3-difluoro-1-methylcyclobutylamine hydrochloride. LC method C; rt: 2.08 min.m/z: 457.0(M-H) -accurate mass: 458.1.¹H NMR(400MHz，DMSO-d₆) δ ppm0.92(t, J ═ 7.3Hz, 3H)1.68-1.85(m, 2H)3.83(s, 3H)4.40-4.52(m, 1H)7.56(t, J ═ 9.1Hz, 1H)7.98(ddd, J ═ 9.2, 4.8, 2.9Hz, 1H)8.14(s, 1H)8.21(dd, J ═ 5.7, 2.6Hz, 1H)9.31(d, J ═ 9.2Hz, 1H)10.74(s, 1H). Differential scanning calorimetry: from 30 ℃ to 300 ℃ at 10 ℃/min: peak: 248.53 deg.C.

Compound 39: 3-chloro-N- (3-cyano-4-fluoro-phenyl) -1-methyl-4- [ 2-oxo-2- [ [1- (trifluoromethyl) Cyclobutyl radical]Amino group]Acetyl group]Pyrrole-2-carboxamides

Compound 39(152mg) was synthesized similarly as described for compound 40, using 1- (trifluoromethyl) cyclobutane-1-amine instead of 3, 3-difluoro-1-methylcyclobutylamine hydrochloride. LC method C; rt: 2.08 min.m/z: 469.1(M-H)^-Accurate quality: 470.1.¹H NMR(400MHz，DMSO-d₆) δ ppm 1.87-2.03(m, 2H)2.40-2.49(m, 2H)2.53-2.67(m, 2H)3.83(s, 3H)7.56(t, J ═ 9.1Hz, 1H)7.98(ddd, J ═ 9.2, 4.8, 2.8Hz, 1H)8.15(s, 1H)8.21(dd, J ═ 5.8, 2.8Hz, 1H)9.32(s, 1H)10.73(br.s., 1H). Differential scanning calorimetry: from 30 ℃ to 300 ℃ at 10 ℃/min: peak: 242.2 deg.C.

Compound 40: 3-chloro-N- (3-cyano-4-fluoro-phenyl) -4- [2- [ (3, 3-difluoro-1-methyl-cyclobutyl) -amino Base of]-2-oxo-acetyl]-1-methyl-pyrrole-2-carboxamide

Methyl 3-chloro-1-methyl-pyrrole-2-carboxylate (6.2g, 35.7mmol) and 5-amino-2-fluorobenzonitrile (6.27g, 44.64mmol) were dissolved in THF (100 mL). To the reaction mixture was added dropwise lithium bis (trimethylsilyl) amide (1M in THF) (44.6mL, 1M, 44.6mmol) at room temperature. After two hours, the mixture was poured into saturated NH₄In a Cl solution. The mixture was extracted with Me-THF. The organic layer was separated and dried (MgSO)₄) Filtered and concentrated in vacuo. The residue is in CH₃Triturate in CN and filter the product. The product was washed with DIPE and dried in vacuo to give 3-chloro-N- (3-cyano-4-fluoro-phenyl) -1-methyl-pyrrole-2-carboxamide as a pale pink solid (5.8 g). 3-chloro-N- (3-cyano-4-fluoro-phenyl) -1-methyl-pyrrole-2-carboxamide (5.8g, 20.9mmol) was dissolved in DCM (100mL) and Me-THF (10 mL). The mixture was cooled with an ice bath. Aluminum (III) chloride (7.24g, 54.31mmol) was added in portions at 0-5 ℃. Ethyloxalyl chloride (3.63 m) was added dropwise to the reaction mixture at 0-5 deg.CL, 31.80 mmol). The mixture was stirred at 0-5 ℃ for 30 minutes and then allowed to warm to room temperature. The mixture was stirred at room temperature for a further 32 hours. The mixture was completely converted into 2- [ 4-chloro-5- [ (3-cyano-4-fluoro-phenyl) carbamoyl]-1-methyl-pyrrol-3-yl]-2-oxo-acetic acid. The mixture was poured onto ice and the organic phase was distilled off. The aqueous layer was extracted with Me-THF, and the organic layer was separated, dried (MgSO)₄) Filtered and concentrated in vacuo. The residue was treated with 1N NaOH solution and the aqueous layer was washed with Me-THF. The aqueous layer was acidified with 1N HCl solution. The aqueous layer was extracted with Me-THF (2 ×), and the organic layers were combined, dried (MgSO)₄) Filtered and concentrated in vacuo to give 2- [ 4-chloro-5- [ (3-cyano-4-fluoro-phenyl) carbamoyl group as a white solid]-1-methyl-pyrrol-3-yl]-2-oxo-acetic acid (3 g). Adding Et₃N (0.238mL, 0.728g/mL, 1.716mmol) was added to 2- [ 4-chloro-5- [ (3-cyano-4-fluoro-phenyl) carbamoyl]-1-methyl-pyrrol-3-yl]-2-oxo-acetic acid (150mg, 0.429mmol), 3-difluoro-1-methylcyclobutylamine hydrochloride (64.946mg, 0.536mmol), HATU (203.868mg, 0.536mmol) in DMF (0.5mL) and stirred at 65 ℃ for 30 min. The mixture was cooled and the solution was subjected to silica gel column chromatography using a gradient from 10% to 100% EtOAc in heptane. The product fractions were concentrated. The product was triturated in DIPE, filtered and dried in vacuo to yield compound 40(135mg) as a white fluffy solid. LC method C; rt: 2.02min. m/z: 451.3(M-H)^-Accurate quality: 452.1.¹H NMR(400MHz，DMSO-d₆) δ ppm 1.50(s, 3H)2.59-2.75(m, 2H)2.95-3.11(m, 2H)3.82(s, 3H)7.56(t, J ═ 9.13Hz, 1H)7.98(ddd, J ═ 9.13, 4.84, 2.75Hz, 1H)8.16-8.25(m, 2H)9.18(s, 1H)10.71(s, 1H). Differential scanning calorimetry: from 30 ℃ to 300 ℃ at 10 ℃/min: peak: 222.1 ℃.

Synthesis of 3- (trifluoromethyl) tetrahydrofuran-3-amine hydrochloride:

3-oxotetrahydrofuran (30g, 348.5mmol), benzylamine (39.2g, 365.8mmol) and MgSO₄(21g，174.5mmol) and CH₂Cl₂(200mL) the mixture was stirred at 28 ℃ for 24 h. The mixture was filtered. The filtrate was concentrated in vacuo and the residue obtained (63.1g) was used directly in the next step. The obtained residue (63g) was dissolved in acetonitrile (600 mL). Trifluoroacetic acid (45g, 394mmol), potassium hydrogen fluoride (22.5g, 288mmol) and DMF (60mL) were added to the mixture at 0 ℃. The mixture was stirred at 0 ℃ for 10 minutes. (trifluoromethyl) trimethylsilane (77g, 541mmol) was added to the reaction mixture and the mixture was stirred at ambient temperature for 12 hours. Adding saturated aqueous Na₂CO₃(200mL) and the mixture was stirred for 5 minutes. The mixture was diluted with water (500mL) and extracted with ethyl acetate (3 × 300 mL). The combined organic layers were washed with water and brine, over Na₂SO₄Dried and evaporated under reduced pressure. The obtained residue was dissolved in 2M HCl/MeOH and the solvent was evaporated. The resulting hydrochloride salt is removed from CH₃CN crystallized to give N-benzyl-3- (trifluoromethyl) tetrahydrofuran-3-amine (30.5 g). A mixture of N-benzyl-3- (trifluoromethyl) tetrahydrofuran-3-amine (30.5g), palladium on alumina (1.5g) and MeOH in H₂Stirring was carried out at 28 ℃ for 12 hours under an atmosphere of (20 psi).

The mixture was filtered and the filtrate was concentrated in vacuo to give 3- (trifluoromethyl) tetrahydrofuran-3-amine hydrochloride (20.5 g).¹H NMR(400MHz，DMSO-d₆)δppm 2.21-2.43(m，2H)3.83-4.16(m，4H)9.68(br.s.，3H)。

Compound 41: 3-chloro-N- (3-cyano-4-fluoro-phenyl) -1, 5-dimethyl-4- [ 2-oxo-2- [ [3- (trifluoromethyl) Yl) tetrahydrofuran-3-yl]Amino group]Acetyl group]Pyrrole-2-carboxamides

3-chloro-N- (3-cyano-4-fluoro-phenyl) -1, 5-dimethyl-4- [ 2-oxo-2- [ [3- (trifluoromethyl) tetrahydrofuran-3-yl]Amino group]Acetyl group]Pyrrole-2-carboxamides (58mg) are as for the compounds43 racemic 3- (trifluoromethyl) tetrahydrofuran-3-amine was used instead of 1- (trifluoromethyl) cyclobutane-1-amine. LC method B; rt: 0.98 min.m/z: 499.0(M-H) -accurate mass: 500.1.¹H NMR(400MHz，DMSO-d₆)δppm 2.25-2.40(m，1H)2.45-2.56(m，4H)3.66(s，3H)3.71-3.84(m，1H)3.85-3.96(m，1H)4.12-4.26(m，2H)7.55(t，J＝9.1Hz，1H)7.99(ddd，J＝9.2，4.8，2.9Hz，1H)8.21(dd，J＝5.7，2.6Hz，1H)9.39(s，1H)10.75(s，1H)。

compound 42: 3-chloro-N- (3-cyano-4-fluoro-phenyl) -1, 5-dimethyl-4- [ 2-oxo-2- [ [ (1R) -1- (trifluoromethyl) propyl group]Amino group]Acetyl group]Pyrrole-2-carboxamides

Synthesis of 3-chloro-N- (3-cyano-4-fluoro-phenyl) -1, 5-dimethyl-4- [ 2-oxo-2- [ [ (1R) -1- (trifluoromethyl) propyl ] e.g. using (R) -1, 1, 1-trifluoro-2-butylamine instead of 1- (trifluoromethyl) cyclobutane-1-amine analogously to the description of Compound 43]Amino group]Acetyl group]Pyrrole-2-carboxamide (5 mg). LC method C; rt: 1.97 min.m/z: 471.1(M-H) -accurate mass: 472.1.¹H NMR(400MHz，DMSO-d₆)δppm0.97(t，J＝7.4Hz，3H)1.59-1.73(m，1H)1.73-1.87(m，1H)2.47(s，3H)3.66(s，3H)4.39-4.55(m，1H)7.55(t，J＝9.1Hz，1H)7.93-8.03(m，1H)8.21(dd，J＝5.7，2.6Hz，1H)9.29(d，J＝8.8Hz，1H)10.75(s，1H)。

compound 43: 3-chloro-N- (3-cyano-4-fluoro-phenyl) -1, 5-dimethyl-4- [ 2-oxo-2- [ [1- (trifluoromethyl) Radical) cyclobutyl]Amino group]Acetyl group]Pyrrole-2-carboxamides

3-chloro-N- (3-cyano-4-fluoro-phenyl) -1-methyl-pyrrole-2-carboxamide (4g, 14.405mmol) was dissolved in DCM (69mL)And the mixture was cooled on an ice bath. Ethyloxalyl chloride (2.50mL, 21.9mmol) was added at 0-5 ℃. Aluminum (III) chloride (4.99g, 37.45mmol) was added portionwise to the reaction mixture at 0-5 ℃. The mixture was stirred at 0-5 ℃ for 30 minutes and then allowed to warm to room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0-5 ℃ with an ice bath. EtOH (20mL) was added carefully. A clear solution formed and the mixture was stirred at room temperature for 1 hour. The mixture was quenched on ice. The organic layer was separated and the aqueous layer was extracted with Me-THF. The organic layers were combined and dried (MgSO)₄) Filtered and concentrated in vacuo. The residue was suspended in a small amount of Me-THF and the product was filtered off to give ethyl 2- [ 4-chloro-5- [ (3-cyano-4-fluoro-phenyl) carbamoyl]-1-methyl-pyrrol-3-yl]-2-oxo-acetate (1.8g) as a white solid. E.g. analogously to the procedure for the synthesis of Compound 47 for 2- [ 2-bromo-4-chloro-5- [ (3-cyano-4-fluoro-phenyl) carbamoyl]-1-methyl-pyrrol-3-yl]Description of (E) -2-oxo-acetic acid using ethyl 2- [ 4-chloro-5- [ (3-cyano-4-fluoro-phenyl) carbamoyl]-1-methyl-pyrrol-3-yl]-2-oxo-acetate instead of 2- [ 4-chloro-5- [ (3-cyano-4-fluoro-phenyl) carbamoyl]-1-methyl-pyrrol-3-yl]-2-oxo-acetic acid, Synthesis of Ethyl 2- [ 2-bromo-4-chloro-5- [ (3-cyano-4-fluoro-phenyl) carbamoyl]-1-methyl-pyrrol-3-yl]-2-oxo-acetate (1.8 g). E.g. analogously to the procedure for the synthesis of Compound 47 for 2- [ 4-chloro-5- [ (3-cyano-4-fluoro-phenyl) carbamoyl]-1, 2-dimethyl-pyrrol-3-yl]Description of (E) -2-oxo-acetic acid Using Ethyl 2- [ 2-bromo-4-chloro-5- [ (3-cyano-4-fluoro-phenyl) carbamoyl]-1-methyl-pyrrol-3-yl]-2-oxo-acetate (1g) instead of 2- [ 2-bromo-4-chloro-5- [ (3-cyano-4-fluoro-phenyl) carbamoyl]-1-methyl-pyrrol-3-yl]-2-oxo-acetic acid, Synthesis of Ethyl 2- [ 4-chloro-5- [ (3-cyano-4-fluoro-phenyl) carbamoyl]-1, 2-dimethyl-pyrrol-3-yl]-2-oxo-acetate (700 mg). Reacting ethyl 2- [ 4-chloro-5- [ (3-cyano-4-fluoro-phenyl) carbamoyl]-1, 2-dimethyl-pyrrol-3-yl]-2-oxo-acetate (700mg, 1.787mmol) was dissolved in 1, 4-dioxane (6.6mL, 77.2mmol) and water (1.5 mL). Lithium hydroxide monohydrate (150mg, 3.57mmol) was added, and the mixture was cooled to room temperatureStirred for 16 hours. The mixture was concentrated in vacuo, and the residue was dissolved in water. Addition of HCl (1M in H)₂O) (3.6mL, 1M, 3.573mmol) and a precipitate formed. The product was filtered off and dried under vacuum to give 2- [ 4-chloro-5- [ (3-cyano-4-fluoro-phenyl) carbamoyl]-1, 2-dimethyl-pyrrol-3-yl]-2-oxo-acetic acid (400mg) as a white solid. Compound 43(33mg) was synthesized as described for Compound 47, starting from 2- [ 4-chloro-5- [ (3-cyano-4-fluoro-phenyl) carbamoyl]-1, 2-dimethyl-pyrrol-3-yl]-2-oxo-acetic acid using 1- (trifluoromethyl) cyclobut-1-amine instead of 3, 3-difluoro-1-methylcyclobutanamine hydrochloride. LC method C; rt: 1.97 min.m/z: 483.1(M-H) -accurate mass: 484.1.¹H NMR(400MHz，DMSO-d₆) δ ppm 1.81-2.10(m, 2H)2.42-2.57(m, 7H)3.66(s, 3H)7.55(t, J ═ 9.1Hz, 1H)7.99(ddd, J ═ 9.1, 4.8, 2.8Hz, 1H)8.21(dd, J ═ 5.7, 2.6Hz, 1H)9.28(s, 1H)10.75(s, 1H). Differential scanning calorimetry: from 30 ℃ to 300 ℃ at 10 ℃/min: peak: 218.9 ℃.

Compound 44: 3-chloro-N- (3-cyano-4-fluoro-phenyl) -1, 5-dimethyl-4- [2- [ (3-methyloxetane) Alk-3-yl) amino]-2-oxo-acetyl]Pyrrole-2-carboxamides

Compound 44(60mg) was synthesized as described for compound 47, using 3-methyloxetan-3-amine instead of 3, 3-difluoro-1-methylcyclobutylamine hydrochloride. LC method C; rt: 1.60min. m/z: 431.1(M-H) -accurate Mass: 432.1.¹H NMR(400MHz，DMSO-d₆) δ ppm 1.59(s, 3H)2.47(s, 3H)3.66(s, 3H)4.37(d, J ═ 6.4Hz, 2H)4.70(d, J ═ 6.4Hz, 2H)7.55(t, J ═ 9.1Hz, 1H)7.99(ddd, J ═ 9.2, 4.8, 2.6Hz, 1H)8.21(dd, J ═ 5.7, 2.6Hz, 1H)9.23(s, 1H)10.73(s, 1H). Differential scanning calorimetry: from 30 to 300 ℃ at 10 ℃/min: peak: 210.4 ℃.

Compound 45: 3-chloro-N- (3-cyano)4-fluoro-phenyl) -4- [2- (isopropylamino) -2-oxo-acetyl]- 1, 5-dimethyl-pyrrole-2-carboxamide

Compound 45(59mg) was synthesized as described for compound 47, using isopropylamine instead of 3, 3-difluoro-1-methylcyclobutylamine hydrochloride. LC method C; rt: 1.76 min.m/z: 403.1(M-H) -accurate Mass: 404.1.¹H NMR(400MHz，DMSO-d₆) δ ppm 1.14(d, J ═ 6.6Hz, 6H)2.45(s, 3H)3.65(s, 3H)3.90-4.02(m, 1H)7.55(t, J ═ 9.1Hz, 1H)7.98(ddd, J ═ 9.2, 4.8, 2.8Hz, 1H)8.21(dd, J ═ 5.7, 2.6Hz, 1H)8.58(d, J ═ 7.7Hz, 1H)10.71(s, 1H). Differential scanning calorimetry: from 30 ℃ to 300 ℃ at 10 ℃/min: peak: 238.3 ℃.

Compound 46: 3-chloro-N- (3-cyano-4-fluoro-phenyl) -4- [2- [ [ (1R) -2, 2-difluoro-1-methyl-propyl ] -2] Amino group]-2-oxo-acetyl]-1, 5-dimethyl-pyrrole-2-carboxamide

Compound 46(64mg) was synthesized as described for compound 47, using (2R) -3, 3-difluorobutan-2-amine instead of 3, 3-difluoro-1-methylcyclobutylamine hydrochloride. LC method C; rt: 1.85 min.m/z: 453.1(M-H) -accurate mass: 454.1.¹H NMR(400MHz，DMSO-d₆) δ ppm 1.21(d, J ═ 6.8Hz, 3H)1.62(t, J ═ 19.3Hz, 3H)2.47(s, 3H)3.66(s, 3H)4.23-4.39(m, 1H)7.55(t, J ═ 9.1Hz, 1H)7.93-8.02(m, 1H)8.21(dd, J ═ 5.7,. 6Hz, 1H)9.03(d, J ═ 9.0Hz, 1H)10.74(s, 1H) differential scanning calorimetry: from 30 ℃ to 300 ℃ at 10 ℃/min: peak: 240.5 ℃.

Compound 47: 3-chloro-N- (3-cyano-4-fluoro-phenyl) -4- [2- [ (3, 3-difluoro-1-methyl-cyclobutyl) -amino Base of]-2-oxo-acetyl]-1，5-dimethyl-pyrrole-2-carboxamide

Reacting 2- [ 4-chloro-5- [ (3-cyano-4-fluoro-phenyl) carbamoyl]-1-methyl-pyrrol-3-yl]-2-oxo-acetic acid (250mg, 0.715mmol) suspended in CH₃CN (4.9mL, 93.3mmol) and DMF (2.4mL, 31.4 mmol). NBS (190.9mg, 1.07mmol) was added, and the mixture was stirred at room temperature for 16 h. Will be the CH₃CN was distilled off and the residue was poured into water. The product was filtered off, washed with water and dried under vacuum to give 2- [ 2-bromo-4-chloro-5- [ (3-cyano-4-fluoro-phenyl) carbamoyl]-1-methyl-pyrrol-3-yl]-2-oxo-acetic acid (306 mg). A solution of 2- [ 2-bromo-4-chloro-5- [ (3-cyano-4-fluoro-phenyl) carbamoyl in DMF (3.4mL)]-1-methyl-pyrrol-3-yl]A solution of-2-oxo-acetic acid (306mg, 0.714mmol), tetramethyltin (0.208mL, 1.43mmol) was flushed with nitrogen for 5 minutes. Tetrakis (triphenylphosphine) palladium (0) (82.5mg, 0.071mmol) was added and the reaction mixture was heated by microwave irradiation at 140 ℃ for 30 min. The reaction mixture was concentrated to give 2- [ 4-chloro-5- [ (3-cyano-4-fluoro-phenyl) carbamoyl]-1, 2-dimethyl-pyrrol-3-yl]-2-oxo-acetic acid (260mg) and used as such in the next step. Adding Et₃N (0.397mL, 2.9mmol) was added to a solution of 2- [ 4-chloro-5- [ (3-cyano-4-fluoro-phenyl) carbamoyl in DMF (0.5mL)]-1, 2-dimethyl-pyrrol-3-yl]-2-oxo-acetic acid (260mg, 0.715mmol), 3, 3-difluoro-1-methylcyclobutylamine hydrochloride (140.8mg, 0.89mmol), HATU (339.7mg, 0.89mmol) and stirred at 65 ℃ for 30 min. The mixture was cooled and the solution was subjected to silica gel column chromatography using a gradient from 10% to 100% EtOAc in heptane and then by preparative HPLC (stationary phase: RP XBridge Prep C18OBD-10 μm, 30x150mm, mobile phase: 0.25% NH in water₄HCO₃Solution of CH₃CN) yielded compound 47(68mg) as a white fluffy solid. LC method D; rt: 5.74min. m/z: 465.0(M-H) -accurate mass: 466.1.¹H NMR(400MHz，DMSO-d₆) δ ppm 1.51(s, 3H)2.47(s, 3H)2.59-2.76(m, 2H)2.93-3.08(m, 2H)3.66(s, 3H)7.55(t, J ═ 9.1Hz, 1H)7.95-8.04(m, 1H)8.21(dd, J ═ 5.5, 2.4Hz, 1H)9.13(s, 1H)10.73(s, 1H). Differential scanning calorimetry: from 30 ℃ to 300 ℃ at 10 ℃/min: peak: 168.1 deg.C.

Compound 48: 4- [2- (tert-butylamino) -2-oxo-acetyl]-3-chloro-N- (3-cyano-4-fluoro-phenyl) - 5-cyclopropyl-1-methyl-pyrrole-2-carboxamide

Compound 48(54mg) was synthesized as described for compound 31, using tert-butylamine instead of (2R) -1, 1, 1-trifluoropropan-2-amine. LC method C; rt: 2.04 min.m/z: 443.1(M-H) -accurate Mass: 444.1.¹H NMR(400MHz，DMSO-d₆) δ ppm 0.47-0.57(m, 2H)0.95-1.05(m, 2H)1.35(s, 9H)1.80-1.87(m, 1H)3.76(s, 3H)7.55(t, J ═ 9.13Hz, 1H)7.93-8.02(m, 1H)8.13(s, 1H)8.20(dd, J ═ 5.72, 2.64Hz, 1H)10.68(s, 1H). Differential scanning calorimetry: from 30 ℃ to 300 ℃ at 10 ℃/min: peak: 198.8 deg.C.

Compound 49: 4- [2- (tert-butylamino) -2-oxo-acetyl]-3-chloro-5-cyano-N- (3-cyano-4-) Fluoro-phenyl) -1-methyl-pyrrole-2-carboxamide

Compound 50(100mg, 0.207mmol), copper (I) cyanide (27.8mg, 0.31mmol) in DMF (5.06mL, 65.03mmol) was charged to a microwave bottle. The bottle was capped and irradiated at 160 ℃ for 30 minutes. The mixture was concentrated in vacuo. The residue was partitioned between water and EtOAc. Addition of NH₄OH, and the organic layer was separated, dried (MgSO)₄) Filtered and concentrated in vacuo. Used in oxidationThe residue obtained is purified by column chromatography on silica (gradient elution: ethyl acetate: heptane from 0% to 100%). The product fractions were collected and concentrated in vacuo. The product was triturated in DIPE, filtered off and dried under vacuum to give compound 49(24mg) as a pale yellow solid. LC method B; rt: 1.05 min.m/z: 428.1(M-H) -accurate Mass: 429.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.32-1.38(m，9H)3.92(s，3H)7.60(t，J＝9.2Hz，1H)7.94-8.02(m，1H)8.21(dd，J＝5.9，2.6Hz，1H)8.59(s，1H)11.16(s，1H)。

methyl 4- [2- (tert-butylamino) -2-oxo-acetyl]Synthesis of (E) -3-chloro-1-methyl-pyrrole-2-carboxylate

Adding Et₃N (5.09mL, 36.6mmol) was added to a solution of 2- (4-chloro-5-methoxycarbonyl-1-methyl-pyrrol-3-yl) -2-oxo-acetic acid (3g, 12.21mmol), 2-methylpropan-2-amine (1.62mL, 15.27mmol), HATU (5.81g, 15.27mmol) in DMF (14.96mL, 193.26mmol) and stirred at 65 ℃ for 30 min. The solution was subjected to silica gel column chromatography using a gradient from 10% to 100% EtOAc in heptane. Concentrating the product fraction to give methyl 4- [2- (tert-butylamino) -2-oxo-acetyl]3-chloro-1-methyl-pyrrole-2-carboxylate (3.2g) as a clear oil which solidifies on standing. LC method B; rt: 1.02min. m/z: 299.1(M-H) -accurate mass: 300.1.

compound 50: 5-bromo-4- [2- (tert-butylamino) -2-oxo-acetyl]-3-chloro-N- (3-cyano-4-fluoro-) Phenyl) -1-methyl-pyrrole-2-carboxamides

As described analogously to Compound 29, methyl 4- [2- (tert-butylamino) -2-oxo-acetyl]-3-chloro-1-methyl-pyrrole-2-carboxylate instead of methyl 3-chloro-1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxylic acid esters, synthetic compoundsSubstance 50(500 mg). LC method B; rt: 1.06 min.m/z: 481.0(M-H) -accurate mass: 482.0.¹H NMR(400MHz，DMSO-d₆) δ ppm 1.35(s, 9H)3.75(s, 3H)7.57(t, J ═ 9.13Hz, 1H)7.94-8.03(m, 1H)8.20(dd, J ═ 5.72, 2.64Hz, 1H)8.38(s, 1-H)10.88(s, 1H). Differential scanning calorimetry: from 30 to 300 ℃ at 10 ℃/min: peak: 204.4 ℃.

Compound 51: n- (3-cyano-4-fluoro-phenyl) -1-methyl-4- [ 2-oxo-2- [ [ (1S) -2, 2, 2-trifluoro-1- Methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxamides

A solution of 2- (5-methoxycarbonyl-1-methyl-pyrrol-3-yl) -2-oxo-acetic acid (0.9g, 3.45mmol) in DMF (20mL) was cooled to 5 ℃ in an ice-water bath. DIPEA (1.8mL, 10.36mmol) and (S) -1, 1, 1-trifluoro-2-propylamine (468.5mg, 4.14mmol) were then added and stirred in an ice-water bath. During continued cooling, a solution of HATU (1444mg, 3.8mmol) in DMF (10mL) was added dropwise. The resulting solution was stirred for 1 hour with cooling. The reaction was quenched with water (25 mL). A beige precipitate formed, which was collected on a filter and washed with water. It was then dried in a vacuum oven at 55 ℃ for 24 hours to give methyl 1-methyl-4- [ 2-oxo-2- [ [ (1S) -2, 2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxylate (872mg) as a beige solid. Reacting methyl 1-methyl-4- [ 2-oxo-2- [ [ (1S) -2, 2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxylate (872mg, 2.85 mmol) was dissolved in THF (20mL), and LiOH (272.8mg, 11.39mmol) in water (2mL) was added. MeOH (2mL) was added to dissolve all reactants. The mixture was stirred at room temperature overnight, then concentrated in vacuo until only water remained. Addition of HCl (1M in H)₂O) (11.4mL, 1M, 11.4mmol) and extracted with Me-THF (3X 10 mL). The combined extracts were washed with brine (20mL) over Na₂SO₄Drying, filtering, and drying in vacuumAerial concentration to give 1-methyl-4- [ 2-oxo-2- [ [ (1S) -2, 2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxylic acid (823mg) as a bright white powder. LC method B; rt: 0.49 min.m/z: 291.0(M-H) -accurate mass: 292.1. 1-methyl-4- [ 2-oxo-2- [ [ (1S) -2, 2, 2-trifluoro-1-methyl-ethyl ] in DMF (1.6mL)]Amino group]Acetyl group]Pyrrole-2-carboxylic acid (300mg, 1.03mmol) and DIPEA (0.53mL, 3.08mmol) were treated with HATU (429.4mg, 1.13 mmol). The resulting mixture was stirred at room temperature for 30 minutes. 5-amino-2-fluorobenzonitrile (209.6mg, 1.54mmol) was then added, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was injected as such on a silica plug and purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0: 100 to 100: 0). The desired fraction was concentrated under reduced pressure to give compound 51(260 mg). LC method B; rt: 1.03 min.m/z: 409.1(M-H) -accurate mass: 410.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.36(d，J＝7.0Hz，3H)，3.97(s，3H)，4.60-4.76(m，1H)，7.53(t，J＝9.1Hz，1H)，7.69(d，J＝1.8Hz，1H)，8.03(ddd，J＝9.2，4.9，2.6Hz，1H)，8.14(d，J＝1.3Hz，1H)，8.23(dd，J＝5.8，2.8Hz，1H)，9.34(d，J＝8.1Hz，1H)，10.42(br.s.，1H)

compound 52: n- (3-cyano-4-fluoro-phenyl) -4- [2- (isopropylamino) -2-oxo-acetyl]-1, 5-bis Methyl-pyrrole-2-carboxamides

NaH (60% dispersion in mineral oil, 5875mg, 147mmol) was added portionwise to a solution of ethyl 5-methyl-1H-pyrrole-2-carboxylate (15000mg, 97.92mmol) and methyl iodide (7.3mL, 117.5mmol) in DMF (40 mL). The reaction was stirred for 1 hour. Addition of HCl (1M in H)₂In O) (49.0mL, 1M, 49.0 mmol). The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organics were washed with brine, over Na₂SO₄Dried, filtered and concentrated in vacuoCrude ethyl 1, 5-dimethylpyrrole-2-carboxylate (8.56g) was produced as a yellow powder, which was used as such. Crude ethyl 1, 5-dimethylpyrrole-2-carboxylate (8560mg) was dissolved in THF (dried over molecular sieves) (144mL) and 5-amino-2-fluorobenzonitrile (7666mg, 56.3mmol) was added. The mixture was cooled in an ice bath. Over a period of 10 minutes, lithium bis (trimethylsilyl) amide (1M in toluene) (102.4mL, 1M) was added dropwise. The ice bath was removed and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated ammonium chloride (300mL) and the resulting mixture was extracted with EtOAc (3 × 150 mL). The combined extracts were washed with brine (200mL) over Na₂SO₄Dried, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography using a gradient elution from heptane to EtOAc (100: 0 to 0: 100). The desired fractions were collected and concentrated in vacuo to yield N- (3-cyano-4-fluoro-phenyl) -1, 5-dimethyl-pyrrole-2-carboxamide (10.2g) as a yellowish powder, which was used as such. LC method B; rt: 0.98 min.m/z: 256.1(M-H) -accurate mass: 257.1. n- (3-cyano-4-fluorophenyl) -1, 5-dimethyl-pyrrole-2-carboxamide (5000mg, 19.44mmol) was dissolved in DCM (50mL) and cooled on ice under nitrogen. A solution of ethyl 2-chloro-2-oxo-acetate (3.3mL) in DCM (10mL) was added dropwise and the mixture was stirred for 15min. Mixing AlCl₃(5183mg, 38.9mmol) was added in portions. The mixture was heated at 0 ℃ under N₂Stirred for 5 hours. The mixture was diluted with Me-THF (200mL) and added dropwise to ice water (500 mL). The mixture was extracted with EtOAc (3X 150 mL). The combined organic layers were washed with water and brine and dried (Na)₂SO₄) And evaporated to dryness to give crude ethyl 2- [5- [ (3-cyano-4-fluoro-phenyl) carbamoyl]-1, 2-dimethyl-pyrrol-3-yl]-2-oxo-acetate (9.4g), as a yellow powder, was used as such. LC method B; rt: 1.04 min.m/z: 356.1(M-H) -accurate Mass: 357.1. subjecting crude ethyl 2- [5- [ (3-cyano-4-fluoro-phenyl) carbamoyl]-1, 2-dimethyl-pyrrol-3-yl]-2-oxo-acetate (9.4g, 26.4mmol) was dissolved in THF (200mL) and NaOH (1) was added theretoM is in H₂In O, 39.6 mL). The resulting mixture was stirred at room temperature for 30 minutes, then concentrated in vacuo until only water remained. Then HCl (aq/1M/40mL) was added and extracted with Me-THF (3X 100 mL). The combined extracts were washed with brine, over Na₂SO₄Dried, filtered, and concentrated in vacuo to give crude 2- [5- [ (3-cyano-4-fluoro-phenyl) carbamoyl]-1, 2-dimethyl-pyrrol-3-yl]-2-oxo-acetic acid (8.02g), as a yellow solid, was used as such. LC method B; rt: 0.58min. m/z: 328.0(M-H) -accurate mass: 329.1. the crude 2- [5- [ (3-cyano-4-fluoro-phenyl) carbamoyl group in DMF (0.5mL)]-1, 2-dimethyl-pyrrol-3-yl]-2-oxo-acetic acid (100mg) and DIPEA (0.13mL, 0.77mmol) were treated with HATU (106.7mg, 0.28 mmol). The resulting mixture was stirred at room temperature for 30 minutes. Isopropylamine (18.09mg, 0.31mmol) was then added and the resulting mixture was stirred at room temperature for 2 hours, followed by 50 ℃ for 2 hours. The mixture was injected as such on a silica plug and purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0: 100 to 100: 0). And further purified by preparative HPLC (RP SunAire PrepC18OBD-10 μm, 30X150 mm). Mobile phase (0.25% NH in water)₄HCO₃Solution, MeOH). The desired fractions were concentrated under reduced pressure and co-evaporated twice (2 × 15mL MeOH) and the residue was dried in a vacuum oven at 55 ℃ for 18 hours to yield compound 52 as an off-white solid. LC method B; rt: 0.99 min.m/z: 369.1(M-H) -accurate Mass: 370.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.15(d，J＝6.6Hz，6H)，2.57(s，3H)，3.84(s，3H)，3.91-4.10(m，1H)，7.52(t，J＝9.1Hz，1H)，7.72(s，1H)，8.02(ddd，J＝9.2，5.0，2.8Hz，1H)，8.22(dd，J＝5.7，2.6Hz，1H)，8.51(d，J＝7.9Hz，1H)，10.42(s，1H)。

compound 53: n- (3-cyano-4-fluoro-phenyl) -1, 5-dimethyl-4- [2- [ [ (1R) -1-methylpropyl)]Ammonia Base of]-2-oxo-acetyl]Pyrrole-2-carboxamides

Compound 53 is prepared as described for compound 52 using (R) - (-) 2-aminobutane instead of isopropylamine. LC method B; rt: 1.06 min.m/z: 383.1(M-H) -accurate mass: 384.2.¹H NMR(400MHz，DMSO-d₆)δ0.86(t，J＝7.3Hz，3H)，1.12(d，J＝6.6Hz，3H)，1.42-1.57(m，2H)，2.57(s，3H)，3.73-3.87(m，4H)，7.52(t，J＝9.2Hz，1H)，7.73(s，1H)，8.02(ddd，J＝9.2，5.0，2.8Hz，1H)，8.22(dd，J＝5.7，2.6Hz，1H)，8.45(d，J＝8.4Hz，1H)，10.43(s，1H)。

synthesis of (2R) -3, 3-difluorobutan-2-amine

(R) -2- ((tert-butoxycarbonyl) amino) propionic acid (30g, 159mmol), N, O-dimethylhydroxylamine hydrochloride (17.5g, 178mmol), HATU (74g, 195mmol) and N, N-diisopropylethylamine (30g, 232mmol) were dissolved in DMF (300mL) and stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in CH₂Cl₂(500mL) and washed with brine (3 × 200 mL). Subjecting the organic layer to Na₂SO₄Dried and concentrated in vacuo. The residue was purified by silica gel chromatography using petroleum ether EtOAc 2: 1 as eluent to give tert-butyl N- [ (1R) -2- [ methoxy (methyl) amino group]-1-methyl-2-oxo-ethyl]Carbamate (28.9 g). Reacting tert-butyl N- [ (1R) -2- [ methoxy (methyl) amino group]-1-methyl-2-oxo-ethyl]The carbamate was dissolved in THF (300mL) and cooled to 0 ℃. Methylmagnesium bromide 3.0m in diethyl ether (85mL, 255mmol) was added dropwise and the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was washed with saturated NH₄Quenched with Cl and CH₂Cl₂(3X 100mL) extraction. Subjecting the combined organic layers to Na₂SO₄Dried, filtered and evaporated to dryness. The resulting residue was purified by silica gel chromatography to give tert-butyl N- [ (1R) -1-methyl-2-oxo-propyl]Carbamate (1)8.9 g). To in CH₂Cl₂Cooled (-78 ℃ C.) in (200mL) tert-butyl N- [ (1R) -1-methyl-2-oxo-propyl]To a solution of carbamate (10g, 53.4mmol) was added bis (2-methoxyethyl) aminosulfur trifluoride (18.9g, 117.5mmol) dropwise and stirring was continued at-78 ℃ for 2 hours. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with saturated NaHCO₃Quenched and extracted with EtOAc. The combined organic layers were washed with brine, over MgSO₄Dried, filtered and evaporated to dryness. The residue was purified by silica gel chromatography using a gradient from petroleum ether to petroleum ether EtOAc 1: 1 to give tert-butyl N- [ (1R) -2, 2-difluoro-1-methyl-propyl ester]Carbamate (6.77 g). Reacting tert-butyl N- [ (1R) -2, 2-difluoro-1-methyl-propyl]Carbamate (6.77g) was dissolved in EtOAc (50 mL). HCl in EtOAc was added at 0 ℃ and the reaction mixture was stirred at room temperature for 4 hours. The precipitate formed was filtered off and dried under high vacuum to give (2R) -3, 3-difluorobutan-2-amine hydrochloride (3.5 g).

Compound 54: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ [ (1R) -2, 2-difluoro-1-methyl-propyl ] -2]Amino group]- 2-oxo-acetyl]-1, 5-dimethyl-pyrrole-2-carboxamide

One vial was filled with crude 2- [5- [ (3-cyano-4-fluoro-phenyl) carbamoyl]-1, 2-dimethyl-pyrrol-3-yl]-2-oxo-acetic acid (250mg), HATU (266.74mg, 0.7mmol), (2R) -3, 3-difluorobutan-2-amine hydrochloride (0.77mmol) and DMF (1 mL). The mixture was heated and stirred at 65 ℃. DIPEA (0.33mL, 1.91mmol) was then added and the mixture was stirred for 20min. The mixture was cooled to room temperature and poured directly into a silica plug and purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0: 100 to 100: 0). The desired fraction was concentrated under reduced pressure and dried in a vacuum oven at 55 ℃ for 18 hours. The resulting solid was crystallized from iPrOH. Will be provided withThe crystals were collected on a filter and dried in a vacuum oven at 55 ℃ for 18 hours to give compound 54(124mg) as a white powder. LC method B; rt: 1.06 min.m/z: 419.1(M-H) -accurate mass: 420.1.¹H NMR(400MHz，DMSO-d₆)δppm1.23(d，J＝6.8Hz，3H)，1.62(t，J＝19.3Hz，3H)，2.58(s，3H)，3.85(s，3H)，4.28-4.43(m，1H)，7.52(t，J＝9.1Hz，1H)，7.65(s，1H)，7.98-8.05(m，1H)，8.21(dd，J＝5.7，2.6Hz，1H)，8.92(d，J＝9.2Hz，1H)，10.44(s，1H)。

synthesis of (2S) -3, 3-difluorobutan-2-amine hydrochloride

(S) -2- ((tert-butoxycarbonyl) amino) propionic acid (39g, 206mmol), N, O-dimethylhydroxylamine hydrochloride (24g, 246mmol), HATU (117g, 308mmol) and N, N-diisopropylethylamine (66.3g, 513mmol) were dissolved in DMF (500mL) and stirred at room temperature for 16 hours. The reaction mixture was poured into water (500mL) and the precipitate formed was filtered off. The filter cake was washed with water (1L) and dried to give tert-butyl N- [ (1S) -2- [ methoxy (methyl) amino group]-1-methyl-2-oxo-ethyl]Carbamate (36g) as a white powder. Reacting tert-butyl N- [ (1S) -2- [ methoxy (methyl) amino group]-1-methyl-2-oxo-ethyl]The carbamate (35g, 151mmol) was dissolved in THF (500mL) and cooled to 0 deg.C. Methylmagnesium bromide (3.0M in diethyl ether, 140mL) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water (100mL) and evaporated to dryness. The residue was dissolved in EtOAc, washed with water and taken over Na₂SO₄Dried, filtered and evaporated to dryness to give tert-butyl N- [ (1S) -1-methyl-2-oxo-propyl]Carbamate (22g) as a white powder. To a cooled (-78 ℃ C.) in CH₂Cl₂Tert-butyl N- [ (1S) -1-methyl-2-oxo-propyl ] in (200mL)]To a solution of carbamate (12g, 64.1mmol) was added bis (2-methoxyethyl) aminethitrifluoride (18.9g, 117.5 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into water and charged with CH₂Cl₂And (4) extracting. The organic layer was washed with water and Na₂SO₄Dried, filtered and evaporated to dryness. The resulting residue was purified by silica gel chromatography to give tert-butyl N- [ (1S) -2, 2-difluoro-1-methyl-propyl ester]Carbamate (5.8g) as a pale yellow solid. Reacting tert-butyl N- [ (1S) -2, 2-difluoro-1-methyl-propyl]The carbamate (5.8g, 27.7mmol) was dissolved in EtOAc (100 mL). HCl (g) gas was bubbled in for 30 minutes, then the volatiles were removed under reduced pressure to give (2S) -3, 3-difluorobutan-2-amine hydrochloride (3.8g)¹H NMR(400MHz，DMSO-d₆)δppm 8.69(br.s.，3H)，3.76-3.63(m，1H)，1.72(t，J＝19.7Hz，3H)，1.28(d，J＝6.8Hz，3H)。

Compound 55: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ [ (1S) -2, 2-difluoro-1-methyl-propyl ] -2]Amino group]- 2-oxo-acetyl]-1, 5-dimethyl-pyrrole-2-carboxamide

Compound 55(130mg) was prepared as described for compound 54 using (2S) -3, 3-difluorobut-2-amine hydrochloride instead of (2R) -3, 3-difluorobut-2-amine hydrochloride. LC method B; rt: 1.06 min.m/z: 419.1(M-H) -accurate mass: 420.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.23(d，J＝6.8Hz，3H)，1.62(t，J＝19.3Hz，3H)，2.58(s，3H)，3.85(s，3H)，4.28-4.44(m，1H)，7.52(t，J＝9.1Hz，1H)，7.65(s，1H)，7.98-8.05(m，1H)，8.21(dd，J＝5.7，2.6Hz，1H)，8.92(d，J＝9.2Hz，1H)，10.44(s，1H)。

compound 56: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ (3, 3-difluoro-1-methyl-cyclobutyl) amino]-2- Oxo-acetyl]-1, 5-dimethyl-pyrrole-2-carboxamide

As analogously as described for compound 54, use is made of 3, 3-bisCompound 56(147mg) was prepared by substituting fluoro-1-methyl-cyclobutylamine hydrochloride for (2R) -3, 3-difluorobut-2-amine hydrochloride. LC method B; rt: 1.08 min.m/z: 431.1(M-H) -accurate Mass: 432.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.52(s，3H)，2.58(s，3H)，2.61-2.77(m，2H)，2.91-3.13(m，2H)，3.85(s，3H)，7.52(t，J＝9.1Hz，1H)，7.73(s，1H)，7.99-8.06(m，1H)，8.22(dd，J＝5.8，2.8Hz，1H)，9.10(s，1H)，10.45(s，1H)。

compound 57: n- (3-cyano-4-fluoro-phenyl) -1, 5-dimethyl-4- [ 2-oxo-2- [ [1- (trifluoromethyl) cyclo Propyl radical]Amino group]Acetyl group]Pyrrole-2-carboxamides

Compound 57(138mg) was prepared as described for compound 54 using 1-trifluoromethyl-1-cyclopropylamine instead of (2R) -3, 3-difluorobutan-2-amine hydrochloride. LC method B; rt: 1.07 min.m/z: 435.1(M-H) -accurate Mass: 436.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.09-1.19(m，2H)，1.28-1.36(m，2H)，2.56(s，3H)，3.84(s，3H)，7.52(t，J＝9.1Hz，1H)，7.68(s，1H)，7.97-8.06(m，1H)，8.21(dd，J＝5.7，2.6Hz，1H)，9.49(s，1H)，10.46(s，1H)。

compound 58: n- (3-cyano-4-fluoro-phenyl) -1, 5-dimethyl-4- [ 2-oxo-2- [ (2, 2, 2-trifluoro-1, 1-dimethyl-ethyl) amino]Acetyl group]Pyrrole-2-carboxamides

Compound 58(129mg) was prepared as described for compound 54 using 2, 2, 2-trifluoro-1, 1-dimethyl-ethylamine instead of (2R) -3, 3-difluorobutan-2-amine hydrochloride. LC method B; rt: 1.14min. m/z: 437.1(M-H) -accurate mass: 438.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.60(s，6H)，2.56(s，3H)，3.84(s，3H)，7.48-7.57(m，2H)，8.02(s，1H)，8.21(dd，J＝5.8，2.8Hz，1H)，8.62(s，1H)，10.48(s，1H)

compound 59: 4- [2- (tert-butylamino) -2-oxo-acetyl]-N- (3-cyano-4-fluoro-phenyl) -1, 5- Dimethyl-pyrrole-2-carboxamide

Compound 59(54mg) was prepared as described for compound 54 using tert-butylamine instead of (2R) -3, 3-difluorobutan-2-amine hydrochloride. LC method B; rt: 1.10min. m/z: 383.1(M-H) -accurate mass: 384.2.¹H NMR(400MHz，DMSO-d₆)δppm 1.36(s，9H)，2.56(s，3H)，3.84(s，3H)，7.52(t，J＝9.1Hz，1H)，7.65(s，1H)，7.98-8.05(m，1H)，8.08(s，1H)，8.22(dd，J＝5.7，2.6Hz，1H)，10.46(s，1H)

compound 60: n- (3-cyano-4-fluoro-phenyl) -1, 5-dimethyl-4- [2- [ (3-methyloxetane-3- Radical) amino]-2-oxo-acetyl]Pyrrole-2-carboxamides

Compound 60(149mg) was prepared as described for compound 54 using 3-methyl-3-oxetane instead of (2R) -3, 3-difluorobutan-2-amine hydrochloride. LC method B; rt: 0.90 min.m/z: 397.1(M-H) -accurate mass: 398.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.59(s，3H)，2.58(s，3H)，3.85(s，3H)，4.37(d，J＝6.6Hz，2H)，4.72(d，J＝6.4Hz，2H)，7.52(t，J＝9.1Hz，1H)，7.77(s，1H)，7.98-8.06(m，1H)，8.21(dd，J＝5.8，2.8Hz，1H)，9.22(s，1H)，10.45(s，1H)。

compound 61: n- (3-cyano-4-fluoro-phenyl)) -5-cyclopropyl-1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxamides

Compound 25(100mg, 0.2mmol), potassium cyclopropyltrifluoroborate (45mg, 0.31mmol), Cs₂CO₃(133mg, 0.41mmol), DME (2.3mL) and water (0.23mL) were charged to a microwave bottle. The mixture is mixed with N₂Purge 5 minutes. Tetrakis (triphenylphosphine) palladium (0) (47.24mg, 0.041mmol) was added and the vial was capped. The mixture was stirred at 110 ℃ for 16 hours. The mixture was cooled and the residue was taken up in saturated NH₄The Cl solution and Me-THF were partitioned. The organic layer was separated and dried (MgSO)₄) And concentrated in vacuo. The crude material was purified using silica gel chromatography (gradient elution: EtOAc-heptane 0: 100 to 100: 0) and further purified by preparative HPLC (RP SunAire Prep C18OBD-10 μm, 30X150 mm). Mobile phase (0.25% NH in water)₄HCO₃Solution, MeOH), compound 61(16mg) as a white powder.

LC method B; rt: 1.11min. m/z: 449.1(M-H) -accurate mass: 450.1.¹H NMR(400MHz，DMSO-d₆)δppm 0.61-0.70(m，2H)，1.02-1.13(m，2H)，1.34(d，J＝7.0Hz，3H)，1.76-1.90(m，1H)，3.96(s，3H)，4.70(dq，J＝15.5，7.7Hz，1H)，7.52(t，J＝9.2Hz，1H)，7.56(s，1H)，7.96-8.06(m，1H)，8.21(dd，J＝5.8，2.8Hz，1H)，9.25(d，J＝8.8Hz，1H)，10.42(s，1H)。

compounds 62, 63, 65 to 72 and 74 to 82 were prepared as described for compound 73, using the corresponding amine instead of (1-aminocyclopropyl) methanol.

Compound 62: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ [ (3R, 4S) -3-hydroxy-1-methyl-4-piperidinyl] Amino group]-2-oxo-acetyl]-1, 5-dimethyl-pyrrole-2-carboxamide

(3R, 4S) -4-amino-1-methylpiperidin-3-ol was used as an amine to give compound 62(40.3 mg).¹H NMR(400MHz，DMSO-d₆) δ ppm 1.46-1.65(m, 1H), 1.79-1.93(m, 1H), 1.98-2.09(m, 1H), 2.12-2.25(m, 4H), 2.54-2.70(m, 5H), 3.69-3.80(m, 2H), 3.84(s, 3H), 4.60-4.88(m, 1H), 7.52(t, J ═ 9.2Hz, 1H), 7.82(s, 1H), 7.98-8.09(m, 2H), 8.22(dd, J ═ 5.7, 2.6Hz, 1H), 10.43(s, 1H). LC method B; rt: 0.74min. m/z: 440.2(M-H) -accurate Mass: 441.2.

compound 63: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ [ (1S) -1- (hydroxymethyl) pentyl]Amino group]-2-oxygen Substituted-acetyl]-1, 5-dimethyl-pyrrole-2-carboxamide

(S) - (+) -2-amino-1-hexanol was used as the amine to give compound 63(33.7 mg).¹H NMR(400MHz，DMSO-d₆) δ ppm 0.80-0.91(m, 3H), 1.19-1.47(m, 5H), 1.50-1.69(m, 1H), 2.57(s, 3H), 3.34-3.52(m, 2H), 3.73-3.91(m, 4H), 4.64-4.81(m, 1H), 7.52(t, J ═ 9.1Hz, 1H), 7.77(s, 1H), 8.03(ddd, J ═ 9.2, 4.8, 2.6Hz, 1H), 8.22(dd, J ═ 5.7, 2.6Hz, 1H), 8.29(d, J ═ 9.0Hz, 1H), 10.47(s, 1H). LC method C; rt: 1.89 min.m/z: 427.3(M-H) -accurate mass: 428.2.

compound 65: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ [ (1S, 2S) -2-hydroxycyclopentyl]Amino group]-2-oxygen Substituted-acetyl]-1, 5-dimethyl-pyrrole-2-carboxamide

(1S, 2S) -trans-2-aminocyclopentanol hydrochloride was used as the amine to give compound 65(27.1 mg).¹H NMR(400MHz，DMSO-d₆) δ ppm 1.40-1.53(m, 2H), 1.55-1.73(m, 2H), 1.75-1.90(m, 1H), 1.92-2.05(m, 1H), 2.57(s, 3H), 3.84(s, 3H), 3.87-4.00(m, 2H), 4.78(d, J ═ 4.0Hz, 1H), 7.52(t, J ═ 9.1Hz, 1H), 7.71(s, 1H), 8.02(ddd, J ═ 9.2, 4.9, 2.6Hz, 1H), 8.22(dd, J ═ 5.7, 2.6Hz, 1H), 8.54(d, J ═ 7.5Hz, 1H), 10.45(s, 1H). LC method C; rt: 1.74min. m/z: 411.4(M-H) -accurate mass: 412.2.

compound 66: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ [ (1S, 2R, 5R) -2-hydroxy-5-methyl-cyclopentyl] Amino group]-2-oxo-acetyl]-1, 5-dimethyl-pyrrole-2-carboxamide

(1R, 2S, 3R) -2-amino-3-methyl-cyclopentanol hydrochloride was used as the amine to give compound 66(38.2 mg).¹H NMR(400MHz，DMSO-d₆) δ ppm 0.98(d, J ═ 6.6Hz, 3H), 1.05-1.32(m, 2H), 1.48-1.62(m, 1H), 1.82-2.09(m, 3H), 2.58(s, 3H), 3.50-3.60(m, 1H), 3.85(s, 3H), 4.89(d, J ═ 4.2Hz, 1H), 7.52(t, J ═ 9.1Hz, 1H), 7.92(s, 1H), 7.96-8.06(m, 2H), 8.22(dd, J ═ 5.8, 2.8Hz, 1H), 10.46(s, 1H). LC method B; rt: 0.94 min.m/z: 425.1(M-H) -accurate Mass: 426.2.

compound 67: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ [ (1S, 2S) -2-hydroxycyclohexyl]Amino group]-2-oxygen Substituted-acetyl]-1, 5-dimethyl-pyrrole-2-carboxamide

Use of trans- (1S, 2S) -2-aminocyclohexanol hydrochloride as an amine to produce a compound67(42.5mg)。¹H NMR(400MHz，DMSO-d₆) δ ppm 1.19-1.35(m, 4H), 1.51-1.71(m, 2H), 1.78-1.94(m, 2H), 2.57(s, 3H), 3.35-3.58(m, 2H), 3.84(s, 3H), 4.64(d, J ═ 4.8Hz, 1H), 7.52(t, J ═ 9.1Hz, 1H), 7.79(s, 1H), 8.02(ddd, J ═ 9.2, 4.9, 2.6Hz, 1H), 8.22(dd, J ═ 5.9, 2.6Hz, 1H), 8.36(d, J ═ 8.4Hz, 1H), 10.45(s, 1H). LC method C; rt: 1.78min. m/z: 425.2(M-H) -accurate Mass: 426.2.

compound 68: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ [ (1S) -1- (hydroxymethyl) -2-methyl-propyl]Ammonia Base of]-2-oxo-acetyl]-1, 5-dimethyl-pyrrole-2-carboxamide

(S) - (+) -2-amino-3-methyl-1-butanol was used as an amine to give compound 68(43.9 mg).¹H NMR(400MHz，DMSO-d₆) δ ppm 0.80-0.95(m, 6H), 1.83-1.95(m, 1H), 2.58(s, 3H), 3.49(t, J ═ 5.2Hz, 2H), 3.63-3.74(m, 1H), 3.84(s, 3H), 4.64(t, J ═ 5.2Hz, 1H), 7.52(t, J ═ 9.1Hz, 1H), 7.78(s, 1H), 8.02(ddd, J ═ 9.2, 4.8, 2.9Hz, 1H), 8.18-8.26(m, 2H), 10.46(s, 1H). LC method B; rt: 0.90 min.m/z: 413.2(M-H) -accurate Mass: 414.2.

compound 69: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ [ (1S, 2S) -1- (hydroxymethyl) -2-methyl-butyl] Amino group]-2-oxo-acetyl]-1, 5-dimethyl-pyrrole-2-carboxamide

L-isoleucinol was used as the amine to give compound 69(34.8 mg).¹H NMR(400MHz，DMSO-d₆)δppm0.81-0.91(m，6H)，1.02-1.15(m，1H)，1.33-1.54(m，1H)，1.55-1.76(m，1H)，2.55-2.61(m，3H)，3.45-3.57(m，2H)，3.68-3.79(m, 1H), 3.84(s, 3H), 4.53-4.69(m, 1H), 7.52(t, J ═ 9.1Hz, 1H), 7.79(s, 1H), 8.03(ddd, J ═ 9.2, 5.0, 2.8Hz, 1H), 8.17-8.29(m, 2H), 10.47(s, 1H). LC method C; rt: 1.88min. m/z: 427.3(M-H)^-Accurate quality: 428.2.

compound 70: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ [ 3-hydroxy-1- (methoxymethyl) -1-methyl-propane Base of]Amino group]-2-oxo-acetyl]-1, 5-dimethyl-pyrrole-2-carboxamide

3-amino-4-methoxy-3-methylbutan-1-ol was used as the amine to give compound 70(13.5 mg).¹H NMR(400MHz，DMSO-d₆) δ ppm 1.35(s, 3H), 1.72-1.83(m, 1H), 1.92-2.04(m, 1H), 2.56(s, 3H), 3.28(s, 3H), 3.54(q, J ═ 9.1Hz, 4H), 3.83(s, 3H), 4.54-4.70(m, 1H), 7.52(t, J ═ 9.1Hz, 1H), 7.80(s, 1H), 8.03(ddd, J ═ 9.2, 4.9, 2.9Hz, 1H), 8.18-8.27(m, 2H), 10.48(s, 1H). LC method B; rt: 0.92 min.m/z: 443.1(M-H)^-Accurate quality: 444.2.

compound 71: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ [3- (hydroxymethyl) oxetan-3-yl]Amino group]- 2-oxo-acetyl]-1, 5-dimethyl-pyrrole-2-carboxamide

(3-Aminooxetan-3-yl) methanol was used as the amine to give compound 71(36.4 mg).¹H NMR(400MHz，DMSO-d₆) δ ppm 2.58(s, 3H), 3.66-3.74(m, 2H), 3.85(s, 3H), 4.54(d, J ═ 6.6Hz, 2H), 4.66(d, J ═ 6.6Hz, 2H), 5.14-5.31(m, 1H), 7.52(t, J ═ 9.1Hz, 1H), 7.77(s, 1H), 7.98-8.07(m, 1H), 8.22(dd, J ═ 5.6, 2.5Hz, 1H), 9.12(s, 1H), 10.46(s, 1H). LC method B; rt:0.78min.m/z：413.1(M-H)^-accurate quality: 414.1.

compound 72: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ (2-hydroxy-1, 2-dimethyl-propyl) amino]-2- Oxo-acetyl]-1, 5-dimethyl-pyrrole-2-carboxamide

3-amino-2-methylbutan-2-ol was used as the amine to give compound 72(6.3 mg).

¹H NMR(400MHz，DMSO-d₆) δ ppm 1.08(s, 3H), 1.09-1.15(m, 6H), 2.56-2.60(m, 3H), 3.75-3.89(m, 4H), 4.51(s, 1H), 7.52(t, J ═ 9.1Hz, 1H), 7.79(s, 1H), 8.02(ddd, J ═ 9.2, 5.0, 2.8Hz, 1H), 8.13(d, J ═ 9.5Hz, 1H), 8.20-8.24(m, 1H), 10.45(s, 1H). LC method C; rt: 1.78min. m/z: 413.4(M-H)^-Accurate quality: 414.2.

compound 73: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ [1- (hydroxymethyl) cyclopropyl ] methyl ester]Amino group]-2-oxo-ethane Acyl radical]-1, 5-dimethyl-pyrrole-2-carboxamide

To a vial of (1-aminocyclopropyl) methanol (32mg, 0.37mmol) was added HATU (128.03mg, 0.34mmol), followed by DMF (0.48mL, 6.17mmol) and 2- [5- [ (3-cyano-4-fluoro-phenyl) carbamoyl in DIPEA (0.16mL, 0.75g/mL, 0.92mmol)]-1, 2-dimethyl-pyrrol-3-yl]-2-oxo-acetic acid (120mg, 0.31 mmol). The resulting mixture was stirred at room temperature for 5 hours. Water (5mL) was then added and CH used₂Cl₂Extraction was performed (2 × 5 mL). The combined organics were concentrated and the mixture was subjected to preparative HPLC (stationary phase: RP Xbridge PrepC18OBD-10 μm, 30X150mm, mobile phase: 0.25% NH)₄HCO₃Dissolving in waterLiquid, MeOH), and further purified by silica gel column chromatography (gradient elution: EtOAc-heptane 0: 100 to 100: 0). The desired fractions were concentrated in vacuo and the residue was dried in a vacuum oven at 55 ℃ for 24 h to yield compound 73(14 mg).¹H NMR(400MHz，DMSO-d₆) δ ppm 0.67-0.81(m, 4H), 2.55(s, 3H), 3.52(d, J ═ 4.8Hz, 2H), 3.84(s, 3H), 4.67-4.80(m, 1H), 7.52(t, J ═ 9.2Hz, 1H), 7.71(s, 1H), 8.02(ddd, J ═ 9.3, 4.9, 2.8Hz, 1H), 8.22(dd, J ═ 5.8, 2.8Hz, 1H), 8.78(s, 1H), 10.46(s, 1H). LC method B; rt: 0.80 min.m/z: 397.1(M-H)^-Accurate quality: 398.1.

compound 74: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ (1-cyclopropyl-3-hydroxy-propyl) amino]-2-oxygen Substituted-acetyl]-1, 5-dimethyl-pyrrole-2-carboxamide

3-amino-3-cyclopropyl-propan-1-ol was used as the amine to give compound 74(40 mg).¹H NMR(400MHz，DMSO-d₆) δ ppm 0.18-0.26(m, 1H), 0.27-0.41(m, 2H), 0.42-0.52(m, 1H), 0.91-1.03(m, 1H), 1.76(q, J ═ 6.9Hz, 2H), 2.57(s, 3H), 3.35-3.54(m, 3H), 3.84(s, 3H), 4.32-4.49(m, 1H), 7.52(t, J ═ 9.2Hz, 1H), 7.75(s, 1H), 8.02(ddd, J ═ 9.2, 4.9, 2.9Hz, 1H), 8.22(dd, J ═ 5.8, 2.8Hz, 1H), 8.54(d, J ═ 8.8, 1H), 10.46(s, 1H). LC method C; rt: 1.75min. m/z: 425.2(M-H)^-Accurate quality: 426.2

Compound 75: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ [ (1R) -1- (hydroxymethyl) pentyl]Amino group]-2-oxygen Substituted-acetyl]-1, 5-dimethyl-pyrrole-2-carboxamide

(R) - (-) -2-amino-1-hexanol was used as the amine to give compound 75(22 mg).¹H NMR(400MHz，DMSO-d₆) δ ppm 0.80-0.90(m, 3H), 1.19-1.46(m, 5H), 1.52-1.66(m, 1H), 2.57(s, 3H), 3.33-3.49(m, 2H), 3.75-3.89(m, 4H), 4.68-4.75(m, 1H), 7.52(t, J ═ 9.1Hz, 1H), 7.77(s, 1H), 8.03(ddd, J ═ 9.2, 5.0, 2.8Hz, 1H), 8.22(dd, J ═ 5.8, 2.8Hz, 1H), 8.28(d, J ═ 8.8Hz, 1H), 10.46(s, 1H). LC method C; rt: 1.93 min.m/z: 427.4(M-H)^-Accurate quality: 428.2

Compound 76: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ [1- (hydroxymethyl) -1-methyl-propyl ] methyl]Amino group]-2- Oxo-acetyl]-1, 5-dimethyl-pyrrole-2-carboxamide

2-amino-2-methylbutan-1-ol was used as the amine to give compound 76(26 mg).¹H NMR(400MHz，DMSO-d₆) δ ppm 0.81(t, J ═ 7.5Hz, 3H), 1.26(s, 3H), 1.62-1.88(m, 2H), 2.57(s, 3H), 3.39-3.47(m, 1H), 3.51-3.59(m, 1H), 3.84(s, 3H), 4.83-5.02(m, 1H), 7.52(t, J ═ 9.1Hz, 1H), 7.76(s, 1H), 7.80(s, 1H), 8.03(ddd, J ═ 9.2, 5.0, 2.8Hz, 1H), 8.22(dd, J ═ 5.7, 2.6Hz, 1H), 10.47(s, 1H). LC method C; rt: 1.87min. m/z: 413.4(M-H)^-Accurate quality: 414.2

Compound 77: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ (1-cyclopropyl-2-hydroxy-1-methyl-ethyl) amino Base of]-2-oxo-acetyl]-1, 5-dimethyl-pyrrole-2-carboxamide

2-amino-2-cyclopropylpropan-1-ol was used as the amine to give compound 77(24 mg).¹H NMR(400MHz，DMSO-d₆)δppm 0.28-0.41(m3H), 0.42-0.51(m, 1H), 1.10(s, 3H), 1.20-1.33(m, 1H), 2.57(s, 3H), 3.47-3.56(m, 1H), 3.59-3.66(m, 1H), 3.84(s, 3H), 4.92-4.99(m, 1H), 7.52(t, J ═ 9.2Hz, 1H), 7.75(s, 1H), 7.82(s, 1H), 8.03(ddd, J ═ 9.1, 5.0, 2.6Hz, 1H), 8.22(dd, J ═ 5.8, 2.8Hz, 1H), 10.48(s, 1H). LC method B; rt: 0.98 min.m/z: 425.2(M-H)^-Accurate quality: 426.2.

compound 78: n- (3-cyano-4-fluoro-phenyl) -1, 5-dimethyl-4- [2- [ (3-methyltetrahydropyran-3-yl) Amino group]-2-oxo-acetyl]Pyrrole-2-carboxamides

3-Methyloxieth-3-amine was used as the amine to give compound 78(15 mg).¹H NMR(400MHz，DMSO-d₆) δ ppm 1.31(s, 3H), 1.40-1.70(m, 3H), 2.24(m, J ═ 12.8Hz, 1H), 2.57(s, 3H), 3.34-3.38(m, 1H), 3.38-3.47(m, 1H), 3.62-3.70(m, 1H), 3.84(s, 3H), 3.88-3.95(m, 1H), 7.52(t, J ═ 9.1Hz, 1H), 7.73(s, 1H), 7.97-8.07(m, 2H), 8.22(dd, J ═ 5.9, 2.6Hz, 1H), 10.47(s, 1H). LC method B; rt: 0.99 min.m/z: 425.1(M-H)^-Accurate quality: 426.2.

compound 79: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ (2-methoxy-1, 1-dimethyl-ethyl) amino]- 2-oxo-acetyl]-1, 5-dimethyl-pyrrole-2-carboxamide

1-methoxy-2-amino-2-methylpropane was used as an amine to give compound 79(31 mg).¹H NMR(400MHz，DMSO-d₆)δppm 1.33(s，6H)，2.56(s，3H)，3.30(s，3H)，3.45(s，2H)，3.84(s，3H)，7.52(t，J＝9.1Hz，1H)，7.70(s，1H)，7.95-8.08(m，2H)，8.22(dd，J＝5.8, 2.8Hz, 1H), 10.48(s, 1H). LC method C; rt: 2.02min. m/z: 413.2(M-H)^-Accurate quality: 414.2.

compound 80: n- (3-cyano-4-fluoro-phenyl) -1, 5-dimethyl-4- [ 2-oxo-2- [ [2, 2, 2-trifluoro-1- (methoxymethyl) -1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxamides

1, 1, 1-trifluoro-3-methoxy-2-methylpropan-2-amine hydrochloride was used as the amine to give compound 80(52 mg).¹HNMR(400MHz，DMSO-d₆) δ ppm 1.60(s, 3H), 2.57(s, 3H), 3.34(s, 3H), 3.67(d, J ═ 9.7Hz, 1H), 3.84(s, 3H), 3.96(d, J ═ 9.7Hz, 1H), 7.52(t, J ═ 9.1Hz, 1H), 7.63(s, 1H), 8.01(ddd, J ═ 9.2, 5.0, 2.8Hz, 1H), 8.22(dd, J ═ 5.8, 2.8Hz, 1H), 8.53(s, 1H), 10.51(s, 1H). LC method B; rt: 1.11min. m/z: 467.1(M-H)^-Accurate quality: 468.1.

compound 81: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ (3-hydroxy-1, 1-dimethyl-propyl) amino]-2- Oxo-acetyl]-1, 5-dimethyl-pyrrole-2-carboxamide

3-amino-3-methylbutan-1-ol was used as the amine to give compound 81(24 mg).¹H NMR(400MHz，DMSO-d₆) δ ppm 1.38(s, 6H), 1.84(t, J ═ 6.6Hz, 2H), 2.56(s, 3H), 3.51-3.61(m, 2H), 3.84(s, 3H), 4.58-4.72(m, 1H), 7.52(t, J ═ 9.2Hz, 1H), 7.78(s, 1H), 8.03(ddd, J ═ 9.2, 4.9, 2.6Hz, 1H), 8.22(dd, J ═ 5.8, 2.8Hz, 1H), 8.34(s, 1H), 10.46(s, 1H). LC method B; rt: 0.93min m/z: 413.2(M-H)^-Accurate quality: 414.2.

compound 82: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ [ 4-hydroxy-1- (trifluoromethyl) cyclohexyl]Amino group]- 2-oxo-acetyl]-1, 5-dimethyl-pyrrole-2-carboxamide

4-amino-4- (trifluoromethyl) cyclohexan-1-ol was used as the amine to give compound 82(10 mg).¹H NMR(400MHz，DMSO-d₆) δ ppm 1.23-1.39(m, 2H), 1.45-1.62(m, 2H), 1.69-1.82(m, 2H), 2.54-2.72(m, 6H), 3.84(s, 3H), 4.71(br.s., 1H), 7.52(t, J ═ 9.1Hz, 1H), 7.57(s, 1H), 8.02(ddd, J ═ 9.1, 5.0, 2.6Hz, 1H), 8.21(dd, J ═ 5.8, 2.8Hz, 1H), 8.44(s, 1H), 10.52(br.s., 1H). LC method B; rt: 1.00 min.m/z: 493.1(M-H)^-Accurate quality: 494.2.

compound 83: n- (3-cyano-4-fluoro-phenyl) -3-fluoro-1-methyl-4- [ 2-oxo-2- [ [3- (trifluoromethyl) Tetrahydrofuran-3-yl]Amino group]Acetyl group]Pyrrole-2-carboxamides

Compound 83 was prepared in analogy to the description for compound 34 using 3- (trifluoromethyl) tetrahydrofuran-3-amine hydrochloride instead of 2-methylpropan-2-amine. The obtained residue was dissolved in methanol under heating, and the product was crystallized upon addition of water to give compound 83(298mg) as a white solid. LC method C; rt: 1.94 min.m/z: 469.3(M-H)^-Accurate quality: 470.1.¹H NMR(400MHz，DMSO-d₆)δppm 2.26-2.42(m，1H)2.54-2.69(m，1H)3.69-3.81(m，1H)3.82-3.94(m，4H)4.14(d，J＝10.6Hz，1H)4.27(d，J＝10.6Hz，1H)7.54(t，J＝9.0Hz，1H)7.92-8.04(m，2H)8.18(dd，J＝5.7，2.6Hz，1H)9.40(s，1H)10.37(s，1H)。

compound 84: n- (3-cyano-4-fluoro-phenyl) -3-Fluoro-1-methyl-4- [ 2-oxo-2- [ [1- (trifluoromethyl) Cyclobutyl radical]Amino group]Acetyl group]Pyrrole-2-carboxamides

Compound 84 was prepared similarly as described for compound 34 using 1- (trifluoromethyl) cyclobutan-1-amine instead of 2-methylpropan-2-amine.¹H NMR(400MHz，DMSO-d₆) δ ppm 1.87-2.02(m, 2H)2.39-2.48(m, 2H)2.52-2.67(m, 2H)3.86(s, 3H)7.54(t, J ═ 9.1Hz, 1H)7.97(ddd, J ═ 9.2, 4.9, 2.6Hz, 1H)8.04(d, J ═ 4.4Hz, 1H)8.18(dd, J ═ 5.7, 2.6Hz, 1H)9.33(s, 1H)10.36(s, 1H). LC method B; rt: 1.12min. m/z: 453.1(M-H)^-Accurate quality: 454.1. differential scanning calorimetry: from 30 to 300 ℃ at 10 ℃/min: peak: 194.7 ℃.

Compound 85: n- (3-cyano-4-fluoro-phenyl) -3-fluoro-1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2-III Fluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxamides

Compound 85 was prepared in analogy to the description for compound 34 using (R) -1, 1, 1-trifluoro-2-propylamine instead of 2-methylpropan-2-amine. LC method C; rt: 1.95min. m/z: 427.2(M-H)^-Accurate quality: 428.1.¹H NMR(400MHz，DMSO-d₆) δ ppm 1.35(d, J ═ 7.0Hz, 3H)3.86(s, 3H)4.58-4.75(m, 1H)7.54(t, J ═ 9.1Hz, 1H)7.97(ddd, J ═ 9.2, 4.8, 2.9Hz, 1H)8.04(d, J ═ 4.4Hz, 1H)8.18(dd, J ═ 5.7, 2.6Hz, 1H)9.39(d, J ═ 9.0Hz, 1H)10.37(s, 1H). Differential scanning calorimetry: from 30 to 300 ℃ at 10 ℃/min: peak: 197.1 deg.C.

Compound 86: 3, 5-dichloro-N- (3-cyano-4-fluoro-phenyl) -1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2-trifluoro-1-methyl-Ethyl radical]Amino group]Acetyl group]Pyrrole-2-carboxamides

Compound 64(50mg, 0.12mmol) was dissolved in CH₃CN (1.25mL) and DMF (0.25 mL). NCS (24.41mg, 0.18mmol) was added and the mixture was stirred at room temperature for 5 hours, then heated to superheat at 40 ℃. The mixture was injected as such on a silica gel column and purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0: 100 to 100: 0) to give compound 86(26 mg). LC method B; rt: 1.04 min.m/z: 477.0(M-H)^-Accurate quality: 478.0.¹H NMR(400MHz，DMSO-d₆)δppm 1.33(d，J＝7.0Hz，3H)，3.75(s，3H)，4.70(dq，J＝15.5，7.6Hz，1H)，7.57(t，J＝9.1Hz，1H)，7.92-8.01(m，1H)，8.20(dd，J＝5.7，2.6Hz，1H)，9.50(d，J＝8.8Hz，1H)，10.91(br.s.，1H)。

compound 87: 5-chloro-N- (3-cyano-4-fluoro-phenyl) -1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-tris Fluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxamides

To a solution of compound 64(25mg, 0.061mmol) in HOAc (0.5mL,) was added NCS (12.2mg, 0.091mmol) followed by trifluoromethanesulfonic acid (10 μ L, 0.11 mmol). The resulting mixture was stirred at room temperature for 18 hours. The mixture was then poured into water and CH was used₂Cl₂Extraction was performed (3X15 mL). The combined extracts were extracted with NaHCO₃(20mL, aq/sat) in Na₂SO₄Dried, filtered and concentrated in vacuo. The residue obtained was purified by preparative HPLC on (RP SunAire Prep C18OBD-10 μm, 30X150 mm). Mobile phase (0.25% NH₄HCO₃Aqueous solution, MeOH) to giveCompound 87(3 mg). LC method B; rt: 1.09 min.m/z: 443.0(M-H)^-Accurate quality: 444.1.¹HNMR (600MHz, chloroform-d) δ ppm 1.44(d, J ═ 6.9Hz, 3H), 4.02(s, 3H), 4.65 (dqin, J ═ 9.8, 7.0, 7.0, 7.0, 7.0Hz, 1H), 7.22(t, J ═ 8.7Hz, 1H), 7.45(d, J ═ 9.7Hz, 1H), 7.71(ddd, J ═ 9.1, 4.5, 2.8Hz, 1H), 7.96(s, 1H), 8.06(dd, J ═ 5.4, 2.8Hz, 1H), 8.11(s, 1H).

Compound 88: 5-chloro-N- (3-cyano-4-fluoro-phenyl) -1-methyl-4- [ 2-oxo-2- [ [ (1S) -2, 2, 2-tris Fluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxamides

Compound 88 was prepared similarly as described for compound 87 (stirring at room temperature for 6 hours instead of 18 hours), starting from compound 51 (instead of compound 64).¹H NMR(400MHz，DMSO-d₆) δ ppm 1.35(d, J ═ 7.0Hz, 3H), 3.93(s, 3H), 4.62-4.79(m, 1H), 7.54(t, J ═ 9.1Hz, 1H), 7.79(s, 1H), 8.01(ddd, J ═ 9.2, 4.8, 2.9Hz, 1H), 8.21(dd, J ═ 5.7, 2.6Hz, 1H), 9.44(br.s., 1H), 10.59(br.s., 1H) LC method B; rt: 1.12min. m/z: 443.0(M-H)^-Accurate quality: 444.1.

compound 89: 5-chloro-N- (3-cyano-4-fluoro-phenyl) -3-fluoro-1-methyl-4- [ 2-oxo-2-[[3-(trifluoro benzene sulfonic acid Methyl) tetrahydrofuran-3-yl]Amino group]Acetyl group]Pyrrole-2-carboxamides

Compound 83(84mg, 0.179mmol) was suspended in dry acetonitrile (1.7mL) and DMF (0.61 mL). The mixture was cooled on an ice bath and NCS (35.8mg, 0.268mmol) was added. The mixture was allowed to warm to room temperature and then heated at 55 ℃ for 16 hours. The purification is carried out byBy preparative HPLC (stationary phase: RP Xbridge Prep C18 ODB-5 μm, 30X250mm, mobile phase: 0.25% NH)₄HCO₃Aqueous solution, CH₃CN) to give compound 89(10 mg). LC method C; rt: 1.88min. m/z: 503.1(M-H)^-Accurate quality: 504.1.¹H NMR(400MHz，DMSO-d₆)δppm 2.28-2.42(m，1H)2.45-2.59(m，1H)3.75-3.84(m，4H)3.85-3.97(m，1H)4.10(d，J＝10.3Hz，1H)4.23(d，J＝10.6Hz，1H)7.55(t，J＝9.1Hz，1H)7.96(ddd，J＝9.2，4.8，2.9Hz，1H)8.16(dd，J＝5.7，2.9Hz，1H)9.54(s，1H)10.61(s，1H)。

compound 90: 5-chloro-N- (3-cyano-4-fluoro-phenyl) -3-fluoro-1-methyl-4- [ 2-oxo-2- [ [1 [)-(trifluoro benzene sulfonic acid Methyl) cyclobutyl]Amino group]Acetyl group]Pyrrole-2-carboxamides

Compound 90(29mg) was prepared similarly as described for compound 89, starting from compound 84 (instead of 83). LC method C; rt: 2.02min. m/z: 487.1(M-H)^-Accurate quality: 488.1. differential scanning calorimetry: from 30 ℃ to 300 ℃ at 10 ℃/min: peak: 174.9 deg.C.¹H NMR(400MHz，DMSO-d₆)δppm 1.84-2.08(m，2H)2.40-2.57(m，4H)3.81(s，3H)7.56(s，1H)7.91-8.00(m，1H)8.16(dd，J＝5.8，2.8Hz，1H)9.41(s，1H)10.60(br.s，1H)。

Compound 91: 5-chloro-N- (3-cyano-4-fluoro-phenyl) -3-fluoro-1-methyl-4- [ 2-oxo-2- [ [ (1R) -2, 2, 2-trifluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxamides

Compound 91 was prepared similarly as described for compound 89, starting from compound 85 (instead of 83). LC method C; rt: 1.92 min.m/z: 461.1(M-H)^-Accurate quality: 462.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.32(d，J＝7.0Hz，3H)3.80(s，3H)4.60-4.77(m，1H)7.55(s，1H)7.95(ddd，J＝9.2，4.8，2.9Hz，1H)8.16(dd，J＝5.8，2.8Hz，1H)9.48(d，J＝8.6Hz，1H)10.58(br.s.，1H)。

compound 92: 3-chloro-N- (3-cyano-4-fluoro-phenyl) -4- [2- [ (2-hydroxy-1, 1-dimethyl-ethyl) amino Base of]-2-oxo-acetyl]-1-methyl-pyrrole-2-carboxamide

Adding Et₃N (0.18mL, 1.287mmol) was added to 2- [ 4-chloro-5- [ (3-cyano-4-fluoro-phenyl) carbamoyl]-1-methyl-pyrrol-3-yl]-2-oxo-acetic acid (150mg, 0.429mmol), HATU (204mg, 0.536mmol) and 2-amino-2-methyl-1-propanol (0.051mL, 0.536mmol) in DMF (1.1mL) and stirred at room temperature for 30 min. The solution was purified by silica gel column chromatography using a gradient from 0 up to 50% EtOAc in heptane. The product fractions were concentrated and dissolved in THF (3mL) and water (1 mL). Lithium hydroxide monohydrate (30mg) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, and the residue was taken up in water and CH₂Cl₂Are distributed among the devices. The organic layer was separated and concentrated in vacuo. The residue obtained was crystallized from MeOH and water. The product was filtered off and washed with water and diisopropyl ether. The product was dried in vacuo to give compound 92(41mg) as a white solid.¹H NMR(400MHz，DMSO-d₆) δ ppm 1.29(s, 6H)3.45(d, J ═ 5.7Hz, 2H)3.82(s, 3H)4.99(t, J ═ 5.8Hz, 1H)7.56(t, J ═ 9.1Hz, 1H)7.90(s, 1H)7.98(ddd, J ═ 9.2, 4.9, 2.6Hz, 1H)8.21(dd, J ═ 5.8, 2.8Hz, 1H)8.26(s, 1H)10.71(s, 1H). LC method C; rt: 1.72min. m/z: 419.2(M-H)^-Accurate quality: 420.1.

compound 93: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ [ (1R) -2, 2-difluoro-1-methylpropyl]Amino group]- 2-oxo-acetyl]-3-fluoro-1-methyl-pyrrole-2-carboxamide

Compound 93(130mg) was prepared in analogy to the description for compound 34 using (2R) -3, 3-difluorobutan-2-amine hydrochloride instead of 2-methylpropan-2-amine. LC method C; rt: 1.97 min.m/z: 423.4(M-H)^-Accurate quality: 424.1. differential scanning calorimetry: from 30 ℃ to 300 ℃ at 10 ℃/min: peak: 206.8 ℃.¹H NMR(400MHz，DMSO-d₆)δppm1.23(d，J＝7.0Hz，3H)，1.61(t，J＝19.3Hz，3H)，3.86(s，3H)，4.25-4.40(m，1H)，7.54(t，J＝9.1Hz，1H)，7.97(ddd，J＝9.1，5.0，2.6Hz，1H)，8.02(d，J＝4.2Hz，1H)，8.18(dd，J＝5.7，2.6Hz，1H)，8.97(d，J＝9.2Hz，1H)，10.35(br.s.，1H)。

Compound 94: n- (3-cyano-4-fluoro-phenyl) -4- [2- [ (2-hydroxy-1, 1-dimethyl-ethyl) amino]-2- Oxo-acetyl]-1, 5-dimethyl-pyrrole-2-carboxamide

Compound 94(46mg) was prepared in analogy to the description for compound 73 using 2-amino-2-methyl-1-propanol instead of (1-aminocyclopropyl) methanol. LC method C; rt: 1.72min. m/z: 399.2(M-H)^-Accurate quality: 400.2.¹HNMR(400MHz，DMSO-d₆)δppm 1.30(s，6H)2.56(s，3H)3.45(d，J＝5.9Hz，2H)3.84(s，3H)4.97(t，J＝5.7Hz，1H)7.52(t，J＝9.1Hz，1H)7.80(s，1H)7.89(s，1H)8.03(ddd，J＝9.2，5.0，2.8Hz，1H)8.22(dd，J＝5.9，2.6Hz，1H)10.45(s，1H)

compound 95: n- (3-cyano-4-fluoro-phenyl) -3-fluoro-4- [2- [ [ (1R) -2-hydroxy-1-methyl-ethyl]Ammonia Base of]-2-oxo-acetyl]-1-methyl-pyrrole-2-carboxamide

Compound 95(28mg) was prepared similarly as described for compound 34, using D-alaninol instead of 2-methylpropan-2-amine. LC method C; rt: 1.54min. m/z: 389.2(M-H)^-Accurate quality: 390.1. differential scanning calorimetry: from 30 to 300 ℃ at 10 ℃/min: peak: 191.8 ℃.¹H NMR(400MHz，DMSO-d₆)δppm 1.10(d，J＝6.8Hz，3H)3.32-3.46(m，2H)3.81-3.92(m，4H)4.76(t，J＝5.6Hz，1H)7.54(t，J＝9.1Hz，1H)7.97(ddd，J＝9.1.4.8，2.8Hz，1H)8.12(d，J＝4.4Hz，1H)8.18(dd，J＝5.7，2.6Hz，1H)8.42(d，J＝8.4Hz，1H)10.34(s，1H)。

Compound 96: n- (3-cyano-4-fluoro-phenyl) -3-fluoro-4- [2- [ (2-methoxy-1, 1-dimethyl-ethyl) amino Base of]-2-oxo-acetyl]-1-methyl-pyrrole-2-carboxamide

Compound 96(145mg) was prepared in analogy to the description for compound 34 using 1-methoxy-2-methylpropan-2-amine instead of 2-methylpropan-2-amine. LC method C; rt: 1.98min. m/z: 417.2(M-H)^-Accurate quality: 418.1.¹HNMR (400MHz, chloroform-d) δ ppm 1.43(s, 6H)3.38-3.45(m, 5H)3.99(s, 3H)7.18-7.24(m, 1H)7.45(s, 1H)7.66(ddd, J ═ 9.1, 4.5, 2.8Hz, 1H)7.87-7.97(m, 1H)8.05(dd, J ═ 5.5, 2.6Hz, 1H)8.24(d, J ═ 4.6Hz, 1H).

Compound 97: 5-chloro-N- (4-fluoro-3-methyl-phenyl) -1-methyl-4- [ 2-oxo-2- [ [ (1S) -2, 2, 2-tris Fluoro-1-methyl-ethyl]Amino group]Acetyl group]Pyrrole-2-carboxamides

2- (5- (4-fluoro-3-methylphenylcarbamoyl) -1-methyl-1H-pyrrol-3-yl) -2-oxoacetic acid (500mg, 1.64mmol) was dissolved in HOAc (25 mL). Trifluoromethanesulfonic acid (218. mu.L) was added, followed by NCS (219mg, 1.64mmol) in portions. This was stirred at room temperature for 4 hours. The mixture was poured into water (20mL) and then extracted using dichloromethane (3 × 25 mL). The combined extracts were extracted with NaHCO₃(2X 25mL/sat./aq.) washing, brine (25mL) washing, Na₂SO₄Dried, filtered and concentrated in vacuo. The combined extracts were washed with brine (200mL) over Na₂SO₄Dried, filtered, and concentrated in vacuo. The crude product obtained was purified by column chromatography on silica gel (gradient elution: EtOAc-heptane 0: 100 to 100: 0) to give 2- [ 2-chloro-5- [ (4-fluoro-3-methyl-phenyl) carbamoyl group as an oil]-1-methyl-pyrrol-3-yl]-2-oxo-acetic acid (109mg), which was used as such. Vial was charged with 2- [ 2-chloro-5- [ (4-fluoro-3-methyl-phenyl) carbamoyl group]-1-methyl-pyrrol-3-yl]-2-oxo-acetic acid (109.4mg, 0.32mmol), (S) -1, 1, 1-trifluoro-2-propylamine (43.8mg, 0.39mmol), DMF (1mL) and DIPEA (0.17mL) followed by HATU (135mg, 0.36mmol) addition. The resulting mixture was stirred at room temperature for 2 hours. Water (5mL) was added and the mixture was taken up with CH₂Cl₂Extraction was performed (2X 15 mL). The mixture was purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0: 100 to 100: 0). The desired fraction was concentrated in vacuo and the residue obtained was dried in a vacuum oven at 55 ℃ for 24 h to yield compound 97(17 mg). LC method B; rt: 1.18min. m/z: 432.1(M-H) -accurate mass: 433.1.¹H NMR(400MHz，DMSO-d₆)δppm 1.34(d，J＝7.0Hz，3H)，2.23(d，J＝1.8Hz，3H)，3.92(s，3H)，4.63-4.79(m，1H)，7.11(t，J＝9.2Hz，1H)，7.48-7.56(m，1H)，7.63(dd，J＝7.0，2.2Hz，1H)，7.73(s，1H)，9.42(d，J＝7.9Hz，1H)，10.24(s，1H)。

compound 98: 4- [2- (tert-butyl) sAmino) -2-oxo-acetyl]-5-chloro-N- (3-cyano-4-fluoro-phenyl) - 1-methyl-pyrrole-2-carboxamides

Compound 98(17mg) was prepared similarly as described for compound 87 (stirring 5 hours instead of 18 hours at room temperature), starting from compound 15 (instead of compound 64). The crude product obtained is purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0: 100 to 100: 0).¹H NMR (400MHz, chloroform-d) δ ppm 1.37(s, 9H), 3.92(s, 3H), 7.53(t, J ═ 9.1Hz, 1H), 7.76(s, 1H), 8.02(ddd, J ═ 9.2, 4.9, 2.6Hz, 1H), 8.14-8.28(m, 2H), 10.48-10.68(m, 1H). LC method B; rt: 1.15min. m/z: 403.2(M-H)^-Accurate quality: 404.1.

compound 99: n- (3-cyano-4-fluoro-phenyl) -3-fluoro-4- [2- [ (2-hydroxy-1, 1-dimethyl-ethyl) amino Base of]-2-oxo-acetyl]-1-methyl-pyrrole-2-carboxamide

Use of 2-amino-2-methyl-1-propanol instead of 2-methylpropan-2-amine with a compound directed against ethyl 4- [2- (tert-butylamino) -2-oxo-acetyl]Preparation of ethyl 3-fluoro-4- [2- [ (2-hydroxy-1, 1-dimethyl-ethyl) amino ] methyl-1-methyl-pyrrole-2-carboxylate analogously to what has been described]-2-oxo-acetyl]-1-methyl-pyrrole-2-carboxylate and stirring at room temperature for 2 hours (instead of stirring at 65 ℃ for 30 minutes). Using ethyl 3-fluoro-4- [2- [ (2-hydroxy-1, 1-dimethyl-ethyl) amino]-2-oxo-acetyl]-1-methyl-pyrrole-2-carboxylate instead of ethyl 4- [2- (tert-butylamino) -2-oxo-acetyl]-3-fluoro-1-methyl-pyrrole-2-carboxylate, compound 99(5mg) was prepared in analogy to the description for compound 34. Compound 99 was purified by silica gel column chromatography using a gradient from 0 up to 50% EtOAc in heptane and byPreparative HPLC (stationary phase: RP Xbridge Prep C18OBD-10 μm, 30X150mm, mobile phase: 0.25% NH)₄HCO₃Aqueous solution, CH3CN) was further purified. LC method B; rt: 0.90 min.m/z: 403.2(M-H)^-Accurate quality: 404.1.¹h NMR (400MHz, chloroform-d) δ ppm 1.39(s, 6H)3.66-3.71(m, 2H)3.72-3.79(m, 1H)4.00(s, 3H)7.17-7.24(m, 1H)7.32-7.39(m, 1H)7.61-7.71(m, 1H)7.88-7.95(m, 1H)8.05(dd, J ═ 5.4, 2.8Hz, 1H)8.23(d, J ═ 4.6Hz, 1H)

Compound 100: 5-chloro-N- (3-cyano-4-fluoro-phenyl) -1-methyl-4- [2- [ (3-methyloxetane-3- Radical) amino]-2-oxo-acetyl]Pyrrole-2-carboxamides

Compound 100(12.8mg) was prepared similarly as described for compound 87 (stirring at room temperature for 5 hours instead of 18 hours, using DMF (4, 84mL) instead of HOAc), starting from compound 16 (instead of compound 64). The crude product obtained is purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0: 100 to 100: 0). LC method B; rt: 0.94 min.m/z: 417.1(M-H)^-Accurate quality: 418.08.¹H NMR(400MHz，DMSO-d6)δppm 1.60(s，3H)，3.93(s，3H)，4.37(d，J＝6.6Hz，2H)，4.73(d，J＝6.4Hz，2H)，7.53(t，J＝9.1Hz，1H)，7.90(s，1H)，8.02(ddd，J＝9.2，4.9，2.6Hz，1H)，8.21(dd，J＝5.7，2.6Hz，1H)，9.34(s，1H)，10.58(br.s.，1H)。

compound 101: n- (3-cyano-4-fluoro-phenyl) -3-fluoro-1-methyl-4- [ 2-oxo-2- [ [1- (trifluoromethyl) Cyclopropyl group]Amino group]Acetyl group]Pyrrole-2-carboxamides

Using 1-trifluoromethyl-1-cyclopropylamine instead of 2-methylpropan-2-amine, compound 101(17mg) prepared in analogy to that described for compound 34. LC method B; rt: 1.05 min.m/z: 439.1(M-H)^-Accurate quality: 440.09. 1H NMR (400MHz, DMSO-d6) δ ppm 1.07-1.20(m, 2H), 1.26-1.37(m, 2H), 3.85(s, 3H), 7.53(t, J ═ 9.1Hz, 1H), 7.96(ddd, J ═ 9.2, 4.8, 2.9Hz, 1H), 8.04(d, J ═ 4.4Hz, 1H), 8.18(dd, J ═ 5.8, 2.8Hz, 1H), 9.57(s, 1H), 10.37(br.s., 1H).

Compound 102: n- (3-cyano-4-fluoro-phenyl) -3-fluoro-4- [2- [ [1- (hydroxymethyl) cyclopropyl ] methyl ester]Amino group]-2- Oxo-acetyl]-1-methyl-pyrrole-2-carboxamide

Compound 102(37.7mg) was prepared in analogy to the description for compound 34, using 1-amino-cyclopropylmethanol instead of 2-methylpropan-2-amine. LC method B; rt: 0.81 min.m/z: 401.2(M-H)^-Accurate quality: 402.11. 1H NMR (400MHz, DMSO-d6) δ ppm 1.36(s, 9H), 2.56(s, 3H), 3.84(s, 3H), 7.52(t, J ═ 9.1Hz, 1H), 7.65(s, 1H), 7.98-8.05(m, 1H), 8.08(s, 1H), 8.22(dd, J ═ 5.7, 2.6Hz, 1H), 10.46(s, 1H)

Biological example anti-HBV Activity of Compounds of formula (IA)

The stable transfected cell line hepg2.2.15 was used to measure anti-HBV activity. This cell line is described as secreting relatively consistent high levels of HBV virion particles, which have been shown to cause acute and chronic infection and disease in chimpanzees.

For antiviral, assay cells were treated twice in 96-well plates with serial dilutions of compounds in duplicate for three days. After 6 days of treatment, antiviral activity was determined by quantifying purified HBV DNA from secreted virions using real-time PCR and HBV-specific primer sets and probes.

anti-HBV activity was also determined using hepg2.117 cell line, a stable, HBV-production-inducing cell line that replicates HBV in doxycycline-deficient (tetracycline-off (Tet-off) system). For the antiviral assay, HBV replication was induced, followed by treatment with serial dilutions of the compound in 96-well plates, repeated twice. After 3 days of treatment, antiviral activity was determined by quantification of intracellular HBV DNA using real-time PCR and HBV specific primer sets and probes.

The cytotoxicity of these compounds was tested using HepG2 cells, which were incubated for 4 days in the presence of the compounds. Cell viability was assessed using the resazurin assay. The results are shown in table 1.

Table 1.

Claims (12)

1. A compound of formula (IA)

(IA)

Or one stereoisomer or tautomeric form thereof, wherein:

each X independently represents CR⁷；

R¹、R²And R³Independently selected from the group consisting of: hydrogen, fluorine, chlorine,Bromine, -CHF₂、-CH₂F、-CF₃、-CN、C₁-C₃Alkyl or C₃-C₄A cycloalkyl group;

R⁴is hydrogen, C₁-C₃Alkyl or C₃-C₄A cycloalkyl group;

R⁵is hydrogen;

R⁶selected from the group consisting of: c₁-C₆An alkyl group and optionally a 3-7 membered saturated ring comprising one or more heteroatoms each independently selected from the group consisting of: o, S and N, C₁-C₆Alkyl or 3-7 membered saturated ring is optionally substituted with one or more substituents selected from the group consisting of: fluorine, C₃-C₄Cycloalkyl, -OR⁸Oxo, -CN, -C (= O) -OR⁸、-C(=O)-N(R⁸)₂Or C optionally substituted by one or more fluorine₁-C₃An alkyl group;

each R⁷Independently represent hydrogen, C₃-C₄Cycloalkyl, -CN, fluoro, chloro, bromo or C optionally substituted by one or more fluoro₁-C₃An alkyl group;

R⁸represents hydrogen or C₁-C₃An alkyl group;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein R¹Selected from hydrogen, fluorine, chlorine, -CHF₂、-CN、-CF₃Or a methyl group.

3. The compound of claim 1 or 2, wherein R⁴Is methyl.

4. A compound according to claim 1 or 2, wherein R⁶Comprising a 3-7 membered saturated ring optionally containing an oxygen, the 3-7 membered saturated ring being optionally substituted with one or more substituents selected from: fluorine or C optionally substituted by one or more fluorine₁-C₃An alkyl group.

5. A compound according to claim 1 or 2, wherein R⁶Is a 4 or 5 membered saturated ring optionally containing an oxygen, the 4 or 5 membered saturated ring being optionally substituted with one or more substituents selected from: c optionally substituted by one or more fluorine₁-C₃Alkyl or fluoro.

6. The compound of claim 1 or 2, wherein R⁶Is a branch C optionally substituted by one or more fluorine₁-C₆An alkyl group.

7. The compound according to claim 1 or 2, of formula (Ia)

(Ia)。

8. The compound according to claim 1 or 2, of formula (Ib)

(Ib)。

9. Use of a compound according to any one of claims 1-8 in the manufacture of a medicament for the prevention or treatment of HBV infection in a mammal.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, and a pharmaceutically acceptable carrier.

11. A product containing (a) a compound of formula (IA) as defined in any one of claims 1 to 8, and (b) another HBV inhibitor, as a combined preparation for simultaneous, separate use in the treatment of HBV infection.

12. A product containing (a) a compound of formula (IA) as defined in any one of claims 1 to 8, and (b) another HBV inhibitor, as a combined preparation for sequential use in the treatment of HBV infection.