OA17673A

OA17673A - Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B.

Info

Publication number: OA17673A
Application number: OA1201600033
Authority: OA
Inventors: Koen Vandyck; Bart Rudolf Romanie Kesteleyn; Serge Maria Aloysius Pieters; Geert Rombouts; Wim Gaston Verschueren; Pierre Jean-Marie Bernard Raboisson
Original assignee: Janssen Sciences Ireland Uc
Priority date: 2013-07-25
Filing date: 2014-07-25
Publication date: 2017-07-04

Abstract

The present invention provides, in part, compounds of formula l : and pharmaceutically acceptable salts thereof; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds or salts, and their uses for treating D1-mediated (or D1-associated) disorders including, e.g., schizophrenia (e.g., its cognitive and negative symptoms), cognitive impairment (e.g., cognitive impairment associated with schizophrenia, AD, PD, or pharmacotherapy therapy), age-related cognitive decline, dementia, and Parkinson's disease.

Description

GLYOXAMIDE SUBSTITUTED PYRROLAMIDE DERIVATIVES AND THE USE

THEREOF AS MEDICAMENTS FOR THE TREATMENT OF HEPATITIS B

Background Art

The Hepatitis B virus (HBV) is an enveloped, partially double-stranded DNA (dsDNA) virus of the Hepadnavirus family (Hepadnaviridae). Its genome contains 4 overlapping reading frames: the precore/core gene; the polymerase gene; the L, M, and S genes, which encode for the 3 envelope proteins; and the X gene.

Upon infection, the partially double-stranded DNA genome (the relaxed circular DNA; rcDNA) is converted to a covalently closed circular DNA (cccDNA) in the nucléus of the 10 host cell and the viral mRNAs are transcribed. Once encapsidated, the pregenomic RNA (pgRNA), which also codes for core protein and Pol, serves as the template for reverse transcription, which regenerates the partially dsDNA genome (rcDNA) in the nucleocapsid.

HBV has caused épidémies in parts of Asia and Africa, and it is endemic in China. HBV has infected approximately 2 billion people worldwide of which approximately 350 million 15 people hâve developed chronic infections. The virus causes the disease hepatitis B and chronic infection is correlated with a strongly increased risk for the development cirrhosis and hepatocellular carcinoma.

Transmission of hepatitis B virus results from exposure to infectious blood or body fluids, while viral DNA has been detected in the saliva, tears, and urine of chronic carriers with 20 high titer DNA in sérum.

An effective and well-tolerated vaccine exists, but direct treatment options are currently limited to interferon and the following antivirals; tenofovir, lamivudine, adefovir, entecavir and telbivudine.

In addition, heteroaryldihydropyrimidines (HAPs) were identifïed as a class of HBV 25 inhibitors in tissue culture and animal models (Weber et al., Antiviral Res. 54: 69-78).

WO2013/006394, published on January 10, 2013, relates to a subclass of Sulphamoylarylamides active against HBV. WO2013/096744, published on June 26, 2013 relates to compounds active against HBV.

In addition, W02014/033170 and WO2014/033176, published on March 6, 2014 relate 30 further compounds active against HBV.

Amongst the problems which HBV direct antivirals may encounter are toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability, low solubility and diffîculty of synthesis.

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

Description of the Invention

The présent invention relates to a compound of Formula (IA)

^r3 (LA) or a stereoisomer or tautomeric form thereof, wherein:

Each X independently represents CR⁷;

R¹, R² and R³ are independently selected from the group consisting of Hydrogen, Fluoro, Chloro, Bromo, -CHF₂, -CH₂F, -CF₃, -CN, Ci-C₃alkyl or C₃-C₄cycloalkyl;

R⁴ is Hydrogen Ci-C₃alkyl or C₃-C4cycloalkyl;

R⁵ is Hydrogen;

R⁶ is selected from the group consisting of Ci-Côalkyl and a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such Ci-Cgalkyl or 3-7 membered saturated ring optionally substituted with one or more substituents selected from the group consisting of 20 Fluoro, C3-C4cycloalkyl, -OR⁸ ,oxo, -CN, -C(=O)-OR⁸, -C(=O)-N(R⁸)2 or Ci-C₃alkyl optionally substituted with one or more Fluoro;

Each R⁷ independently represents hydrogen, C₃-C₄cycloalkyl, -CN, Fluoro, Chloro,

Bromo or Ci-C₃alkyl optionally substituted with one or more Fluoro;

R⁸ represents hydrogen or Ci-C₃alkyl;

I

-3or a pharmaceutically acceptable sait or a solvaté 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 compounds of Formula (IA) for use as a médicament, preferably for use in the prévention or treatment of an HBV infection in a mammal.

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

Définitions

The term Ci_3alkyl as a group or part of a group refers to a hydrocarbyl radical of Formula CnHzn+i wherein n is a number ranging from 1 to 3. In case Ci^alkyl is coupled to a further radical, it refers to a Formula C_nH2_n.· Cualkyl groups comprise from 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms. Ci^alkyl includes ail linear, or branched alkyl groups with between 1 and 3 carbon atoms, and thus includes such as for example methyl, ethyl, w-propyl, and z-propyl.

Ci_4alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicale having from 1 to 4 carbon atoms such as the group defined for Ci^alkyl and butyl and the like.

Ci_6alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicale having from 1 to 6 carbon atoms, such as the groups defined for · Ci_4alkyl and pentyl, hexyl, 2-methylbutyl and the like.

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

Such saturated ring optionally contains 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, moipholinyl, thiolane 1,1-dioxide and pyrrolidinyl. Preferred are saturated cyclic hydrocarbon with 3 or 4 carbon atoms and 1 oxygen atom. Examples include oxetane, and tetrahydrofuranyl.

It should be noted that different isomers of the various heterocycles may exist within the définitions as used throughout the spécification. For example, pyrrolyl may be

-4ΙΗ-pyrrolyl or 2H-pyrrolyl.

The term halo and halogen are generic to Fluoro, Chloro, Bromo or Iodo. Preferred halogens are Fluoro and Chloro.

It should also be noted that the radical positions on any molecular moiety used in the définitions may be anywhere on such moiety as long as it is chemically stable. For instance pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; pentyl includes 1-pentyl, 2-pentyl and

3-pentyl.

Positions indicated on phenyl (e.g. ortho, meta and/or para) are indicated relative to the bond connecting the phenyl to the main structure. An example with regard to the position of R¹, any location is indicated relative to the nitrogen (*) connected to the main structure:

^R3 (I)

When any variable (e.g. halogen or Cualkyl) occurs more than one time in any constituent, each définition is independent.

For therapeutic use, the salts of the compounds of Formula (IA) are those wherein the counter ion is pharmaceutically or physiologically acceptable. However, salts having a pharmaceutically unacceptable counter ion may also find use, for example, in the préparation or purification of a pharmaceutically acceptable compound of Formula (IA). Ail salts, whether pharmaceutically acceptable or not are included within the ambit of the présent invention.

The pharmaceutically acceptable or physiologically tolerable addition sait forms which the compounds of the présent invention are able to form can conveniently be prepared using the appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfiiric; hemisulphuric, nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, aspartic, dodecylsulphuric, heptanoic, hexanoic, nicotinic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, 7?-toluenesulfonic, cyclamic, salicylic,/2-aminosalicylic, pamoic and the like acids.

Conversely said acid addition sait forms can be converted by treatment with an appropriate base into the free base form.

The term “salts” also comprises the hydrates and the solvent addition forms that the compounds of the présent invention are able to form. Examples of such forms are e.g.

hydrates, alcoholates and the like.

The présent compounds may also exist in their tautomeric forms. For example, tautomeric forms of amide (-C(=O)-NH-) groups are iminoalcohols (-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 présent invention.

The term stereochemically isomeric forms of compounds of the présent invention, as used hereinbefore, defïnes ail possible compounds made up 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 présent invention may possess. Unless otherwise mentioned or indicated, the chemical désignation of a compound encompasses the mixture of ail possible stereochemically isomeric forms which said compound may possess. Said mixture may contain ail diastereomers and/or enantiomers of the basic molecular structure of said compound. Ail stereochemically isomeric forms of the compounds of the présent invention both in pure form or in admixture with each other are intended to be embraced within the scope of the présent invention.

Pure stereoisomeric forms of the compounds and intermediates as mentioned herein are defïned as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term 'stereoisomerically pure' concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i. e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%. The terms 'enantiomerically pure' and 'diastereomerically pure’ should be understood in a similar way, but then having regard to the enantiomeric excess, respectively the diastereomeric excess of the mixture in question.

Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by the application of art-known procedures. For instance, enantiomers may be separated from each other by the sélective crystallization of their diastereomeric salts with

optically active acids or bases. Examples thereof are tartaric acid, dibenzoyltartanc acid, ditoluoyltartaric acid and camphosulfonic acid. Altematively, enantiomers may be separated by chromatographie techniques using chiral stationary phases. Said 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 spécifie stereoisomer is desired, said compound will be synthesized by stereospecific methods of préparation. These methods will advantageously employ enantiomerically pure starting materials.

The diastereomeric forms of Formula (IA) can be obtained separately by conventional methods. Appropriate physical séparation methods that may advantageously be employed are, for example, sélective crystallization and chromatography, e.g. column chromatography.

The présent invention is also intended to include ail isotopes of atoms occurring on the présent compounds. 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 “compounds of formula (IA)”,

or “the présent compounds” or similar term is meant to include the compounds of general formula (ΙΑ), (I), (la), (Ib), salts, stereoisomeric forms and racemic mixtures or any subgroups thereof.

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

or a stereoisomer or tautomeric form thereof, wherein:

Each X independently représente CR⁷;

R¹, R² and R³ are independently selected from the group consisting of Hydrogen, Fluoro, Chlore, Bromo, -CHF₂, -CH₂F, -CF₃, -CN, C1-C3alkyl or C₃-C₄cycloalkyl;

R⁴ is Hydrogen Ci-C₃alkyl or C₃-C4cycloalkyl;

R⁵ is Hydrogen;

R⁶ is selected from the group consisting of Ci-Cgalkyl and a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such Ci-Cgalkyl or 3-7 membered saturated ring optionally substituted with one or more substituents selected from the group consisting of Fluoro, C₃-C₄cycloalkyl, -OR⁸ .oxo, -CN, -C(=O)-OR⁸, -C(=O)-N(R⁸)₂ or Ci-C₃alkyl optionally substituted with one or more Fluoro;

Each R⁷ independently represents hydrogen, C₃-C4cycloalkyl, -CN, Fluoro, Chlore, Bromo or Ci-C₃alkyl optionally substituted with one or more Fluoro;

R⁸ represents hydrogen or Ci-C₃alkyl;

or a pharmaceutically acceptable sait or a solvaté thereof.

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

or a stereoisomer or tautomeric form thereof, wherein:

Each X independently represents CR⁷;

R² is Hydrogen or Fluoro;

-8R¹ and R³ are independently selected from the group consisting of Hydrogen, Fluoro, Chloro, Bromo, -CHF2, -CH2F, -CF3, -CN and methyl;

R⁴ is Hydrogen or methyl;

R⁵ is Hydrogen;

R⁶ is selected from the group consisting of Ci-Cgalkyl and a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such Ci-Cgalkyl or 3-7 membered saturated ring optionally substituted with one or more substituents selected from the group consisting of Fluoro, Ci-C3alkyl, -CN, -C(=O)-OR⁸or -C(=O)-N(R⁸)2;

R⁷ représente hydrogen or methyl;

R⁸ représente hydrogen or Ci-C₃alkyl;

or a pharmaceutically acceptable sait or a solvaté thereof.

In a further aspect, the invention provides compounds of Formula (la) or (Ib)

H

R6^Nl· ^r3 (la) (Ib) or a stereoisomer or tautomeric form thereof, wherein:

Each X independently représente CR⁷;

R² is Hydrogen or Fluoro;

R¹ and R³ are independently selected from the group consisting of Hydrogen, Fluoro,

Chloro, Bromo, -CHF2, -CH2F, -CF3, -CN and methyl;

R⁴ is Hydrogen or methyl;

R⁵ is Hydrogen;

-9R⁶ is selected from the group consisting of Ci-Côalkyl and a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected fforn the group consisting of O, S and N, such Ci-C^alkyl or 3-7 membered saturated ring optionally substituted with one or more substituents selected from the group consisting of Fluoro, Ci-C3alkyl, -CN, -C(=O)-OR⁸or -C(=O)-N(R⁸)2;

R⁷ représente hydrogen or methyl;

R⁸ représente hydrogen or Ci-C3alkyl;

or a pharmaceutically acceptable salts or a solvaté thereof.

In a first embodiment, compounds of Formula (ΙΑ, (I), (la) and (Ib) are disclosed wherein R¹is selected from either hydrogen, Fluoro, Chloro, -CHF2, -CN, -CF3 or methyl. In another embodiment, R¹ is selected from either hydrogen, Fluoro, Chloro, CHF2, -CN, -CF₃ or methyl and at least one of R¹ and R³ is Fluoro or hydrogen. In yet a further embodiment, at least one of R¹ and R³ is Fluoro, and the other R¹ or R³ is selected from hydrogen, Fluoro, Chloro, -CHF₂, -CN, -CF₃ or methyl.

In yet another embodiment, compounds of the présent invention are disclosed wherein R⁴ is methyl.

In a further embodiment, compounds of the présent invention are disclosed wherein R⁶contains a 3-7 membered saturated ring optionally containing one oxygen, such 3-7 membered saturated ring optionally substituted with methyl. In a further embodiment, R⁶ is a 4 or 5 membered saturated ring containing one oxygen, such 4 or 5 membered saturated ring optionally substituted with methyl.

In another embodiment, R⁶ is a branched Ci-Cgalkyl, optionally substituted with one or more substituents selected from the group consisting of Fluoro, -CN, -C(=O)-OR or -C(=O)N(R⁸)₂. In a further embodiment, R⁶ is a branched Ci-Côalkyl.

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

(a) R⁴ is methyl and R⁶ is selected from the group consisting of Ci-Côalkyl optionally being substituted with one or more Fluoro;

(b) R² is Hydrogen or Fluoro.

(c) R¹ and R³are independently selected from the group consisting of Hydrogen, Fluoro, Chloro -CN and methyl.

(d) At least one R⁷ is Chloro or methyl.

(e) R² is Hydrogen or Fluoro and R¹ and R³ are independently selected from the group consisting of Hydrogen, Fluoro, Chloro and-CN.

(f) R⁶ contains a 3-7 membered saturated ring optionally containing one oxygen, more specifïcally R⁶ is a 4 or 5 membered saturated ring optionally containing one oxygen, such 4 or 5 membered saturated ring optionally substituted with one or more substituents selected from Cj-Cjalkyl optionally substituted with one or more Fluoro or Fluoro.

(g) R⁶ comprises a branched Cs-Cgalkyl optionally substituted with one or more Fluoro, or wherein R⁶ comprises a C₃-C6cycloalkyl wherein such Cs-Cgcycloalkyl is substituted with one or more Fluoro or substituted with Ci-C^alkyl substituted with one or more Fluoro, or wherein R⁶ comprises a Cs-Cgcycloalkyl optionally substituted with one or more Fluoro and/or substituted with Ci-C3alkyl optionally substituted with one or more Fluoro.

(h) R⁴ is methyl; R⁶ is selected from the group consisting of CpCgalkyl optionally being substituted with one or more Fluoro and R² is Fluoro.

Further combinations of any of the embodiments are also envisioned to be in the scope of the présent invention.

Preferred compounds according to the invention are compound or a stereoisomer or tautomeric form thereof with a Formula (ΙΑ), (I), (la), (Ib), as represented in the synthesis of compounds section and of which the activity is displayed in Table 1.

In a further aspect, the présent invention concems a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound of Formula (IA) as specifïed herein, and a pharmaceutically acceptable carrier. A prophylactically effective amount in this context is an amount sufficient to prevent HBV infection in subjects being at risk of being infected. A therapeutically effective amount in this context is an amount sufficient to stabilize HBV infection, to reduce HBV infection, or to eradicate HBV infection, in infected subjects. In still a further aspect, this invention relates to a process of preparing a pharmaceutical composition as specifïed herein, which comprises intimately mixing a pharmaceutically acceptable carrier with a therapeutically or prophylactically effective amount of a compound of Formula (IA), as specifïed herein.

Therefore, the compounds of the présent invention or any subgroup thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate

compositions there may be cited ali compositions usually employed for systemically administering drugs. To préparé the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition sait form, as the active ingrédient is combined in intimate admixture with a pharmaceutically acceptable carrier, 5 which carrier may take a wide variety of forms depending on the form of préparation desired for administration. These pharmaceutical compositions are désirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parentéral 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 10 and the like in the case of oral liquid préparations such as suspensions, syrups, élixirs, émulsions 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 in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are 15 employed. For parentéral compositions, the carrier will usually comprise stérile water, at least in large part, though other ingrédients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the 20 like may be employed. Also included are solid form préparations intended to be converted, shortly before use, to liquid form préparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a pénétration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a signifïcant deleterious effect on the skin. 25 The compounds of the présent invention may also be administered via oral inhalation or insufflation in the form of a solution, a suspension or a dry powder using any art-known delivery System.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions 30 in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrète units suitable as unitary dosages, each unit containing a predetermined quantfty of active ingrédient 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, 35 suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.

The compounds of Formula (IA) are active as inhibitors of the HBV réplication cycle and

-12can be used in the treatment and prophylaxie of HBV infection or diseases associated with HBV. The latter include progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, end-stage liver disease, and hepatocellular carcinoma.

Due to their antiviral properties, particularly their anti-HBV properties, the compounds of Formula (IA) or any subgroup thereof, are useful in the inhibition of the HBV réplication cycle, in particular in the treatment of warm-blooded animais, in particular humans, infected with HBV, and for the prophylaxie of HBV infectione. The preeent invention furthermore relates to a method of treating a warm-blooded animal, in particular human, infected by HBV, or being at risk of infection by HBV, said method comprising the administration of a therapeutically effective amount of a compound of Formula (IA).

The compounds of Formula (IA), as specified herein, may therefore be used as a medicine, in particular as medicine to treat or prevent HBV infection. Said use as a medicine or method of treatment comprises the systemic administration to HBV infected subjects or to subjects susceptible to HBV infection of an amount effective to combat the conditions associated with HBV infection or an amount effective to prevent HBV infection.

The présent invention also relates to the use of the présent compounds in the manufacture of a médicament for the treatment or the prévention of HBV infection.

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

The présent invention also concems combinations 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 containing (a) a compound of Formula (IA), as specified above, and (b) at least one other compound capable of treating HBV infection (herein designated as anti-HBV agent), as a combined préparation for simultaneous, separate or sequential use in treatment of HBV infections. In an embodiment, the invention concems combination of a compound of Formula (IA) or any subgroup thereof with at least one antiHBV agent. In a particular embodiment, the invention concems combination of a compound of Formula (IA) or any subgroup thereof with at least two anti-HBV agents. In a particular embodiment, the invention concems combination of a compound of Formula (IA) or any subgroup thereof with at least three anti-HBV agents. In a particular embodiment, the

invention concems combination of a compound of Formula (IA) or any subgroup thereof with at least four anti-HBV agents.

The term anti-HBV agent also includes compounds capable of treating HBV infection via immunomodulation. Examples of immunomodulators are interferon-α (IFN-a), pegylated 5 interferon-a or stimulants of the innate immune System such as Toll-like receptor 7 and/or 8 agonists. One embodiment of the présent invention relates to combinations of a compound of Formula (IA) or any subgroup thereof, as specified herein with an immunomodulating compound, more specifîcally a Toll-like receptor 7 and/or 8 agonist.

The combination of previously known anti-HBV agents, such as interferon-α (IFN-a), pegylated interferon-α, 3TC, adefovir or a combination thereof, and, a compound of Formula (IA) or any subgroup thereof can be used as a medicine in a combination therapy.

Generic synthesis:

The substituents represented by R^1,2,3, R⁶or R⁷ in this general synthesis section are meant to include any substituent or reactive species that is suitable for transformation into any R¹’^2,3, 15 R⁶or R⁷ substituent according to the présent invention without undue burden for the person skilled in the art.

Scheme 1

Scheme ΙΑ

The synthesis of compounds of general Formula (I) can be performed as outlined in Scheme

1. Each R^x independently représente lower alkyl, preferably Ci-C3alkyl and even more preferred methyl or ethyl. A carboxylic acid of general formula (a) can be coupled with an aniline of general formula (b) using a peptide coupling reagent like for example HATU in the presence of an organic amine base such as TEA or DIPEA. The resulting compound of general formula (c) can be reacted with an oxalyl chloride monoalkyl ester of general formula (d) in the presence of a Lewis acid like for example AICI3 to provide a compound of general formula (f). Altematively, compounds of general formula (f) can be obtained by inversion of the order of the aforementioned reaction steps, in particular by reaction of a carboxylic acid of general formula (a) with oxalyl chloride monoalkyl ester of general formula (d) in the presence of a Lewis acid like for example AICI3 to provide a compound of 15 general formula (e), followed by coupling of (e) with an aniline of general formula (b) using a peptide coupling reagent like for example HATU in the presence of a organic amine base such as TEA or DIPEA. Reaction of a compound of general formula (f) with an amine of general formula (g) in a suitable solvent such as for example EtOH, provides a compound of general formula (I). Altematively, compounds of general formula (I) can be obtained from a 20 compound of general formula (f) in a two-step procedures that involves hydrolysis of the ester moiety of a compound of general formula (f) with an inorganic base of general formula

(h) like for example NaOH, followed by coupling of the resulting alpha-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 a organic amine base such as TEA or DIPEA. Similarly as described for the synthesis of compounds of general Formula (I) in Scheme 1, the synthesis of compounds of general formula IA is described in Scheme IA.

(Π)

(h)

R₄

Ri r₂ (p)

Scheme 2

Scheme 2A

-16The synthesis of compounds of general formula (I) can also be performed as outlined in Scheme 2. Each R^x independently represents lower alkyl, preferably Ci-C₃alkyl and even more preferred methyl or ethyl. A carboxylic ester of general formula 0) can be reacted with an oxalyl chloride monoalkyl ester of general formula (d) in the presence of a Lewis acid like for example A1C1₃ to provide a compound of general formula (k). Hydrolysis of (k) with an inorganic base of general formula (h) like NaOH provides the corresponding alpha-ketoacid of general formula (m). Compounds of general formula (n) can be obtained by coupling of (m) with an amine of general formula (g) using a peptide coupling reagent like for example HATU in the presence of a organic amine base such as TEA or DIPEA. Alternatively, compounds of general formula (n) can be obtained from carboxylic ester of general formula (j) in a two-step one-pot procedure that includes reaction of (j) with oxalyl chloride, followed by treatment of the intermediate of general formula (o) with an amine of general formula (g). A compound of general formula (n) can be hydrolysed with an inorganic base of general formula (h) like for example NaOH. The resulting carboxylic acid of general formula (p) can be coupled with an aniline of general formula (b) using a peptide coupling reagent like for example HATU in the presence of a organic amine base such as TEA or DIPEA, to provide compounds of general formula (I). Similarly as described for the synthesis of compounds of general Formula (I) from a compound of general formula (p) and aniline (b) shown in Scheme 2, the synthesis of compounds of general formula IA can be performed from aniline (bA) and a compound of general formula (p) as described in Scheme 2A.

Alternatively, intermediates of the general formula (cA) and compounds of the general formula (IA) can be synthesized as depicted in scheme 3 A. In this case a compound of general formula 0) or (n) is reacted with an aniline of general formula (bA) under influence of a base like lithium bis(trimethylsilyl)amide (LiHMDS), resulting in compound of general formula (cA) and (IA) respectively.

Scheme 3A

General procedure LCMS methods

The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specifîed in the respective methods. If necessary, additional detectors were included (see table of methods below).

Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time...) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software.

Compounds are described by their experimental rétention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]⁺ (protonated molécule) and/or [M-H]' (deprotonated molécule). In case the compound was not directly ionizable the type of adduct is specifîed (i.e. [M+NH4]⁺, [M+HCOO]', etc...). Ail results were obtained with experimental uncertainties that are commonly associated with the method used.

Hereinafter, “SQD” means Single Quadrupole Detector, “MSD” Mass Sélective Detector, “RT” room température, “BEH” bridged ethylsiloxane/silica hybrid, “DAD” Diode Array Detector, ”HSS” High Strength silica., “Q-Tof” Quadrupole Time-of-flight mass spectrometers, “CLND”, ChemiLuminescent Nitrogen Detector, “ELSD” Evaporative Light Scanning Detector.

LCMS Methods

(Flow expressed in mL/min; column température (T) in °C; Run time in minutes).

Method code	Instrument	Column	Mobile phase	Gradient	Flow Col T	Run time
A	Waters: Acquity® UPLC®- D AD and SQD	Waters : HSS T3 (1.8pm, 2.1*10 0mm)	A: lOmM CH3COONH4 in 95% H₂O + 5% CH3CN B: CH3CN	From 100% A to 5% A in 2.10min, to 0% A in 0.90min, to 5% A in 0.5min	0.8 55	3.5
B	Waters: Acquity® UPLC® DAD and SQD	Waters : BEH C18 (1.7.um, 2.1*50 mm)	A: lOmM CH3COONH4 in 95% H₂O + 5% CH3CN . B: CH3CN	From 95% A to 5% A in 1.3 min, held for 0.7 min.	0.8 55	2
C	Waters: Acquity® UPLC®DAD and SQD	Waters : HSS T3 (1.8pm, 2.1*10 0mm)	A: lOmM CH3COONH4 in 95% H₂O + 5% CH3CN B: CH₃CN	From 100% A to 5% A in 2.10min, to 0% A in 0.90min, to 5% A in 0.5min	0.7 55	3.5
D	Waters: Alliance®- DADZQ and ELSD 2000 Alltech	Waters : Xterra MS C18 (3.5,um, 4.6*10 0mm)	A: 25mM CH3COONH4 in 95% H2O + 5% CH3CN B: CH₃CN C: CH3OH D: (40% CH3CN and 40% CH3OH and20%H2O with 0.25% CH3COOH	From 100% A to 1% A, 49% B and 50% C in 6.5 min, to 1% A and 99% B in 0.5 min,to 100% D in 1 min held for 1.0 minto 100% A in 0.5 min and held for 1.5min.	1.6 40	11

Synthesis of examples

Compound 1 : (7?)-4-(2-(ô^,ec-butvlamino)-2-oxoacetyl)-V-(4-fluoro-3-methvlphenvl)-lmethyl- lH-üvrrole-2-carboxamide

H₂N

AICI3

DCM, 0°C 3h

HATU, DIPEA

DMF, rt16h

l-Methyl-lB-pyrrole-2-carboxylic acid (2.0 g, 16 mmol), 4-fluoro-3-methylaniline (2.0 g, 16 mmol) and A/V-diisopropylethylamme (DIPEA, 6.2 g, 48 mmol) were dissolved in 30 mL DMF and cooled on ice under N₂. 2-(7-Aza-177-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU, 6.69 g, 17.6 mmol) was added, the ice bath was removed and the mixture was stirred ovemight at room température. The reaction mixture was diluted with 200 mL EtOAc and washed with IN HCl, NaHCO₃ solution and brine. The organic layer was dried over Na₂SO4, filtered, and concentrated under reduced pressure. The residue was crystallized from a mixture of 30 mL MeOH and 15 mL water. The crystals were filtered off and dried in vacuum to provide V-(4-fluoro-3-methylphenyl)-l-methyl-117pyrrole-2-carboxamide (3.22 g) as gray needles, mp = 111.3°C. LC method B; Rt: 0.99 min.

m/z : 233.2 (M+H)⁺ Exact mass: 232.1. *H NMR (400 MHz, DMSO-dô) δ ppm 2.22 (s, 3 H), 3.87 (s, 3 H), 6.08 (dd, J=4.0,2.6 Hz, 1 H), 6.95 - 7.03 (m, 2 H), 7.07 (t, J=9.1 Hz, 1 H), 7.44 - 7.54 (m, 1 H), 7.62 (dd, J=7.3, 2.4 Hz, 1 H), 9.69 (s, 1 H).

TV-(4-Fluoro-3-methylphenyl)-l-methyl-lH-pyrrole-2-carboxamide (2.0 g, 8.6 mmol) was dissolved in 30 mL dichloromethane and cooled on ice under N₂. A solution of ethyl chlorooxoacetate (2.94 g, 21.5 mmol) in 5 ml dichloromethane was added drop wise and the mixture was stirred for 30 min at 0°C. AluminiumÇHI) chloride (3.44 g, 25.8 mmol) was added in portions and the reaction mixture was stirred at 0°C for 3 hours. The reaction mixture was poured into 100 ml vigorously stirred ice water and extracted with EtOAc (2x). The combined organic layers were washed with NaHCO₃ solution and brine, dried over

Na₂SO4, filtered, and concentrated under reduced pressure. The residue was crystallized from 40 ml EtOH, the crystals were filtered off and dried in vacuum to provide ethyl

-202-(5-(4-fluoro-3-methylphenylcarbamoy 1)-1 -methyl-lW-pyrrol-3-yl)-2-oxoacetate (1.29 g) as a white solid, mp = 126.3°C. LC method B; Rt: 1.04 min. m/z : 333.1 (M+H)⁺ Exact mass: 332.1. ^XH NMR (400 MHz, DMSO-dg) 8 ppm 1.33 (t, .7=7.2 Hz, 3 H), 2.23 (d, >1.8 Hz, 3 H), 3.95 (s, 3 H), 4.35 (q, >7.0 Hz, 2 H), 7.10 (t, >9.2 Hz, 1 H), 7.48 - 7.55 (m, 1 H), 7.58 (d, >1.8 Hz, 1 H), 7.65 (dd, >7.0, 2.4 Hz, 1 H), 8.01 (d, >1.5 Hz, 1 H), 10.07 (s, 1H).

Ethyl 2-(5 -(4-fluoro-3 -methylphenylcarbamoyl)-1 -methyl-1 H-pyrrol-3 -yl)-2-oxoacetate (300 mg, 0.9 mmol) and (R)-(-)-2-aminobutane (196 mg, 2.7 mmol) were mixed in 5 ml EtOH and stirred at room température in a closed vessel for 7 days. The reaction mixture was concentrated under reduced pressure and then purified by préparative HPLC (stationary phase: RP Vydac Denali C18 - 10 pm, 200 g, 5 cm), mobile phase: 0.25% NH4HCO3 solution in water, CH3CN). The product fractions were concentrated, dissolved in MeOH and concentrated again yielding (R)-4-(2-(sec-butyIamino)-2-oxoacetyl)-V-(4-fluoro-3methylphenyl)-l-methyl-177-pyrrole-2-carboxamide (Compound 1,238 mg), as a white powder, mp = 136.5°C. LC method B; Rt: 1.07 min. m/z : 358.1 (M-H) Exact mass: 359.1. *H NMR (400 MHz, DMSO-d₆) 8 ppm 0.84 (t, >7.4 Hz, 3 H), 1.12 (d, >6.6 Hz, 3 H), 1.39 - 1.61 (m, 2 H), 2.23 (d, >1.5 Hz, 3 H), 3.72 - 3.88 (m, 1 H), 3.95 (s, 3 H), 7.09 (t, >9.2 Hz, 1 H), 7.47 - 7.58 (m, 1 H), 7.64 (d, >1.8 Hz, 1 H), 7.66 (dd, >7.2, 2.5 Hz, 1 H), 8.13 (s, 1 H), 8.38 - 8.53 (m, 1 H), 10.04 (s, 1 H).

Compound 2: W-(4-fluoro-3-methylphenyl)-4-(2-(isopropvlamino)-2-oxoacetyl~)-l-methyllW-nvrrole-2-carboxamide

Compound 2 was prepared similarly as Compound 1 by reaction of ethyl 2-(5-(4-fluoro-3methylphenylcarbamoyl)-l-methyl-177-pyrrol-3-yl)-2-oxoacetate with 10 équivalents of isopropylamine by ovemight stirring at room température in EtOH in a closed vessel. The reaction mixture was concentrated under reduced pressure and then purified by préparative HPLC (stationary phase: RP Vydac Denali Cl8 -10 pm, 200 g, 5 cm), mobile phase: 0.25% NH4HCO3 solution in water, CH3CN). The product fractions were concentrated, dissolved in MeOH and concentrated again yielding 7V-(4-fluoro-3-methylphenyl)-4-(2-(isopropylamino)-2-oxoacetyl)-l-methyl- 177-pyrrole-2-carboxamide (Compound 2, 229 mg), as a foam. LC method A; Rt: 1.84 min. m/z : 344.1 (M-H) Exact mass: 345.2. Tl NMR

(400 MHz, DMSO-de) δ ppm 1.15 (d, 7=6.6 Hz, 6 H), 2.23 (d, 7=1.8 Hz, 3 H), 3.95 (s, 3 H),

3.96 - 4.07 (m, 1 H), 7.09 (t, 7=9.2 Hz, 1 H), 7.49 - 7.57 (m, 1 H), 7.63 (d, 7=1.8 Hz, 1 H),

7.66 (dd, 7=7.2,2.5 Hz, 1 H), 8.14 (d, 7=1.5 Hz, 1 H), 8.52 (d, 7=8.1 Hz, 1 H), 10.04 (s,

1H).

Compound 3: 4-(2-(ferAbutvlamino)-2-oxoacetvl)-N-(4-fluoro-3 -methylphenyl)-1 -methyl177-pyrrole-2-carboxamide

Ethyl 2-(5-(4-fluoro-3-methylphenylcarbamoyl)-l-methyl-177-pyrrol-3-yl)-2-oxoacetate (980 mg, 2.9 mmol) was dissolved in 20 ml EtOH. A IN aqueous solution of NaOH (8.8 mL, 8.8 mmol) was added drop wise. The reaction mixture was stirred for 5 min at room température and was then cooled on ice. IN HCl was added until pH = 2. The reaction mixture was diluted by the addition of water (50 mL) causing the formation of a white precipitate. The solid material was filtered off, rinsed with water, and dried in vacuum to provide 2-(5-(4-fluoro-3-methylphenylcarbamoyl)-l-methyl-177-pyrrol-3-yl)-2-oxoacetic acid (530 mg) as white crystals, mp = 180.8°C. LC method B; Rt: 0.61 min. m/z : 303.1 (Μ-H)’ Exact mass: 304.1. ^!H NMR (400 MHz, DMSO-dg) δ ppm 2.23 (d, 7=1.8 Hz, 3 H),

3.95 (s, 3 H), 7.09 (t, 7=9.2 Hz, 1 H), 7.49 - 7.55 (m, 1 H), 7.57 (d, 7=1.8 Hz, 1 H), 7.65 (dd, 7=7.0, 2.4 Hz, 1 H), 7.97 (d, 7=1.5 Hz, 1 H), 10.06 (s, 1 H), 14.05 (br. s., 1 H).

2-(5-(4-Fluoro-3-methylphenylcarbamoyl)-l-methyl-177-pyrrol-3-yl)-2-oxoacetic acid (530 mg, 1.74 mmol) ), ieri-butylamine (127 mg, 1.74 mmol), and ΛζΑ-diisopropylethylamine (DIPEA, 675 mg, 5.2 mmol) were dissolved in 10 mL DMF and cooled on ice under N₂. 2-(7-Aza-177-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU, 728 mg, 1.92 mmol) was added, the ice bath was removed and the mixture was stirred at room température for 5 hours. The reaction mixture was diluted with

EtOAc (100 mL) and washed with IN HCl, NaHCO₃ solution, and brine. The organic layer was dried over Na₂SO4, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of 10 mL MeOH and 5 mL water. The crystals were filtered off and dried in vacuum to provide 4-(2-(ierLbutylamino)-2-oxoacetyl)-N-(4-fluoro-3-methylphenyl)-l-methyl-177-pyrrole-2-carboxamide (Compound 3, 517 mg) as a white powder.

LC method B; Rt: 1.12 min. m/z : 358.2 (M-H)’ Exact mass: 359.2. ⁽Η NMR (400 MHz, DMSO-dô) δ ppm 1.36 (s, 9 H), 2.23 (d, 7=1.8 Hz, 3 H), 3.95 (s, 3 H), 7.09 (t, 7=9.2 Hz,

H), 7.50 - 7.56 (m, 1 H), 7.61 (d, >1.8 Hz, 1 H), 7.66 (dd, >7.0, 2.2 Hz, 1 H), 7.95 (s,

H), 8.10 (d, >1.5 Hz, 1 H), 10.05 (s, 1 H).

Compound 4: 7V-(4-fluoro-3 -methylphenyl·)-1 -methyl-4-(2-(3 -methyloxetan-3 -ylamino)-2oxoacetvD-17/-nvrrole-2-carboxamide

HATU, DIPEA

DMF, rt 5h

2-(5-(4-Fluoro-3-methylphenylcarbamoyl)-l-methyl-177-pyrrol-3-yl)-2-oxoacetic acid (410 mg, 1.35 mmol), 3-methyl-3-oxetanamine hydrochloride (183 mg, 1.48 mmol),and A/TV-diisopropylethylamine (DIPEA, 870 mg, 6.74 mmol) were dissolved in 10 mL of DMF and cooled on ice under N₂. 2-(7-Aza-17f-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium 10 hexafluorophosphate (HATU, 563 mg, 1.48 mmol) was added, the ice bath was removed and the mixture was stirred at room température for 5 hours. The reaction mixture was diluted with 100 mL EtOAc and washed with IN HCl, NaHCCh solution, and brine. The organic layer was evaporated under reduced pressure. The residue was purifïed by Préparative HPLC (stationary phase: Uptisphere Cl8 ODB - lOpm, 200g, 5cm), mobile 15 phase: 0.25% NH4HCO3 solution in water, MeOH). The product fractions were concentrated, dissolved in MeOH, and concentrated again. The residue was crystallized from a mixture of 10 mL MeOH and 5 mL water. The crystals were filtered off and dried in vacuum to provide 7V-(4-fluoro-3-methylphenyl)-l-methyl-4-(2-(3-methyloxetan-3-ylamino)-2-oxoacetyl)-177-pyrrole-2-carboxamide (Compound 4, 183 mg) as a white powder, 20 mp = 145.1°C. LC method A; Rt: 1.63 min. m/z : 372.0 (M-H)' Exact mass: 373.1. ^JH NMR (400 MHz, DMSO-dg) δ ppm 1.58 (s, 3 H), 2.23 (d, >1.8 Hz, 3 H), 3.95 (s, 3 H), 4.35 (d, >6.8 Hz, 2 H), 4.72 (d, >6.4 Hz, 2 H), 7.09 (t, >9.2 Hz, 1 H), 7.48 - 7.58 (m, 1 H), 7.65 (d, >1.8 Hz, 1 H), 7.67 (d, >2.4 Hz, 1 H), 8.17 (d, >1.3 Hz, 1 H), 9.26 (s, 1 H), 10.05 (s, 1H).

-23Compound 5: (7?)-A-(4-fluoro-3-methvlphenyl)-l-methvl-4-(2-oxo-2-(LLl-tnfluoropropan2-vlamino~)acetvl)-lH-PVrrole-2-carboxamide

P>k^NH₂

HATU, DIPEA

DMF, rt6h

2-(5-(4-Fluoro-3-methylphenylcarbamoyl)-l-methyl-127-pyrrol-3-yl)-2-oxoacetic acid (300 mg, 0.95 mmol), (7?)-l,l,l-trifluoro-2-propylamine (118 mg, 1.04 mmol), and Λζ/V-diisopropylethylamine (DIPEA, 367 mg, 2.84 mmol) were dissolved in 5 mL DMF under N₂. 2-(7-Aza-177-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU, 396 mg, 1.04 mmol) was added and the mixture was stirred at room température for 6 hours. The reaction mixture was diluted with 100 mL EtOAc and washed with IN HCl, NaHCCh solution and brine. The organic layer was evaporated under reduced pressure. The residue was crystallized from a mixture of 10 mL MeOH and 5 mL water. The crystals were filtered off and dried in vacuum to provide (7?)-Æ-(4-fluoro-3-methylphenyl)-lmethyl-4-(2-oxo-2-( 1,1,1 -trifluoropropan-2-ylamino)acetyl)- lH-pyrrole-2-carboxamide (Compound 5, 182 mg) as a white powder, mp =156.9°C. LC method B; Rt: 1.10 min. m/z :

398.2 (Μ-H)’ Exact mass: 399.1. ^JH NMR (400 MHz, DMSO-d₆) δ ppm.1.35 (d, J=7.0 Hz, 3 H), 2.23 (d, >1.8 Hz, 3 H), 3.95 (s, 3 H), 4.59 - 4.79 (m, 1 H), 7.09 (t, J=9.1 Hz, 1 H), 7.45 - 7.58 (m, 1 H), 7.60 - 7.71 (m, 2 H), 8.10 (d, >1.3 Hz, 1 H), 9.32 (d, J=9.0 Hz, 1 H), 10.07 (s, 1 H). .

Compound 6: (_lS)-A'-(4-fluoro-3-methylphenyl)-l -methyl-4-(2-oxo-2-(tetrahydrofuran-3vlamino)acetyl)-177-pyrrole-2-carboxamide

^γΝΗ₂

O> .HCl

HATU, DIPEA

DMF, rt 3h

2-(5-(4-Fluoro-3-methylphenylcarbamoyl)-1 -methyl-1 A-pyrrol-3 -yl)-2-oxoacetic acid (300 mg, 0.95 mmol), (,S)-tetrahydrofuran-3-amine hydrochloride (128 mg, 1.04 mmol) and A/V-diisopropylethylamine (DIPEA, 611 mg, 4.73 mmol) were dissolved in 5 mL of DMF under N₂. 2-(7-Aza-127-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU, 396 mg, 1.04 mmol) was added and the mixture was stirred at room

-24temperature for 3 hours. The reaction mixture was diluted with 100 mL EtOAc and washed with IN HCl, NaHCO₃ solution, and brine. The organic layer was evaporated under reduced pressure. The residue was crystallized from a mixture of 10 mL MeOH and 5 mL water. The crystals were filtered off and dried in vacuum to provide {>S)-V-(4-fluoro-3-methylphenyl)-lmethyl-4-(2-oxo-2-(tetrahydrofuran-3-ylamino)acetyl)-127-pyrrole-2-carboxamide (Compound 6, 248 mg) as a white powder, mp =155.7°C. LC method B; Rt: 0.90 min. m/z :

372.2 (Μ-H)' Exact mass: 373.1. *H NMR (400 MHz, DMSO-d₆) δ ppm 1.86 - 1.99 (m, 1 H), 2.07 - 2.18 (m, 1 H), 2.23 (d, >1.8 Hz, 3 H), 3.57 (dd, >8.9, 4.5 Hz, 1 H), 3.71 (td, >8.1, 5.7 Hz, 1 H), 3.78 - 3.87 (m, 2 H), 3.95 (s, 3 H), 4.30 - 4.42 (m, 1 H), 7.09 (t, >9.2 Hz, 1 H), 7.49 - 7.56 (m, 1 H), 7.62 (d, >1.8 Hz, 1 H), 7.66 (dd, >7.2, 2.3 Hz, 1 H), 8.11 (d, >1.3 Hz, 1 H), 8.88 (d, >6.8 Hz, 1 H), 10.05 (s, 1 H).

Compound 7: methyl 2-(2-(5-(4-fluoro-3-methylphenylcarbamovl~)-l-methvl-lÆ-pvrrol-3vl)-2-oxoacetamido)-2-methylpropanoate

° .HCl

HATU, DIPEA

DMF, rt 16h

2-(5-(4-Fluoro-3-methylphenylcarbamoyl)-l-methyl-lH-pyrrol-3-yl)-2-oxoacetic acid (800 mg, 2.58 mmol), 2,2-dimethylglycine methylester hydrochloride (435 mg, 2.83 mmol) and 77,A'-diisopropylethylamine (DIPEA, 1.67 mg, 12.9 mmol) were dissolved in 15 mL of DMF and cooled on ice under N2. 2-(7-Aza-177-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU, 1078 mg, 2.83 mmol) was added, the ice bath was removed and the mixture was stirred ovemight at room température. The reaction mixture was diluted with 150 mL EtOAc and washed with IN HCl, NaHCO3 solution, and brine. The organic layer was evaporated under reduced pressure. The residue was crystallized from a mixture of 20 mL MeOH and 5 mL water. The crystals were filtered off and dried in vacuum to provide methyl 2-(2-(5-(4-fluoro-3-methylphenylcarbamoyl)-l-methyl-177pyrrol-3-yl)-2-oxoacetamido)-2-methylpropanoate (Compound 7, 905 mg) as a white powder, mp = 161.0°C. LC method B; Rt: 1.04 min. m/z : 402.2 (M-H) Exact mass: 403.2. ^XHNMR (400 MHz, DMSO-d₆) δ ppm 1.46 (s, 6 H), 2.23 (d, >1.8 Hz, 3 H), 3.64 (s, 3 H),

3.95 (s, 3 H), 7.09 (t, >9.2 Hz, 1 H), 7.49 - 7.57 (m, 1 H), 7.62 (d, >1.8 Hz, 1 H), 7.66 (dd, >7.2, 2.3 Hz, 1 H), 8.07 (d, >1.3 Hz, 1 H), 8.93 (s, 1 H), 10.07 (s, 1 H).

Compound 8: 4- [r(2-Amino-l, l-dimethyl-2-oxoethyl)amino1(oxo)acetyl)-N-(4-fluoro-3methylphenyl)-1 -methyl-1 H-pyrrole-2-carboxamide

Compound 8 (300 mg, 0.74 mmol) was dissolved in 7 Μ NH3 in MeOH (15 mL) and stirred for 2 days at room température. The volatiles were removed under reduced pressure and the residue was dispensed in 7 Μ NH3 in MeOH (50 mL) and stirred for 2 days more. The volatiles were removed under reduced pressure and the residue was purified via prep. HPLC followed by trituration with diisopropylether, resulting in compound 8 (96 mg) as an off white powder. LC method B; Rt: 0.86 min. m/z : 387.2 (M-H)' Exact mass: 388.2.

Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: Peak: 237.0 °C. ^XHNMR (400 MHz, DMSO-cU) δ ppm 1.52 (s, 6 H), 2.23 (d, J=1.8 Hz, 3 H), 3.95 (s, 3 H), 7.09 (t, J=9.2 Hz, 1 H), 7.17 (br. s., 1 H), 7.43 (br. s., 1 H), 7.50 - 7.57 (m, 1 H), 7.63 - 7.70 (m, 2 H), 8.25 (d, J=1.3 Hz, 1 H), 8.55 (s, 1 H), 10.06 (s, 1 H).

Compound 9: 4-Γ fr(lR)-2-Cyano-l-methvlethvl1amino)(oxo)acetyll-N-(4-fluoro-3-methylphenyl)-1 -methyl-1 H-pyrrole-2-carboxamide

/

Compound 9 (430 mg) was prepared similarly as described for compound 5 using (3R)-3-aminobutanenitrile instead of (R)-l,l,l-trifluoro-2-propylamine. LC method B; Rt: 0.95 min. m/z: 369.1 (M-H)’ Exact mass: 370.1. TlNMR (400 MHz, DMSO-cL) δ ppm 1.23 (d, J=6.6 Hz, 3 H), 2.23 (d, J=1.8 Hz, 3 H), 2.70-2.85 (m, 2 H), 3.95 (s, 3 H), 4.12-4.28 (m, 1 H), 7.09 (t, J=9.2 Hz, 1 H), 7.49 - 7.57 (m, 1 H), 7.66 (d, J=1.8 Hz, 1 H), 7.67 (d, J=2.2 Hz, 1 H), 8.17 (d, J=1.3 Hz, 1 H), 8.94 (d, J=8.4 Hz, 1 H), 10.06 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: Peak: 138.3 °C.

-26Compound 10: 4-(2-(rer/-butylamino)-2-oxoacetyl)-iV-(3,4-difluorophenyl)-1 -methyl-177pynOle-2-carboxamide

1-M ethyl-177-pyrrole-2-carboxylic acid (2.0 g, 16 mmol) was dissolved in 50 mL dichloromethane and cooled on ice under N₂. A solution of ethyl chlorooxoacetate (5.45 g, 40 mmol) in 10 ml dichloromethane was added drop wise and the mixture was stirred for 10 min at 0°C. Aluminium(III) chloride (6.39 g, 48 mmol) was added in portions and the reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was poured into 200 mL vigorously stirred ice water causing précipitation of a white solid. The precipitate was filtered off and rinsed with water, isopropanol, and diisopropyl ether, and dried in vacuum to afford 4-(2-ethoxy-2-oxoacetyl)-l-methyl-177-pyrrole-2-carboxylic acid (1.44g) as a white powder. LC method B; Rt: 0.38 min. m/z : 224.0 (M-H)’ Exact mass: 225.1. ^JHNMR (400 MHz, DMSO-de) δ ppm 1.31 (t, .7=7.0 Hz, 3 H), 3.92 (s, 3 H), 4.33 (q, 7=7.1 Hz, 2 H), 7.25 (d, 7=1.5 Hz, 1 H), 8.01 (s, 1 H), 12.86 (br. s., 1 H).

To a solution of 4-(2-ethoxy-2-oxoacetyl)-l-methyl-l/7-pyrrole-2-carboxylic acid (750 mg, 3.30 mmol) and triethylamine (917 pL, 6.59 mmol) in DMF (7.5 mL), 2-(7-aza-177benzotriazole-l-yl)-l,l,3,3-tetramethyluroniumhexafluorophosphate (HATU, 1504 mg,

3.96 mmol) was added and the mixture was stirred at room température for 10 min. 3,4-Difluoroaniline (851 mg, 6.59 mmol) was added and the mixture was stirred for 2 hours. The mixture was poured out into 100 mL water and the precipitate was filtered off and rinsed with water. The wet powder was dissolved in dichloromethane, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to provide ethyl 2-(5-(3,4-difluorophenylcarbamoyl)-l-methyl-177-pyrrol-3-yl)-2-oxoacetate (947 mg) as a brown powder. LC method B; Rt: 1.04 min. m/z : 335.1 (M-H)’Exact mass: 336.3.

A solution of ethyl 2-(5-(3,4-difluorophenylcarbamoyl)-l-methyl-177-pyrrol-3-yl)-2oxoacetate (937 mg, 2.79 mmol) in 30 ml EtOH was treated with IN NaOH solution (8.36 mL, 8.36 mmol) and the reaction mixture was heated to 60°C for 10 min. The reaction

-27mixture was cooled to room température and neutralized by the addition of triethylamine hydrochloride (1.53 g, 11.14 mmol). The mixture was evaporated under reduced pressure and the dry residue was co-evaporated twice with toluene (50 mL) to remove remaining traces of water. The crude reaction product 2-(5-(3,4-difluorophenylcarbamoyl)-l-methyllÆ-pyrrol-3-yl)-2-oxoacetic acid (LC method B; Rt: 0.59 min. m/z : 307.1 (M-H)' Exact mass: 308.2) was taken up in dry DMF (20 mL) and divided in two equal portions of 10 mL each for the synthesis of Compounds 10 and 11.

For the synthesis of Compound 10, a solution of crude 2-(5-(3,4-difluorophenylcarbamoyl)- l-methyl-l//-pyrrol-3-yl)-2-oxoacetic acid (roughly 1.4 mmol) in 10 mL of DMF was mixed with triethylamine (582 pL, 4.2 mmol) and 2-(7-aza-177-benzotriazole-l-yl)-l,l,3,3tetramethyluronium hexafluorophosphate (HATU, 637 mg, 1.67 mmol) and stirred for 10 min at room température. tert-Butylamine (204 mg, 2.79 mmol) was added and the mixture was stirred at room température for 3 hours. The reaction mixture was poured out into 100 mL water and the precipitate was fïltered off and washed with water. The powder was purified by chromatography over silica gel using a solvent gradient from 0% to 100% EtOAc in heptane as the mobile phase, to afford 4-(2-(teri-butylamino)-2-oxoacetyl)-A(3,4-difluorophenyl)-l-methyl-17ï-pyrrole-2-carboxamide (Compound 10, 220 mg) as a white powder, mp = 170.7°C. LC method B; Rt: 1.12 min. m/z : 362.2 (M-H)’ Exact mass: 363.1. ^JH NMR (400 MHz, DMSO-d₆) δ ppm 1.37 (s, 9 H), 3.95 (s, 3 H), 7.40 (dt, J=10.6,

9.2 Hz, 1 H), 7.48 - 7.54 (m, 1 H), 7.64 (d, J=1.8 Hz, 1 H), 7.88 (ddd, J=13.4, 7.6, 2.5 Hz, 1 H), 7.96 (br. s, 1 H), 8.13 (d, J=1.7 Hz, 1 H), 10.26 (s, 1 H).

Compound 11: A-(3.4-difluorophenvl)-l-methyl-4-(2-(3-methyloxetan-3-ylamino)-2oxoacetyl)-lff-pyrrole-2-carboxamide

A solution of crude 2-(5-(3,4-difluorophenylcarbamoyl)-l-methyl-177-pyrrol-3-yl)-2oxoacetic acid (roughly 1.4 mmol; as described in the procedure for the synthesis of Compound 10) in 10 mL DMF was mixed with triethylamine (776 pL, 5.58 mmol) and 2-(7-aza-1 H-benzotriazole-1 -yl)-1,1,3,3 -tetramethyluronium hexafluorophosphate (HATU, 637 mg, 1.67 mmol) and stirred for 10 min at room température. 3-Methyl-3-oxetanamine (243 mg, 2.79 mmol) was added and the mixture was stirred at room température for 3 hours. The reaction mixture was poured out into 100 mL water and the precipitate was

-28filtered off and washed with water. The sohd residue was re-crystallized from a mixture of 10 mL MeOH and 5 mL water, filtered off and dried in vacuum to afford /V-(3,4-difluorophenyl)-1 -methyl-4-(2-(3 -methyloxetan-3-ylamino)-2-oxoacetyl)- lÆ-pyrrole-2-carboxamide (Compound 11, 221 mg) as a beige powder, mp = 180.7°C. LC method B; Rt: 0.92 min. m/z : 376.2 (M-H)' Exact mass: 377.1. ^NMR^OO MHz, DMSO-cU) δ ppm 1.58 (s, 3 H), 3.96 (s, 3 H), 4.35 (d, 7=6.6 Hz, 2 H), 4.72 (d, 7=6.4 Hz, 2 H), 7.36 - 7.45 (m, 1 H), 7.48 - 7.56 (m, 1 H), 7.68 (d, 7=1.5 Hz, 1 H), 7.89 (ddd, 7=13.4, 7.5, 2.4 Hz, 1 H), 8.20 (br. d, 7=1.1 Hz, 1 H), 9.27 (br. s, 1 H), 10.26 (br. s, 1 H).

Compound 12: 4-(2-(fer/-butylammo)-2-oxoacetyl)-1 -methyl-Α-(3 -(trifluoromethvDphenyl)177-pyrrole-2-carboxamide

HATU, TEA

DMF, rt 3h nh₂

4-(2-Ethoxy-2-oxoacetyl)-l-methyl-UT-pyrrole-2-carboxylic acid (750 mg, 3.30 mmol) and triethylamine (917 pL, 6.59 mmol) were mixed in 7.5 mL of DMF. 2-(7-Aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU, 1504 mg,

3.96 mmol) was added and the mixture was stirred for 10 min. 3-Trifluoromethylaniline (1062 mg, 6.59 mmol) was added and the mixture was stirred for 2 hours at room température and was subsequently heated to 40°C for 30 min. The mixture was poured out into 100 mL water and the precipitate was filtered off and washed with water. The powder was dried in vacuum to provide ethyl 2-(l-methyl-5-(3-(trifluoromethyl)phenylcarbamoyl)lH-pyrrol-3-yl)-2-oxoacetate (650 mg) as a beige powder. LC method B; Rt: 1.12 min. m/z : 367.1 (M-H)‘Exact mass: 368.1.

A solution of ethyl 2-(l-methyl-5-(3-(trifluoromethyl)phenylcarbamoyl)-l/7-pyrrol-3-yl)-2oxoacetate (650 mg, 1.76 mmol) in 30 ml EtOH was treated with IN NaOH solution (5.3 mL, 5.3 mmol) and the reaction mixture was stirred at room température for 20 min. The reaction mixture was neutralized by the addition of triethylamine hydrochloride (1.22 g, 8.82 mmol). The mixture was evaporated under reduced pressure and the dry residue was co-evaporated twice with 50 ml toluene to remove remaining traces of water. The crude reaction product 2-(l-methyl-5-(3-(trifluoromethyl)phenylcarbamoyl)-177-pyrrol-3-yl)-217673

oxoacetic acid (LC method B; Rt: 0.68 min. m/z : 339.1 (M-H) Exact mass: 340.1) was taken up in 10 ml of dry DMF and divided in two equal portions of 5 mL each for the synthesis of Compounds 12 and 13.

For the synthesis of Compound 12, a solution of crude 2-(l-methyl-5-(3-(trifluoromethyl)phenylcarbamoyl)-lA^r-pyrrol-3-yl)-2-oxoacetic acid (roughly 0.88 mmol) in 5 mL of DMF was mixed with triethylamine (490 pL, 3.53 mmol) and 2-(7-aza-177-benzotriazole-l-yl)1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 1006 mg, 2.64 mmol) and stirred for 10 min at room température. Zeri-Butylamine (193 mg, 2.65 mmol) was added and the mixture was stirred at room température for 3 hours. The reaction mixture was poured out into 100 mL water and the precipitate was filtered off and washed with water. The powder was purifîed by chromatography over silica gel using a solvent gradient from 0% to 100% EtOAc in heptane as the mobile phase, to afford 4-(2-(ieri-butylamino)-2-oxoacetyl)-lmethyl-A-(3-(trifluoromethyl)phenyl)-177-pyrrole-2-carboxamide (Compound 12, 321 mg) as an amorphous white powder. LC method B; Rt: 1.19 min. m/z : 394.2 (M-H) Exact mass: 395.2. ^JH NMR (360 MHz, DMSO-rig) δ ppm 1.38 (s, 9 H), 3.98 (s, 3 H), 7.43 (d, J=7.7 Hz, 1 H), 7.58 (br. t, J=8.1, 8.1 Hz, 1 H), 7.72 (d, J=1.8 Hz, 1 H), 7.99 - 8.04 (m, 2 H), 8.16 (d, J=l.l Hz, 1 H), 8.21 - 8.26 (m, 1 H), 10.39 (s, 1 H).

Compound 13: l-methyl-4-(2-(3-methyloxetan-3-ylamino)-2-oxoacetyl)-V-(3-(trifluoromethyl)phenyl)-17T-pyrrole-2-carboxamide

A solution of crude 2-(l-methyl-5-(3-(trifluoromethyl)phenylcarbamoyl)-l/7-pyrrol-3-yl)-2oxoacetic acid (roughly 0.88 mmol; as described in the procedure for the synthesis of Compound 12) in 5 mL of DMF was mixed with triethylamine (490 pL, 2.65 mmol) and

2-(7-aza- l/Z-benzotriazole-1 -yl)-1,1,3,3 -tetramethyluronium hexafluorophosphate (HATU, 1005 mg, 2.65 mmol) and stirred for 10 min at room température. 3-Methyl-3-oxetanamine (230 mg, 2.65 mmol) was added and the mixture was stirred at room température for 3 hours. The reaction mixture was poured out into 100 mL water and the precipitate was filtered off and washed with water. The solid residue was dried in vacuum to afford l-methyl-4-(2-(3-methyloxetan-3-ylamino)-2-oxoacetyl)-lV-(3-(trifluoromethyl)phenyl)-177'pyrrole-2-carboxamide (Compound 13, 316 mg) as an amorphous white powder. LC method B; Rt: 1.01 min. m/z : 408.2 (M-H/Exact mass: 409.1. ’H NMR (400 MHz, DMSO-d₆) δ ppm 1.58 (s, 3 H), 3.97 (s, 3 H), 4.35 (d, >6.6 Hz, 2 H), 4.72 (d, >6.4 Hz, 2 H), 7.43 (d, >7.7 Hz, 1 H), 7.58 (br. t, >7.9,7.9 Hz, 1 H), 7.74 (d, >1.8 Hz, 1 H), 7.98 - 8.04 (m, 1 H), 8.18 - 8.24 (m, 2 H), 9.28 (s, 1 H), 10.36 (s, 1 H).

Compound 14: 4-(2-('/βΓ/^πίν1Ηπιίη.ο)-2-οχοΗθ6ίν1)-ΐν'-(3-ού1θΓθ-4,5-άίΑποΓορΙΐ6ην1)-1methyl- lff-pyrrole-2-carboxamide

o ci'V^{1 2}O _r cich₂ch₂ci

38°C 2h

γ_Η2

DIPEA

ACN,rt18h

Oxalylchloride (2 mL, 23.3 mmol) was added slowly to a stirred solution of methyl l-methyl-177-pyrrole-2-carboxylate (2 g, 14.4 mmol) in 10 ml dichloroethane atroom température. The mixture was subsequently heated to 38°C for 2 hours. The solvent was removed under reduced pressure and the residue was dissolved in 25 mL of acetonitrile and added portion wise to a stirred solution of fôri-butylamine (3.05 mL, 28.7 mmol), and DIPEA (4.95 mL, 28.7 mmol) in 25 mL of acetonitrile. After ovemight stirring, the volatiles were removed by évaporation under reduced pressure. The residue was mixed with water, extracted with 2-methyl tetrahydrofuran, dried over Na₂SO4, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography over silica gel using a solvent mixture of heptane and dichloromethane as the mobile phase. Product fractions were combined and evaporated, and finally co-evaporated with MeOH under reduced pressure:

1) Elution with a mixture of heptane : DCM in a ratio of 60:40 provided methyl

5-(2-(terAbutylamino)-2-oxoacetyl)-l-methyl-lH-pyrrole-2-carboxylate (820 mg) as the first fraction. *H NMR (360 MHz, DMSO-^ ) δ ppm 1.34 (s, 9 H), 3.82 (s, 3 H), 4.17 (s, 3 H), 6.91 (d, J=4.4 Hz, 1 H), 6.99 (d, >4.4 Hz, 1 H), 8.35 (s, 1 H).

2) Elution with a mixture of heptane : DCM in a ratio of 50:50 provided methyl 4-(2-(te/-Abutylamino)-2-oxoacetyl)-l-methyl-lÆ-pyrrole-2-carboxylate (830 mg) as the second fraction. *H NMR (360 MHz, DMSO-ûfc) δ ppm 1.35 (s, 9 H), 3.78 (s,

H), 3.93 (s, 3 H), 7.32 (d, >1.8 Hz, 1 H), 8.02 (s, 1 H), 8.13 (d, >1.8 Hz, 1 H)

-31Methyl 4-(2-(terAbutylamino)-2-oxoacetyl)-l-methyl-lH-pyrrole-2-carboxylate (780 mg, 2.9 mmol) was dissolved in 10 mL of MeOH and to the stirred solution IN NaOH (6.44 mL, 6.44 mmol) was added. After ovemight stirring at room température, IN HCl (7 mL) was added slowly. Précipitation was completed by the addition of 30 mL water and after stirring for 5 min, the solids were fîltered off, washed with water, and dried in vacuum to provide 4-(2-(te77-butylamino)-2-oxoacetyl)-l-methyl-lH-pyrrole-2-carboxylic acid (700 mg) as a white powder. LC method B; Rt: 0.49 min. m/z : 251.1 (M-H)' Exact mass: 252.1. ¹H NMR (400 MHz, DMSO-de) δ ppm 1.35 (s, 9 H), 3.91 (s, 3 H), 7.25 (d, >1.8 Hz, 1 H), 7.96 (s, 1 H), 8.06 (d, >1.5 Hz, 1 H), 12.78 (br. s., 5 H).

4-(2-(terEbutylamino)-2-oxoacetyl)-l-methyl-l/f-pyrrole-2-carboxylic acid (250 mg, mmol), 3-chloro-4,5-difluoroaniline (162 mg, 1 mmol) and A/TV-diisopropylethylamine (DIPEA, 384 mg, 3 mmol) were dissolved in 5 mL DMF under N₂. 2-(7-Aza-177-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU, 414 mg,

1.09 mmol) was added and the mixture was stirred at 50°C for 2 days. The reaction mixture was diluted with 100 mL EtOAc and washed with IN HCl, NaHCCh solution, and brine. The organic layer was evaporated under reduced pressure and the residue was crystallized from a mixture of 10 mL MeOH and 4 mL water. The crystals were fîltered off and dried in vacuum to provide 4-(2-(teri-butylamino)-2-oxoacetyl)-yV-(3-chloro-4,5-difluorophenyl)-lmethyl-l/Z-pyrrole-2-carboxamide (Compound 14, 249 mg) as an amorphous beige powder. LC method B; Rt: 1.25 min. m/z : 396.2 (M-H)’ Exact mass: 397.1. *H NMR (400 MHz, DMSO-de) δ ppm 1.36 (s, 9 H), 3.95 (s, 3 H), 7.66 (d, >1.8 Hz, 1 H), 7.79 - 7.88 (m, 2 H),

7.97 (s, 1 H), 8.15 (d, >1.3 Hz, 1 H), 10.33 (s, 1 H).

Compound 15: 4-(^,2-('ferAbutvlamino)-2-oxoacetvl)-zV-('3-cvano-4-fluoroDhenvl)-l-methvllH-nvrrole-2-carboxamide

4-(2-(tert-Butylamino)-2-oxoacetyl)-l-methyl- 127-pyrrole-2-carboxylic acid (250 mg, mmol), 3-cyano-4-fluoroaniline (134 mg, 1 mmol), and ΑξΑΖ-diisopropylethylamine (DIPEA, 384 mg, 3 mmol) were dissolved in 5 mL of DMF under N₂. 2-(7-Aza-177benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU, 414 mg, 1.09 mmol) was added and the mixture was stirred ovemight at 50°C. The reaction mixture was diluted with 100 mL EtOAc and washed with IN HCl, NaHCO3 solution, and brine.

-32The organic layer was evaporated under reduced pressure and the residue was crystallized from a mixture of 10 mL MeOH and 5 mL water. The crystals were filtered off and dried in vacuum to provide 4-(2-(ter/-butylamino)-2-oxoacetyl)-A-(3-cyano-4-fluorophenyl)-lmethyl-lÆ-pyrrole-2-carboxamide (Compound 15, 292 mg) as an amorphous beige powder. LC method B; Rt: 1.08 min. m/z : 369.2 (M-H)' Exact mass: 370.1. ^XH NMR (400 MHz, DMSO-dô) δ ppm 1.37 (s, 9 H), 3.96 (s, 3 H), 7.52 (t, >9.1 Hz, 1 H), 7.67 (d, J=2.0 Hz, 1 H), 7.97 (s, 1 H), 8.03 (ddd, >9.2, 5.0, 2.8 Hz, 1 H), 8.14 (d, >1.3 Hz, 1 H), 8.23 (dd, >5.8, 2.8 Hz, 1 H), 10.39 (s, 1 H).

Compound 16 : N-(3-Cvano-4-fluoronhenvl)-1 -methyl-4- ( Γ(3 -methyloxetan-3-yl)amino1(oxo)acetyll - lH-pyrrole-2-carboxamide

Oxalylchloride (7.41 mL, 0.086 mol) was added slowly to a stirring solution of methyl l-methylpyrrole-2-carboxylate (6 g, 0.0431 mol ) in dichloroethane (30 mL ). The reaction mixture was stirred as an open vessel for 1 minute, then stirred in a closed vessel at T-int = 38°C (oil-bath = 45°C) for 3 hours, and at room température for 18 hours. Methyl 4-(2-chloro-2-oxo-acetyl)-l-methyl-pyrrole-2-carboxylate (1.45 g) was filtered off, washed with dichloroethane (2x), and used as such. Methyl 4-(2-chloro-2-oxo-acetyl)-l-methylpyrrole-2-carboxylate (1.45 g, 6.32 mmol) was added portionwise to a stirring solution of

3-methyloxetan-3-amine (1.1 g, 12.6 mmol), DIPEA (2.2 mL, 12.6 mmol), in acetonitrile (50 mL) under N2-atm. The reaction mixture was stirred at room température for 1 hour. The volatiles were evaporated. The residue was stirred in H₂O (15 mL), filtered off, washed with H₂O (3x), and dried at 50°C, resulting in methyl l-methyl-4-[2-[(3-methyloxetan-3-yl)amino]-2-oxo-acetyl]pyrrole-2-carboxylate (839 mg). LC method A; Rt: 1.29 min. m/z : 278.9 (M-H)' Exact mass:.280.1. Tl NMR (400 MHz, DMSO-d₆) δ ppm 1.56 (s, 3 H), 3.78 (s, 3 H), 3.93 (s, 3 H), 4.34 (d, >6.6 Hz, 2 H), 4.70 (d, >6.4 Hz, 2 H), 7.37 (d, >2.0 Hz, 1 H), 8.20 (d, >1.3 Hz, 1 H), 9.25 (s, 1 H). NaOH (IM in H₂O, 6.6 mL) was added to a stirring mixture of methyl l-methyl-4-[2-[(3-methyloxetan-3-yl)amino]-2-oxo-acetyl]pyrrole-2-carboxylate (939 mg, 2.99 mmol) in MeOH (10 mL). The reaction mixture was stirred at room température for 5 h. HCl IN (7 mL) was added slowly, and précipitation occurred. After stirring for 10 minutes, the mixture was left standing for 16 hours, filtered off, washed with H₂O-MeOH 3/1 (2x), and dried at 50°C in vacuo resulting in l-methyl-4[2-[(3-methyloxetan-3-yl)amino]-2-oxo-acetyl]pyrrole-2-carboxylic acid (0.66 g). *H NMR (400 MHz, DMSO-dg) δ ppm 1.56 (s, 3 H), 3.92 (s, 3 H), 4.34 (d, >6.6 Hz, 2 H), 4.70 (d,

-33>6.4 Hz, 2 H), 7.31 (d, >1.8 Hz, 1 H), 8.15 (d, >1.5 Hz, 1 H), 9.22 (s, 1 H), 12.80 (br. s., 1 H). Triethylamine (0.504 mL, 3.63 mmol ) was added to a stirring mixture of I-methyl-4[2-[(3-methyloxetan-3-yl)amino]-2-oxo-acetyl]pyrrole-2-carboxylic acid (0.322 g, 1.21 mmol ), and CH3CN (dried on molecular sieves, 7.5 mL ) under N2-atm. To the resulting solution was added 5-amino-2-fluorobenzonitrile (0.187 g, 1.33 mmol) then HATU (0.483 g, 1.27 mmol ). The reaction mixture was stirred at 50°C for 18 hours. The reaction mixture was allowed to reach room température, and poured slowly into stirring H2O (25 mL). After stirring for 10 minutes, the product was filtered off, washed with H2O (3x), and dried at 50°C in vacuo, resulting in compound 16 (291 mg). LC method A; Rt: 1.55 min. m/z : 383.0 (M-H)’ Exact mass: 384.1. ^JH NMR (400 MHz, DMSO-d₆) δ ppm 1.58 (s, 3 H), 3.96 (s, 3 H), 4.35 (d, >6.6 Hz, 2 H), 4.72 (d, J=6.4 Hz, 2 H), 7.53 (dd, >9.1 Hz, 1 H), 7.71 (d, >1.8 Hz, 1 H), 8.04 (ddd, >9.2, 4.8, 2.6 Hz, 1 H), 8.20 - 8.26 (m, 2 H), 9.28 (s, 1 H), 10.40 (s, 1 H).

Compound 17: N-(3 -Chloro-4.5-difluorophenyl)-l-methyl-4-fr(3-methyloxetan-3-yl)aminol(oxo)acetyl) -1 H-pyrrole-2-carboxamide

Compound 17 (251 mg) 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)' Exact mass: 411.1. ^NMR (400 MHz, DMSO-dô) δ ppm 1.58 (s, 3 H), 3.95 (s, 3 H), 4.35 (d, >6.6 Hz, 2 H), 4.72 (d, >6.4 Hz, 2 H), 7.70 (d, >1.5 Hz, 1 H), 7.79 - 7.88 (m, 2 H), 8.22 (d, >1.3 Hz, 1 H), 9.28 (s, 1 H), 10.34 (s, 1 H).

Compound 18 : N-(3-Chloro-4.5-difluorophenyl)-1 -methyl-4-(oxo ( Γ(lR)-2.2.2-trifluoro-1 methylethyl] amino } acetyl)-1 H-pyrro le-2-carboxamide

F

	-ΖΊ	rn Yf
Cl ç/	N—	' 0
	!

Ethyl 2-chloro-2-oxo-acetate (12.3 g, 89.8 mmol) was dissolved in CH2CI2 (70 mL), and the mixture was cooled on ice / N2. AICI3 (14.4 g, 108 mmol) was added. A solution of methyl l-methylpyrrole-2-carboxylate (5 g, 35.9 mmol) in CH2C12(30 mL) was added dropwise

-34over 15 minutes while cooling on ice. The mixture was stirred at 0°C for 2 hours. The mixture was poured out in ice water (300 mL) and stirred for 10 minutes. The organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water, dried (Na₂SO4), and concentrated in vacuo, resulting in an oil which was triturated from diisopropylether (100 mL), resulting in methyl

4-(2-ethoxy-2-oxo-acetyl)-l-methyl-pyrrole-2-carboxylate (6.1 g), containing 2-(5-methoxycarbonyl-l-methyl-pyrrol-3-yl)-2-oxo-acetic acid as a white powder.^JH NMR (400 MHz, DMSO-dg) δ ppm 1.31 (t, >7.2 Hz, 3 H), 3.79 (s, 3 H), 3.94 (s, 3 H), 4.33 (q, >7.2 Hz,

H), 7.30 (d, >2.0 Hz, 1 H), 8.06 (d, >1.8 Hz, 1 H). LC method B; Rt: 0.84 min. m/z : 240.2 (M+H)⁺ Exact mass: 239.1. Methyl 4-(2-ethoxy-2-oxo-acetyl)-l-methyl-pyrrole-2carboxylate (6.1 g) was suspended in EtOH (40 mL) and the mixture was cooled on ice. NaOH (IM, 24.5 mL), and H2O was added (30 mL), and the mixture was stirred at 0°C for 30 minutes. IN HCl was added until pH = 1. Brine (50 mL) was added, and the aqueous layer was extracted with EtOAc (5x). The combined organic layers were washed with brine, dried on Na2SO4, and evaporated to dryness, resulting in a white powder (5.45 g). The powder was re-crystallized from acetonitrile (50 mL) to provide 2-(5-methoxycarbonyl-lmethyl-pyrrol-3-yl)-2-oxo-acetic acid (2.48 g) as a white powder. LC method A; Rt: 0.69 min. m/z : 210.0 (M-H)' Exact mass: 211.0. 2-(5-methoxycarbonyl-l-methyl-pyrrol-3-yl)-2oxo-acetic acid (2.48 g, 11.6 mmol) (2R)-l,l,l-trifluoropropan-2-amine (1.3 g, 11.6 mmol), and DIPEA (4.5 g, 34.8 mmol) were mixed in DMF (30 mL), and the mixture was cooled in an ice bath. HATU (4.9 g, 12.8 mmol) was added and after 45 minutes the mixture was further stirred at room température. After 4 hours the reaction mixture was fïltered off, the precipitate was washed with EtOAc, and dried in vacuo, resulting in methyl l-methyl-4[2-oxo-2-[[(lR)-2,2,2-trifluoro-l-methylethyl]amino]acetyl]pyrrole-2-carboxylate as a white powder (1.4 g). ^{H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (d, >7.0 Hz, 3 H), 3.78 (s,

H), 3.93 (s, 3 H), 4.51 - 4.85 (m, 1 H), 7.35 (d, >1.8 Hz, 1 H), 8.10-8.15 (1 H), 9.32 (d, >8.8 Hz, 1 H). LC method B; Rt: 0.93 min. m/z : 305.1 (M-H)‘ Exact mass: 306.1. The filtrate was mixed with 200 mL EtOAc, washed with IN HCl, NaHCO₂, and brine, and evaporated to dryness, resulting in a white powder (2.3 g). Methyl l-methyl-4-[2-oxo-2[[(l/?)-2,2,2-trifluoro-l-methyl-ethyl]amino]acetyl]pyrrole-2-carboxylate (3.7 g) was mixed with MeOH (35 mL). To the resulting suspension, NaOH (IM, 34.9 mL) was added, and the reaction mixture was heated at reflux. After 1 hour, the mixture was cooled on ice, and concentrated HCl was added until pH = 1 -2. A white precipitate was formed, isolated by filtration, rinced with water and, dried in vacuo at 50°C, resulting in l-methyl-4-[2-oxo-2[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]amino]acetyl]pyrrole-2-carboxylic acid (2.94 g) as an off-white powder. *HNMR (400 MHz, DMSO-d₆) δ ppm 1.34 (d, >7.0 Hz, 3 H), 3.92 (s,

H), 4.51 - 4.86 (m, 1 H), 7.29 (d, >2.0 Hz, 1 H), 8.07 (d, >1.3 Hz, 1 H), 9.29 (d, >9.0 Hz, 1 H), 12.83 (br. s., 1 H). LC method B; Rt: 0.49 min. m/z : 291.1 (M-H)' Exact mass:

292.1. l-methyl-4-[2-oxo-2-[[(lR)-2,2,2-frifluoro-l-methylethyl]amino]acetyl]pyrrole-2carboxylic acid (300 mg, 1.03 mmol), 3-chloro-4,5-difluoro-aniline hydrochloride (205 mg, 1.03 mmol), HATU (429 mg, 1.13 mmol) and DIPEA (663 mg, 5.1 mmol) were mixed in DMF (8 mL), and stirred at room température for 15 minutes, and next at 50-60°C. After hour and 15 minutes at 50-60°C, 1 equiv. more 3-chloro-4,5-difluoro-aniline hydrochloride was added and the mixture was stirred at 50°C overweekend. EtOAc (100 mL) was added and the mixture was washed with IN HCl, NaHCOs and brine. After concentration in vacuo, the obtained residue was purified by preperative HPLC (Stationary phase: Uptisphere C18 ODB - 10 pm), Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN), resulting in compound 18 (253 mg). LC method B; Rt: 1.20 min. m/z : 436.1 (M-H)' Exact mass:

437.1. ^XHNMR (400 MHz, DMSO-d_e) δ ppm 1.36 (d, J=7.0 Hz, 3 H), 3.95 (s, 3 H), 4.58 -

4.81 (m, 1 H), 7.68 (d, >1.8 Hz, 1 H), 7.75 - 7.89 (m, 2 H), 8.14 (d, >1.5 Hz, 1 H), 9.33 (br. s., 1 H), 10.30 (br. s„ 1 H).

Compound 19: 4-r(tert-Butylamino)(oxo)acetyl]-N-(3-cvano-4-fluorophenyl)-l ,3,5trimethyl-1 H-pyrrole-2-carboxamide

Ethyl l,3,5-trimethylpyrroIe-2-carboxylate (2 g, 11.0 mmol) was dissolved inCH₂Cl2 (30 mL) and cooled on ice. A solution of ethyl 2-chloro-2-oxo-acetate (3.8 g, 27.6 mmol) in CH2CI2 (10 mL) was added dropwise, followed by AICI3 (4.4 g, 33.1 mmol) in portions. The mixture was further stirred at 0°C. After 2.5 hours, the mixture was poured out into ice water (150 mL) and extracted with EtOAc (2x). The combined organic layers were washed with water and brine, dried (Na₂SO4) and evaporated to dryness, resulting in crude ethyl 4-(2-ethoxy-2-oxo-acetyl)-l,3,5-trimethyl-pyrrole-2-carboxylate as an oil (4.6 g). LC method B; Rt: 1.06 min. m/z : 282.1 (M+H)⁺ Exact mass: 281.1. Crude ethyl 4-(2-ethoxy-2oxo-acetyl)-l,3,5-trimethyl-pyrrole-2-carboxylate (4.6 g) was taken up in EtOH (30 mL), NaOH was added (33.1 mL, IM) was added and the mixture was stirred for 10 minutes at room température. The mixture was cooled on ice and IN HCl was added until pH = 1. Water (30 mL) was added and the precipitate was filtered off and dried in vacuo, resulting in

2-(5-ethoxycarbonyl-l,2,4-trimethyl-pyrrol-3-yl)-2-oxo-acetic acid (1.97 g), as a white powder. LC method B; Rt: 0.47 min. m/z : 252.2 (M-H)' Exact mass: 253.1?Η NMR (400 MHz, DMSO-de) δ ppm 1.30 (t, >7.2 Hz, 3 H), 2.39 (s, 3 H), 2.42 (s, 3 H), 3.73 (s, 3 H), 4.27 (q, >7.0 Hz, 2 H). 2-(5-ethoxycarbonyl-l,2,4-trimethyl-pyrrol-3-yl)-2-oxo-acetic acid (930 mg, 3.5 mmol), 2-methylpropan-2-amine (258 mg, 3.5 mmol) and DIPEA (1.4 g,

10.6 mmol) were mixed in DMF (15 mL). HATU (1.47 g, 3.9 mmol) was added at 0°C. After 10 min, the ice bath was removed and the mixture was stirred at room température. After 3 hours, EtOAc (150 mL) was added and the mixture was washed with IN HCl, NaHCO₃ and brine. After drying over Na₂SO4 the mixture was concentrated to dryness, resulting in crude ethyl 4-[2-(tert-butylamino)-2-oxo-acetyl]-l,3,5-trimethyl-pyrrole-2carboxylate (1.52 g). Crude ethyl 4-[2-(tert-butylamino)-2-oxo-acetyl]-l,3,5-trimethylpyrrole-2-carboxylatewas dissolved in EtOH (20 mL), NaOH (IM, 10.6 mL) was added and the mixture was stirred at room température ovemight. While cooling on ice, IM HCl was added until pH=l and the formed white precipitate was collected by filtration and dried in vacuo, resulting in 4-[2-(tert-butylamino)-2-oxo-acetyl]-l,3,5-trimethyl-pyrrole-2-carboxylic acid (760 mg). LC method B; Rt: 0.45 min. m/z : 279.1 (M-H)’ Exact mass: 280.1. NMR (400 MHz, DMSO-dé) δ ppm 1.33 (s, 9 H), 2.39 (s, 3 H), 2.39 (s, 3 H), 3.74 (s, 3 H), 8.18 (s, 1 H).4-[2-(tert-butylamino)-2-oxo-acetyl]-l,3,5-trimethyl-pyrrole-2-carboxylic acid (250 mg, 0.89 mmol), 5-amino-2-fluoro-benzonitrile (121 mg, 0.89 mmol), HATU (373 mg,

0.98 mmol) and DIPEA (346 mg, 2.68 mmol) were mixed in DMF (8 mL) and stirred at room température in a closed vessel for 3 hours at room température and further at 50-60°C for 3 hours. 5 equiv. more 5-amino-2-fluoro-benzonitrile were added and the mixture was stirred at 50°-60°C for 2 days. More HATU (100 mg) was added and the mixture was further stirred ovemight. The reaction was quenched with a small amount of MeOH, EtOAc was added, the mixture was washed with IN HCl, NaHCO3 and brine, and concentrated in vacuo, resulting an oil (450 mg) which was purified by preperative HPLC (Stationary phase: RP Vydac Denali Cl8 - 10pm, 200g, 5cm), Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN), resulting in compound 19 (150 mg) as an off-white powder. LC method A; Rt: 1.76 min. m/z: 397.0 (M-H)’ Exact mass: 398.2. ^!H NMR (400 MHz, DMSO-d₆) δ ppm

1.34 (s, 9 H), 2.27 (s, 3 H), 2.42 (s, 3 H), 3.59 (s, 3 H), 7.53 (t, J=9.1 Hz, 1 H), 7.98 (ddd,

J=9.2, 4.8, 2.9 Hz, 1 H), 8.16 - 8.26 (m, 2 H), 10.49 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: Peak: 188.7 °C.

Compound 20: 4-r(tert-Butylamino)(oxo)acetyl1-N-(3.4-difluorophenyl')-L3.5-trimethyl-lHpyrro le-2-carboxamide

Compound 20 (126 mg) was prepared similarly as described for compound 19, using 3,4-difluoroaniline instead of 5-amino-2-fluoro-benzonitrile. LC method A; Rt: 1.84 min. m/z: 390.0 (M-H)’ Exact mass: 391.2. ^!H NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (s, 9 H),

2.26 (s, 3 H), 2.42 (s, 3 H), 3.58 (s, 3 H), 7.35 - 7.50 (m, 2 H), 7.80 - 7.93 (m, 1 H), 8.21 (s, 1 H), 10.37 (s, 1 H).

Compound 21: 4-r(tert-ButvlaminoXoxo)acetyl]-N-(3,4-difluorophenyl)-L3-dimethyl-lHpyrrole-2-carboxamide

Ethyl l,3-dimethylpyrrole-2-carboxylate (2 g, 11.72 mmol) was dissolved in CH2CI2 (40 mL) under N2-atmosphere. The mixture was cooled to 0°C and ethyl 2-chloro-2-oxoacetate (1.5 mL) dissolved in CH2CI2 (10 mL) was added dropwise. AICI3 (3.1g,

23.4 mmol) was added in portions to the reaction mixture at 0°C. The mixture was strirred at 10 0°C for 1 hour. The mixture was poured out in ice water (150 mL). The organic layer was separated and the water layer was extracted with CH2CI2. The organic fractions were combined, dried (MgSCU), filtered and concentrated in vacuo to resulting in crude ethyl 4-(2-ethoxy-2-oxo-acetyl)-l,3-dimethyl-pyrrole-2-carboxylate. Crude Ethyl 4-(2-ethoxy-2oxo-acetyl)-l,3-dimethyl-pyrrole-2-carboxylate was dissolved in EtOH (20 mL) and NaOH 15 (23.4 mL, 1 M) was added. The mixture was stirred at room température for 10 minutes.The mixture was cooled on a ice bath and HCl (IM in H2O, 23.4 mL, 1 M) was added dropwise. Aprecipitate was formed. water (20 mL) was added and the precipitate was filtered off, washed with water and diisopropylether and dried in vacuo, resulting in 2-(5-ethoxycarbonyl-l,4-dimethyl-pyrrol-3-yl)-2-oxo-acetic acid (1.8 g) as a white solid. ^NMR 20 (400 MHz, DMSO-de) δ ppm 1.31 (t, J=7.1 Hz, 3H), 2.52 (s, 3 H), 3.87 (s, 3 H), 4.27 (q,

J=7.1 Hz, 2 H), 7.91 (s, 1 H), 14.01 (br. s., 1 H). 2-(5-ethoxycarbonyl-l,4-dimethyl-pyrrol-

3-yl)-2-oxo-acetic acid (1.8 g, 7.524 mmol), 2-methylpropan-2-amine (877 pL, 8.3 mmol), Hunig's base (3.9 mL, 22.6 mmol) were mixed in DMF (30 mL). HATU (3.15 g, 8.3 mmol) was added portionwise at 0°C. After 30 min, the ice bath was removed and the mixture was 25 stirred at 5°C for 1 h. The mixture was poured out in EtOAc (200 mL) and washed with IN

HCl solution, sat. NaHCO₃ solution and brine. The organic layer was dried (MgSO^, filtered and concentrated in vacuo resulting in an oil which was purified by silica gel column chromatography by eluding with CH2CI2. The product fractions were collected and concentrated in vacuo resulting in ethyl 4-[2-(tert-butylamino)-2-oxo-acetyl]-l,3-dimethyl30 pyrrole-2-carboxylate (1.8 g) which solidifîed on standing. LC method B; Rt: 1.16 min. m/z:

293.1 (M-H)' Exact mass: 294.2.

Ethyl 4-[2-(tert-butylamino)-2-oxo-acetyl]-l,3-dimethyl-pyrrole-2-carboxylate (1.8 g,

-386.1 mmol) was dissolved m 1,4-dioxane (22.5 mL, 264.1 mmol) and lithium hydroxide monohydrate (513 mg, 12.2 mmol) was added. The mixture was stirred at room température for 16 hours. The mixture was concentrated in vacuo. The residue was dissolved in water and neutralized with HCl (IM in H₂O) (11.7 mL, 1 Μ, 11.7 mmol). The precipitate was filtered off, washed with water and dried in vacuo resulting in 4-[2-(tert-butylamino)-2-oxoacetyl]-l,3-dimethyl-pyrrole-2-carboxylic acid (1.3 g) as a white solid. 4-[2-(tert-butylamino)-2-oxo-acetyl]-l,3-dimethyl-pyrrole-2-carboxylic acid (600 mg, 2.253 mmol), 3,4-difluoroaniline (0.281 mL, 2.82 mmol) DIPEA (1.17 mL, 6.76mmol) was dissolved in DMF (3.67 mL, 47.3 mmol), HATU (1070 mg, 2.8 mmol) was added and the mixture was stirred at 50°C for 32 hours. The mixture was poured out in ice water (100 mL) and was extracted with EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The products were purified silica gel column chromatography using gradient elution with Heptane-EtOAc 100-0 to 50-50. The product fractions were collected and concentrated in vacuo. The product was crystallized from 2-propanoI/water, filtered off and dried in vacuo resulting in compound 21 (490 mg) as a solid. LC method B; Rt: 1.13 min. m/z: 376.2 (M-H)' Exact mass: 377.2. *HNMR (400 MHz, DMSO-dô) δ ppm 1.35 (s, 9 H) 2.38 (s, 3 H) 3.76 (s, 3 H) 7.37 - 7.48 (m, 2 H)

7.82 - 7.90 (m, 1 H) 7.96 (s, 1 H) 8.03 (s, 1 H) 10.38 (s, 1 H).

Compound 22: 4-r(tert-Butvlamino)(oxo)acetyl1-N-(3-cyano-4-fluorophenyl)-L3-dimethyl1 H-pyrrole-2-carboxamide

Compound 22 was prepared similarly as described for compound 21, using of 5-amino-2fluoro-benzonitrile instead of 3,4-difluoroaniline. LC method B; Rt: 1.07 min. m/z:

383.2 (M-H)' Exact mass: 384.2. ^JH NMR (400 MHz, DMSO-dô) δ ppm 1.36 (s, 9 H) 2.39 (s, 3 H) 3.77 (s, 3 H) 7.54 (t, J=9.0 Hz, 1 H) 7.94 - 8.00 (m, 2 H) 8.04 (s, 1 H) 8.17 - 8.22 (m, 1 H) 10.50 (s, 1 H).

Comppund23i4JXtert₌ButylnminoXo2ço)açetylj232çhloro₌N^(32ÇYano24₌fluorophenyl)2L· methyl-1 H-pyrrole-2-carboxamide

Sodium hydride (1.37 g, 34.3 mmol) was added portionwise over a period of 10 minutes to a mixture of methyl 3-chloro-lH-pyrrole-2-carboxylate (4.8 g, 28.6 mmol) and iodomethane (2.1 g, 34.3 mmol) in DMF (50 mL, 645.7 mmol) cooled with an ice bath. The reaction mixture was allowed to cool to room température and stirred for 1 hour. The reaction mixture was acidifîed with IM HCl (8 mL) and evaporated to dryness. The residue was dissolved in CH2CI2 (25 mL) and washed with water (25 mL). The product was purified by silica gel chromatography using gradient eluent heptane-EtOAc; 100-0 to 50-50. The product fractions were combined and concentrated in vacuo yielding methyl 3-chloro-lmethyl-pyrrole-2-carboxylate (4.2 g). Methyl 3-chloro-l-methyl-pyrrole-2-carboxylate (2 g,

11.5 mmol) was dissolved in CH2CI2 (40 mL) under N2 atmosphère. The mixture was cooled to 0°C and ethyl 2-chloro-2-oxo-acetate (2.6 mL, 23.0 mmol) dissolved in CH2CI2 (10 mL) was added dropwise. AICI3 (6.15 g, 46.1 mmol) was added in portions to the reaction mixture at 0°C. The mixture was strirred at 0°C for 1 hour. The mixture was poured out in ice water (150 mL). The organic layer was separated and the water layer was extracted with CH2CI2. The organic fractions were combined, dried (MgSCU), filtered and concentrated in vacuo resulting in crude methyl 3-chloro-4-(2-ethoxy-2-oxo-acetyl)-l-methyl-pyrrole-2carboxylate as an oil. This crude methyl 3-chloro-4-(2-ethoxy-2-oxo-acetyl)-l-methylpyrrole-2-carboxylate was dissolved in EtOH (30 mL) and NaOH (34.6 mL, 1 M,

34.6 mmol) was added. The mixture was stirred room température for 10 minutes. The mixture was cooled on an ice bath and HCl (IM in H2O) was added dropwise till pH~4. A precipitate was formed. Water (20 mL) was added and the product was filtered off, washed with water and diisopropylether and dried in vacuo resulting in 2-(4-chloro-5-methoxycarbonyl-l-methyl-pyrrol-3-yl)-2-oxo-acetic acid (1.93 g) as a white solid. 2-(4-chloro-5methoxycarbonyl-l-methyl-pyrrol-3-yl)-2-oxo-acetic acid (1 g, 4.07 mmol), 2-methylpropan-2-amine (0.48 mL, 4.48mmol), Hunig's base (2.11 mL, 12.2mmol) were mixed in DMF (16 mL). HATU (1.70 g, 4.48 mmol) was added portionwise at 0°C. After 10 minutes the ice bath was removed and the mixture was stirred for 1 hour. The mixture was poured out in ice water (150 mL). The mixture was extracted with EtOAc and the organic layer was separated, dried (MgSCL), filtered and concentrated in vacuo resulting in an oil. The product was purified by silica gel chromatography by elution with CH2CI2. The product fractions were collected and concentrated in vacuo resulting in methyl 4-[2-(tert-butylamino)-2-oxoacetyl]-3-chloro-l-methyl-pyrrole-2-carboxylate (800 mg) which solidified on standing. LC method C; Rt: 1.92 min. m/z: 299.0 (M-H)- Exact mass: 300.1. Methyl 4-[2-(tert-butylamino)-2-oxo-acetyl]-3-chloro-l-methyl-pyrrole-2-carboxylate (100 mg, 0.333 mmol) was dissolved in dry tetrahydrofuran (1 mL). To this was added 5-amino-2-fluorobenzonitrile (58.3 mg, 0.416 mmol) and the mixture was cooled in an ice water bath and purged with nitrogen. Lithium bis(trimethylsilyl)amide (IM in toluene, 0.67 mL, 1 M, 0.67 mmol) was added dropwise under cooling over a period of 2 minutes. The resulting mixture was stirred

-40for 1 hour while cooling was continued, then the mixture was further stirred at room température for 16 hours. The mixture was quenched with sat. NH4CI-S0I. The organic layer was separated, dried (MgSCfi), filtered and concentrated in vacuo. The product was purified by silica gel column chromatography using gradient elution with Heptane-EtOAc; 100-0 -> 50-50. The product fractions were collected and concentrated in vacuo. The product was triturated in diisopropylether, filtered and dried in vacuo, resulting in compound 23 (37 mg) as a solid. LC method B; Rt: 1.11 min. m/z: 403.2 (M-H)- Exact mass: 404.1. ^JH NMR (400 MHz, DMSO-dg) δ ppm 1.36 (s, 9 H) 3.82 (s, 3 H) 7.56 (t, J=9.13 Hz, 1 H) 7.93 - 8.02 (m, 1 H) 8.11 (s, 1 H) 8.14 (s, 1 H) 8.20 (dd, J=5.8, 2.8Hz, 1 H) 10.70 (s, 1 H).

Compound 24: 3-chloro-N-(3-cyano-4-fluoro-phenyl)-1 -methyl-4-Γ2-οχο-2-ΓΓ( 1 R)-2,2.2trifluoro-1 -methyl-ethyf] amino1acetyl]pyrrole-2-carboxamide

N

2-(4-chloro-5-methoxycarbonyl-l-methyl-pyrrol-3-yl)-2-oxo-acetic acid (1 g, 4.071 mmol), (7?)-l,l,l-trifluoro-2-propylamine (582 mg, 4.89 mmol), Hunig's base (2.11 mL,

12.21 mmol) were mixed in DMF (16 mL). HATU (2012 mg, 5.29 mmol) was added portionwise at 5°C. The mixture was stirred at room température for 16 hours. The mixture was poured out in EtOAc (200 mL) and washed with IN HCl solution, sat. NaHCCh solution and brine. The organic layer was dried (MgSCU), filtered and concentrated in vacuo. The mixture was purified by silica gel column chromatography using gradient eluent (heptane-EtOAc; 100-0 -> 50-50). The product fractions were collected and concentrated in vacuo resulting in methyl 3-chloro-l-methyl-4-[2-oxo-2-[[(17?)-2,2,2-trifluoro-l-methylethyl]amino]acetyl]pyrrole-2-carboxylate (657 mg) as a fluffy solid. Methyl 3-chloro-lmethyl-4-[2-oxo-2-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]amino]acetyl]pyrrole-2-carboxylate (657 mg, 1.928 mmol) was dissolved in 1,4-dioxane (7.1 mL,) and water (1.6 mL,

87.4 mmol). Lithium hydroxide monohydrate (162 mg, 3.86 mmol) was added. The mixture was stirred at room température for 16 hours. The mixture was concentrated in vacuo. The residue was dissolved in water and neutralized with HCl (IM in H₂O) (3.86 mL, 1 M, 3.86 mmol). The mixture was extracted with CH2CI2 and the organic layer was separated, dried (MgSCU), filtered and concentrated in vacuo. The residue was co-evaporated with diisopropylether, resulting in 3-chloro-l-methyl-4-[2-oxo-2-[[(lR)-2,2,2-trifluoro-l-methylethyl]amino]acetyl]pyrrole-2-carboxylic acid (450 mg) as a white solid.3-chloro-l-methyl-4[2-oxo-2-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]amino]acetyl]pyrrole-2-carboxylic acid

(450 mg, 1.38 mmol, 5-amino-2-fluorobenzonitrile (242 mg, 1.72 mmol), DIPEA(0.71 mL, 4.13 mmol) were dissolved in DMF (10 mL). HATU (655 mg, 1.72 mmol) was added and the mixture was stirred at 50°C for 32 hours. The mixture was poured out in ice water (100 mL) and the precipitated product was filtered off and dried in vacuo. The product was crystallized from CH3CN, filtered off and dried in vacuo, resulting in compound 24 (246 mg) as a fluffy white solid. ^XH NMR (400 MHz, DMSO-d₆) δ ppm 1.35 (d, J=7.04 Hz, 3 H)

3.82 (s, 3 H) 4.63 - 4.72 (m, 1 H) 7.56 (t, J=9.13 Hz, 1 H) 7.98 (ddd, J=9.24, 4.84, 2.64 Hz, 1 H) 8.15 (s, 1 H) 8.21 (dd, J=5.83, 2.75 Hz, 1 H) 9.39 (d, J=8.80 Hz, 1 H) 10.74 (s, 1 H). LC method C; Rt: 1.97 min. m/z: 443.2 (M-H)- Exact mass: 444.1.

Compound 64: N-(3-cyano-4-fhioro-phenyl)-l-methvl-4-r2-oxo-2-rr(lR)-2.,2.,2-trifluoro-lmethyl-ethyllaminolacetyllpvrrole-2-carboxamide

Methyl-4-[2-oxo-2-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]amino]acetyl]pyrrole-2-carboxylic acid (1700 mg, 5.82 mmol)) was dispersed in DMF (5 mL). Then DIPEA (3.0 mL,

17.45 mmol) was added and this mixture was stirred for 20 minutes. Then HATU (2433 mg,

6.4 mmol) was added followed by 5-amino-2-fluorobenzonitrile (1584 mg, 11.6 mmol).The reaction mixture was stirred at room température for 2 hours. Then this mixture was injected directly onto a silica plug. The mixture was purified by silica gel column chromatography using gradient elution from heptane to EtOAc. (100:0 to 0:100) yielding compound 64 as a bright white powder (2.1 g). LC method C; Rt: 1.94 min. m/z: 409.0 (M-H)’ Exact mass: 410.1. *H NMR (400 MHz, DMSO-d₆) δ ppm 1.30 - 1.41 (m, 3 H), 3.94 - 4.01 (m, 3 H), 4.60 - 4.79 (m, 1 H), 7.48 - 7.59 (m, 1 H), 7.67 - 7.73 (m, 1 H), 7.99 - 8.08 (m, 1 H), 8.11 - 8.17 (m, 1 H), 8.20 - 8.27 (m, 1 H), 9.23 - 9.45 (m, 1 H), 10.43 (br. s., 1 H)

Compound 25 :5-bromo-N-(3-cyano-4-fhioro-phenyl)-l-methyl-4-f2-oxo-2-IT(lR)-2.,2.225 trifluoro-1 -methyl-ethyll aminol acetvll pvrrole-2-carboxamide

Compound 26: 3-bromo-N-(3-cyano-4-fluoro-phenyl)-1 -methyl-4-r2-oxo-2-riï 1 R)-2,2,2trifluoro-1 -methyl-ethvllaminolacetyllpyrrole-2-carboxamide

Compound 27: 3,5-dibromo-N-(3-cyano-4-fhioro-phenyr)-l-methyl-4-r2-oxo-2-[T(TR)5 2,2,2-trifluoro-1 -methvl-ethyll aminol acetyllpvrrole-2-carboxamide

A mixture of compound 64 (2.1 g, 4.99 mmol) in acetonitrile (80 mL) and DMF (15 mL) was cooled to 0°C. To this was added NBS (888 mg, 4.99 mmol) portionwise while stirring.The resulting mixture was stirred at room température for 2 hours. The resulting 10 mixture was concentrated in vacuo and the crude was purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0:100 to 100:0) and further via preperative HPLC (Stationary phase: Uptisphere C18 ODB - 10pm, 200g, 5cm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN). The collected fractions were concentrated in vacuo and co-evaporated twice using ACN/MeOH (2 x 20 mL/ 20 mL).

Resulting in compound 25 (714 mg), 26 (225 mg) and 27 (117 mg) as bright white powders. Also compound 64 was recuperated (14.2 mg). Compound 25: ^!H NMR (400 MHz, DMSOdô) δ ppm 1.35 (d, J=7.0 Hz, 3 H), 3.95 (s, 3 H), 4.58 - 4.82 (m, 1 H), 7.54 (t, >9.1 Hz,

H), 7.81 (s, 1 H), 7.98 - 8.05 (m, 1 H), 8.20 (dd, >5.8, 2.8 Hz, 1 H), 9.23 - 9.58 (m, 1 H), 10.58 (br. s., 1 H). LC method B; Rt: 1.13 min. m/z: 487.0 (M-H)- Exact mass: 488.0.

Compound 26: Ή NMR (400 MHz, DMSO-d₆) δ ppm 1.35 (d, J=7.0 Hz, 3 H), 3.81 (s,

H), 4.60 - 4.76 (m, 1 H), 7.57 (t, >9.1 Hz, 1 H), 7.95 - 8.02 (m, 1 H), 8.17 (s, 1 H), 8.21 (dd, >5.7,2.6 Hz, 1 H), 9.31 - 9.44 (m, 1 H), 10.81 (br. s., 1 H). LC method B; Rt: 1.08 min. m/z: 489.0 (M-H)- Exact mass: 490.0. Compound 27: ^LH NMR (400 MHz, DMSO-cU) δ ppm 1.35 (d, >7.0 Hz, 3 H), 3.74 (s, 3 H), 4.59 - 4.80 (m, 1 H), 7.57 (t, >9.1 Hz, 1 H), 25 7.91 - 8.01 (m, 1 H), 8.20 (dd, >5.7, 2.6 Hz, 1 H), 9.50 (d, >6.4 Hz, 1 H), 10.96 (br. s.,

H). LC method B; Rt: 1.06 min. m/z: 566.9 (M-H)- Exact mass: 567.9.

-43Compound 28 : N-(3-cyano-4-fhioro-phenyl)-L5-dimethyl-4-r2-oxo-2-IT(lR)-2,2.2trifluoro-1 -methyl-ethyllaminol acetyllpyrrole-2-carboxamide

Compound 25 (50 mg, 0.1 mmol), tetramethyltin (0.03 mL, 0.2 mmol) in DMF (0.49 mL, 6.29 mmol) was flushed with nitrogen during 5 minutes.

Tetrakis(triphenylphosphine)palladium(0) (11.8 mg, 0.01 mmol) was added and the reaction mixture was irradiated at 140°C during 30 minutes by microwave irradiation. The reaction mixture was concentrated and the obtained residue was purified by silica gel column chromatography (gradient from 0 till 100% EtOAc in heptane). The product fractions were concentrated yielding compound 28 as a white powder (104 mg). LC method B; Rt: 1.09 min. m/z: 423.1 (M-H) Exact mass: 424.1. NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (d, J=7.0 Hz, 3 H), 2.58 (s, 3 H), 3.85 (s, 3 H), 4.64 - 4.77 (m, 1 H), 7.52 (t, J=9.1 Hz, 1 H), 7.65 (s, 1 H), 8.02 (ddd, J=9.2, 4.9, 2.6 Hz, 1 H), 8.21 (dd, J=5.9, 2.6 Hz, 1 H), 9.31 (d, J=8.8 Hz, 1 H), 10.46 (br. s., 1 H)

Compound 29: 5-bromo-3-chloro-N-(3-cyano-4-fluoro-phenyf)-1 -methyl-4-r2-oxo-2-rr( 1R)-

2.2,2-trifluoro-l-methvl-ethvllaminolacetyl]pvrrole-2-carboxamide

Methyl 3 -chloro-1 -methyl-4-[2-oxo-2-[[( 1 R)-2,2,2-trifluoro-l -methyl-ethyl] aminojacetyl]pyrrole-2-carboxylate (1.9 g, 5.577 mmol) was suspended in acetonitrile (100 mL) and DMF (19 mL). NBS (1489 mg, 8.37 mmol) was added and the mixture was stirred at room température for 16 hours. The mixture was concentrated in vacuo. The product was partioned between water and EtOAc. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The product was purified by silica gel chromatography using gradient eluent Heptane-EtOAc; 100-0 to 50-50. The product fractions were collected and concentrated in vacuo resulting in methyl 5-bromo-3-chloro-l-methyl-4-[2-oxo-2[[(lR)-2,2,2-trifhioro-l-methyl-ethyl]amino]acetyl]pyrrole-2-carboxylate (1.75 g) as a pale yellow solid. Methyl 5-bromo-3-chloro-l-methyl-4-[2-oxo-2-[[(lR)-2,2,2-trifluoro-lmethyl-ethyl]amino]acetyl]pyrrole-2-carboxylate (1 g, 2.383 mmol) was dissolved in

I, 4-dioxane (9 mL) and water (2 mL). Lithium hydroxide monohydrate (200 mg,

4.77 mmol) was added and the mixture was stirred at room température for 16 hour. The mixture was concentrated in vacuo and the residue dissolved in water. HCl (IM in H₂O) (4.767 mL, 1 M, 4.767 mmol) was added and a precipitate was formed. After stirring for 5 minutes the product was filtered off and dried under vacuum resulting in 5-bromo-3-chloro- l-methyl-4-[2-oxo-2-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]amino]acetyl]pyrrole-2carboxylic acid (856 mg) as a white solid. Et₃N (0.88 mL, 6.33 mmol) was added to 5-bromo-3-chloro-l-methyl-4-[2-oxo-2-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]amino]acetyl]pyrrole-2-carboxylic acid (856 mg, 2.111 mmol), HATU (1003 mg, 2.64 mmol), 5-amino-2- fluorobenzonitrile (385 mg, 2.74 mmol) in DMF (4.6 mL, 58.9 mmol) and the reaction mixture was stirred 4 hours at 65°C. The mixture was cooled to room température and poured out in ice water. The mixture was extracted with EtOAc and the organic layer was separated, dried (MgSCL), filtered and concentrated in vacuo. A purification was performed via Preperative HPLC (Stationary phase: Uptisphere C18 ODB - lOpm, 200g, 5cm, Mobile phase: 0.25% NH4HCCL solution in water, CH₃CN) resulting in compound 29 (203 mg). LC method B; Rt: 1.06 min. m/z: 520.9 (M-H)' Exact mass: 522.0. Ή NMR (400 MHz, DMSO4) δ ppm 1.34 (d, J=7.0 Hz, 3 H) 3.76 (s, 3 H) 4.62 - 4.74 (m, 1 H) 7.56 (t, >9.1 Hz, 1 H)

7.97 (ddd, >9.2, 4.8, 2.9 Hz, 1 H) 8.20 (dd, >5.7, 2.6 Hz, 1 H) 9.32 - 9.65 (m, 1 H) 10.30 -

II. 17 (m, 1 H).

Compound 30: 3-chloro-N-(3-cvano-4-fluoro-phenyl)-1.5-dimethyl-4-r2-oxo-2-rr(lR)-2,2,2trifluoro-1 -methyl-ethyll aminol acetyll pyrrole-2-carboxamide

Amicrowave vial was charged with methyl 5-bromo-3-chloro-l-methyl-4-[2-oxo-2-[[(17?)-

2,2,2-trifluoro-l-methyl-ethyl]amino]acetyl]pyiTole-2-carboxylate (200 mg, 0.477 mmol) and tetramethyltin (139.0 pL, 1.291 g/mL, 0.95 mmol) dissolved in DMF (1.5 mL).The mixture was purged with N₂ for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (55.1 mg, 0.048 mmol) was added and the vial was capped. The mixture was irradiated at 140°C for 30 minutes. The mixture was concentrated in vacuo. The product was purifïed by silica gel chromatography (using gradient eluent Heptane-EtOAc; 100-0 to 50-50. The product fractions were collected and concentrated in vacuo resulting in methyl 3-chloro-l,5dimethyl-4-[2-oxo-2-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]amino]acetyl]pyrrole-2carboxylate (94 mg) as a white solid. Methyl 3-chloro-l,5-dimethyl-4-[2-oxo-2-[[(lR)-2,2,2trifluoro-l-methyl-ethyl]amino]acetyl]pyrrole-2-carboxylate (94 mg, 0.265 mmol) was

-45dissolved in 1,4-dioxane (1 mL) and water (0.22 mL, 12.0 mmol). Lithium hydroxide monohydrate (22.2 mg, 0.53 mmol) was added and the mixture was stirred at room température for 16 hours. The mixture was concentrated in vacuo and then dissolved in water. HCl (IM in H₂O) (0.53 mL, 1 M, 0.53 mmol) was added and the mixture was stirred for 5 minutes at room température The mixture was extracted with Me-THF and the organic layer was dried (MgSO₄), filtered and concentrated in vacuo resulting in 3-chloro-l,5dimethyl-4-[2-oxo-2-[[( 1 R)-2,2,2-trifluoro-1 -methyl-ethyl] amino]acetyl]pyrrole-2carboxylic acid (85 mg) as a solid. 3-chloro-l,5-dimethyl-4-[2-oxo-2-[[(lR)-2,2,2-trifluoro1-methyl-ethyl]amino]acetyl]pyrrole-2-carboxylic acid (85 mg, 0.249 mmol), 5-amino-2fluorobenzonitrile (43.8 mg, 0.31 mmol) and DIPEA (0.129 mL, 0.75 g/mL, 0.748 mmol) was dissolved in DMF (1.8 mL). HATU (118.6 mg, 0.31 mmol) was added and the mixture was stirred at 50°C for 16 hour. The mixture was concentrated in vacuo. The residue was partioned between water and EtOAc. The organic layer was separated, dried (MgSO₄), filtered and concentrated in vacuo. A purification was performed via preperative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10pm,30x150 mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) resulting in 3-chloro-N-(3-cyano-4-fluoro-phenyl)1,5-dimethyl-4-[2-oxo-2-[[( 1 R)-2,2,2-trifluoro-1 -methyl-ethyl] amino]acetyl]pyrrole-2carboxamide (40 mg) as a white solid. LC method B; Rt: 1.03 min. m/z: 457.0 (M-H)' Exact mass: 458.1. ^!H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (d, >7.0 Hz, 3 H) 2.47 (s, 3 H) 3.66 (s, 3 H) 4.62 - 4.74 (m, 1 H) 7.55 (t, >9.1 Hz, 1 H) 7.95 - 8.02 (m, 1 H) 8.21 (dd, >5.8, 2.5 Hz, 1 H) 9.37 (d, >8.8 Hz, 1 H) 10.75 (s, 1 H).

Compound 31 :3-chloro-N-(3-cyano-4-fluoro-phenyl)-5-cyclopropyl-l-methyl-4-r2-oxo-2ΓΓ (lR)-2,2,2-trifluorô-l -methyl-ethylteminolacetvl]pvrrole-2-carboxamide

A microwave vial was charged with methyl 5-bromo-3-chloro-l-methyl-4-[2-oxo-2-[[(lR)-

2,2,2-trifluoro-l-methyl-ethyl]amino]acetyl]pyrrole-2-carboxylate (150 mg, 0.36 mmol), potassium cyclopropyltrifluoroborate (79.4 mg, 0.54 mmol), Cs₂CC>3 (349 mg, 1.07 mmol), DME (4 mL) and water (0.4 mL). The mixture was purged with N₂ for 5 minutes. Tetrakïs(triphenylphosphine)palladium(0) (82.6 mg, 0.072 mmol) was added and the vial was capped. The mixture was stirred at 110°C for 16 hours. The mixture was cooled and the residue partioned between sat. NH4CI-S0I and Me-THF. The organic layer was separated, dried (MgSCL), filtered and concentrated in vacuo. The product was purified by silica gel

chromatography (10 g, liquid phase) using gradient eluent Heptane-EtOAc; 100-0 to 50-50. The product fractions were collected and concentrated in vacuo resulting in methyl 3-chloro5-cyclopropyl-l-methyl-4-[2-oxo-2-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]amino]acetyl]pyrrole-2-carboxylate (114 mg) as a solid. 3-chloro-N-(3-cyano-4-fluoro-phenyl)-5-cyclo5 propyl-l-methyl-4-[2-oxo-2-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]amino]acetyl]pyrrole-2carboxamide ( 22 mg) was synthesized similarly as described for compound 30 using methyl 3-chloro-5-cyclopropyl-l-methyl-4-[2-oxo-2-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]amino]acetyl]pyrrole-2-carboxylate instead of methyl 3-chloro-l,5-dimethyl-4-[2-oxo-2[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]amino]acetyl]pyrrole-2-carboxylate.LC method C; Rt:

1.99 min. m/z: 483.0 (M-H)- Exact mass: 484.0. ⁽Η NMR (400 MHz, DMSO-dô) δ ppm

0.47 - 0.57 (m, 2 H) 0.94 - 1.05 (m, 2 H) 1.30 - 1.38 (m, 3 H) 1.77 - 1.86 (m, 1 H) 3.77 (s,

H) 4.61 - 4.73 (m, 1 H) 7.54 (t, J=9.1 Hz, 1 H) 7.92 - 7.99 (m, 1 H) 8.20 (dd, >5.7, 2.6 Hz, 1 H) 9.32 (d, J=9.0 Hz, 1 H) 10.75 (br. s., 1 H)

Compound 32: 4-r2-(tert-butylamino')-2-oxo-acetyl1-3-chloro-N-(3-cyano-4-fluoro-phenyl)15 l,5-dimethyl-pyrrole-2-carboxamide

Compound 32 (81 mg) was synthesized similarly as described for compound 30, using methyl 5-bromo-4-[2-(tert-butylamino)-2-oxo-acetyl]-3-chloro-l-methyl-pyrrole-2• carboxylate instead of methyl 5-bromo-3-chloro-l-methyl-4-[2-oxo-2-[[( 17?)-2,2,2-trifluoro20 l-methyl-ethyl]amino]acetyl]pyrrole-2-carboxylate. LC method B; Rt: 1.03 min. m/z: 417.1 (M-H) Exact mass: 418.1. ^JH NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (s, 9 H) 2.46 (s, 3 H) 3.65 (s, 3 H) 7.55 (t, >9.1 Hz, 1 H) 7.94 - 8.04 (m, 1 H) 8.21 (dd, >5.7,2.6 Hz, 1 H) 8.27 (s, 1 H) 10.70 (s, 1 H).

Compound 33:4-r2-(tert-butvlamino)-2-oxo-acetvll-3-chloro-N-(3-cyano-4-fluoro-phenyl)25 l-methyl-5-(trifluoromethyl)pyrrole-2-carboxamide

Compound 50 (100 mg, 0.207 mmol) was dissolved in DMF (2 mL). 4-methylmorpholine (45.5 pL, 0.413 mmol), copper (I) iodide (19.7 mg, 0.103 mmol) and fluorosulfonyl17673

(difluoro)acetic acid methyl ester (78.1 pL, 0.62 mmol) were added. The resulting mixture was stirred at 70°C for 16 hours. The mixture was cooled and water was added. Saturated ammonium chloride solution (10 mL) was added to the reaction mixture. Then this was extracted using EtOAc (3 x 15mL). The combined extracts were dried (MgSCU), filtered and 5 concentrated in vacuo. The obtained residue was purified using column chromatography on silica (gradient elution: ethylacetate: heptane from 0 to 100%). The product fractions were collected and concentrated in vacuo resulting in compound 33 (60 mg) as a white flufiy solid. LC method C; Rt: 2.16 min. m/z: 471.1 (M-H)' Exact mass: 472.1. ^XH NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (s, 9 H) 3.84 (s, 3 H) 7.59 (t, J=9.13 Hz, 1 H) 7.93 - 8.02 10 (m, 1 H) 8.21 (dd, J=5.72,2.64 Hz, 1 H) 8.37 (s, 1 H) 11.15 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: Peak: 195.7 °C.

Compound 34: 4-r2-(tert-butvlamino)-2-oxo-acetyl1-N-(3-cvano-4-fluoro-phenvl')-3-fluoro1 -methyl-pyrro le-2-carboxamide

Sodium hydride (5.3 g, 138.7 mmpol, 60%) was added portionwise to ethyl 3-fluoro-lHpyrrole-2-carboxylate (18.2 g, 115.6 mmol) and iodomethane (19.7 g, 138.7 mmol) in DMF (150 mL) under nitrogen in an icebath and stirred ovemigth at room température. The reaction mixture was acidified with IM HCl and concentrated. The obtained residue was dissolved in water/EtOAc. The organic layer was dried over Na₂SC>4, filtered and concentrated. The residue was dissolved in CH3CN (150 mL), washed with heptane and concentrated at 60°C and 40 mbar yielding a brown liquid which was submitted to silica gel column chromatography using a gradient from 10 till 25% EtOAc in heptane. The product fractions were concentrated yielding ethyl 3-fluoro-l-methyl-pyrrole-2-carboxylate as a clear oil (10.7 g). More ethyl 3-fluoro-l-methyl-pyrrole-2-carboxylate (1.7 g) was recuperated from the evaporated solvent. Ethyl 3 -fluoro-1 -methyl-pyrrole-2-carboxylate (1.96 g, 11.5 mmol), ethyl 2-chloro-2-oxo-acetate (1.99 mL, 17.46 mmol) was dissolved in DCM (100 mL) and cooled in an ice bath. A1C1₃ (3.06 g, 22.9 mmol) was added and the solution was strirred at 0°C during 1 hour. The reaction mixture was stirred futher 1 hour at room température. 1 extra eq of AICI3 was added and stirred 1 hour. The reaction mixture was cooled in an ice bath and quenched with ice water. The mixture was acidified with HCl IM. The organic layer was dried over magnésium sulphate filtered and concentrated, resulting in crude ethyl 4-(2-ethoxy-2-oxo-acetyl)-3-fluoro-l -methyl-pyrrole-2-carboxylate (3.29 g). The residue was dissolved in EtOH (20 mL), NaOH (IM in H₂O) (11.5 mL, 1 M,

-4811.5 mmol) was added and the reaction mixture was stirred for 10 minutes. The reaction mixture was neutralised with HCl (IM in H₂O) (11.5 mL, 1 M, 11.5 mmol), partially concentrated and extracted with EtOAc/water. The organic layer was dried over magnésium sulphate, fïltered and concentrated. The residue was purifïed by silica gel column chromatography using a gradient from 10 till 100% EtOAc in heptane. The fractions were concentrated yielding 2-(5-ethoxycarbonyl-4-fluoro-l-methyl-pyrrol-3-yl)-2-oxo-acetic acid (1.2 g) as a white powder. LC method C; Rt: 0.89 min. m/z: 242.0 (M-H)' Exact mass: 243.1. Et₃N (1.02 mL, 7.35 mmol) was added to a solution of 2-(5-ethoxycarbonyl-4fluoro-l-methyl-pyrrol-3-yl)-2-oxo-acetic acid (596 mg, 2.45 mmol), 2-methylpropan-2amine (223.9 mg, 3.06 mmol), and HATU (1164 mg, 3.061 mmol) in DMF (3 mL) and stirred 30 minutes at 65°C. The solution was subjected to silica gel column chromatography using a gradient from 10 till 100% EtOAc in heptane. The product fractions were concentrated yielding ethyl 4-[2-(tert-butylamino)-2-oxo-acetyl]-3-fluoro-l-methyl-pyrrole-

2-carboxylate (714 mg) as a clear oil which solidified upon standing . LC method C; Rt:

1.98 min. m/z: 299.1 (M+H)⁺ Exact mass: 298.1. A mixture of ethyl 4-[2-(tert-butylamino)-

2- oxo-acetyl]-3-fluoro-l-methyl-pyrrole-2-carboxylate (204 mg, 0.684 mmol), LiOH (49.1 mg, 2.05 mmol) water (10 mL,) and THF (20 mL) was stirred ovemight. HCl (IM, 2.1 mL) was added and the THF was distilled off. The formed white precipitate was fïltered off and dried in vacuo at 50°C ovemight, resulting in 4-[2-(tert-butylamino)-2-oxo-acetyl]-

3- fhioro-l-methyl-pyrrole-2-carboxylic acid (121 mg) as a white powder. LC method C; Rt: 1.03 min. m/z: 269.3 (M-H) Exact mass: 270.1. ^!H NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (s, 9 H), 3.86 (s, 3 H), 7.97 (d, >4.4 Hz, 1 H), 8.05 (s, 1 H), 13.05 (br. s, 1 H). Et₃N (0.18 mL, 1.29 mmol) was added to 4-[2-(tert-butylamino)-2-oxo-acetyl]-3-fluoro-l-methylpyrrole-2-carboxylic acid (115.9 mg, 0.43 mmol), HATU (203.8 mg, 0.54 mmol), 5-amino2-fluoro-benzonitrile (116.76 mg, 0.86 mmol) dissolved in DMF (0.9 mL) and heated at 65°C during 4 hours. The reaction mixture was subjected directly to silica gel column chromatography using a gradient from 10 till 100 % EtOAc in heptane. The product fractions were concentrated resulting in compound 34 (171 mg) as white crystals which were dried ovemight in vacuo at 50°C. LC method C; Rt: 2.03 min. m/z: 387.1 (M-H)’ Exact mass: 388.1. Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: Peak: 179.2 °C. *H NMR (360 MHz, DMSO-d₆) δ ppm 1.35 (s, 9 H), 3.85 (s, 3 H), 7.54 (t, >9.1 Hz, 1 H), 7.93 - 7.99 (m, 1 H), 8.04 (d, >4.4 Hz, 1 H), 8.12 (s, 1 H), 8.18 (dd, >5.7, 2.7 Hz, 1 H), 10.37 (s, 1 H).

Compound 35: N-(3-cyano-4-fluoro-phenyl)-4-[2-r(3.3-difluoro-l-methvl-cyclobutyl)aminol-2-oxo-acetyll -3 -fluoro-1 -methyl-pyrrole-2-carboxamide

Compound 35 was prepared similarly as described for compound 34, using 4-[2-[(3,3-difluoro-l-methyl-cyclobutyl)amino]-2-oxo-acetyl]-3-fluoro-l-methyl-pyrrole-2-carboxylic acid instead of 4-[2-(tert-butylamino)-2-oxo-acetyl]-3-fluoro-l-methyl-pyrrole-2-carboxylic acid. Compound 35 (345 mg) was crystallised by addition of water to a MeOH solution.

4-[2-[(3,3 -difluoro-1 -methyl-cyclobutyl)amino]-2-oxo-acetyl]-3-fluoro-1 -methyl-pyrrole-2carboxylic acid was prepared similarly as described for 4-[2-(tert-butylamino)-2-oxoacetyl]-3-fluoro-l-methyl-pyrrole-2-carboxylic acid using 3,3-difluoro- 1-methylcyclobutanamine hydrochloride (commercial from Pharmablock PBN20121019) instead of 2-methylpropan-2-amine. LC method C; Rt: 1.99 min. m/z: 435.4 (M-H)' Exact mass: 436.1. Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: Peak: 195.0 °C. Ή NMR (400 MHz, DMSO-de) δ ppm 1.50 (s, 3 H), 2.61 - 2.73 (m, 2 H), 2.96 - 3.10 (m, 2 H), 3.85 (s, 3 H), 7.54 (t, J=9.1 Hz, 1 H), 7.97 (ddd, J=9.2, 4.9, 2.6 Hz, 1 H), 8.10 (d, J=4.4 Hz, 1 H), 8.18 (dd, J=5.7, 2.6 Hz, 1 H), 9.19 (s, 1 H), 10.34 (s, 1 H).

Compound 36 :4-r2-(tert-butylamino)-2-oxo-acetyll-N-(3-cyano-4-fluoro-phenyl)-3-fluoro1.5-dimethyl-pyrrole-2-carboxamide

Ethyl4-[2-(tert-butylamino)-2-oxo-acetyl]-3-fluoro-l-methyl-pyrrole-2-carboxylate (510 mg, 1.71 mmol), NBS (456.4mg, 2.56 mmol), DMF (2 mL), ACN (2 mL, 0.786 g/mL, 38.29 mmol) was stirred ovemight. Another 1.5 eq NBS was added and the mixture was stirred 30 minutes further. The solution was purified directly by silica gel column chromatography using a gradient from 10 till 100% EtOAc in heptane. The product fractions were concentrated yielding ethyl 5-bromo-4-[2-(tert-butylamino)-2-oxo-acetyl]-3-fluoro-lmethyl-pyrrole-2-carboxylate (255 mg) as a clear oil. ^rH NMR (360 MHz, DMSO-dg) δ ppm 1.28 (t, J=7.1 Hz, 3 H), 1.32 (s, 9 H), 3.88 (s, 3 H), 4.29 (q, J=7.3 Hz, 2 H), 8.37 (s, 1 H). Tetrakis(triphenylphosphine)palladïum(0) (65.9 mg, 0.057 mmol) was added to ethyl

5-bromo-4-[2-(tert-butylamino)-2-oxo-acetyl]-3-fluoro-l-methyl-pyrrole-2-carboxylate (215 mg, 0.57 mmol) and tetramethyltin (214.6 mg, 1.14 mmol) dissolved in DMF (3 mL) and the reaction mixture was heated at 140°C during 90 minutes by microwave irradiation. The reaction mixture was filtered and concentrated. The obtained residue was purified by silica gel column chromatography using a gradient from 10 till 100% EtOAc in heptane. The product fractions were concentrated yielding ethyl 4-[2-(tert-butylamino)-2-oxo-acetyl]-3fluoro-l,5-dimethyl-pyrrole-2-carboxylate (149 mg) as a clear colorless resin . ^XH NMR (400 MHz, DMSO-de) δ ppm 1.27 (t, J=7.0 Hz, 3 H), 1.32 (s, 9 H), 2.48 (s, 3 H), 3.77 (s, 3 H), 4.26 (q, J=7.1 Hz, 2 H), 8.23 (s, 1 H). A mixture of ethyl 4-[2-(tert-butylamino)-2-oxoacetyl]-3-fluoro-l,5-dimethyl-pyrrole-2-carboxylate (146 mg, 0.467 mmol), LiOH (33.5 mg, 1.4 mmol), THF (5 mL, 61.44 mmol), water (5 mL, 276.98 mmol) was stirred ovemight. HCl (IM in H2O (1.4 mL, 1 M, 1.40 mmol) was added and THF distilled off. The formed white precipitate was filtered off and dried in vacuo at 50°C resulting in 4-[2-(tertbutylamino)-2-oxo-acetyl]-3-fluoro-l,5-dimethyl-pyrrole-2-carboxylic acid (95 mg) as a white powder. LC method C; Rt: 0.93 min. m/z: 283.1 (M-H) Exact mass: 284.1. *H NMR (360 MHz, DMSO-d₆) δ ppm 1.31 (s, 9 H), 2.48 (s, 3 H), 3.77 (s, 3 H), 8.24 (s, 1 H), 12.92 (br. s, 1 H). Et₃N (0.14 mL, 0.97 mmol) was added to a solution of 4-[2-(tert-butylamino)-2oxo-acetyl]-3-fluoro-l,5-dimethyl-pyrrole-2-carboxylic acid (92 mg, 0.32 mmol), HATU (153.8 mg, 0.41 mmol) and 5-amino-2-fluoro-benzonitrile (88.1 mg, 0.65 mmol) in DMF (1 mL) and the mixture was stirred ovemight at 40°C. The reacton mixture was purified directly by silica gel chromatography using a gradient from 10 toi00% EtOAc in heptane. The product fractions were concentrated. The residue was dissolved in methanol (10 mL). The product crystallised upon addition of water. The white crystals were filtered off and dried ovemight in vacuo at 50°C, resulting in compound 36 (68 mg). LC method C; Rt:

1.99 min, m/z: 401.1 (M-H)'Exact mass: 402.2. Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: Peak: 153.4 °C. ^JH NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (s, 9 H), 2.50 (s, 3 H), 3.71 (s, 3 H), 7.52 (t, J=9.1 Hz, 1 H), 7.93 - 7.99 (m, 1 H), 8.16 (dd, J=5.9, 2.6 Hz, 1 H), 8.25 (s, 1 H), 10.36 (s, 1 H).

Compound 37: N-(3-cyano-4-fluoro-phenvl)-4-r2-r(3,3-difluoro-l-methyl-cvclobutvl)aminol-2-oxo-acetvl1-3-fluoro-L5-dimethyl-pyrrole-2-carboxamide

NBS (230.0 mg, 1.29 mmol) was added to a solution of compound 35 (282 mg, 0.646 mmol) in ACN (1 mL) and DMF (1 mL) and stirred 1 hour. The reaction mixture was purified by

sihca gel column chromatography usmg a gradient from 10 till 100% EtOAc in heptane. The product fractions were concentrated and the residue crystallised from methanol (20 mL) upon 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-2carboxamide (154 mg) was fîltered off and dried in vacuo at 50°C. LC method C; Rt: 1.96 min. m/z: 513.0 (M-H)' Exact mass: 514.0. Nitrogen was bubbled through a solution of crude 5-bromo-N-(3-cyano-4-fluoro-phenyl)-4-[2-[(3,3-difluoro-l-methyl-cyclobutyl)amino]-2-oxo-acetyl]-3-fluoro-l-methyl-pyrrole-2-carboxamide (154 mg), tetramethyltin (112.5 mg, 0.60 mmol) in DMF (2 mL) during 5 minutes.

Tetrakis(triphenylphosphine)palladium(0) (34.5 mg, 0.030 mmol) was added and the reaction mixture was heated at 140°C during 90 minutes by microwave irradiation. The solution was purified by silica gel column chromatography using a gradient from 10 till 100% EtOAc in heptane. The product fractions were concentrated. The residue was dissolved in methanol (10 mL) and the product crystallised upon addition of water. The white powder was dried in vacuo at 50°C, resulting in compound 37 (64 mg). LC method C; Rt: 1.92 min. m/z: 449.1 (M-H)' Exact mass: 450.1.'H NMR (400 MHz, DMSO-d₆) δ ppm 1.50 (s, 3 H), 2.51 (s, 3 H), 2.62 - 2.74 (m, 2 H), 2.90 - 3.03 (m, 2 H), 3.71 (s, 3 H), 7.53 (t, >9.1 Hz, 1 H), 7.96 (ddd, >9.2,4.9,2.6 Hz, 1 H), 8.16 (dd, >5.7,2.6 Hz, 1 H), 9.14 (s, 1 H), 10.40 (s, 1 H).

Compound 38:3 -chloro-N-(3 -cyano-4-fluoro-phenyl)-1 -methyl-4- Γ 2-οχο-2-Γ Γ( 1 R)-1 (trifluoromethyl)propvllaminolacetyripvrrole-2-carboxamide

Compound 38 (91 mg) was synthesized similarly as described for compound 40 using (R)-1,1,1 -trifluoro-2-buty lamine instead of 3,3 -difluoro-1 -methylcyclobutanamine hydrochloride. LC method C; Rt: 2.08 min. m/z: 457.0 (M-H)- Exact mass: 458.1. ⁽Η NMR (400 MHz, DMSO-dg) δ ppm 0.92 (t, >7.3 Hz, 3 H) 1.68 - 1.85 (m, 2 H) 3.83 (s, 3 H) 4.40 4.52 (m, 1 H) 7.56 (t, >9.1 Hz, 1 H) 7.98 (ddd, >9.2, 4.8, 2.9 Hz, 1 H) 8.14 (s, 1 H) 8.21 (dd, >5.7, 2.6 Hz, 1 H) 9.31 (d, >9.2 Hz, 1 H) 10.74 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: Peak: 248.53 °C.

-52Compound 39: 3-chloro-N-(3-cvano-4-fluoro-phenyl)-l-methyl-4-r2-oxo-2-rri-(trifluoromethyl)cvclobutvllaminolacetvllpyrrole-2-carboxamide

Compound 39 (152 mg) was synthesized similarly as described for compound 40 using l-(trifluoromethyl)cyclobutan-l-amine instead of 3,3-difluoro-l-methylcyclobutanamine hydrochloride. LC method C; Rt: 2.08 min. m/z: 469.1 (M-H)’ Exact mass: 470.1. *H NMR (400 MHz, DMSO-dô) δ ppm 1.87 - 2.03 (m, 2 H) 2.40 - 2.49 (m, 2 H) 2.53 - 2.67 (m, 2 H) 3.83 (s, 3 H) 7.56 (t, J=9.1 Hz, 1 H) 7.98 (ddd, J=9.2, 4.8, 2.8 Hz, 1 H) 8.15 (s, 1 H) 8.21 (dd, J=5.8, 2.8 Hz, 1 H) 9.32 (s, 1 H) 10.73 (br. s., 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: Peak: 242.2 °C.

Compound 40: 3-chloro-N-(3-cyano-4-fluoro-phenyl)-4-r2-r(3,3-difluoro-l-methylcyclobutyl)amino1-2-oxo-acetyll-1 -methyl-pyrrole-2-carboxamide

Methyl 3-chloro-l-methyl-pyrrole-2-carboxylate (6.2 g, 35.7 mmol) and 5-amino-2fluorobenzonitrile (6.27 g, 44.64 mmol) were dissolved in THF (100 mL). Lithium bis(trimethylsilyl)amide (1 M in THF) (44.6 mL, 1 M, 44.6 mmol) was added dropwise to the reaction mixture at room température. After 2 hours the mixture was poured out in sat. NH4CI-S0I. The mixture was extracted with Me-THF. The organic layer was separated, dried (MgSCU), filtered and concentrated in vacuo. The residue was triturated in CH3CN and the product was filtered off. The product was washed with DIPE and dried under vacuum resulting in 3-chloro-N-(3-cyano-4-fluoro-phenyl)-l-methyl-pyrrole-2-carboxamide (5.8 g) as a pale pink solid. 3-chloro-N-(3-cyano-4-fluoro-phenyl)-l-methyl-pyrrole-2-carboxamide (5.8 g, 20.9 mmol) was dissolved in DCM (100 mL) and Me-THF (10 mL). The mixture was cooled on an ice bath. At 0-5°C. Ahiminium(III) chloride (7.24 g, 54.3 Immol) was added portionwise. At 0-5°C ethyl chlorooxoacetate (3.63 mL, 31.80 mmol) was added dropwise to the reaction mixture. The mixture was stirred for 30 minutes at 0-5°C and was then allowed to rise to room température. The mixture was further stirred at room température for 32 hours. The mixture was fully converted to 2-[4-chloro-5-[(3-cyano-4-fluoro-phenyl)

-53carbamoyl]-l-methyl-pyrrol-3-yl]-2-oxo-acetic acid.The mixture was poured out on ice and the organic phase was distilled off. The water layer was extracted with Me-THF and the organic layer was separated, dried (MgSOQ, filtered and concentrated in vacuo. The residue was treated with 1 N NaOH solution and the water layer was washed with Me-THF. The water layer was acidified with IN HCl solution. The water layer was extracted with MeTHF (2x) and the organic layers were combined, dried (MgSOQ, filtered and concentrated in vacuo resulting in 2-[4-chloro-5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-l-methyl-pyrrol-

3-yl]-2-oxo-acetic acid (3 g) as a white solid. Et₃N (0.238 mL, 0.728 g/mL, 1.716 mmol) was added to a solution of 2-[4-chloro-5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-l-methylpyrrol-3-yl]-2-oxo-acetic acid (150 mg, 0.429 mmol), 3,3-difluoro-l-methylcyclobutanamine hydrochloride (64.946 mg, 0.536 mmol), HATU (203.868 mg, 0.536 mmol) in DMF (0.5 mL,) and stirred 30 minutes at 65°C. The mixture was cooled and the solution was subjected to silica gel column chromatography using a gradient from 10 till 100% EtOAc in heptane. The product fractions were concentrated. The product was triturated in DIPE, filtered and dried in vacuo resulting in compound 40 (135 mg) as a white flufïy solid. LC method C; Rt: 2.02 min. m/z: 451.3 (M-H) Exact mass: 452.1.³H NMR (400 MHz, DMSOde) δ ppm 1.50 (s, 3 H) 2.59 - 2.75 (m, 2 H) 2.95 - 3.11 (m, 2 H) 3.82 (s, 3 H) 7.56 (t, J=9.13 Hz, 1 H) 7.98 (ddd, J=9.13, 4.84, 2.75 Hz, 1 H) 8.16 - 8.25 (m, 2 H) 9.18 (s, 1 H) 10.71 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: Peak: 222.1 °C.

Synthesis of 3-(trifluoromethvl)tetrahvdrofuran-3-amine hydrochloride:

A mixture of 3-oxotetrahydrofuran (30 g, 348.5 mmol), benzylamine (39.2 g, 365.8 mmol), MgSCL (21 g, 174.5.mmôl) and CH2CI2 (200 mL) was stirred at 28°C for 24 hours. The mixture was filtrated. The filtrate was concentrated in vacuo and the obtained residue (63.1 g) was used directly in the next step. The obtained residue (63 g) was dissolved in acetonitrile (600 mL). Trifluoroacetic acid (45 g, 394 mmol), potassium hydrogenfluoride (22.5 g, 288 mmol) and DMF (60 mL) were added to the mixture at 0°C. The mixture was stirred at 0° for 10 minutes, (trifluoromethyl)trimethylsilane (77 g, 541 mmol) was added to the reaction mixture and the mixture was stirred at ambient température for 12 h. Saturated aqueous Na₂CO3 (200 mL) was added and the mixture was stirred for 5 min. The mixture was diluted with water (500 mL), and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with water and brine, dried over Na₂SO4 and evaporated under reduced pressure. The obtained residue was dissolved in 2M HCl/MeOH and the solvent was evaporated. The resulting hydrochloride sait was crystallized from CH₃CN to provide N-benzyl-3-(trifluoromethyl)tetrahydrofuran-3-amine (30.5 g). A mixture of N-benzyl-3-(trifluoromethyl)tetrahydrofuran-3-amine (30.5 g), palladium on alumina (1.5 g) and MeOH was stirred under H₂ (20 psi) atmosphère at 28 °C for 12 hours.

-54The mixture was filtered and the fïltrate was concentrated in vacuo resulting in 3-(trifluoromethyl)tetrahydrofuran-3-amine hydrochloride (20.5 g). ^rH NMR (400 MHz, DMSO-dô) δ ppm 2.21 - 2.43 (m, 2 H) 3.83 - 4.16 (m, 4 H) 9.68 (br. s., 3 H).

Compound 41: 3-chloro-N-(3-cyano-4-fhioro-phenyl)-l .5-dimethyl-4-r2-oxo-2-IT3-(trifluoromethvl)tetrahvdrofuran-3-vl1aminolacetvl]r>vrrole-2-carboxamide

3-chloro-N-(3-cyano-4-fluoro-phenyl)-l,5-dimethyl-4-[2-oxo-2-[[3-(trifluoromethyl)tetrahydrofuran-3-yl]amino]acetyl]pyrrole-2-carboxamide (58 mg) was synthesized similarly as described for compound 43 using racemic 3-(trifluoromethyl)tetrahydrofuran3-amine instead of l-(trifluoromethyl)cyclobutan-l-amine. LC method B; Rt: 0.98 min. m/z: 499.0 (M-H)- Exact mass: 500.1. ^XH NMR (400 MHz, DMSO-d₆) δ ppm 2.25 - 2.40 (m, 1 H) 2.45 - 2.56 (m, 4 H) 3.66 (s, 3 H) 3.71 - 3.84 (m, 1 H) 3.85 - 3.96 (m, 1 H) 4.12 - 4.26 (m, 2 H) 7.55 (t, >9.1 Hz, 1 H) 7.99 (ddd, >9.2, 4.8, 2.9 Hz, 1 H) 8.21 (dd, >5.7, 2.6 Hz, 1 H) 9.39 (s, 1 H) 10.75 (s, 1 H).

Compound 42: 3-chloro-N-(3-cvano-4-fluoro-phenyl)-1.5-dimethyl-4-r2-oxo-2-rr(lR)-l(trifluoromethyl)propyllamino1acetyl1pyrrole-2-carboxamide

3-chloro-N-(3-cyano-4-fluoro-phenyl)-l,5-dimethyl-4-[2-oxo-2-[[(lR)-l-(trifluoromethyl)propyl]amino]acetyl]pyrrole-2-carboxamide (5 mg) was synthesized similarly as described for compound 43 using (R)-l,l,l-trifluoro-2-butylamine instead of l-(trifluoromethyl)cyclobutan-l-amine. LC method C; Rt: 1.97 min. m/z: 471.1 (M-H)Exact mass: 472.1. ^JH NMR (400 MHz, DMSO-d₆) δ ppm 0.97 (t, >7.4 Hz, 3 H) 1.59 1.73 (m, 1 H) 1.73 - 1.87 (m, 1 H) 2.47 (s, 3 H) 3.66 (s, 3 H) 4.39 - 4.55 (m, 1 H) 7.55 (t, >9.1Hz, 1 H) 7.93 - 8.03 (m, 1 H) 8.21 (dd, >5.7, 2.6 Hz, 1 H) 9.29 (d, >8.8 Hz, 1 H) 10.75 (s, 1 H).

Compound43: 3-chloro-N-(3-cyano-4-fluoro-phenyl)-1.5-dimethyl-4-r2-oxo-2-ITl-(trifluoromethvl)cvclobutvl1amino1acetyl1pvrrole-2-carboxamide

3- chloro-N-(3-cyano-4-fhioro-phenyl)-l-methyl-pyrrole-2-carboxamide (4 g, 14.405 mmol) was dissolved in DCM (69 mL) and the mixture was cooled on an ice bath. At 0-5°C ethyl chlorooxoacetate (2.50 mL, 21.9 mmol) was added. At 0-5°C aluminium (III) chloride (4.99 g, 37.45 mmol) was added portionwise to the reaction mixture. The mixture was stirred for 30 minutes at 0-5°C and was then allowed to rise to room température. The mixture was stirred at room température for 1 hour. The mixture was cooled to 0-5°C with an ice bath. EtOH (20 mL) was carefully added. A clear solution was formed and the mixture was stirred at room température for lh. The mixture was quenched on ice. The organic layer was separated and the water layer was extracted with Me-THF. The organic layers were combined, dried (MgSCU), filtered and concentrated in vacuo. The residue was suspended in little Me-THF and the product was filtered off resulting in ethyl 2-[4-chloro-5-[(3-cyano-4fluoro-phenyl)carbamoyl]-l-methyl-pyrrol-3-yl]-2-oxo-acetate (1.8 g) as a white solid. Ethyl

2- [2-bromo-4-chloro-5-[(3-cyano-4-fhioro-phenyl)carbamoyl]-l-methyl-pyrroL3-yl]-2-oxoacetate (1.8 g) was synthesized similarly as described for 2-[2-bromo-4-chloro-5-[(3-cyano-

4- fluoro-phenyl)carbamoyl]-l-methyl-pyrrol-3-yl]-2-oxo-acetic acid in the synthesis of compound 47 using ethyl 2-[4-chloro-5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-l-methylpyrrol-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. Ethyl 2-[4-chloro-5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-l,2-dimethyl-pyrrol-3-yl]-2-oxo-acetate (700 mg) was synthesized similarly as described for 2-[4-chloro-5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-l ,2-dimethyl-pyrrol-

3- yl]-2-oxo-acetic acid in the synthesis of compound 47 using ethyl 2-[2-bromo-4-chloro-5[(3-cyano-4-fluoro-phenyl)carbamoyl]-l-methyl-pyrrol-3-yl]-2-oxo-acetate (1 g) instead of

2- [2-bromo-4-chloro-5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-l-methyl-pyrrol-3-yl]-2-oxoacetic acid. Ethyl 2-[4-chloro-5-[(3-cyano-4-fhioro-phenyl)carbamoyl]-l,2-dimethyl-pyrrol-

3- yl]-2-oxo-acetate (700 mg, 1.787 mmol) was dissolved in 1,4-dioxane (6.6 mL,

77.2 mmol) and water (1.5 mL). Lithium hydroxide monohydrate (150 mg, 3.57 mmol) was added and the mixture was stirred at room température for 16 hours. The mixture was concentrated in vacuo and the residue dissolved in water. HCl (IM in H₂O) (3.6 mL, 1 M, 3.573 mmol) was added and a precipitate was formed. The product was filtered off and dried under vacuum resulting in 2-[4-chloro-5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-l,217673

-56dimethyl-pyrrol-3-yl]-2-oxo-acetic acid (400 mg) as a white solid. Compound 43 (33 mg) was synthesized similarly as described for compound 47 starting from 2-[4-chloro-5-[(3cyano-4-fluoro-phenyl)carbamoyl]-l,2-dimethyl-pyrrol-3-yl]-2-oxo-acetic acid using l-(trifluoromethyl)cyclobutan-l-amine instead of 3,3-difluoro-l-methylcyclobutanamine hydrochloride. LC method C; Rt: 1.97 min. m/z: 483.1 (M-H)' Exact mass: 484.1. *H NMR (400 MHz, DMSO-de) δ ppm 1.81 - 2.10 (m, 2 H) 2.42 - 2.57 (m, 7 H) 3.66 (s, 3 H) 7.55 (t, >9.1 Hz, 1 H) 7.99 (ddd, >9.1,4.8, 2.8 Hz, 1 H) 8.21 (dd, >5.7, 2.6 Hz, 1 H) 9.28 (s, 1 H) 10.75 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: Peak: 218.9 °C.

Compound 44: 3-chloro-N-(3-cyano-4-fluoro-phenyl)-1.5-dimethyl-4-r2-r(3-methyloxetan3-yl)aminol-2-oxo-acetyl1pyrrole-2-carboxamide

Compound 44 (60 mg) was synthesized similarly as described for compound 47 using 3-methyloxetan-3-amine instead of 3,3-difluoro-l-methylcyclobutanamine hydrochloride.

LC method C; Rt: 1.60 min. m/z: 431.1 (M-H)' Exact mass: 432.1. ^!H NMR (400 MHz, DMSO-dô) δ ppm 1.59 (s, 3 H) 2.47 (s, 3 H) 3.66 (s, 3 H) 4.37 (d, J=6.4 Hz, 2 H) 4.70 (d, >6.4 Hz, 2 H) 7.55 (t, >9.1 Hz, 1 H) 7.99 (ddd, >9.2, 4.8, 2.6 Hz, 1 H) 8.21 (dd, >5.7, 2.6 Hz, I H) 9.23 (s, 1 H) 10.73 (s, 1 H). Differential scanning calorimetry: From 30 to 300°C at 10°C/min: Peak: 210.4 °C.

Compound 45: 3-chloro-N-(3-cyano-4-fluoro-phenvl')-4-r2-(isonropylamino')-2-oxo-acetyllL5-dimethyl-pyrrole-2-carboxamide

Compound 45 (59 mg) was synthesized similarly as described for compound 47 using isopropylamine instead of 3,3-difluoro-l-methylcyclobutanamine hydrochloride. LC method

C; Rt: 1.76 min. m/z: 403.1 (M-H)’ Exact mass: 404.1. ^JH NMR (400 MHz, DMSO-d₆) δ ppm 1.14 (d, >6.6 Hz, 6 H) 2.45 (s, 3 H) 3.65 (s, 3 H) 3.90 - 4.02 (m, 1 H) 7.55 (t, >9.1 Hz, 1 H) 7.98 (ddd, >9.2, 4.8, 2.8 Hz, 1 H) 8.21 (dd, >5.7, 2.6 Hz, 1 H) 8.58 (d, >7.7 Hz, 1 H) 10.71 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min:

-57Peak: 238.3 °C.

Compound 46:3 -chloro-N-O -cyano-4-fluoro-phenyl)-4- Γ2- ΓΓ ί 1 Rl-2,2-difluoro-1 -methylpropyll aminol -2-oxo-acetyll -1,5-dimethyl-pyrro le-2-carboxamide

Compound 46 (64 mg) was synthesized similarly as described for compound 47 using (2R)3,3-difluorobutan-2-amine instead of 3,3-difluoro-l-methylcyclobutanamine hydrochloride. LC method C; Rt: 1.85 min. m/z: 453.1 (M-H)- Exact mass: 454.1. ^XHNMR (400 MHz, DMSO-d₆) δ ppm 1.21 (d, >6.8 Hz, 3 H) 1.62 (t, >19.3 Hz, 3 H) 2.47 (s, 3 H) 3.66 (s, 3 H) 4.23 - 4.39 (m, 1 H) 7.55 (t, >9.1 Hz, 1 H) 7.93 - 8.02 (m, 1 H) 8.21 (dd, >5.7, .6 Hz, 1 H) 9.03 (d, >9.0 Hz, 1 H) 10.74 (s, 1 H) Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: Peak: 240.5 °C.

Compound 47: 3-chloro-N-(3-cyano-4-fluoro-phenyl)-4-r2-r(3,3-difluoro-l-methyl-cyclobutyljaminol -2-oxo-acetyl] -1,5-dimethyl-pyrrole-2-carboxamide

2-[4-chloro-5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-l-methyl-pyrrol-3-yl]-2-oxo-acetic acid (250 mg, 0.715 mmol) was suspended in CH3CN (4.9 mL, 93.3 mmol) and DMF (2.4 ml., 31.4 mmol). NBS (190.9 mg, 1.07 mmol) was added and the mixture was stirred at room température for 16 h. The CH3CN was distilled of and the residue was poured out in water. The product was filtered off, washed with water and dried under vacuum resulting in 2-[2-bromo-4-chloro-5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-l-methyl-pyrrol-3-yl]-2-oxoacetic acid (306 mg). A solution of 2-[2-bromo-4-chloro-5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-l-methyl-pyrrol-3-yl]-2-oxo-acetic acid (306 mg, 0.714 mmol), tetramethyltin (0.208 mL, 1.43mmol) in DMF (3.4 mL) was flushed with nitrogen during 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (82.5 mg, 0.071mmol) was added and the reaction mixture was heated at 140°C during 30 min by microwave irradiation. The reaction mixture was concentrated resulting in 2-[4-chloro-5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-l,2dimethyl-pyrrol-3-yl]-2-oxo-acetic acid (260 mg) and used as such in the next step. Et3N (0.397 mL, 2.9 mmol) was added to a solution of 2-[4-chloro-5-[(3-cyano-4-fluoro-phenyl)17673

-58carbamoyl]-l,2-dimethyl-pyrrol-3-yl]-2-oxo-acetic acid (260 mg, 0.715 mmol), 3,3-difluoro-l-methylcyclobutanamme hydrochloride (140.8 mg, 0.89 mmol), HATU (339.7 mg, 0.89 mmol) in DMF (0.5 mL) and stirred 30 minutes at 65°C. The mixture was cooled and the solution was subjected to silica gel column chromatography using a gradient from 10 till 100% EtOAc in heptane and further by preperative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10pm,30xl50mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH₃CN) resulting in compound 47 (68 mg) as a white fluffy solid. LC method D; Rt: 5.74 min. m/z: 465.0 (M-H)- Exact mass: 466.1.¾ NMR (400 MHz, DMSO-dô) δ ppm 1.51 (s, 3 H) 2.47 (s, 3 H) 2.59 - 2.76 (m, 2 H) 2.93 - 3.08 (m, 2 H) 3.66 (s, 3 H) 7.55 (t, >9.1 Hz, 1 H) 7.95 - 8.04 (m, 1 H) 8.21 (dd, >5.5, 2.4 Hz, 1 H) 9.13 (s, 1 H) 10.73 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: Peak: 168.1 °C.

Compound 48 :4-r2-(tert-butvlamino)-2-oxo-acetvll-3-chloro-N-(3-cvano-4-fluoro-phenyl)-

5-cyclopropyl-1 -methyl-pyrrole-2-carboxamide

Compound 48 (54 mg) was synthesized similarly as described for compound 31 using tertButylamine instead of (2R)-l,l,l-trifluoropropan-2-amine. LC method C; Rt: 2.04 min. m/z: 443.1 (M-H)‘ Exact mass: 444.1. ^JH NMR (400 MHz, DMSO-d₆) δ ppm 0.47 - 0.57 (m, 2 H) 0.95 - 1.05 (m, 2 H) 1.35 (s, 9 H) 1.80 - 1.87 (m, 1 H) 3.76 (s, 3 H) 7.55 (t, >9.13 Hz, 1 H) 7.93 - 8.02 (m, 1 H) 8.13 (s, 1 H) 8.20 (dd, >5.72, 2.64 Hz, 1 H) 10.68 (s, 1 H).

Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: Peak: 198.8 °C.

Compound 49: 4-r2-(tert-butylamino)-2-oxo-acetyll-3-chloro-5-cyano-N-(3-cyano-4-fluorophenyl)-1 -methyl-pyrrole-2-carboxamide

A microwave vial was charged with compound 50 (100 mg, 0.207 mmol), copper (I) cyanide (27.8 mg, 0.31 mmol) in DMF (5.06 mL, 65.03 mmol). The vial was capped and irradiated at 160°C for 30 minutes. The mixture was concentrated in vacuo. The residue was partioned

between water and EtOAc. NH4OH was added and the organic layer was separated, dried (MgSCU), filtered and concentrated in vacuo. The obtained residue was purified using 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 resulting in compound 49 (24 mg) as a pale yellow solid. LC method B; Rt: 1.05 min. m/z: 428.1 (M-H)' Exact mass: 429.1. Ή NMR (400 MHz, DMSO-dô) δ ppm 1.32 - 1.38 (m, 9 H) 3.92 (s, 3 H) 7.60 (t, >9.2 Hz, 1 H) 7.94 8.02 (m, 1 H) 8.21 (dd, >5.9, 2.6 Hz, 1 H) 8.59 (s, 1 H) 11.16 (s, 1 H).

Synthesis of methvl 4-r2-(tert-butylamino)-2-oxo-acetyll-3-chloro-l-methyl-pyrrole-2carboxylate

Et₃N (5.09 mL, 36.6 mmol) was added to a solution of 2-(4-chloro-5-methoxycarbonyl-lmethyl-pyrrol-3-yl)-2-oxo-acetic acid (3 g, 12.21 mmol), 2-methylpropan-2-amine (1.62 mL, 15.27 mmol), HATU (5.81 g, 15.27 mmol) in DMF (14.96 mL, 193.26 mmol) and stirred 30 minutes at 65°C. The solution was subjected to silica gel column chromatography using a gradient from 10 till 100% EtOAc in heptane. The product fractions were concentrated resulting in methyl 4-[2-(tert-butylamino)-2-oxo-acetyl]-3-chloro-l-methylpyrrole-2-carboxylate (3.2 g) as a clear oil, which solidified on standing. LC method B; Rt: 1.02 min. m/z: 299.1 (M-H)' Exact mass: 300.1.

Compound 50: 5-bromo-4-r2-(tert-butylamino)-2-oxo-acetyll-3-chloro-N-(3-cyano-4-fluorophenyl)-1 -methyl-pyrrole-2-carboxamide

Cl

Compound 50 (500 mg) was synthesized similarly as described for compound 29 using methyl 4- [2-(tert-butylamino)-2-oxo-acetyl] -3 -chloro-1 -methyl-pyrro le-2-carboxylate instead of methyl 3-chloro-l-methyl-4-[2-oxo-2-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]amino]acetyl]pyrrole-2-carboxylate. LC method B; Rt: 1.06 min. m/z: 481.0 (M-H)’ Exact mass: 482.0. ^XH NMR (400 MHz, DMSO-d₆) δ ppm 1.35 (s, 9 H) 3.75 (s, 3 H) 7.57 (t, >9.13 Hz, 1 H) 7.94 - 8.03 (m, 1 H) 8.20 (dd, >5.72, 2.64 Hz, 1 H) 8.38 (s, 1-H) 10.88 (s, 1 H).Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: Peak: 204.4 °C.

-60Compound 51: N-(3-cyano-4-fluoro-phenyl)-l-methyl-4-r2-oxo-2-riïlS)-2,2,2-trifluoro-lmethyl-ethvllaminolacetyllpyrrole-2-carboxamide

A solution of 2-(5-methoxycarbonyl-l-methyl-pyrrol-3-yl)-2-oxo-acetic acid (0.9 g,

3.45 mmol) in DMF (20 mL) was cooled to 5°C in an ice water bath. Then DIPEA (1.8 mL, 10.36 mmol) and (S)-l,l,l-trifluoro-2-propylamine (468.5 mg, 4.14 mmol) were added and stirred in an ice water bath. A solution of HATU (1444 mg, 3.8 mmol) in DMF (10 mL) was added dropwise while cooling was continued. The obtained solution was stirred for 1 hour under cooling. The reaction was quenched with water (25 mL). A beige précipitation was formed which was collected on a fîlter and rinsed with water. Then it was dried in a vacuum oven at 55°C for 24 hours resulting in methyl l-methyl-4-[2-oxo-2-[[(lS)-2,2,2-trifluoro-lmethyl-ethyl]amino]acetyl]pyrrole-2-carboxylate (872 mg) as a beige solid. Methyl 1 -methyl-4- [2-oxo-2-[ [( 1 S)-2,2,2-trifluoro-1 -methyl-ethyl] amino] acetyl]pyrrole-2carboxylate (872 mg, 2.85-mmol) was dissolved in THF (20 mL), LiOH (272.8 mg, 11.39 mmol) in water (2 mL) was added. MeOH (2 mL) was added to dissolve ail the reactants.The mixture was stirred ovemight at room température and next concentrated in vacuo untill only water remained. HCl (IM in H₂O) (11.4 mL, 1 Μ, 11.4 mmol) was added and this was extracted using Me-THF (3X10 mL). The combined extracts were washed with brine (20 mL), dried on Na₂SO4, filtered, and concentrated in vacuo yielding 1-methyl4-[2-oxo-2-[[(lS)-2,2,2-trifluoro-l-methyl-ethyl]amino]acetyl]pyrrole-2-carboxylic acid (823 mg) as a bright white powder. LC method B; Rt: 0.49 min. m/z: 291.0 (M-H)’ Exact mass: 292.1. 1 -methyl-4-[2-oxo-2-[[(lS)-2,2,2-trifluoro-1 -methyl-ethyl]amino]acetyl]~ pyrrole-2-carboxylic acid (300 mg, 1.03 mmol) in DMF (1.6 mL) with DIPEA (0.53 mL, 3.08 mmol) was treated with HATU (429.4 mg, 1.13 mmol). The resulting mixture was stirred at room température for 30 minutes. Then 5-ammo-2-fluorobenzonitrile (209.6 mg, 1.54 mmol) was added and the resulting mixture was stirred for 2 hours at room température. The mixture was injected as such on a silicaplug and purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0:100 to 100:0). The desired fractions were concentrated under reduced pressure, resulting in compound 51 (260 mg). LC method B; Rt: 1.03 min. m/z: 409.1 (M-H)' Exact mass: 410.1. ^!H NMR (400 MHz, DMSOcU) δ ppm 1.36 (d, J=7.0 Hz, 3 H), 3.97 (s, 3 H), 4.60 - 4.76 (m, 1 H), 7.53 (t, >9.1 Hz, 1 H), 7.69 (d, >1.8 Hz, 1 H), 8.03 (ddd, >9.2,4.9, 2.6 Hz, 1 H), 8.14 (d, >1.3 Hz, 1 H), 8.23 (dd, >5.8, 2.8 Hz, 1 H), 9.34 (d, >8.1 Hz, 1 H), 10.42 (br. s., 1 H)

Compound 52: N-(3-cyano-4-fluoro-phenyl)-4-r2-(isopropylamino)-2-oxo-acetyl1-1,5dimethyl-pyrrole-2-carboxamide

NaH (60% dispersion in minerai oil, 5875 mg, 147 mmol) was added portionwise to a solution of ethyl 5-methyl-lH-pyrrole-2-carboxylate (15000 mg, 97.92 mmol) and iodomethane (7.3 mL, 117.5 mmol) in DMF (40 mL). The reaction was stirred for 1 hour. HCl (IM in H₂O) (49.0mL, 1 M, 49.0 mmol) was added.The resulting mixture was extracted using EtOAc (3 X 100 mL). The combined organics were washed with brine, dried on Na₂SO4, filtered and concentrated in vacuo yielding crude ethyl l,5-dimethylpyrrole-210 carboxylate (8.56 g) as a yellow powder which was used as such. Crude ethyl 1,5-dimethylpyrrole-2-carboxylate (8560 mg) was dissolved in THF (dried on molecular sieves) (144 mL) and 5-amino-2-fiuorobenzonitrile (7666 mg, 56.3 mmol) was added.This mixture was cooled in an ice bath. Lithium bis(trimethylsilyl)amide (IM in toluene) (102.4 mL, 1 M) was added dropwise over a period of 10 minutes. The ice bath was removed and the mixture was stirred for 1 hour at room température .The mixture was quenched with saturated ammonium chloride (300 mL) and the resulting mixture was extracted using EtOAc (3 x 150 mL). The combined extracts were washed with brine (200 mL), dried on Na₂SO4, filtered and concentrated in vacuo. The obtained residue was purified by column chromatography using gradient elution from heptane to EtOAc (100:0 to 0:100). The desired fractions were collected and concentrated in vacuo yielding N-(3-cyano-4-fluoro-phenyl)-l,5dimethyl-pyrrole-2-carboxamide (10.2 g) as a slightly yellow powder which was used as such. LC method B; Rt: 0.98 min. m/z: 256.1 (M-H)‘ Exact mass: 257.1. N-(3-cyano-4fluorophenyl)-l,5-dimethyl-pyrrole-2-carboxamide (5000 mg, 19.44 mmol) was dissolved in DCM (50 mL) and cooled on ice under nitrogen. A solution of ethyl 2-chloro-2-oxo-acetate (3.3 mL) in DCM (10 mL) was added dropwise and the mixture was stirred for 15 minutes.

AICI3 (5183 mg, 38.9 mmol) was added in portions. The mixture was stirred at 0°C under N₂for 5 hours. The mixture was diluted with Me-THF (200 mL) and this was added dropwise into ice water (500 mL). This mixture was extracted with EtOAc (3 X 150 mL). The combined organic layers were washed with water and brine, dried (Na₂SÜ4) and evaporated to dryness, resulting in crude ethyl 2-[5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-l,2dimethyl-pyrrol-3-yI]-2-oxo-acetate (9.4 g) as a yellow powder which was used as such. LC method B; Rt: 1.04 min. m/z: 356.1 (M-H)^- Exact mass: 357.1. Crude ethyl 2-[5-[(3-cyano4-fluoro-phenyl)carbamoyl]-l,2-dimethyl-pyrrol-3-yl]-2-oxo-acetate (9.4 g, 26.4 mmol) was

-62dissolved in THF (200 mL) and to this was added NaOH (IM m H₂O, 39.6 mL). The resulting mixture was stirred at room température for 30 minutes and next concentrated in vacuo until only water remained. Then HCl (aq / IM / 40 mL) was added and this was extracted using Me-THF (3 X 100 mL). The combined extracts were washed with brine, dried onNa₂SO4, filtered and concentrated in vacuo, resulting in crude 2-[5-[(3-cyano-4fluoro-phenyl)carbamoyl]-l,2-dimethyl-pyrrol-3-yl]-2-oxo-acetic acid (8.02 g) as a yellow solid which was used as such. LC method B; Rt: 0.58 min. m/z: 328.0 (M-H)' Exact mass: 329.1. Crude 2-[5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-l,2-dimethyl-pyrrol-3-yl]-2-oxoacetic acid (100 mg) in DMF (0.5 mL) with DIPEA (0.13 mL, 0.77 mmol) was treated with HATU (106.7 mg, 0.28 mmol). The resulting mixture was stirred at room température for 30 minutes. Then isopropylamine (18.09 mg, 0.31 mmol) was added and the resulting mixture was stirred for 2 hours at room température and next at 50°C for 2 hours. The mixture was injected as such on a silicaplug and purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0:100 to 100:0). And further by Preperative HPLC (RP SunFire Prep C18 OBD-10pm, 30x150mm). Mobile phase (0.25% NH4HCO3 solution in water, MeOH). The desired fractions were concentrated under reduced pressure and coevaporated twice (2x15 mL MeOH) and the residue was dried in a vacuum oven at 55°C for 18 hours resulting in compound 52 as an off white solid. LC method B; Rt: 0.99 min. m/z: 369.1 (M-H)' Exact mass: 370.1. *H NMR (400 MHz, DMSO-d₆) δ ppm 1.15 (d, >6.6 Hz, 6 H), 2.57 (s, 3 H), 3.84 (s, 3 H), 3.91 - 4.10 (m, 1 H), 7.52 (t, >9.1 Hz, 1 H), 7.72 (s, 1 H), 8.02 (ddd, >9.2, 5.0, 2.8 Hz, 1 H), 8.22 (dd, >5.7, 2.6 Hz, 1 H), 8.51 (d, >7.9 Hz, 1 H), 10.42 (s, 1 H).

Compound 53: N-(3-cyano-4-fhioro-phenvl)-L5-dimethvl-4-r2-IT(TR)-l-methvlpropvllamino]-2-oxo-acetyl1pyrrole-2-carboxamide

Compound 53 was prepared similarly 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)^- Exact mass: 384.2. ^XH NMR (400 MHz, DMSO-d₆) δ 0.86 (t, >7.3 Hz, 3 H), 1.12 (d, >6.6 Hz, 3 H), 1.42 - 1.57 (m, 2 H), 2.57 (s, 3 H), 3.73 - 3.87 (m, 4 H), 7.52 (t, >9.2 Hz, 1 H), 7.73 (s, 1 H), 8.02 (ddd, >9.2, 5.0, 2.8 Hz, 1 H), 8.22 (dd, >5.7, 2.6 Hz, 1 H), 8.45 (d, >8.4 Hz, 1 H), 10.43 (s, 1 H).

Synthesis of (2R)-3.3-difluorobutan-2-amine (R)-2-((tert-butoxycarbonyl)amino)propanoic acid (30 g, 159 mmol), N,O-dimethylhydroxylamine hydrochloride (17.5 g, 178 mmol), HATU (74 g, 195 mmol) and N,N-diisopropylethylamine (30 g, 232 mmol) were dissolved in DMF (300 mL) and stirred at room température for 15 hours. The reaction mixture was concentrated under vacuum and the residue was dissolved in CH2CI2 (500 mL) and washed with brine (3 x 200 mL). The organic layer was dried over Na₂SC>4 and concentrated in vacuo. The residue was purifïed via silica gel chromatography using petroleum ether: EtOAc 2:1 as eluent yielding tert-butyl N-[(17?)-2-[methoxy(methyl)amino]-l-methyl-2-oxo-ethyl]carbamate (28.9 g). Tert-butyl

N-[(lR)-2-[methoxy(methyl)amino]-l-methyl-2-oxo-ethyl]carbamate was dissolved in THF (300 mL) and cooled to 0°C. Méthylmagnésium bromide 3.0 m in diethyl ether (85 mL, 255 mmol) was added dropwise and the reaction mixture was stirred 15 hours at room température. The reaction mixture was quenched with sat. NH₄C1 and extracted with CH₂C1₂(3 x 100 mL). The combined organic layers were dried over Na₂SC>4, filtered and evaporated to dryness. The obtained residue was purified via silica gel chromatography yielding tert-butyl N-[(lR)-l-methyl-2-oxo-propyl]carbamate (18.9 g). To a cooled (-78°C) solution of tert-butylN-[(lR)-l-methyl-2-oxo-propyl]carbamate (10 g, 53.4 mmol) in CH2CI2 (200 mL) bis(2-methoxyethyl)aminosulfur trifluoride (18.9 g, 117.5 mmol) was added dropwise and stirring was continued for 2 hours at -78°C. The reaction mixture was allowed to warm to room température and stirred ovemight. The reaction mixture was quenched with sat. NaHCCL and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, 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 yielding tert-butyl N-[(lR)-2,2-difluoro-l-methyl-propyl]carbamate (6.77 g). Tert-butyl N-[(lR)-2,2-difhioro-l-methyl-propyl]carbamate (6.77 g) was dissolved in EtOAc (50 mL). HCl in EtOAc was added at 0°C and the reaction mixture was stirred for 4 hours at room température. The formed precipitate was filtered off and dried under high vacuum yielding (2R)-3,3-difluorobutan-2-amine hydrochloride (3.5 g).

Compound 54 : N-(3-cyano-4-fluoro-phenyl)-4-r2-rr ( 1 R)-2.2-difluoro-1 -methyl-prop yll30 aminol-2-oxo-acetyll-1.5-dimethyl-pyrrole-2-carboxamide

A vial was loaded with crude 2-[5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-l,2-dimethylpyrrol-3-yl]-2-oxo-acetic acid (250 mg,), HATU (266.74 mg, 0.7 mmol), (2R)-3,3-difluoro

-64butan-2-amine hydrochlonde (0.77 mmol) and DMF (1 mL). This mixture was heated and stirred at 65°C. Then DIPEA (0.33 mL, 1.91 mmol) was added and the mixture was stirred for 20 minutes. The mixture was cooled to room température and injected directly onto a silica plug and purified using silica gel column chromatography (gradient elution: EtOAcheptane 0:lOOto 100:0). The desired fractions were concentrated under reduced pressure and dried in a vacuum oven at 55°C for 18 hours. The obtained solids was crystallised out of iPrOH. The crystals were collected on a filter and dried in a vacuum oven at 55°C for hours yielding compound 54 (124 mg) as white powder. LC method B; Rt: 1.06 min. m/z: 419.1 (M-H)’ Exact mass: 420.1. ‘HNMR (400 MHz, DMSO-d₆) δ ppm 1.23 (d, >6.8 Hz, 3 H), 1.62 (t, >19.3 Hz, 3 H), 2.58 (s, 3 H), 3.85 (s, 3 H), 4.28 - 4.43 (m, 1 H), 7.52 (t, >9.1 Hz, 1 H), 7.65 (s, 1 H), 7.98 - 8.05 (m, 1 H), 8.21 (dd, >5.7, 2.6 Hz, 1 H), 8.92 (d, >9.2 Hz, 1 H), 10.44 (s, 1 H).

Synthesis of (2S)-3.3-difluorobutan-2-amine hydrochloride (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (39 g, 206 mmol), N,O-dimethylhydroxylamine hydrochloride (24 g, 246 mmol), HATU (117 g, 308 mmol) and N,N-diisopropylethylamine (66.3 g, 513 mmol) were dissolved in DMF (500 mL) and stirred at room température for 16 hours. The reaction mixture was poured into water (500 mL) and the formed precipitate was fïltered off. The filter cake was washed with water (1 L) and dried to give tert-butyl N-[(lS)-2-[methoxy(methyl)amino]-l-methyl-2-oxoethyljcarbamate (36 g) as a white powder. tert-butyl N-[(lS)-2-[methoxy(methyl)amino]-lmethyl-2-oxo-ethyl]carbamate (35 g, 151 mmol) was dissolved in THF (500 mL) and cooled to 0°C. Méthylmagnésium bromide (3.0 M in diethyl ether, 140 mL) was added and the reaction mixture was stirred 16 hours at room température. The reaction mixture was poored into water (100 mL) and evaporated to dryness. The residue was dissolved in EtOAc, washed with water, dried over Na₂SO4, fïltered and evaporated to dryness yielding tert-butyl N-[(lS)-l-methyl-2-oxo-propyl]carbamate (22 g) as a white powder. To a cooled (-78°C) solution of tert-butyl N-[(lS)-l-methyl-2-oxo-propyl]carbamate (12 g, 64.1 mmol) in CH₂C1₂ (200 mL) bis(2-methoxyethyl)aminosulfur trifluoride (18.9 g, 117.5 mmol) was added. The reaction mixture was allowed to warm to room température and stirred ovemight. The reaction mixture was poored into water and extracted with CH₂C1₂. The organic layer was washed with water, dried over Na₂SO4, fïltered and evaporated to dryness. The obtained residue was purified by silica gel chromatography yielding tert-butyl N-[(lS)-2,2-difluoro-l-methyl-propyl]carbamate (5.8 g) as a pale yellow solid. Tert-butyl N-[(lS)-2,2-difluoro-l-methyl-propyl]carbamate (5.8 g, 27.7 mmol) was dissolved in EtOAc (100 mL). HCl (g) was bubbled through for 30 minutes and then the volatiles were removed under reduced pressure yielding (2S)-3,3-difluorobutan-2-amine hydrochloride

-65(3.8 g) Ή NMR (400MHz, DMSO-d₆) δ ppm 8.69 (br. s„ 3H), 3.76 - 3.63 (m, 1H), 1.72 (t, >19.7 Hz, 3H), 1.28 (d, J=6.8 Hz, 3H).

Compound 55: N-(3-cyano-4-fluoro-phenyl)-4-r2-rr( 1 S)-2,2-difluoro-1 -methyl-propyllaminol-2-oxo-acetyll-1.5-dimethvl-pvrrole-2-carboxamide

Compound 55 (130 mg) was prepared similarly as described for compound 54, using (25)-3,3-difluorobutan-2-amine hydrochlori.de instead of (27?)-3,3-difluorobutan-2-amine hydrochloride. LC method B; Rt: 1.06 min. m/z: 419.1 (M-H)' Exact mass: 420.1. ^XH NMR (400 MHz, DMSO-de) δ ppm 1.23 (d, >6.8 Hz, 3 H), 1.62 (t, >19.3 Hz, 3 H), 2.58 (s, 3 H),

3.85 (s, 3 H), 4.28 - 4.44 (m, 1 H), 7.52 (t, >9.1 Hz, 1 H), 7.65 (s, 1 H), 7.98 - 8.05 (m,

H), 8.21 (dd, >5.7, 2.6 Hz, 1 H), 8.92 (d, >9.2 Hz, 1 H), 10.44 (s, 1 H).

Compound 56 : N-(3-cvano-4-fluoro-phenvr)-4-r2-[ï3,3-difluoro-l-methyl-cvclobutyf)aminol-2-oxo-acetvll-1,5-dimethyl-nvrrole-2-carboxamide

Compound 56 (147 mg) was prepared similarly as described for compound 54, using 3,3-difluoro-l-methyl-cyclobutanamine hydrochloride instead of (2/?)-3,3-difluorobutan2-amine hydrochloride. LC method B; Rt: 1.08 min. m/z: 431.1 (M-H)^- Exact mass: 432.1. Ή NMR (400 MHz, DMSO-d₆) δ ppm 1.52 (s, 3 H), 2.58 (s, 3 H), 2.61 - 2.77 (m, 2 H), 2.91 - 3.13 (m, 2 H), 3.85 (s, 3 H), 7.52 (t, >9.1 Hz, 1 H), 7.73 (s, 1 H), 7.99 - 8.06 (m, 1 H), 8.22 (dd, >5.8, 2.8 Hz, 1 H), 9.10 (s, 1 H), 10.45 (s, 1 H).

Compound 57: N-(3-cyano-4-fluoro-phenyl)-L5-dimethyl-4-r2-oxo-2-rri-(trifluoromethyl)cyclopropyllamino1acetyllpyrrole-2-carboxamide

-66Compound 57 (138 mg) was prepared similarly as described for compound 54, usmg

1-trifluoromethyl-l-cyclopropylamine instead of (2R)-3,3-difluorobutan-2-amine hydrochloride. LC method B; Rt: 1.07 min. m/z: 435.1 (M-H)' Exact mass: 436.1. *H NMR (400 MHz, DMSO-dô) δ ppm 1.09 - 1.19 (m, 2 H), 1.28 - 1.36 (m, 2 H), 2.56 (s, 3 H), 3.84 (s, 3 H), 7.52 (t, J=9.1 Hz, 1 H), 7.68 (s, 1 H), 7.97 - 8.06 (m, 1 H), 8.21 (dd, >5.7,2.6 Hz, 1 H), 9.49 (s, 1 H), 10.46 (s, 1 H).

Compound 58: N-(3-cyano-4-fluoro-phenyl)-l,5-dimethyl-4-r2-oxo-2-r(2,2.2-trifluoro-l.ldimethyl-ethyl)aminolacetyllpyrrole-2-carboxamide

Compound 58 (129 mg) was prepared similarly as described for compound 54, using 2,2,2-trifluoro-l,l-dimethyl-ethylamine instead of (2R)-3,3-difluorobutan-2-amine hydrochloride. LC method B; Rt: 1.14 min. m/z: 437.1 (M-H) Exact mass: 438.1. *H NMR (400 MHz, DMSO-de) δ ppm 1.60 (s, 6 H), 2.56 (s, 3 H), 3.84 (s, 3 H), 7.48 - 7.57 (m, 2 H), 8.02 (s, 1 H), 8.21 (dd, >5.8, 2.8 Hz, 1 H), 8.62 (s, 1 H), 10.48 (s, 1 H)

Compound 59: 4-r2-(tert-butylamino)-2-oxo-acetyl1-N-(3-cyano-4-fluoro-phenyl)-1.5dimethvl-pvrrole-2-carboxamide

Compound 59 (54 mg) was prepared similarly as described for compound 54, using tertbutylamine instead of (2R)-3,3-difluorobutan-2-amine hydrochloride. LC method B; Rt:

1.10 min. m/z: 383.1 (M-H)'Exactmass: 384.2. ΉNMR (400 MHz, DMSO-dô) δ ppm 1.36 (s, 9 H), 2.56 (s, 3 H), 3.84 (s, 3 H), 7.52 (t, >9.1 Hz, 1 H), 7.65 (s, 1 H), 7.98 - 8.05 (m,

H), 8.08 (s, 1 H), 8.22 (dd, >5.7, 2.6 Hz, 1 H), 10.46 (s, 1 H)

-67Compound 60: N-(3-cyano-4-fluoro-phenyl)-L5-dmietliyl-4-r2-r(3-methvloxetan-3-yl)amino1-2-oxo-acetvllnvrrole-2-carboxamide

Compound 60 (149 mg) was prepared similarly as described for compound 54, using 3-meth.yl-3-oxetanamine instead of (2R)-3,3-difhiorobutan-2-amine hydrochloride. LC method B; Rt: 0.90 min. m/z: 397.1 (M-H)' Exact mass: 398.1. NMR (400 MHz, DMSOdg) δ ppm 1.59 (s, 3 H), 2.58 (s, 3 H), 3.85 (s, 3 H), 4.37 (d, J=6.6 Hz, 2 H), 4.72 (d, >6.4 Hz, 2 H), 7.52 (t, >9.1 Hz, 1 H), 7.77 (s, 1 H), 7.98 - 8.06 (m, 1 H), 8.21 (dd, >5.8, 2.8 Hz, 1 H), 9.22 (s, 1 H), 10.45 (s, 1 H).

Compound 61: N-(3-cvano-4-fluoro-nhenvl)-5-cvclopropvl-l-methvl-4-f2-oxo-2-rr(lR)2,2,2-trifluoro-1 -methyl-ethyllaminol acetyllpyrrole-2-carboxamide

A microwave vial was charged with compound 25 (100 mg, 0.2 mmol), potassium cyclopropyltrifluoroborate (45mg, 0.31 mmol), CS2CO3 (133 mg, 0.41 mmol), DME (2.3 mL) and water (0.23 mL). The mixture was purged with N₂ for 5 minutes.

Tetrakis(triphenylphosphine)palladîum(0) (47.24 mg, 0.041 mmol) was added and the vial was capped. The mixture was stirred at 110°C for 16 hours. The mixture was cooled and the residue partioned between sat. NH4CI-S0I and Me-THF. The organic layer was separated, dried (MgSCU), filtered and concentrated in vacuo. The crude was purifîed using silica gel column chromatography (gradient elution: EtOAc-heptane 0:100 to 100:0) and further by préparative HPLC (RP SunFire Prep C18 OBD-lOpm, 30x150mm). Mobile phase (0.25% NH4HCO3 solution in water, MeOH), compound 61 (16 mg) as a white powder.

LC method B; Rt: 1.11 min. m/z: 449.1 (M-H)’ Exact mass: 450.1. ^!HNMR (400 MHz, DMSO-d₆) δ ppm 0.61 - 0.70 (m, 2 H), 1.02 -1.13 (m, 2 H), 1.34 (d, >7.0 Hz, 3 H), 1.76 1.90 (m, 1 H), 3.96 (s, 3 H), 4.70 (dq, >15.5, 7.7 Hz, 1 H), 7.52 (t, >9.2 Hz, 1 H), 7.56 (s, 1 H), 7.96 - 8.06 (m, 1 H), 8.21 (dd, >5.8, 2.8 Hz, 1 H), 9.25 (d, >8.8 Hz, 1 H), 10.42 (s, 1H).

-68Compound 62, 63, 65 to 72 and 74 to 82 were prepared similarly as described for compound 73, using the corresponding amine instead of (l-aminocyclopropyl)methanol.

Compound 62: N-(3-cyano-4-fluoro-phenyl)-4-r2-rr(3R,4S)-3-hydroxy-l-methyl-4piperidyll aminol-2-oxo-acetyll -1.5-dimethyl-pvrrole-2-carboxamide

(3R,46)-4-amino-l-methylpiperidin-3-ol was used as amine, resulting in compound 62 (40.3 mg). ^XH NMR (400 MHz, DMSO-d₆) δ ppm 1.46 - 1.65 (m, 1 H), 1.79 - 1.93 (m, 1 H), 1.98 - 2.09 (m, 1 H), 2.12 - 2.25 (m, 4 H), 2.54 - 2.70 (m, 5 H), 3.69 - 3.80 (m, 2 H), 3.84 (s, 3 H), 4.60 - 4.88 (m, 1 H), 7.52 (t, J=9.2 Hz, 1 H), 7.82 (s, 1 H), 7.98 - 8.09 (m, 2 H), 8.22 (dd, J=5.7, 2.6 Hz, 1 H), 10.43 (s, 1 H). LC method B; Rt: 0.74 min. m/z: 440.2 (M-H)’ Exact mass: 441.2.

Compound 63: N-(3-cyano-4-fluoro-phenyl)-4-r2-[Tί 1 S)-1 -(hydroxymethyl)pentyllaminol-

2-oxo-acetyl] -1.5-dimethyl-pyrrole-2-carboxamide

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

Compound 65: N-(3-cyano-4-fluoro-phenyl)-4-r2-rr(lS.2S)-2-hydroxycyclopentyllamino12-oxo-acetyll-1,5-dimethyl-pvrrole-2-carboxamide

(lS,2S)-trans-2-aminocyclopentanol hydrochloride was used as amine, resulting in compound 65 (27.1 mg). ’H NMR (400 MHz, DMSO-d₆) δ ppm 1.40 - 1.53 (m, 2 H), 1.55 1.73 (m, 2 H), 1.75 - 1.90 (m, 1 H), 1.92 - 2.05 (m, 1 H), 2.57 (s, 3 H), 3.84 (s, 3 H), 3.87 4.00 (m, 2 H), 4.78 (d, >4.0 Hz, 1 H), 7.52 (t, >9.1 Hz, 1 H), 7.71 (s, 1 H), 8.02 (ddd, >9.2,4.9, 2.6 Hz, 1 H), 8.22 (dd, >5.7, 2.6 Hz, 1 H), 8.54 (d, >7.5 Hz, 1 H), 10.45 (s, 1 H). LC method C; Rt: 1.74 min. m/z: 411.4 (M-H) Exact mass: 412.2.

Compound 66 : N-(3-cvano-4-fluoro-phenvl)-4-['2-rr(lS,2R.5R)-2-hydroxv-5-methvlcyclopentyl1aminol-2-oxo-acetyll-L5-dimethyl-pyrrole-2-carboxamide

(lR,2S,3R)-2-amino-3-methyl-cyclopentanol hydrochloride was used as amine, resulting in compound 66 (38.2 mg). ^XH NMR (400 MHz, DMSO-d_ô) δ ppm 0.98 (d, >6.6 Hz, 3 H), 1.05 - 1.32 (m, 2 H), 1.48 - 1.62 (m, 1 H), 1.82 - 2.09 (m, 3 H), 2.58 (s, 3 H), 3.50 - 3.60 (m, 1 H), 3.85 (s, 3 H), 4.89 (d, >4.2 Hz, 1 H), 7.52 (t, >9.1 Hz, 1 H), 7.92 (s, 1 H), 7.96 - 8.06 (m, 2 H), 8.22 (dd, >5.8, 2.8 Hz, 1 H), 10.46 (s, 1 H). LC method B; Rt: 0.94 min. m/z: 425.1 (M-H) Exact mass: 426.2.

Compound 67 : N-(3-cyano-4-fluoro-phenyl)-4-r2-rr(lS,2S)-2-hvdroxycyclohexyllamino12-oxo-acetyll-1,5-dimethyl-pyrrole-2-carboxamide

HO

Trans-( 15,25)- 2-aminocyclohexanol hydrochloride was used as amine, resulting in compound 67 (42.5 mg). *H NMR (400 MHz, DMSO-d₆)dppm 1.19 - 1.35 (m, 4 H), 1.51 17673

1.71 (m, 2 H), 1.78 - 1.94 (m, 2 H), 2.57 (s, 3 H), 3.35 - 3.58 (m, 2 H), 3.84 (s, 3 H), 4.64 (d, >4.8 Hz, 1 H), 7.52 (t, >9.1 Hz, 1 H), 7.79 (s, 1 H), 8.02 (ddd, >9.2, 4.9, 2.6 Hz, 1 H), 8.22 (dd, >5.9, 2.6 Hz, 1 H), 8.36 (d, J=8.4 Hz, 1 H), 10.45 (s, 1 H). LC method C; Rt: 1.78 min. m/z: 425.2 (M-H)' Exact mass: 426.2.

Compound 68: N-(3-cyano-4-fluoro-phenyl)-4-r2-rr(lS)-l-(hydroxymethyl)-2-methylpropyll aminol -2-oxo-acetyll-1,5-dimethyl-pyrro le-2-carboxamide (S)-(+)-2-amino-3-methyl-l-butanol was used as amine, resulting in compound 68 (43.9 mg). ^JH NMR (400 MHz, DMSO-d₆) δ ppm 0.80 - 0.95 (m, 6 H), 1.83 - 1.95 (m, 1 H), 2.58 (s, 3 H), 3.49 (t, J=5.2 Hz, 2 H), 3.63 - 3.74 (m, 1 H), 3.84 (s, 3 H), 4.64 (t, >5.2 Hz, 1 H), 7.52 (t, >9.1 Hz, 1 H), 7.78 (s, 1 H), 8.02 (ddd, >9.2, 4.8, 2.9 Hz, 1 H), 8.18 - 8.26 (m, 2 H), 10.46 (s, 1 H). LC method B; Rt: 0.90 min. m/z: 413.2 (M-H)' Exact mass: 414.2.

Compound 69 : N-(3-cyano-4-fluoro-phenyl')-4-r2-rr(lS.2S)-l-(hydroxymethyl)-2-methylbutyl1amino1-2-oxo-acetyll-L5-dimethyl-pyrrole-2-carboxamide

L-isoleucinol was used as amine, resulting in compound 69 (34.8 mg). *H NMR (400 MHz, DMSO-dô) δ ppm 0.81 - 0.91 (m, 6 H), 1.02 - 1.15 (m, 1 H), 1.33 - 1.54 (m, 1 H), 1.55 1.76 (m, 1 H), 2.55 - 2.61 (m, 3 H), 3.45 - 3.57 (m, 2 H), 3.68 - 3.79 (m, 1 H), 3.84 (s, 3 H), 4.53 - 4.69 (m, 1 H), 7.52 (t, >9.1 Hz, 1 H), 7.79 (s, 1 H), 8.03 (ddd, >9.2, 5.0, 2.8 Hz, 1 H), 8.17 - 8.29 (m, 2 H), 10.47 (s, 1 H). LC method C; Rt: 1.88 min. m/z: 427.3 (M-H)’ Exact mass: 428.2.

-71Compound 70: N-(3-cyano-4-fluoro-phenyD-4-r2-[T3-hvdroxy-l-(methoxvmethyD-lmethyl-propyllaminol-2-oxo-acetyll-L5-dimethyl-pyrrole-2-carboxamide

OH

3-amino-4-methoxy-3-methylbutan-l-ol was used as amine, resulting in compound 70 (13.5 mg). Ή NMR (400 MHz, DMSO-d₆) δ ppm 1.35 (s, 3 H), 1.72 - 1.83 (m, 1 H), 1.92 2.04 (m, 1 H), 2.56 (s, 3 H), 3.28 (s, 3 H), 3.54 (q, >9.1 Hz, 4 H), 3.83 (s, 3 H), 4.54 - 4.70 (m, 1 H), 7.52 (t, >9.1 Hz, 1 H), 7.80 (s, 1 H), 8.03 (ddd, >9.2, 4.9, 2.9 Hz, 1 H), 8.18 8.27 (m, 2 H), 10.48 (s, 1 H). LC method B; Rt: 0.92 min. m/z: 443.1 (M-H)' Exact mass: 444.2.

Compound 71 : N-(3-cvano-4-fluoro-phenyl~)-4-r2-rr3-(hydroxvmethvl)oxetan-3-vl1aminol2-oxo-acetyll-1,5-dimethyl-pyrrole-2-carboxamide

(3-aminooxetan-3-yl)methanol was used as amine, resulting in compound 71 (36.4 mg). ^rH NMR (400 MHz, DMSO-d₆) δ ppm 2.58 (s, 3 H), 3.66 - 3.74 (m, 2 H), 3.85 (s, 3 H), 4.54 (d, >6.6 Hz, 2 H), 4.66 (d, >6.6 Hz, 2 H), 5.14 - 5.31 (m, 1 H), 7.52 (t, >9.1 Hz, 1 H), 7.77 (s, 1 H), 7.98 - 8.07 (m, 1 H), 8.22 (dd, >5.6, 2.5 Hz, 1 H), 9.12 (s, 1 H), 10.46 (s, 1 H). LC method B; Rt: 0.78 min. m/z: 413.1 (M-H)' Exact mass: 414.1.

Compound 72: N-(3-cyano-4-fluoro-phenyl')-4-r2-r(2-hydroxv-L2-dimethyl-propyl)amino12-oxo-acetyll-1,5-dimethyl-pyrrole-2-carboxamide

3-amino-2-methylbutan-2-ol was used as amine, resulting in compound 72 (6.3 mg).

^JH NMR (400 MHz, DMSO-d₆) δ ppm 1.08 (s, 3 H), 1.09 - 1.15 (m, 6 H), 2.56 - 2.60 (m, 3 H), 3.75 - 3.89 (m, 4 H), 4.51 (s, 1 H), 7.52 (t, >9.1 Hz, 1 H), 7.79 (s, 1 H), 8.02 (ddd, >9.2, 5.0, 2.8 Hz, 1 H), 8.13 (d, J=9.5 Hz, 1 H), 8.20 - 8.24 (m, 1 H), 10.45 (s, 1 H).LC method C; Rt: 1.78 min. m/z: 413.4 (M-H)' Exact mass: 414.2.

Compound 73: N-(3-cvano-4-fluoro-phenyl)-4-r2-rri-(hydroxymethyl)cyclopropyllaminol2-oxo-acetyll-1,5-dimethyl-pyrrole-2-carboxamide

To a vial containing (l-aminocyclopropyl)methanol (32 mg, 0.37 mmol), HATU (128.03 mg, 0.34 mmol) was added followedby 2-[5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-l,2-dimethyl-pyrrol-3-yl]-2-oxo-acetic acid (120 mg, 0.31 mmol) in DMF (0.48 mL, 6.17 mmol) and DIPEA (0.16 mL, 0.75 g/mL, 0.92 mmol). The resulting mixture was stirred for 5 hours at room température. Then water (5 mL) was added and the mixture was extracted using CH2CI2 (2x5 mL). The combined organics were concentrated and the mixture purified via preperative HPLC (Stationary phase: RP XBridge Prep Cl8 OBD10pm,30xl50mm, Mobile phase: 0.25% NH4HCO3 solution in water, MeOH) and further 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°C for 24 hours yielding compound 73 (14 mg). ^}H NMR (400 MHz, DMSO-dg) δ ppm 0.67 - 0.81 (m, 4 H), 2.55 (s, 3 H), 3.52 (d, J=4.8 Hz, 2 H), 3.84 (s, 3 H), 4.67 - 4.80 (m, 1 H), 7.52 (t, >9.2 Hz, 1 H), 7.71 (s, 1 H), 8.02 (ddd, >9.3,4.9, 2.8 Hz, 1 H), 8.22 (dd, >5.8, 2.8 Hz, 1 H), 8.78 (s, 1 H), 10.46 (s, 1 H). LC method B; Rt: 0.80 min. m/z: 397.1 (M-H)' Exact mass: 398.1.

Compound 74 : N-(3 -cyano-4-fluoro-phenyl)-4-r2- Γ( 1 -cyclopropyl-3 -hydroxy-propvl)aminol-2-oxo-acetyll-1,5-dimethyl-pyrrole-2-carboxamide

3-amino-3-cyclopropyl-propan-l-ol was used as amine, resulting in compound 74 (40 mg). Xi NMR (400 MHz, DMSO-d₆) δ ppm 0.18 - 0.26 (m, 1 H), 0.27 - 0.41 (m, 2 H), 0.42 0.52 (m, 1 H), 0.91 - 1.03 (m, 1 H), 1.76 (q, >6.9 Hz, 2 H), 2.57 (s, 3 H), 3.35 - 3.54 (m, 3 H), 3.84 (s, 3 H), 4.32 - 4.49 (m, 1 H), 7.52 (t, >9.2 Hz, 1 H), 7.75 (s, 1 H), 8.02 (ddd, >9.2, 4.9, 2.9 Hz, 1 H), 8.22 (dd, >5.8, 2.8 Hz, 1 H), 8.54 (d, >8.8 Hz, 1 H), 10.46 (s,

H). LC method C; Rt: 1.75 min. m/z: 425.2 (M-H)’ Exact mass: 426.2

Compound 75: N-(3-cyano-4-fluoro-phenvl)-4-r2-rRlR)-l-(hydroxymethvl)pentyllaminol2-oxo-acetyll - L5 -dimethyl-pyrrole-2-carboxamide

(R)-(-)-2-amino-l-hexanol was used as amine, resulting in compound 75 (22 mg). *H NMR (400 MHz, DMSO-dô) δ ppm 0.80 - 0.90 (m, 3 H), 1.19 - 1.46 (m, 5 H), 1.52 - 1.66 (m, 1 H), 2.57 (s, 3 H), 3.33 - 3.49 (m, 2 H), 3.75 - 3.89 (m, 4 H), 4.68 - 4.75 (m, 1 H), 7.52 (t, >9.1 Hz, 1 H), 7.77 (s, 1 H), 8.03 (ddd, >9.2, 5.0, 2.8 Hz, 1 H), 8.22 (dd, >5.8, 2.8 Hz, 1 H), 8.28 (d, >8.8 Hz, 1 H), 10.46 (s, 1 H). LC method C; Rt: 1.93 min. m/z: 427.4 (M-H)’ Exact mass: 428.2

Compound 76: N-(3-cyano-4-fluoro-phenyl)-4-r2-rri-(hydroxymethyl)-l-methyl-propyllamino]-2-oxo-acetvll - L 5-dimethyl-pyrro le-2-carboxamide

2-amino-2-methylbutan-l-ol was used as amine, resulting in compound 76 (26 mg). ^rH NMR (400 MHz, DMSO-d₆) δ ppm 0.81 (t, J=7.5 Hz, 3 H), 1.26 (s, 3 H), 1.62 - 1.88 (m, 2 H), 2.57 (s, 3 H), 3.39 - 3.47 (m, 1 H), 3.51 - 3.59 (m, 1 H), 3.84 (s, 3 H), 4.83 - 5.02 (m, 1 H), 7.52 (t, >9.1 Hz, 1 H), 7.76 (s, 1 H), 7.80 (s, 1 H), 8.03 (ddd, >9.2, 5.0, 2.8 Hz, 1 H), 8.22 (dd, >5.7, 2.6 Hz, 1 H), 10.47 (s, 1 H). LC method C; Rt: 1.87 min. m/z: 413.4 (M-H)’ Exact mass: 414.2

Compound 77 : N-(3 -cyano-4-fluoro-phenyl)-4-r2- Γ( 1 -cyclopropyl-2-hydroxy-1 -methylethvl)amino1-2-oxo-acetyl]-L5-dimethyl-pyrrole-2-carboxamide

2-amino-2-cyclopropylpropan-l-ol was used as amine, resulting in compound 77 (24 mg).

-74Ή NMR (400 MHz, DMSO-d₆) δ ppm 0.28 - 0.41 (m, 3 H), 0.42 - 0.51 (m, 1 H), 1.10 (s,

H), 1.20 - 1.33 (m, 1 H), 2.57 (s, 3 H), 3.47 - 3.56 (m, 1 H), 3.59 - 3.66 (m, 1 H), 3.84 (s, 3 H), 4.92 - 4.99 (m, 1 H), 7.52 (t, >9.2 Hz, 1 H), 7.75 (s, 1 H), 7.82 (s, 1 H), 8.03 (ddd, >9.1, 5.0, 2.6 Hz, 1 H), 8.22 (dd, >5.8, 2.8 Hz, 1 H), 10.48 (s, 1 H). LC method B;

Rt: 0.98 min. m/z: 425.2 (M-H)' Exact mass: 426.2.

Compound 78: N-(3-cyano-4-fluoro-phenyl)-l ,5-dimethyl-4-|~2-lï3-methvltetrahvdropvran3-yl)aminol-2-oxo-acetyl1pyrrole-2-carboxamide

3-methyloxan-3-amine was used as amine, resulting in compound 78 (15 mg). ^}H NMR (400 MHz, DMSO-de) δ ppm 1.31 (s, 3 H), 1.40 - 1.70 (m, 3 H), 2.24 (m, >12.8 Hz, 1 H), 2.57 (s, 3 H), 3.34 - 3.38 (m, 1 H), 3.38 - 3.47 (m, 1 H), 3.62 - 3.70 (m, 1 H), 3.84 (s, 3 H), 3.88 - 3.95 (m, 1 H), 7.52 (t, >9.1 Hz, 1 H), 7.73 (s, 1 H), 7.97 - 8.07 (m, 2 H), 8.22 (dd, >5.9, 2.6 Hz, 1 H), 10.47 (s, 1 H). LC method B; Rt: 0.99 min. m/z: 425.1 (M-H) Exact mass: 426.2.

Compound 79 : N-(3-cyano-4-fluoro-phenvl)-4-r2-F(2-methoxy-l,l-dimethyl-ethyl)amino12-oxo-acetyll-1,5-dimethyl-pyrrole-2-carboxamide l-methoxy-2-amino-2-methylpropane was used as amine, resulting in compound 79 (31 mg). ^JH NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (s, 6 H), 2.56 (s, 3 H), 3.30 (s, 3 H), 3.45 (s, 2 H), 3.84 (s, 3 H), 7.52 (t, >9.1 Hz, 1 H), 7.70 (s, 1 H), 7.95 - 8.08 (m, 2 H), 8.22 (dd, >5.8, 2.8 Hz, 1 H), 10.48 (s, 1 H). LC method C; Rt: 2.02 min. m/z: 413.2 (M-H)’ Exact mass: 414.2.

-75Compound 80: N-(3-cyano-4-fluoro-phenyl)-L5-dmiethyl-4-r2-oxo-2-rr2,2,2-tnfluoro-l(methoxvmethvl)-l-methvl-ethyllaminolacetvl1pvrrole-2-carboxamide

l,l,l-trifluoro-3-methoxy-2-methylpropan-2-amine hydrochloride was used as amine, resulting in compound 80 (52 mg). NMR (400 MHz, DMSO-dé) δ ppm 1.60 (s, 3 H), 2.57 (s, 3 H), 3.34 (s, 3 H), 3.67 (d, >9.7 Hz, 1 H), 3.84 (s, 3 H), 3.96 (d, >9.7 Hz, 1 H), 7.52 (t, >9.1 Hz, 1 H), 7.63 (s, 1 H), 8.01 (ddd, >9.2, 5.0, 2.8 Hz, 1 H), 8.22 (dd, >5.8, 2.8 Hz, 1 H), 8.53 (s, 1 H), 10.51 (s, 1 H). LC method B; Rt: 1.11 min. m/z: 467.1 (M-H)’ Exact mass: 468.1.

Compound 81: N-(3-cyano-4-fluoro-phenyl)-4-r2-r(3-hydroxy-Ll-dimethyl-propyl)amino12-oxo-acetvl1-1.5-dimethyl-pyrrole-2-carboxamide

3-amino-3-methylbutan-l-ol was used as amine, resulting in compound 81 (24 mg).¹H NMR (400 MHz, DMSO-dô) δ ppm 1.38 (s, 6 H), 1.84 (t, >6.6 Hz, 2 H), 2.56 (s, 3 H), 3.51 - 3.61 (m, 2 H), 3.84 (s, 3 H), 4.58 - 4.72 (m, 1 H), 7.52 (t, J=9.2 Hz, 1 H), 7.78 (s, 1 H), 8.03 (ddd, >9.2, 4.9, 2.6 Hz, 1 H), 8.22 (dd, >5.8, 2.8 Hz, 1 H), 8.34 (s, 1 H), 10.46 (s, 1 H). LC method B; Rt: 0.93 min. m/z: 413.2 (M-H)' Exact mass: 414.2.

Compound 82: N-(3-cyano-4-fluoro-phenvl)-4-r2-rr4-hydroxy-l-(trifluoromethyl)cyclohexyl]amino1-2-oxo-acetyl1-L5-dimethyl-pynOle-2-carboxamide

4-amino-4-(trifluoromethyl)cyclohexan-l-ol was used as amine, resulting in compound 82 (10 mg). ^!H NMR (400 MHz, DMSO-d₆) δ ppm 1.23 - 1.39 (m, 2 H), 1.45 - 1.62 (m, 2 H), 1.69 - 1.82 (m, 2 H), 2.54 - 2.72 (m, 6 H), 3.84 (s, 3 H), 4.71 (br. s., 1 H), 7.52 (t, >9.1 Hz,

H), 7.57 (s, 1 H), 8.02 (ddd, J=9.1,5.0,2.6 Hz, 1 H), 8.21 (dd, J=5.8,2.8 Hz, 1 H), 8.44 (s,

H), 10.52 (br. s., 1 H). LC method B; Rt: 1.00 min. m/z: 493.1 (M-H)' Exact mass: 494.2.

Compound 83: N-(3-cvano-4-fluoro-phenyl)-3-fluoro-1 -methyl-4-r2-oxo-2-rr3-(trifluoromethyl)tetrahydrofuran-3-yllamino]acetyl]pyrrole-2-carboxamide

Compound 83 was prepared similarly as described 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 crystallized upon addition of water, resulting in compound 83 (298 mg) as a white solid. LC method C; Rt: 1.94 min. m/z: 469.3 (M-H)’ Exact mass: 470.1. NMR (400 MHz, DMSO-d₆) δ ppm 2.26 - 2.42 (m, 1 H) 2.54 - 2.69 (m, 1 H) 3.69 - 3.81 (m, 1 H) 3.82 - 3.94 (m, 4 H) 4.14 (d, >10.6 Hz, 1 H) 4.27 (d, >10.6 Hz, 1 H) 7.54 (t, >9.0 Hz, 1 H) 7.92 - 8.04 (m, 2 H) 8.18 (dd, >5.7, 2.6 Hz, 1 H) 9.40 (s, 1 H) 10.37 (s, 1 H).

Compound 84: N-(3-cvano-4-fhioro-phenvl)-3-fluoro-l-methyl-4-r2-oxo-2-ITl-itrifluoromethyl)cyclobutyllamino1acetyl1pyrrole-2-cafboxamide

Compound 84 was prepared similarly as described for compound 34, using l-(trifluoromethyl)cyclobutan-l-amine instead of 2-methylpropan-2-amine. ^:H NMR (400 MHz, DMSO-de) δ ppm 1.87 - 2.02 (m, 2 H) 2.39 - 2.48 (m, 2 H) 2.52 - 2.67 (m, 2 H) 3.86 (s, 3 H) 7.54 (t, >9.1 Hz, 1 H) 7.97 (ddd, >9.2, 4.9, 2.6 Hz, 1 H) 8.04 (d, >4.4 Hz, 1 H) 8.18 (dd, >5.7, 2.6 Hz, 1 H) 9.33 (s, 1 H) 10.36 (s, 1 H). LC method B; Rt: 1.12 min. m/z: 453.1 (M-H) Exact mass: 454.1. Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: Peak: 194.7 °C.

Compound 85: N-(3-cyano-4-fluoro-phenyl~)-3-fluoro-l-methyl-4-r2-oxo-2-rr(lR)-

2,2,2-trifluoro-l-methyl-ethvl1aminolacetyllpyrrole-2-carboxamide

Compound 85 was prepared similarly as described for compound 34, using (R)-l,l,l-trifluoro-2-propylamine instead of 2-methylpropan-2-amine. LC method C; Rt: 1.95 min. m/z: 427.2 (M-H)’ Exact mass: 428.1. ^!H NMR (400 MHz, DMSO-d₆) δ ppm 1.35 (d, >7.0 Hz, 3 H) 3.86 (s, 3 H) 4.58 - 4.75 (m, 1 H) 7.54 (t, >9.1 Hz, 1 H) 7.97 (ddd, >9.2, 4.8, 2.9 Hz, 1 H) 8.04 (d, J=4.4 Hz, 1 H) 8.18 (dd, >5.7, 2.6 Hz, 1 H) 9.39 (d, J=9.0 Hz, 1 H) 10.37 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: Peak: 197.1 °C.

Compound 86 :3.5-dichloro-N-(3-cyano-4-fluoro-phenyl)-l-methyl-4-r2-oxo-2-[T(lR)-

2,2,2-trifluoro-l-methyl-ethvllamino1acetyllpyrrole-2-carboxamide ·

Compound 64 (50 mg, 0.12 mmol) was dissolved in CH3CN (1.25 mL) and DMF (0.25 mL). NCS (24.41 mg, 0.18 mmol) was added and the mixture was stirred for 5 hours at room température and next heated at 40°C ovemight. The mixture was injected on a silica gel column as such and purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0:100 to 100:0), resulting in compound 86 (26 mg). LC method B; Rt:

1.04 min. m/z: 477.0 (M-H)‘ Exact mass: 478.0.²H NMR (400 MHz, DMSO-dg) δ ppm 1.33 (d, >7.0 Hz, 3 H), 3.75 (s, 3 H), 4.70 (dq, >15.5, 7.6 Hz, 1 H), 7.57 (t, >9.1 Hz, 1 H), 7.92 - 8.01 (m, 1 H), 8.20 (dd, >5.7,2.6 Hz, 1 H), 9.50 (d, >8.8 Hz, 1 H), 10.91 (br. s., 1 H).

Compound 87: 5-chloro-N-(3-cvano-4-fluoro-phenyl)-l-methyl-4-r2-oxo-2-rr(lR)-2,2,2trifhioro-l-methyl-ethyllaminolacetvllpvrrole-2-carboxamide

To a solution of compound 64 (25 mg, 0.061 mmol) in HOAc (0.5 mL,), NCS (12.2 mg, 0.091 mmol) was added followed by trifluoromethanesulfonic acid (10 pL, 0.11 mmol). The

resulting mixture was stirred at room température for 18 hours. Then it was poured into water and extracted using CH2CI2 (3X15 mL). The combined extracts were washed with NaHCÛ3 (20 mL, aq / sat), dried on Na₂SO4, filtered and concentrated in vacuo. The obtained residue was purified by Preperative HPLC on (RP SunFire Prep Cl8 OBD-lOpm,

30x150mm). Mobile phase (0.25% NH4HCO3 solution in water, MeOH), resulting in compound 87 (3 mg). LC method B; Rt: 1.09 min. m/z: 443.0 (M-H) Exact mass: 444.1. *H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.44 (d, >6.9 Hz, 3 H), 4.02 (s, 3 H), 4.65 (dquin, >9.8, 7.0, 7.0, 7.0, 7.0 Hz, 1 H), 7.22 (t, >8.7 Hz, 1 H), 7.45 (d, >9.7 Hz, 1 H), 7.71 (ddd, >9.1, 4.5, 2.8 Hz, 1 H), 7.96 (s, 1 H), 8.06 (dd, >5.4, 2.8 Hz, 1 H), 8.11 (s, 1 H).

Compound 88: 5-chloro-N-(3-cyano-4-fluoro-phenyl)-l-methyl-4-r2-oxo-2-rr(lS)-2.2.2trifluoro-1 -methyl-ethvl] aminolacetyllpyrrole-2-carboxamide

Compound 88 was prepared similarly as described for compound 87 (stirring at room température for 6 hours instead of 18 hours), starting from compound 51 instead of compound 64. Ή NMR (400 MHz, DMSO-de) δ ppm 1.35 (d, >7.0 Hz, 3 H), 3.93 (s, 3 H), 4.62 - 4.79 (m, 1 H), 7.54 (t, >9.1 Hz, 1 H), 7.79 (s, 1 H), 8.01 (ddd, >9.2, 4.8,2.9 Hz, 1 H), 8.21 (dd, >5.7, 2.6 Hz, 1 H), 9.44 (br. s., 1 H), 10.59 (br. s., 1 H) LC method B; Rt: 1.12 min. m/z: 443.0 (M-H)' Exact mass: 444.1.

Compound 89 :5-chloro-N-(3-cyano-4-fluoro-phenyl)-3-fluoro-l-methyl-4-r2-oxo20 2-Γ Γ3 -(trifluoromethyl)tetrahydrofuran-3 -vil aminol acetyllpyrrole-2-carboxamide

Compound 83 (84 mg, 0.179 mmol) was suspended in dry acetonitrile (1.7 mL) and DMF (0.61 mL). The mixture was cooled on an ice bath and NCS (35.8 mg, 0.268 mmol) was added. The mixture was allowed to rise to room température and was then heated at 55°C for 25 16 hour. Purification was performed via Preperative HPLC (Stationary phase: RP XBridge

Prep C18 ODB- 5pm, 30x250mm, Mobile phase: 0.25% NH4HCO3 solution in water,

CH3CN), resulting in compound 89 (10 mg). LC method C; Rt: 1.88 min. m/z: 503.1

(M-H)' Exact mass: 504.1. Ή NMR (400 MHz, DMSO-d₆) δ ppm 2.28 - 2.42 (m, 1 H) 2.452.59 (m, 1 H) 3.75 - 3.84 (m, 4 H) 3.85 - 3.97 (m, 1 H) 4.10 (d, >10.3 Hz, 1 H) 4.23 (d, >10.6 Hz, 1 H) 7.55 (t, >9.1 Hz, 1 H) 7.96 (ddd, >9.2,4.8,2.9 Hz, 1 H) 8.16 (dd, >5.7, 2.9 Hz, 1 H) 9.54 (s, 1 H) 10.61 (s, 1 H).

Compound 90: 5-chloro-N-(3-cyano-4-fluoro-phenyl)-3-fluoro-l-methyl-4-r2-oxo-2rri-(trifluoromethyl)cvclobutyllamino1acetyllpvrrole-2-carboxamide

Compound 90 (29 mg) was prepared similarly as described for compound 89, starting from compound 84 instead of 83. LC method C; Rt: 2.02 min. m/z: 487.1 (M-H)' Exact mass: 488.1. Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: Peak: 174.9 °C. ^!H NMR (400 MHz, DMSO-d₆) δ ppm 1.84 - 2.08 (m, 2 H) 2.40 - 2.57 (m, 4 H) 3.81 (s, 3 H) 7.56 (s, 1 H) 7.91 - 8.00 (m, 1 H) 8.16 (dd, >5.8, 2.8 Hz, 1 H) 9.41 (s, 1 H) 10.60 (br. s, 1 H).

Compound 91 : 5-chk)ro-N-(3-cvano-4-fhioro-phenyr)-3-fluoro-l-methvl-4-r2-oxo-2-IT(TR)-

2,2.2-trifluoro-1 -methyl-ethyllaminol acetyllpyrrole-2-carboxamide

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)' Exact mass: 462.1. *H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (d, >7.0 Hz, 3 H) 3.80 (s, 3 H) 4.60 4.77 (m, 1 H) 7.55 (s, 1 H) 7.95 (ddd, >9.2, 4.8, 2.9 Hz, 1 H) 8.16 (dd, >5.8, 2.8 Hz, 1 H) 9.48 (d, >8.6 Hz, 1 H) 10.58 (br. s., 1 H).

Compound 92: 3-chloro-N-(3-cyano-4-fluoro-phenyl)-4-r2-r(2-hydroxy-l.l-dimethylethvl)amino1-2-oxo-acetyll-l-methvl-pvrrole-2-carboxamide

OH

Et₃N (0.18 mL, 1.287 mmol) was added to a solution of 2-[4-chloro-5-[(3-cyano-4-fluorophenyl)carbamoyl]-l-methyl-pyrrol-3-yl]-2-oxo-acetic acid (150 mg, 0.429 mmol), HATU (204 mg, 0.536 mmol), 2-amino-2-methyl-l-propanol (0.051 mL, 0.536 mmol) in DMF (1.1 mL) and stirred 30 minutes at room température. The solution was purifîed by silica gel column chromatography using a gradient from 0 till 50% EtOAc in heptane. The product fractions were concentrated, dissolved in THF (3 mL) and water (1 mL,). lithium hydroxide monohydrate (30 mg) was added and the mixture was stirred for 1 h at room température. The mixture was concentrated in vacuo and the residue partioned between water and CH2CI2. The organic layer was separated and concentrated in vacuo. The obtained residue was crystallized from MeOH and water. The product was filtered off and washed with water and diisopropylether. The product was dried in vacuo resulting in compound 92 (41 mg) as a white solid. ^JH NMR (400 MHz, DMSO-d₆) δ ppm 1.29 (s, 6 H) 3.45 (d, J=5.7 Hz, 2 H) 3.82 (s, 3 H) 4.99 (t, >5.8 Hz, 1 H) 7.56 (t, J=9.1 Hz, 1 H) 7.90 (s, 1 H) 7.98 (ddd, >9.2, 4.9, 2.6 Hz, 1 H) 8.21 (dd, >5.8, 2.8 Hz, 1 H) 8.26 (s, 1 H) 10.71 (s, 1 H). LC method C; Rt: 1.72 min. m/z: 419.2 (M-H)' Exact mass: 420.1.

Compound 93: N-(3-cyano-4-fluoro-phenyl)-4-r2-rrί 1 R)-2,2-difluoro-l-methylpropvllaminol-2-oxo-acetyll -3 -fluoro-1 -methyl-pyrro le-2-carboxamide

Compound 93 (130 mg) was prepared similarly as described for compound 34, using (27?)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)' Exact mass: 424.1. Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: Peak: 206.8 °C. NMR (400 MHz, DMSO-dg) δ ppm 1.23 (d, >7.0 Hz, 3 H), 1.61 (t, >19.3 Hz, 3 H), 3.86 (s, 3 H), 4.25 - 4.40 (m, 1 H), 7.54 (t, >9.1 Hz, 1 H), 7.97 (ddd, >9.1, 5.0,2.6 Hz, 1 H), 8.02 (d, J=4.2 Hz, 1 H), 8.18 (dd, >5.7,

-812.6 Hz, 1 H), 8.97 (d, J=9.2 Hz, 1 H), 10.35 (br. s., 1 H).

Compound 94: N-(3-cyano-4-fluoro-phenvl)-4-r2-r(2-hydroxv-L l-dimethvl-ethyl)aminol-2oxo-acetyl1-L5-dimethyl-pyrrole-2-carboxamide

Compound 94 (46 mg) was prepared similarly as described for compound 73, using

2-amino-2-methyl-l-propanol instead of (1-aminocyclopropyl) methanol. LC method C; Rt: 1.72 min. m/z: 399.2 (M-H)' Exact mass: 400.2. ^XH NMR (400 MHz, DMSO-dg) δ ppm 1.30 (s, 6 H) 2.56 (s, 3 H) 3.45 (d, J=5.9 Hz, 2 H) 3.84 (s, 3 H) 4.97 (t, >5.7 Hz, 1 H) 7.52 (t, >9.1 Hz, 1 H) 7.80 (s, 1 H) 7.89 (s, 1 H) 8.03 (ddd, >9.2, 5.0, 2.8 Hz, 1 H) 8.22 (dd, >5.9, 2.6 Hz, 1 H) 10.45 (s, 1 H)

Compound 95: N-f3-cyano-4-fluoro-phenyl)-3-fluoro-4-r2-rr(lR)-2-hydroxy-l-methylethyll aminol -2-oxo-acetyll -1 -methyl-pyrro le-2-carboxamide

Compound 95 (28 mg) was prepared similarly as described for compound 34, using D-alaninol instead of 2-methylpropan-2-amine. LC method C; Rt: 1.54 min. m/z: 389.2 (M-H)’ Exact mass: 390.1. Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: Peak: 191.8 °C. ^XH NMR (400 MHz, DMSO-d₆) δ ppm 1.10 (d, >6.8 Hz, 3 H) 3.32 - 3.46 (m, 2 H) 3.81 - 3.92 (m, 4 H) 4.76 (t, >5.6 Hz, 1 H) 7.54 (t, >9.1 Hz, 1 H) 7.97 (ddd, >9.1, 4.8, 2.8 Hz, 1 H) 8.12 (d, >4.4 Hz, 1 H) 8.18 (dd, >5.7, 2.6 Hz, 1 H) 8.42 (d, >8.4 Hz, 1 H) 10.34 (s, 1 H).

Compound 96: N-(3-cvano-4-fluoro-phenyl)-3-fluoro-4-r2-r(2-methoxv-Ll-dimethylethyl)amino1-2-oxo-acetYll-l-niethyl-pyrrole-2-carboxaniide

-82Compound 96 (145 mg) was prepared similarly as described for compound 34, using l-methoxy-2-methylpropan-2-amine instead of 2-methylpropan-2-amine. LC method C;

Rt: 1.98 min. m/z: 417.2 (M-H) Exact mass: 418.1. *H NMR (400 MHz, CHLOROFORMd) δ ppm 1.43 (s, 6 H) 3.38 - 3.45 (m, 5 H) 3.99 (s, 3 H) 7.18 - 7.24 (m, 1 H) 7.45 (s, 1 H)

7.66 (ddd, >9.1, 4.5, 2.8 Hz, 1 H) 7.87 - 7.97 (m, 1 H) 8.05 (dd, >5.5, 2.6 Hz, 1 H) 8.24 (d, >4.6 Hz, 1 H).

Compound 97: 5-chloro-N-(4-fluoro-3-methyl-phenyl)-1 -methyl-4-r2-oxo-2-lï( 1 S)-2.2,2trifluoro-l-methvl-ethvllaminolacetyllpyrrole-2-carboxamide

2-(5-(4-fluoro-3-methylphenylcarbamoyl)-l-methyl-lH-pyrrol-3-yl)-2-oxoacetic acid (500 mg, 1.64 mmol) was dissolved in HOAc (25 mL). Trifluoromethanesulfonic acid (218 pL) was added, followed by NCS (219 mg, 1.64 mmol) in portions. This was stirred for 4 hours at room température. The mixture was poured into water (20 mL) and then extracted using dichloromethane (3 x 25 mL). The combined extracts were washed withNaHCO₃ (2 x 25 mL / sat. / aq.), washed with brine (25 mL), dried on Na₂SO4, filtered and concentrated in vacuo. The obtained crude was purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0:100 to 100:0) yielding 2-[2-chloro-5-[(4-fluoro3-methyl-phenyl)carbamoyl]-l-methyl-pyrrol-3-yl]-2-oxo-acetic acid (109 mg) as an oil wich was used as such. A vial was charged with 2-[2-chloro-5-[(4-fluoro-3-methyl20 phenyl)carbamoyl]-1 -methyl-pyrrol-3-yl]-2-oxo-acetic acid (109.4 mg, 0.32 mmol), (S)-l,l,l-trifhioro-2-propylamine (43.8 mg, 0.39 mmol), DMF (1 mL) and DIPEA (0.17 mL), followed by addition of HATU (135 mg, 0.36 mmol). The resulting mixture was stirred for 2 hours at room température. Water (5 mL) was added and the mixture was extracted using CH₂C1₂ (2X15 mL). The mixture was purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0:100 to 100:0). The desired fractions were concentrated in vacuo and the obtained residue was dried in a vacuum oven at 55°C for 24 hours, resulting in compound 97 (17 mg). LC method B; Rt: 1.18 min. m/z: 432.1 (M-H) Exact mass: 433.1. ^JH NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (d, >7.0 Hz, 3 H), 2.23 (d, >1.8 Hz, 3 H), 3.92 (s, 3 H), 4.63 - 4.79 (m, 1 H), 7.11 (t, >9.2 Hz, 1 H), 7.48 - 7.56 (m,

1 H), 7.63 (dd, >7.0, 2.2 Hz, 1 H), 7.73 (s, 1 H), 9.42 (d, >7.9 Hz, 1 H), 10.24 (s, 1 H).

Compound 98: 4-[2-(tert-butylamino')-2-oxo-acetvl1-5-chloro-N-(3-cvano-4-fluoro-phenvl)1 -methyl-nyrro le-2-carboxamide

Compound 98 (17 mg) was prepared similarly as described for compound 87 (stirring at room température for 5 hours instead of 18 hours), starting from compound 15 instead of compound 64. The obtained crude was purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0:100 to 100:0). ^!H NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.37 (s, 9 H), 3.92 (s, 3 H), 7.53 (t, >9.1 Hz, 1 H), 7.76 (s, 1 H), 8.02 (ddd, >9.2, 4.9, 2.6 Hz, 1 H), 8.14 - 8.28 (m, 2 H), 10.48 - 10.68 (m, 1 H). LC method B; Rt: 1.15 min. m/z: 403.2 (M-H)’ Exact mass: 404.1.

Compound 99: N-(3-cyano-4-fluoro-r>henyl)-3-fluoro-4-r2-r(2-hvdroxv-Ll-dimethylethyDaminol -2-oxo-acetyll -1 -methyl-pyrro le-2-carboxamide

HO’

Ethyl 3-fluoro-4-[2-[(2-hydroxy-1,l-dimethyl-ethyl)amino]-2-oxo-acetyl]-l-methyl-pyrrole-

2- carboxylate was prepared similarly as described for ethyl 4-[2-(tert-butylamino)-2-oxoacetyl]-3-fluoro-l-methyl-pyrrole-2-carboxylate, using 2-amino-2-methyl-l-propanol instead of 2-methylpropan-2-amine and stirring 2 hours at room température instead of 30 minutes at 65°C. Compound 99 (5 mg) was prepared similarly as described for compound 34, using ethyl 3-fluoro-4-[2-[(2-hydroxy-l,l-dimethyl-ethyl)amino]-2-oxoacetyl]-l-methyl-pyrrole-2-carboxylateinstead of ethyl 4-[2-(tert-butylamino)-2-oxo-acetyl]-

3- fluoro-l-methyl-pyrrole-2-carboxylate. Compound 99 was purified by silica gel column chromatography using a gradient from 0 till 50% EtOAc in heptane and further purified via Preperative HPLC (Stationary phase: RPXBridge Prep C18 OBD-10pm,30xl50mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN). LC method B; Rt: 0.90 min. m/z: 403.2 (M-H)’Exact mass: 404.1. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39 (s, 6 H) 3.66 - 3.71 (m, 2 H) 3.72 - 3.79 (m, 1 H) 4.00 (s, 3 H) 7.17 - 7.24 (m, 1 H) 7.32 7.39 (m, 1 H) 7.61 - 7.71 (m, 1 H) 7.88 - 7.95 (m, 1 H) 8.05 (dd, >5.4, 2.8 Hz, 1 H) 8.23 (d, >4.6 Hz, 1 H)

Compound 100: 5-chloro-N43-cyano-4-fhioro-nhenvl')-l-methvl-4-r2-lï3-methvloxetan-

3-vl)amino]-2-oxo-acetvl1pyrrole-2-carboxamide

Compound 100 (12.8 mg) was prepared similarly as described for compound 87 (stirring at 5 room température for 5 hours instead of 18 hours, using DMF (4,84 mL) instead of HOAc), starting from compound 16 instead of compound 64. The obtained crude was 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) Exact mass: 418.08. Ή NMR (400 MHz, DMSO-d6) δ ppm 1.60 (s, 3 H), 3.93 (s, 3 H), 4.37 (d, >6.6 Hz, 2 H), 4.73 (d, J=6.4 Hz,

2 H), 7.53 (t, >9.1 Hz, 1 H), 7.90 (s, 1 H), 8.02 (ddd, >9.2,4.9,2.6 Hz, 1 H), 8.21 (dd, >5.7, 2.6 Hz, 1 H), 9.34 (s, 1 H), 10.58 (br. s., 1 H).

Compound 101 : N-(3-cyano-4-fluoro-phenyl)-3-fluoro-1 -methyl-4-r2-oxo-2-iï 1 -(trifluoromethyl)cyclopropyl1amino1acetyllpyrrole-2-carboxamide

Compound 101 (17 mg) was prepared similarly as described for compound 34 using 1-trifluoromethyl-l-cyclopropylamine instead of 2-methylpropan-2-amine. LC method B;

Rt: 1.05 min. m/z: 439.1 (M-H)' Exact mass: 440.09. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 - 1.20 (m, 2 H), 1.26 - 1.37 (m, 2 H), 3.85 (s, 3 H), 7.53 (t, >9.1 Hz, 1 H), 7.96 (ddd, >9.2, 4.8, 2.9 Hz, 1 H), 8.04 (d, >4.4 Hz, 1 H), 8.18 (dd, >5.8, 2.8 Hz, 1 H), 9.57 (s, 20 1 H), 10.37 (br. s., 1 H).

-85Compound 102: N-(3-cyano-4-fluoro-phenyl)-3-fluoro-4-r2-[[l-(hydroxymethyl)cyclopropvl1amino1-2-oxo-acetvll-l-methvl-pyrrole-2-carboxamide

Compound 102 (37.7 mg) was prepared similarly as described for compound 34 using

1-amino-cyclopropanemethanol instead of 2-methylpropan-2-amine. LC method B; Rt:

0.81 min. m/z: 401.2 (M-H)’Exact mass: 402.11. 1HNMR(4OO MHz, DMSO-d6) δ ppm 1.36 (s, 9 H), 2.56 (s, 3 H), 3.84 (s, 3 H), 7.52 (t, J=9.1 Hz, 1 H), 7.65 (s, 1 H), 7.98 - 8.05 (m, 1 H), 8.08 (s, 1 H), 8.22 (dd, J=5.7, 2.6 Hz, 1 H), 10.46 (s, 1 H)

Biological examples - anti-HBV activity of compounds of Formula (IA)

The anti-HBV activity was measured using a stable transfected cell line, HepG2.2.15. This cell line was described to secrete relatively consistent high levels of HBV virion particles, which hâve been shown to cause both acute and chronic infection and disease in chimpanzees.

For the antiviral, assay cells were treated twice for three days with serially diluted compound in 96-well plates in duplicate. After 6 days of treatment the antiviral activity was determined by quantification of purified HBV DNA from secreted virions using realtime PCR and an HBV spécifie primer set and probe.

The anti HBV activity was also measured using the HepG2.117 cell line, a stable, inducibly

HBV producing cell line, which replicates HBV in the absence of doxicycline (Tet-off System). For the antiviral assay, FIBV réplication was induced, foliowed by a treatment with serially diluted compound in 96-well plates in duplicate. After 3 days of treatment, the antiviral activity was determined by quantification of intracellular HBV DNA using realtime PCR and an HBV spécifie primer set and probe.

Cytotoxicity of the compounds was tested using HepG2 cells, incubated for 4 days in the presence of compounds. The viability of the cells was assessed using a Resazurin assay. Résulte are displayed in Table 1.

-86Table 1.

Co. No.	HepG 2.2.15 EC50 (μΜ)	HepG2 117 EC50 (μΜ)	HepG2 4 days CC50 (μΜ)
1	0.014	0.10	>25
2	0.029	0.75	>25
3	0.015	0.040	>25
4	0.013	0.015	>25
5	0.056	0.099	>25
6	0.047	0.19	>25
7	0.21	0.058	>25
8	0.052	0.038	>25
9	0.17	0.20	>25
10	0.072	0.042	>25
11	0.050	0.096	>25
12	0.043	0.74	>25
13	0.033	>1	>25
14	0.030	0.038	>25
15	0.027	0.043	>25
16	0.048	0.040	>25
17	0.029	0.57	>25
18	0.054	0.37	>25
19	<0.004	0.002	>100
20	<0.004	0.002	>25
21	0.009	0.011	>25
22	0.010	0.008	>25
23	0.005	0.008	>25
24	0.020	0.024	>25
25		>1	>25
26		0.070	>25
27		0.005	>25
28	<0.004	0.019	>25
29		0.014	>25
30	<0.004	0.003	>25
31	0.012	0.019	>25

Co. No.	HepG 2.2.15 EC50 (pM)	HepG2 117 EC50 (pM)	HepG2 4 days cc₅₀(pM)
32	<0.004	<0.004	>25
33		0.247	>25
34		0.009	>25
35		0.004	>25
36		<0.004	>25
37		0.002	>25
38		0.015	>25
39		0.006	>25
40		0.007	>25
41		0.003	>25
42		0.002	>25
43		0.003	>25
44		0.003	>25
45		0.006	>25
46		0.003	>25
47		<0.004	>25
48		0.022	>25
49		0.034	>25 '
50		0.004	>25
51		0.042	>25
52		0.067	>25
53		0.039	>25
54		0.010	>25
55		0.009	>25
56		0.005	>25
57		0.006	>25
58		0.006	>25
59		0.004	>25
60		0.011	>25
61		0.12	>25
62		0.23	>25

Claims

-88Claims

1. A compound of Formula (IA) or a stereoisomer or tautomeric form thereof, wherein:

Each X independently représente CR⁷;

R¹, R² and R³ are independently selected from the group consisting of Hydrogen, Fluoro, Chloro, Bromo, -CHF2, -CH2F, -CF3, -CN, Ci-Çîalkyl or C3-C4cycloalkyl;

R⁴ is Hydrogen Ci-C3alkyl or C3-C4cycloalkyl;

R⁵ is Hydrogen;

R⁶ is selected from the group consisting of Cj-Cgalkyl and a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such Ci-Côalkyl or 3-7 membered saturated ring optionally substituted with one or more substituents selected from the group consisting of Fluoro, C3-C4cycloalkyl, -OR^? oxo,-CN, -C(=O)-OR⁸, -C(=O)-N(R⁸)2 or Ci-Csalkyl optionally substituted with one or more Fluoro;

Each R⁷ independently représente hydrogen, C3-C4cycloalkyl, -CN, Fluoro, Chloro, Bromo or Ci-C3alkyl optionally substituted with one or more Fluoro;

R⁸ représente hydrogen or Ci-C3alkyl;

or a pharmaceutically acceptable sait or a solvaté thereof.
2. A compound according to claim 1, wherein R¹ is selected from hydrogen, Fluoro, Chloro, -CHF₂, -CN, -CF₃ or methyl.
3. A compound according to claim 1 or 2 wherein R⁴ is methyl.
4. A compound according to any one of the previous daims wherein R⁶ contains a 3-7 membered saturated ring optionally containing one oxygen, such 3-7 membered saturated ring optionally substituted with one or more substituents selected from Fluoro or C4-C3alkyl optionally substituted with one or more.
5. A compound according to any one of the previous daims wherein R⁶ is a 4 or 5 membered saturated ring optionally containing one oxygen, such 4 or 5 membered saturated ring optionally substituted with one or more substituents selected from Ci-C₃alkyl optionally substituted with one or more Fluoro or Fluoro.
6. A compound according to any one of daims 1 to 3, wherein R⁶ is a branched Ci-Cfîalkyl optionally substituted with one or more Fluoro.
7. A compound according to any one of the previous daims with Formula (la).
8. A compound according to any one of the previous daims with Formula (Ib).

(Ib)
9. A compound according to any one of the previous daims for use in the prévention or treatment of an HBV infection in a mammal.
10. A pharmaceutical composition comprising a compound according to any of daims 1 to 8, and a pharmaceutically acceptable carrier.
11. A product containing (a) a compound of Formula (IA) as defined in any one of daims 1 to 8, and (b) another HBV inhibitor, as a combined préparation for simultaneous, separate or sequential use in the treatment of HBV infections.