NZ715253B2 - Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b - Google Patents

Abstract

Inhibitors of HBV replication of Formula (IA), including stereochemically isomeric forms, and salts, hydrates, solvates thereof, wherein X and R1 to R6 have the meaning as defined herein. The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use, alone or in combination with other HBV inhibitors, in hepatitis B therapy. ning them and their use, alone or in combination with other HBV inhibitors, in hepatitis B therapy.

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 (Hepadnavirz’dae). 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 lly double-stranded DNA genome (the relaxed circular DNA; rcDNA) is converted to a covalently closed circular DNA (cchNA) in the nucleus of the host cell and the viral mRNAs are transcribed. Once encapsidated, the pregenomic RNA (pgRNA), which also codes for core protein and P01, serves as the template for reverse transcription, which regenerates the partially dsDNA genome (rcDNA) in the nucleocapsid.

HBV has caused epidemics 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 people have ped chronic infections. The virus causes the disease hepatitis B and chronic infection is ated with a strongly increased risk for the development cirrhosis and hepatocellular oma.

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 c rs with high titer DNA in serum.

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

In addition, heteroaryldihydropyrimidines (HAPs) were identified as a class ofHBV tors 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 Sulphamoyl- arylamides active against HBV. WO2013/096744, published on June 26, 2013 relates to compounds active against HBV.

In addition, /033170 and /033176, published on March 6, 2014 relate fithher compounds active against HBV.

W0 2015/011281 Amongst the problems which HBV direct antivirals may encounter are toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability, low solubility and ulty of synthesis.

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

Descri tion of the Invention The present invention relates to a compound of Formula (IA) R6’N O M, R1 0 /X H R3 (IA) or a stereoisomer or tautomeric form thereof, wherein: Each X ndently represents CR7; R1, R2 and R3 are independently selected from the group consisting of Hydrogen, Fluoro, Chloro, Bromo, -CHF2, -CH2F, -CF3, -CN, C1-C3alkyl or C3-C4cycloalkyl; R4 is Hydrogen C1-C3alkyl or C3-C4cycloalkyl; R5 is Hydrogen; R6 is selected from the group consisting of lkyl and a 3-7 membered ted ring optionally containing one or more atoms each independently selected from the group consisting of O, S and N, such C1-C6alkyl or 3-7 membered saturated ring optionally substituted with one or more substituents selected from the group consisting of Fluoro, C3-C4cycloalkyl, —0R8 ,oxo, -CN, -C(=O)-OR8, -C(=O)-N(R8)2 or C1-C3alkyl optionally substituted with one or more Fluoro; Each R7 independently represents hydrogen, C3-C4cycloalkyl, -CN, Fluoro, Chloro, Bromo or C1-C3alkyl optionally substituted with one or more Fluoro; R8 represents hydrogen or C1-C3alkyl; W0 2015/011281 or a ceutically acceptable salt or a solvate thereof.

The invention further s 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 medicament, preferably for use in the tion or ent 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.

Definitions The term "C1_3alkyl" as a group or part of a group refers to a hydrocarbyl radical of Formula CnH2n+1 wherein n is a number ranging from 1 to 3. In case C1_3alkyl is coupled to a further l, it refers to a Formula CnHZH, C1_3alkyl groups comprise from 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms. C1_3alkyl includes all linear, or branched alkyl groups with between 1 and 3 carbon atoms, and thus includes such as for example methyl, ethyl, n-propyl, and i-propyl.

C1_4alkyl as a group or part of a group defines ht or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as the group defined for C1_3alkyl and butyl and the like.

C1_6alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as the groups defined for kyl and , hexyl, 2-methylbutyl and the like.

As used herein, the term "3-7 ed 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 0. Examples e oxetane, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofilranyl, morpholinyl, thiolane l,l-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 s heterocycles may exist within the definitions as used throughout the specification. For example, pyrrolyl may be WO 11281 lH-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 lar moiety used in the definitions 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 l-pentyl, 2-pentyl and 3-pentyl.

Positions indicated on phenyl (e.g. ortho, meta and/or para) are ted 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 (*) ted to the main ure: When any variable (6.g. halogen or C1_3alkyl) occurs more than one time in any tuent, each definition is ndent.

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 preparation or purification of a pharmaceutically acceptable compound of Formula (IA). All salts, whether pharmaceutically acceptable or not are included within the ambit of the present ion.

The pharmaceutically acceptable or physiologically tolerable addition salt forms which the compounds of the present invention are able to form can conveniently be ed using the appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; hemisulphuric, nitric; phosphoric and the like acids; or c acids such as, for example, acetic, aspartic, dodecylsulphuric, heptanoic, hexanoic, nicotinic, propanoic, hydroxyacetic, lactic, pyruvic, , malonic, succinic, maleic, filmaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. 2014/066093 Conversely said acid addition salt forms can be converted by treatment with an riate base into the free base form.

The term " also comprises the hydrates and the t addition forms that the compounds of the present invention are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.

The present compounds may also exist in their tautomeric forms. For e, tautomeric forms of amide (-C(=O)-NH-) groups are iminoalcohols (-C(OH)=N-). Tautomeric forms, although not itly indicated in the structural formulae ented herein, are ed to be included within the scope of the present invention.

The term stereochemically isomeric forms of compounds of the present invention, as used hereinbefore, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not hangeable, which the compounds of the present invention may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically ic forms which said compound may possess.

Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of the present invention both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.

Pure stereoisomeric forms of the compounds and intermediates as ned herein are defined 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 isomeric 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 tood 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 ted from each other by the selective crystallization of their diastereomeric salts with W0 11281 optically active acids or bases. Examples thereof are ic acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphosulfonic acid. Alternatively, enantiomers may be ted by chromatographic 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 specific stereoisomer is d, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

The diastereomeric forms of Formula (IA) can be obtained separately by tional methods. Appropriate physical tion methods that may advantageously be employed are, for example, selective llization and chromatography, e. g. column chromatography.

The present invention is also intended to include all isotopes of atoms occurring on the t 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-l4.

Detailed descri tion of the invention Whenever used hereinafter, the term "compounds of formula (IA)", R6’N 0 CWX H R3 (IA) or "the t compounds" or similar term is meant to include the compounds of l formula (IA), (I), (Ia), (Ib), salts, stereoisomeric forms and racemic mixtures or any subgroups thereof.

In a first aspect, the invention provides compound of Formula (IA) R6’N 0 CWX H or a stereoisonier or tautonieric 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, C1-C3alkyl or C3-C4cycloalkyl; R4 is Hydrogen C1-C3alkyl or C3-C4cycloalkyl; R5 is Hydrogen; R6 is selected from the group ting of C1-C6alkyl and a 3-7 membered saturated ring optionally ning one or more heteroatonis each independently selected from the group consisting of O, S and N, such C1-C6alkyl or 3-7 membered ted ring optionally substituted with one or more substituents selected from the group consisting of Fluoro, ycloalkyl, —0R8 ,oxo, -CN, -C(=O)-OR8, -C(=O)-N(R8)2 or C1-C3alkyl optionally substituted with one or more Fluoro; Each R7 independently represents hydrogen, C3-C4cycloalkyl, -CN, Fluoro, Chloro, Bromo or C1-C3alkyl optionally substituted with one or more Fluoro; R8 represents hydrogen or C1-C3alkyl; or a ceutically acceptable salt or a solvate thereof.

In one aspect, the invention relates to compounds of Formula (I) or a stereoisonier or tautonieric form thereof, n: Each X ndently represents CR7; R2 is Hydrogen or Fluoro; W0 11281 R1 and R3 are independently selected from the group consisting of Hydrogen, , Chloro, Bromo, -CHF2, -CH2F, -CF3, -CN and methyl; R4 is en or methyl; R5 is Hydrogen; R6 is selected from the group consisting of C1-C6alkyl and a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently ed from the group consisting of O, S and N, such C1-C6alkyl or 3-7 ed saturated ring optionally substituted with one or more substituents selected from the group consisting of Fluoro, C1-C3alkyl, -CN, -C(=O)-OR8 or -C(=O)-N(R8)2; R7 represents hydrogen or methyl; R8 represents hydrogen or C1-C3alkyl; or a pharmaceutically acceptable salt or a solvate thereof.

In a further aspect, the invention provides compounds of a (Ia) or (1b) 1R5 Re/N / 0 R6 N 0 H R1 /\ N O H R1 /\ N "I‘ R2 R3 (181) (1b) or a stereoisomer or tautomeric form thereof, wherein: Each X independently represents 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; W0 2015/011281 R6 is selected from the group consisting of C1-C6alkyl 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 C1-C6alkyl or 3-7 ed ted ring optionally tuted with one or more substituents selected from the group ting of Fluoro, C1-C3alkyl, -CN, -C(=O)-OR8 or -C(=O)-N(R8)2; R7 represents hydrogen or methyl; R8 represents hydrogen or C1-C3alkyl; or a pharmaceutically acceptable salts or a solvate f.

In a first embodiment, compounds of Formula (IA, (I), (Ia) and (Ib) are disclosed wherein R1 is selected from either hydrogen, , , -CHF2, -CN, -CF3 or methyl. In another ment, R1 is selected from either hydrogen, Fluoro, Chloro, CHFZ, -CN, -CF3 or methyl and at least one of R1 and R3 is Fluoro or hydrogen. In yet a fiarther 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 present invention are disclosed wherein R4 is methyl.

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

In another embodiment, R6 is a branched C1-C6alkyl, optionally substituted with one or more substituents selected from the group ting of Fluoro, -CN, -C(=O)-OR8 or -C(=O)- N(R8)2. In a further embodiment, R6 is a branched C1-C6alkyl.

Another embodiment of the present 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 C1-C6alkyl optionally being substituted with one or more ; (b) R2 is Hydrogen or Fluoro. (c) R1 and R3are independently ed from the group consisting of Hydrogen, Fluoro, Chloro -CN and methyl. (d) At least one R7 is Chloro or methyl. (e) R2 is en 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 , more specifically 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 ed from C1-C3alkyl optionally tuted with one or more Fluoro or Fluoro. (g) R6 comprises a ed C3-C6alkyl optionally substituted with one or more Fluoro, or wherein R6 comprises a C3-C6cycloalkyl wherein such C3-C6cycloalkyl is substituted with one or more Fluoro or substituted with lkyl substituted with one or more Fluoro, or wherein R6 comprises a C3-C6cycloalkyl optionally substituted with one or more Fluoro and/or substituted with C1-C3alkyl optionally substituted with one or more Fluoro. (h) R4 is methyl; R6 is selected from the group consisting of lkyl 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 present invention. red compounds according to the invention are compound or a stereoisomer or tautomeric form thereof with a Formula (IA), (I), (Ia), (Ib), as represented in the synthesis of compounds section and of which the activity is displayed in Table 1.

In a further aspect, the present invention concerns a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound of Formula (IA) as specified 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 ed. A therapeutically effective amount in this context is an amount sufficient to stabilize HBV infection, to reduce HBV ion, or to eradicate HBV infection, in infected subjects. In still a fiarther aspect, this invention relates to a s of preparing a pharmaceutical ition as ied herein, which comprises intimately mixing a pharmaceutically acceptable carrier with a therapeutically or prophylactically effective amount of a compound of Formula (IA), as specified herein. ore, the compounds of the present ion or any subgroup thereofmay be formulated into various pharmaceutical forms for administration purposes. As appropriate -1 1- itions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms ing on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, ularly, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and ons; or solid carriers such as starches, , kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets.

Because of their ease in stration, tablets and capsules represent the most ageous oral dosage unit forms, in which case solid ceutical carriers are employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be ed.

Inj ectable solutions, for example, may be prepared in which the r 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 like may be employed. Also included are solid form preparations intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a ation enhancing agent and/or a le wetting agent, optionally combined with suitable ves of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.

The compounds of the t invention may also be administered via oral inhalation or ation in the form of a solution, a suspension or a dry powder using any art-known delivery system.

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

The compounds of Formula (IA) are active as inhibitors of the HBV replication cycle and can be used in the treatment and prophylaxis ofHBV 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 up thereof, are useful in the inhibition of the HBV ation cycle, in particular in the treatment of warm-blooded animals, in particular humans, infected with HBV, and for the prophylaxis of HBV ions. The present invention filrthermore 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 , 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 ed subjects or to ts susceptible to HBV infection of an amount effective to combat the ions associated with HBV ion or an amount effective to prevent HBV infection.

The present invention also relates to the use of the present compounds in the manufacture of a medicament for the treatment or the prevention ofHBV 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 riate to administer the ed 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 ingredient per unit dosage form.

The present invention also concerns combinations of a nd of Formula (IA) or any subgroup thereof, as specified herein with other anti-HBV agents. The term "combination" may relate to a t or kit ning (a) a nd of Formula (IA), as specified above, and (b) at least one other compound e of treating HBV ion (herein designated as anti-HBV agent), as a combined preparation for simultaneous, separate or sequential use in treatment of HBV infections. In an embodiment, the invention concerns combination of a compound of Formula (IA) or any subgroup thereof with at least one anti- HBV agent. In a particular embodiment, the invention concerns combination of a compound of Formula (IA) or any subgroup thereof with at least two anti-HBV agents. In a particular embodiment, the invention concerns combination of a compound of Formula (IA) or any subgroup thereof with at least three anti-HBV . In a particular embodiment, the 2014/066093 ion concerns combination of a compound of Formula (IA) or any subgroup f 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-0L (IFN-u), pegylated interferon-0L or stimulants of the innate immune system such as Toll-like receptor 7 and/or 8 agonists. One ment of the present invention relates to combinations of a compound of Formula (IA) or any subgroup thereof, as specified herein with an immunomodulating compound, more specifically a Toll-like receptor 7 and/or 8 agonist.

The combination of preViously known anti-HBV agents, such as interferon-0L (IFN—(x), lO pegylated interferon-0L, 3TC, ir or a combination thereof, and, a nd of Formula (IA) or any subgroup thereof can be used as a medicine in a combination therapy.

Generic synthesis: The substituents represented by Rl’z’3 R6or R7 in this general synthesis section are meant to include any substituent or reactive species that is suitable for transformation into any Rl’z’3 R6or R7 substituent ing to the present invention without undue burden for the person skilled in the art.

H2NQRZR1 0 RoVkCIX , (b) Xr’é H R 1 0 x\\ OH R3 N (d) N —’ \N R4 R4 0 (ER2 \ (8) (c) RXO O H N R \ 2 1 o 'T‘ Rxo 0 R2 RXO R R FX 0' ,x (b) 2 3 X WOH 0 (d) X\ \ OH R3 N N e (h) m o a O OH HO O (a) (e) )\( H R O 1 X: N 2 0 R2 R5’N H R R5 R O 1 X: MN \n/ 6 fi‘ 0 R2 (9) (I) R3 ‘ Scheme 1 H2N \:\ O \ ,7R2 RXO x \R H R1 x’\0H(bA) 3 F N‘xR 0(d) \N \N)\‘( \< 2 R4 0 R4 R3 \ (CA) mo 0 H 1 0 , x R1 N X\N\ R2 \ \ 0 RXO 0 H2" \ ;/R2 F'a o RxofikCI W 4 R \ 3 XTHOHx O , x (m) 0 (d) X\ ‘ 0" (bA) R3 N N O (h) I'R4 o m o OH "O O (a) (e) OWX H R1 R4 0NQRZ (iA) RB’N O O X H R1 R5\ /R6 x ‘ N ‘LR H 'N \,/2 2 (g) y; o \ 4 R3 ‘ (IA) Scheme 1A The synthesis of compounds of general Formula (I) can be performed as outlined in Scheme 1. Each RX ndently represents lower alkyl, preferably C1-C3alkyl and even more preferred methyl or ethyl. A carboxylic acid of general formula (a) can be coupled with an e 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 ing compound of general formula (c) can be reacted with an oxalyl chloride monoalkyl ester of general formula (d) in the ce of a Lewis acid like for example AlC13 to provide a compound of l formula (f). Alternatively, compounds of general a (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 AlC13 to e a compound of 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 nd 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 (1). Alternatively, compounds of general formula (I) can be obtained from a compound of general formula (f) in a two-step ures that involves hydrolysis of the ester moiety of a compound of general formula (f) with an inorganic base of general formula W0 2015/011281 (h) like for example NaOH, followed by coupling of the resulting keto-acid of general formula (i) with an amine of general formula (g) using a peptide coupling reagent like for e HATU in the presence of a organic amine base such as TEA or DIPEA. rly 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 1A.

RXO 0 HO O //_X RXOWHCJ: CI 9 ORx \ OWX 0 ORX OH OWX X (d) X/ \ X/ \ ORX N ' O N NH R4 R4 O 0 (J) (k) (m) \ R5~N.R6H (g) 0 0 R5 0‘ x H OR o X N\ 0 (d) W X/N\ ORX (9) O X/ )\( ORX é O I O N 4 R4 R4 0 (J) (o) (n) Scheme 2A The synthesis of compounds of general formula (I) can also be performed as outlined in Scheme 2. Each RX ndently represents lower alkyl, preferably C1-C3alkyl and even more preferred methyl or ethyl. A carboxylic ester of general formula (j) can be reacted with an oxalyl chloride monoalkyl ester of general formula (d) in the presence of a Lewis acid like for example AlC13 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-keto- acid of general formula (m). Compounds of l formula (11) can be obtained by coupling of (m) with an amine of general formula (g) using a peptide coupling reagent like for e HATU in the presence of a organic amine base such as TEA or DIPEA.

Alternatively, compounds of general formula (11) 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 (0) with an amine of general formula (g). A compound of general formula (11) can be hydrolysed with an inorganic base of general a (h) like for example NaOH. The resulting carboxylic acid of general a (p) can be coupled with an aniline of general formula (b) using a peptide coupling t 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 nd of l formula (p) and aniline (b) shown in Scheme 2, the synthesis of compounds of general formula IA can be performed from e (bA) and a compound of l formula (p) as described in Scheme Alternatively, intermediates of the general formula (cA) and compounds of the general formula (IA) can be synthesized as depicted in scheme 3A. In this case a compound of l formula (j ) or (n) is reacted with an aniline of general formula (bA) under ce of a base like lithium bis(trimethylsilyl)amide (LiHMDS), ing in compound of l formula (cA) and (IA) respectively.

H2N ‘q/ \ R2 \/< H R1 //_X F\X \‘ OR" (bA) Rs N X\ \ \ LRZ XN N | LIHMDS- 0 <2 R4 R4 R3 (J) (CA) Scheme 3A General rocedure LCMS methods The High Performance Liquid Chromatography (HPLC) ement was med using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional ors were included (see table of methods below).

Flow from the column was brought to the Mass Spectrometer (MS) which was red 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 nd’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software.

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

Hereinafter, "SQD" means Single Quadrupole Detector, "MSD" Mass Selective Detector, "RT" room temperature, "BEH" d ethylsiloxane/silica hybrid, "DAD" Diode Array Detector, "HSS" High Strength silica., "Q-Tof’ Quadrupole f—flight mass spectrometers, "CLND", ChemiLurninescent Nitrogen Detector, "ELSD" Evaporative Light Scanning Detector.

LCMS Methods W0 2015/011281 (Flow expressed in ; column temperature (T) in CC; Run time in minutes).

Instrument Column Mobile phase Gradient A: 10mM From 100% A Waters: CH3COONH4 to 5% A in Acquity® in 95% H2O + 2.10min, to 0% UPLC® — % CH3CN A in 0.90min, DAD and to 5% A in B2 CH3CN 0.5min A: 10mM Waters: CH3COONH4 From 95% A Acquity® in 95% H2O + to 5% A in 1.3 UPLC® - % CH3CN min, held for DAD and 0.7 min.

Bi CH3CN A: 10mM From 100% A Waters: Acquity® CH3COONH4 to 5% A in in 95% H2O + 2.10min, to 0% UPLC® — % CH3CN A in 0.90min, DAD and to 5% A in Bi CH3CN 0.5min From 100% A A: 25mM to 1% A, 49% CH3COONH4 B and 50% C Waters: in 95% H20 + in 6.5 min, to Alliance®- 5% CH3CN 1% A and 99% B2 CH3CN DAD — C: CH3OH B in 0.5 min,to ZQ and D: (40% 100% D in 1 ELSD CH3CN and min held for 2000 40% CH3OH and 20% H20 1.0 min to Alltech with 0.25% 100% A in 0.5 CH3COOH min and held for 1.5min.

Sflthesis of examples Com ound 1: R 2- sec-but lamino oxoacet l -N— 4-fiuorometh l hen l -l- meth l-lH— rrolecarboxamide HzN/CEF AOHCI \40 0 /\ OH 0 /\ "g 'T‘ N F o flfigNHUF AICI3 HATU DIPEA | o DCM OC 3h DMF, rt 16h ’\.’NH O NH2 H ° 0 / \ N N F EtOH, rt 7days | O l-Methyl-lH—pyrrolecarboxylic acid (2.0 g, 16 mmol), 4-fluoromethylaniline (2.0 g, 16 mmol) and N,N—diisopropylethylamine (DIPEA, 6.2 g, 48 mmol) were dissolved in 30 mL DMF and cooled on ice under N2. 2-(7-Aza-lH—benzotriazole-l-yl)-l l ,3,3-tetramethyl- uronium hexafiuorophosphate (HATU, 6.69 g, 17.6 mmol) was added, the ice bath was removed and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with 200 mL EtOAc and washed with lN HCl, NaHC03 solution and brine. The organic layer was dried over Na2SO4, filtered, and trated under reduced pressure. The residue was crystallized from a e of 30 mL MeOH and 15 mL water. The crystals were filtered off and dried in vacuum to provide N—(4-fiuoromethylphenyl)-l -methyl-lH- pyrrolecarboxamide (3.22 g) as gray needles, mp = lll.3°C. LC method B; Rt: 0.99 min. m/z : 233.2 (M+H)+ Exact mass: 2321. 1H NMR (400 MHz, DMSO-d6) 8 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.l Hz, 1 H), 7.44 - 7.54 (m, l H), 7.62 (dd, J=7.3, 2.4 Hz, 1 H), 9.69 (s, l H).

N—(4-Fluoromethylphenyl)-l-methyl-lH—pyrrolecarboxamide (2.0 g, 8.6 mmol) was dissolved in 30 mL romethane 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. Aluminium(III) 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 ted with EtOAc (2x).

The combined organic layers were washed with NaHC03 solution and brine, dried over Na2SO4, d, and concentrated under reduced pressure. The residue was crystallized fiom 40 ml EtOH, the ls were d off and dried in vacuum to provide ethyl 2-(5 -(4-fluoro-3 -methylphenylcarbamoyl)methyl-1H-pyrrol-3 -yl)oxoacetate (1 .29 g) as a white solid, mp = C. LC method B; Rt: 1.04 min. m/z : 333.1 (M+H)+ Exact mass: 332.1. 1H NMR (400 MHZ, DMSO-d6) 8 ppm 1.33 (t, J=7.2 Hz, 3 H), 2.23 (d, J=1.8 Hz, 3 H), 3.95 (s, 3 H), 4.35 (q, J=7.0 Hz, 2 H), 7.10 (t, J=9.2 Hz, 1 H), 7.48 - 7.55 (m, 1 H), 7.58 (d, J=1.8 Hz, 1 H), 7.65 (dd, J=7.0, 2.4 Hz, 1 H), 8.01 (d, J=1.5 Hz, 1 H), 10.07 (s, 1 H).

Ethyl 2-(5 -(4-fluoromethylphenylcarbamoyl)-1 l- 1H-pyrrol-3 -yl)oxoacetate (300 mg, 0.9 mmol) and (R)-(-)aminobutane (196 mg, 2.7 mmol) were mixed in 5 ml EtOH and stirred at room temperature in a closed vessel for 7 days. The on mixture was concentrated under reduced pressure and then purified by preparative HPLC (stationary phase: RP Vydac Denali C18 - 10 um, 200 g, 5 cm), mobile phase: 0.25% NH4HC03 solution in water, CH3CN). The product fractions were concentrated, ved in MeOH and trated again yielding (R)(2-(sec-butylamino)—2-oxoacetyl)-N-(4-fluoro methylphenyl)methyl-1H—pyrrolecarboxamide (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. 1H NMR (400 MHz, DMSO-d6) 8 ppm 0.84 (t, J=7.4 Hz, 3 H), 1.12 (d, J=6.6 Hz, 3 H), 1.39 - 1.61 (m, 2 H), 2.23 (d, J=1.5 Hz, 3 H), 3.72 - 3.88 (m, 1 H), 3.95 (s, 3 H), 7.09 (t, J=9.2 Hz, 1 H), 7.47 - 7.58 (m, 1 H), 7.64 (d, J=1.8 Hz, 1 H), 7.66 (dd, J=7.2, 2.5 Hz, 1 H), 8.13 (s, 1 H), 8.38 - 8.53 (m, 1 H), 10.04 (s, 1 H).

Com ound 2: N— 4-fluorometh l hen l 2- iso ro lamino oxoacet th l- 1H—pmolecarboxamide Omflfi >7NH2 T F o OWHflN F EtOH, rt 16h 2 | O Compound 2 was prepared similarly as Compound 1 by reaction of ethyl 2-(5-(4-fluoro methylphenylcarbamoyl)methyl- 1H-pyrrolyl)oxoacetate with 10 lents of isopropylamine by overnight stirring at room temperature in EtOH in a closed vessel. The reaction mixture was concentrated under reduced pressure and then purified by preparative HPLC (stationary phase: RP Vydac Denali C18 - 10 um, 200 g, 5 cm), mobile phase: 0.25% NH4HC03 solution in water, CH3CN). The product fractions were concentrated, dissolved in MeOH and concentrated again yielding N—(4-fluoromethylphenyl)(2-(isopropyl- amino)oxoacetyl)methyl-1H—pyrrolecarboxamide (Compound 2, 229 mg), as a foam. LC method A; Rt: 1.84 min. m/z : 344.1 (M-H)‘ Exact mass: 345.2. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.15 (d, J=6.6 Hz, 6 H), 2.23 (d, J=1.8 Hz, 3 H), 3.95 (s, 3 H), 3.96 — 4.07 (m, 1 H), 7.09 (t, J=9.2 Hz, 1 H), 7.49 — 7.57 (m, 1 H), 7.63 (d, J=1.8 Hz, 1 H), 7.66 (dd, J=7.2, 2.5 Hz, 1 H), 8.14 (d, J=1.5 Hz, 1 H), 8.52 (d, J=8.1 Hz, 1 H), 10.04 (s, 1 H).

Com ound 3: 4- 2- tert—but lamino oxoacet l-N- 4-fluorometh l hen lmeth l- 1H—pmolecarboxamide \,o o 1)NaOH HO 0 > NH2 %NH O OWNS EtOH rt5min H ' OWNSH OWNfiH N 2) HCI N HATU, DIPEA N F F F I O I O I O DMF,rt5h 3 Ethyl 2-(5 -(4-fiuoromethylphenylcarbamoyl)-1 l- 1H-pyrrol-3 -yl)oxoacetate (980 mg, 2.9 mmol) was dissolved in 20 ml EtOH. A 1N aqueous solution ofNaOH (8.8 mL, 8.8 mmol) was added drop wise. The reaction mixture was stirred for 5 min at room temperature and was then cooled on ice. 1N 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 al was filtered off, rinsed with water,and dried in vacuum to provide 2-(5-(4-fiuoromethylphenylcarbamoyl)methyl- 1H-pyrrol-3 -yl)oxoacetic acid (530 mg) as white crystals, mp = 180.8°C. LC method B; Rt: 0.61 min. m/z : 303.1 (M-H)‘ Exact mass: 304.1. 1H NMR (400 MHz, DMSO-d6) 5 ppm 2.23 (d, J=1.8 Hz, 3 H), 3.95 (s, 3 H), 7.09 (t, J=9.2 Hz, 1 H), 7.49 - 7.55 (m, 1 H), 7.57 (d, J=1.8 Hz, 1 H), 7.65 (dd, J=7.0, 2.4 Hz, 1 H), 7.97 (d, J=1.5 Hz, 1 H), 10.06 (s, 1 H), 14.05 (br. s., 1 H). 2-(5 -(4-Fluoromethylphenylcarbamoyl)methyl- 1H-pyrrol-3 -yl)oxoacetic acid (530 mg, 1.74 mmol) ), utylamine (127 mg, 1.74 mmol), and N,N—diisopropylethylamine (DIPEA, 675 mg, 5.2 mmol) were dissolved in 10 mL DMF and cooled on ice under N2. 2-(7-Aza-1H—benzotriazole-l-yl)-1,1,3,3-tetramethyluronium hexafiuoro- phosphate (HATU, 728 mg, 1.92 mmol) was added, the ice bath was removed and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with 1N HCl, NaHC03 solution, and brine. The organic layer was dried over , d 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 tert—butylamino)oxoacetyl)-N-(4-fluoromethyl- phenyl)methyl-1H—pyrrolecarboxamide (Compound 3, 517 mg) as a white .

LC method B; Rt: 1.12 min. m/z : 358.2 (M-H)‘ Exact mass: 359.2. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.36 (s, 9 H), 2.23 (d, J=1.8 Hz, 3 H), 3.95 (s, 3 H), 7.09 (t, J=9.2 Hz, 1 H), 7.50 — 7.56 (m, 1 H), 7.61 (d, J=1.8 Hz, 1 H), 7.66 (dd, J=7.0, 2.2 Hz, 1 H), 7.95 (s, 1 H), 8.10 (d, J=1.5 Hz, 1 H), 10.05 (s, 1 H).

Com ound 4: N— 4-fluorometh l hen lmeth l 2- 3-meth loxetan lamino oxoacet l-1H— rrolecarboxamide mHg O - HCI O H /\ Nfi [In HATU,D|PEA N F F 0 | o DMF, rt 5h 4 2-(5 uoromethylphenylcarbamoyl)methyl- 1H-pyrrol-3 -yl)oxoacetic acid (410 mg, 1.35 mmol), 3-methyloxetanamine hydrochloride (183 mg, 1.48 mmol),and N,N—diisopropylethylamine (DIPEA, 870 mg, 6.74 mmol) were dissolved in 10 mL ofDMF and cooled on ice under N2. 2-(7-Aza-1H—benzotriazole-l-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 563 mg, 1.48 mmol) was added, the ice bath was d and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with 100 mL EtOAc and washed with 1N HCl, NaHC03 solution, and brine. The organic layer was evaporated under reduced pressure. The residue was purified by Preparative HPLC (stationary phase: Uptisphere C18 ODB - 10um, 200g, 5cm), mobile phase: 0.25% NH4HC03 on in water, MeOH). The product fractions were concentrated, dissolved in MeOH, and concentrated again. The residue was llized from a mixture of 10 mL MeOH and 5 mL water. The crystals were filtered off and dried in vacuum to provide N—(4-fluoromethylphenyl)methyl(2-(3-methyloxetanyl- amino)oxoacetyl)-1H—pyrrolecarboxamide (Compound 4, 183 mg) as a white powder, mp = 145.1°C. LC method A; Rt: 1.63 min. m/z : 372.0 (M-H)‘ Exact mass: 373.1. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.58 (s, 3 H), 2.23 (d, J=1.8 Hz, 3 H), 3.95 (s, 3 H), 4.35 (d, J=6.8 Hz, 2 H), 4.72 (d, J=6.4 Hz, 2 H), 7.09 (t, J=9.2 Hz, 1 H), 7.48 - 7.58 (m, 1 H), 7.65 (d, J=1.8 Hz, 1 H), 7.67 (d, J=2.4 Hz, 1 H), 8.17 (d, J=1.3 Hz, 1 H), 9.26 (s, 1 H), 10.05 (s, 1 H).

Com ound 5: R -N— 4-fluorometh l hen lmeth l 2-oxo 1 1 uoro ro an- 2- lamino acet l-1H— rrolecarboxamide F>l\/NH2 /O >HATU DIPEA \ONflF DMF rt 6h 2-(5 -(4-Fluoromethylphenylcarbamoyl)methyl- 1H-pyrrol-3 -yl)oxoacetic acid (300 mg, 0.95 mmol), (R)-1,1,1-trifluoropropylamine (118 mg, 1.04 mmol), and N,N—diisopropylethylamine , 367 mg, 2.84 mmol) were dissolved in 5 mL DMF under N2. 2-(7-Aza-1H—benzotriazole-l-yl)-1,1,3,3-tetramethyluronium hexafluoro- phosphate (HATU, 396 mg, 1.04 mmol) was added and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with 100 mL EtOAc and washed with 1N HCl, NaHC03 solution and brine. The organic layer was ated under reduced pressure. The residue was llized from a mixture of 10 mL MeOH and 5 mL water. The crystals were filtered off and dried in vacuum to provide (R)-N-(4-fluoromethylphenyl) methyl(2-oxo(1 ,1 , 1 -trifluoropropanylamino)acetyl)- 1H-pyrrolecarboxamide (Compound 5, 182 mg) as a white powder, mp =156.9°C. LC method B; Rt: 1.10 min. m/z : 398.2 (M-H)‘ Exact mass: 399.1. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.35 (d, J=7.0 Hz, 3 H), 2.23 (d, J=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, J=1.3 Hz, 1 H), 9.32 (d, J=9.0 Hz, 1 H), .07 (s, 1 H).

Com ound 6: -N— 4-fluorometh l hen lmeth l 2-oxo tetrah drofuran lamino acet 1 -1H— olecarboxamide (jflNHZ.HCI QMNH O o O /\ N HATU DIPEA N F | o DMF rt 3h 6 2-(5 -(4-Fluoromethylphenylcarbamoyl)methyl- 1H-pyrrol-3 -yl)oxoacetic acid (300 mg, 0.95 mmol), (S)-tetrahydrofuranamine hydrochloride (128 mg, 1.04 mmol) and N,N—diisopropylethylamine (DIPEA, 611 mg, 4.73 mmol) were dissolved in 5 mL ofDMF under N2. 2-(7-Aza-1H—benzotriazole-l-yl)-1,1,3,3-tetramethyluronium hexafluoro- phosphate (HATU, 396 mg, 1.04 mmol) was added and the mixture was stirred at room WO 11281 temperature for 3 hours. The reaction mixture was diluted with 100 mL EtOAc and washed with 1N HCl, NaHC03 solution, and brine. The organic layer was evaporated under reduced pressure. The residue was llized from a mixture of 10 mL MeOH and 5 mL water. The crystals were filtered off and dried in vacuum to provide (S)-N—(4-fluoromethylphenyl) methyl(2-oxo(tetrahydrofuranylamino)acetyl)- 1H-pyrrolecarboxamide (Compound 6, 248 mg) as a white powder, mp =155.7°C. LC method B; Rt: 0.90 min. m/z : 372.2 (M-H)" Exact mass: 373.1. 1H NMR (400 MHZ, DMSO-d6) 8 ppm 1.86 - 1.99 (m, 1H), 2.07 - 2.18 (m, 1 H), 2.23 (d, J=1.8 Hz, 3 H), 3.57 (dd, J=8.9, 4.5 Hz, 1 H), 3.71 (td, J=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, J=9.2 Hz, 1 H), 7.49 - 7.56 (m, 1 H), 7.62 (d, J=1.8 Hz, 1 H), 7.66 (dd, J=7.2, 2.3 Hz, 1 H), 8.11 (d, J=1.3 Hz, 1 H), 8.88 (d, J=6.8 Hz, 1 H), 10.05 (s, 1 H).

Com ound 7: meth l2- 2- 5- 4-fluorometh l hen lcarbamo lmeth l-1H— ol l oxoacetamido meth l ro anoate HEW/N O .HCI 0 n N HATU DIPEA N F DMF rt 16h 7 2-(5 -(4-Fluoromethylphenylcarbamoyl)methyl- rol-3 -yl)oxoacetic acid (800 mg, 2.58 mmol), 2,2-dimethylglycine methylester hydrochloride (435 mg, 2.83 mmol) and N,N—diisopropylethylamine (DIPEA, 1.67 mg, 12.9 mmol) were dissolved in 15 mL of DMF and cooled on ice under N2. 2-(7-Aza-1H—benzotriazoleyl)—1,1,3,3-tetramethyl- uronium hexafluorophosphate (HATU, 1078 mg, 2.83 mmol) was added, the ice bath was removed and the mixture was stirred overnight at room temperature. The reaction mixture was d with 150 mL EtOAc and washed with 1N HCl, NaHC03 on, 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 ls were filtered off and dried in vacuum to provide methyl 2-(2-(5-(4-fluoromethylphenylcarbamoyl)methyl-1H- pyrrolyl)oxoacetamido)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. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.46 (s, 6 H), 2.23 (d, J=1.8 Hz, 3 H), 3.64 (s, 3 H), 3.95 (s, 3 H), 7.09 (t, J=9.2 Hz, 1 H), 7.49 - 7.57 (m, 1 H), 7.62 (d, J=1.8 Hz, 1 H), 7.66 (dd, J=7.2, 2.3 Hz, 1 H), 8.07 (d, J=1.3 Hz, 1 H), 8.93 (s, 1 H), 10.07 (s, 1 H).

Com ound 8: 4- 2-Amino-1 1-dimeth loxoeth lamino oxo acet l -N- 4-fluoro meth l hen lmeth l-1H- rrolecarboxamide HZNJ$ Differential scanning calorimetry: From 30 to 300 CC at 10°C/min: Peak: 237.0 °C. 1H NMR (400 MHz, 6) 5 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).

Com ound 9: 4- 1R C anometh leth 1 amino oxo acet l -N- 4-fluorometh l- hen lmeth l-1H- rrolecarboxamide FflWH O I JTV\\\R N N o Compound 9 (430 mg) was prepared similarly as described for compound 5 using (3R)aminobutanenitrile d of (R)-1,1,1-trifluoropropylamine. LC method B; Rt: 0.95 min. m/z: 369.1 (M-H)" Exact mass: 370.1. 1H NMR (400 MHZ, DMSO-d6) 8 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 0C at °C/min: Peak: 138.3 °C.

Com ound 10: 4- 2- tert—but lamino oxoacet l -N— 3 oro hen l meth l-1H— olecarboxamide o F "0&0 \’o O a \,O o H2N F o o I O AICI3 N HATU, TEA I O F DMF rt2h [l] O DCM,0°C2h , emomng éiNHZ #NH O NaOH H F O / \ Mg EtOH, 60°C 10 mln. HATU: TEA [Tl F 1° O DMF,rt3h 1-Methyl-1H—pyrrolecarboxylic acid (2.0 g, 16 mmol) was dissolved in 50 mL dichloromethane and cooled on ice under N2. A solution of ethyl oxoacetate (5.45 g, 40 mmol) in 10 ml dichloromethane was added drop wise and the mixture was stirred for 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 usly stirred ice water causing precipitation of a white solid. The precipitate was filtered off and rinsed with water, panol, and diisopropyl ether, and dried in vacuum to afford 4-(2-ethoxyoxoacetyl)methyl-1H—pyrrolecarboxylic acid (1 .44g) as a white powder. LC method B; Rt: 0.38 min. m/z : 224.0 (M-H)‘ Exact mass: 225.1. 1H NMR (400 MHz, DMSO-ds) 8 ppm 1.31 (t, J=7.0 Hz, 3 H), 3.92 (s, 3 H), 4.33 (q, J=7.1 Hz, 2 H), 7.25 (d, J=1.5 Hz, 1 H), 8.01 (s, 1 H), 12.86 (br. s., 1 H).

To a solution of thoxyoxoacetyl)methyl-1H—pyrrolecarboxylic acid (750 mg, 3.30 mmol) and triethylamine (917 uL, 6.59 mmol) in DMF (7.5 mL), 2-(7-aza-1H— benzotriazole-l-yl)-1,1,3,3-tetramethyluronium hexafiuorophosphate (HATU, 1504 mg, 3.96 mmol) was added and the mixture was stirred at room temperature for 10 min. 3,4-Difiuoroaniline (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-difiuorophenyl- carbamoyl)methyl-1H—pyrrolyl)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 on of ethyl 2-(5 difiuorophenylcarbamoyl)methyl-1H-pyrrolyl) oxoacetate (937 mg, 2.79 mmol) in 30 ml EtOH was treated with 1N NaOH solution (8.36 mL, 8.36 mmol) and the reaction mixture was heated to 60°C for 10 min. The reaction W0 2015/011281 mixture was cooled to room temperature and neutralized by the addition of triethylamine hydrochloride (1.53 g, 11.14 mmol). The mixture was evaporated under d pressure and the dry residue was co-evaporated twice with e (50 mL) to remove remaining traces of water. The crude reaction product 2-(5-(3,4-difluorophenylcarbamoyl)methyl- 1H—pyrrolyl)—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)- 1-methyl-1H—pyrrolyl)oxoacetic acid (roughly 1.4 mmol) in 10 mL of DMF was mixed with triethylamine (582 uL, 4.2 mmol) and 2-(7-aza-1H—benzotriazole-l-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate (HATU, 637 mg, 1.67 mmol) and stirred for min at room temperature. tert—Butylamine (204 mg, 2.79 mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured out into 100 mL water and the precipitate was d off and washed with water. The powder was purified by tography over silica gel using a solvent gradient from 0% to 100% EtOAc in heptane as the mobile phase, to afford tert—butylamino)oxoacetyl)-N- (3,4-difluorophenyl)methyl-1H—pyrrolecarboxamide (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. 1H NMR (400 MHz, DMSO-d6) 8 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).

Com ound 11: N— 3 4-difluoro hen l meth l 2- 3-meth loxetan lamino oxoacet l-1H— rrolecarboxamide HO O /§>NH2 NH O /\ N\©\ 0 /\ Ha I?! F HATU,TEA N o F DMF, rt 3h A solution of crude 3,4-difluorophenylcarbamoyl)methyl-1H-pyrrolyl)—2- oxoacetic 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 uL, 5.58 mmol) and 2-(7-aza-1H—benzotriazoleyl)- 1 , 1 ,3 ,3 -tetramethyluronium hexafluorophosphate (HATU, 637 mg, 1.67 mmol) and stirred for 10 min at room temperature. 3-Methyloxetanamine (243 mg, 2.79 mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured out into 100 mL water and the precipitate was WO 11281 filtered off and washed with water. The solid residue was re-crystallized from a mixture of mL MeOH and 5 mL water, filtered off and dried in vacuum to afford N—(3,4-difiuoro- phenyl)methyl(2-(3 -methyloxetanylamino)oxoacetyl)- 1H-pyrrolecarboxamide (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. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.58 (s, 3 H), 3.96 (s, 3 H), 4.35 (d, J=6.6 Hz, 2 H), 4.72 (d, J=6.4 Hz, 2 H), 7.36 - 7.45 (m, 1 H), 7.48 - 7.56 (m, 1 H), 7.68 (d, J=1.5 Hz, 1 H), 7.89 (ddd, J=13.4, 7.5, 2.4 Hz, 1 H), 8.20 (br. d, J=1.1 Hz, 1 H), 9.27 (br. s, 1 H), 10.26 (br. s, 1 H).

Com ound 12: 4- 2- tert—but lamino oxoacet l meth l-N— 3- trifiuorometh l hen l - 1H— olecarboxamide \’0 0 O \40 0 HO O HZN CF3 NaOH H CF3 N HATU, TEA N EtOH, 60°C 10 min.

| I O DMF, rt 2h 1 O —’ 0 / \ N0 3 HATU, TEA N | O DMF, rt 3h 4-(2-Ethoxyoxoacetyl)methyl-1H—pyrrolecarboxylic acid (750 mg, 3.30 mmol) and triethylamine (917 uL, 6.59 mmol) were mixed in 7.5 mL of DMF. 2-(7-Aza-1H—benzotriazole-l-yl )-1,1,3,3-tetramethyluronium hexafiuorophosphate (HATU, 1504 mg, 3.96 mmol) was added and the mixture was stirred for 10 min. 3-Trifiuoromethylaniline (1062 mg, 6.59 mmol) was added and the mixture was d for 2 hours at room temperature and was subsequently heated to 40°C for 30 min. The mixture was poured out into 100 mL water and the itate was filtered off and washed with water. The powder was dried in vacuum to provide ethyl 2-(1-methyl(3-(trifiuoromethyl)phenylcarbamoyl)- 1H—pyrrolyl)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-(1-methyl(3-(trifiuoromethyl)phenylcarbamoyl)-1H—pyrrolyl) oxoacetate (650 mg, 1.76 mmol) in 30 ml EtOH was treated with 1N NaOH solution (5.3 mL, 5.3 mmol) and the reaction mixture was stirred at room temperature for 20 min.

The reaction mixture was neutralized by the addition of triethylamine hydrochloride (1.22 g, 8.82 mmol). The e was evaporated under reduced pressure and the dry e was co-evaporated twice with 50 ml toluene to remove remaining traces of water. The crude reaction product 2-(1 -methyl(3-(trifiuoromethyl)phenylcarbamoyl)- 1H-pyrrol-3 -yl) 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 on of crude 2-(1-methyl(3 -(trifluoromethyl)- phenylcarbamoyl)-1H—pyrrolyl)oxoacetic acid (roughly 0.88 mmol) in 5 mL of DMF was mixed with triethylamine (490 uL, 3.53 mmol) and 2-(7-aza-1H—benzotriazoleyl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 1006 mg, 2.64 mmol) and stirred for 10 min at room temperature. tert—Butylamine (193 mg, 2.65 mmol) was added and the mixture was stirred at room ature 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 d by chromatography over silica gel using a solvent gradient from 0% to 100% EtOAc in heptane as the mobile phase, to afford tert—butylamino)oxoacetyl)-1 - methyl-N-(3 -(trifluoromethyl)phenyl)-1H—pyrrolecarboxamide (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. 1H NMR (360 MHz, DMSO-d6) 5 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=1.1 Hz, 1 H), 8.21 - 8.26 (m, 1 H), 10.39 (s, 1 H).

Com ound 13: 1-meth l 2- 3-meth loxetan lamino acet l -N— 3- trifiuoro- meth l hen l-1H— rrolecarboxamide HO O NH O O/fi~NH2 o 0 H CF3 \ 0%" CF / 3 N HATU,TEA N | o 13 | o DMF, rt 3h A solution of crude 2-(1-methyl(3-(trifluoromethyl)phenylcarbamoyl)-1H—pyrrolyl) oxoacetic acid (roughly 0.88 mmol; as described in the procedure for the synthesis of nd 12) in 5 mL of DMF was mixed with triethylamine (490 uL, 2.65 mmol) and 2-(7-aza-1H—benzotriazoleyl)- 1 , 1 ,3 ,3 -tetramethyluronium hexafluorophosphate (HATU, 1005 mg, 2.65 mmol) and stirred for 10 min at room ature. 3-Methyloxetanamine (230 mg, 2.65 mmol) was added and the mixture was stirred at room temperature 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 1 -methyl(2-(3-methyloxetanylamino)oxoacetyl)-N-(3-(trifluoromethyl)phenyl)- 1H- pyrrolecarboxamide (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. 1H NMR (400 MHZ, DMSO-d6) 8 ppm 1.58 (s, 3 H), 3.97 (s, 3 H), 4.35 (d, J=6.6 Hz, 2 H), 4.72 (d, J=6.4 Hz, 2 H), 7.43 (d, J=7.7 Hz, 1 H), 7.58 (br. t, J=7.9, 7.9 Hz, 1 H), 7.74 (d, J=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).

Com ound 14: 4- 2- tert—but lamino oxoacet l -N— 3-chloro-4 5-difluoro hen l meth l-1H— rrolecarboxamide CINCI 0 CI 0 0 /\ >‘,NH2 \ o #NH >4 N M\O\ o W o\ < /\o\) I O CICHZCHZCI [\ll DIPEA 0 0%/N\ 38002,] | o NaOH MeOH, rt 16h i O QF NH )NH 0 H CI 0 H2N CI /N\ QFN | O HATU, DIPEA O)’§/—\)\‘(OH 14 F I‘ll 0 DMF, 50°C 2 days Oxalylchloride (2 mL, 23.3 mmol) was added slowly to a stirred solution of methyl 1-methyl-1H—pyrrolecarboxylate (2 g, 14.4 mmol) in 10 ml dichloroethane at room temperature. 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 tert—butylamine (3.05 mL, 28.7 mmol), and DIPEA (4.95 mL, 28.7 mmol) in 25 mL of itrile. After overnight stirring, the volatiles were removed by evaporation 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 porated with MeOH under d pressure: 1) Elution with a mixture of e : DCM in a ratio of 60:40 provided methyl tert—butylamino)oxoacetyl)methyl-1H—pyrrolecarboxylate (820 mg) as the first fraction. 1H NMR (360 MHz, DMSO-dg) 8 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, J=4.4 Hz, 1 H), 8.35 (s, 1 H). 2) n with a mixture of heptane : DCM in a ratio of 50:50 provided methyl 4-(2-(tert—butylamino)oxoacetyl)methyl-1H—pyrrolecarboxylate (830 mg) as the second fraction. 1H NMR (360 MHZ, DMSO-dg) 8 ppm 1.35 (s, 9 H), 3.78 (s, 3 H), 3.93 (s, 3 H), 7.32 (d, J=1.8 Hz, 1 H), 8.02 (s, 1 H), 8.13 (d, J=1.8 Hz, 1 H) Methyl 4-(2-(tert—butylamino)oxoacetyl)methyl-1H-pyrrolecarboxylate (780 mg, 2.9 mmol) was dissolved in 10 mL of MeOH and to the stirred solution 1N NaOH (6.44 mL, 6.44 mmol) was added. After ght stirring at room temperature, 1N HCl (7 mL) was added slowly. Precipitation was completed by the addition of 30 mL water and after stirring for 5 min, the solids were filtered off, washed with water, and dried in vacuum to provide tert—butylamino)oxoacetyl)methyl-1H—pyrrolecarboxylic 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-d6) 8 ppm 1.35 (s, 9 H), 3.91 (s, 3 H), 7.25 (d, J=1.8 Hz, 1 H), 7.96 (s, 1 H), 8.06 (d, J=1.5 Hz, 1 H), 12.78 (br. s., 5 H). 4-(2-(tert—butylamino)oxoacetyl)methyl-1H—pyrrolecarboxylic acid (250 mg, 1 mmol), 3-chloro-4,5-difluoroaniline (162 mg, 1 mmol) and N,N—diisopropylethylamine (DIPEA, 384 mg, 3 mmol) were dissolved in 5 mL DMF under N2. 2-(7-Aza-1H—benzotriazole-l-yl )-1,1,3,3-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 1N HCl, NaHC03 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 filtered off and dried in vacuum to provide 4-(2-(tert—butylamino)—2-oxoacetyl)-N-(3-chloro-4,5-difluorophenyl) methyl-1H—pyrrolecarboxamide (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. 1H NMR (400 MHz, 6) 8 ppm 1.36 (s, 9 H), 3.95 (s, 3 H), 7.66 (d, J=1.8 Hz, 1 H), 7.79 - 7.88 (m, 2 H), 7.97 (s, 1 H), 8.15 (d, J=1.3 Hz, 1 H), 10.33 (s, 1 H).

Com ound 15: 4- 2- tert—but lamino oxoacet l -N— 3-c anofluoro hen l h l- lH- olecarboxamide 0 QF %/NH 0 H2N (3N %NH o O H / \ OH HATU, DIPEA /N\ 'l" N\©\F O DMF, 50°C 16h | o 15 4-(2-(tert—Butylamino)oxoacetyl)- 1 l- 1H-pyrrolecarboxylic acid (250 mg, 1 mmol), 3-cyanofluoroaniline (134 mg, 1 mmol), and N,N—diisopropylethylamine (DIPEA, 384 mg, 3 mmol) were dissolved in 5 mL of DMF under N2. za-1H— benzotriazole-l-yl)-1,1,3,3-tetramethyluronium orophosphate (HATU, 414 mg, 1.09 mmol) was added and the mixture was stirred overnight at 50°C. The reaction mixture was diluted with 100 mL EtOAc and washed with 1N HCl, NaHC03 solution, and brine.

The organic layer was evaporated under reduced pressure and the e was llized from a mixture of 10 mL MeOH and 5 mL water. The crystals were filtered off and dried in vacuum to e 4-(2-(tert—butylamino)—2-oxoacetyl)-N-(3-cyanofluorophenyl) methyl-1H—pyrrolecarboxamide (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. 1H NMR (400 MHz, 6) 8 ppm 1.37 (s, 9 H), 3.96 (s, 3 H), 7.52 (t, J=9.1 Hz, 1 H), 7.67 (d, J=2.0 Hz, 1 H), 7.97 (s, 1 H), 8.03 (ddd, J=9.2, 5.0, 2.8 Hz, 1 H), 8.14 (d, J=1.3 Hz, 1 H), 8.23 (dd, J=5.8, 2.8 Hz, 1 H), 10.39 (s, 1 H).

Com ound 16:N— 3-C anofiuoro hen lmeth l 3-meth n lamino - goxo )acetyl }- 1 H-pmolecarboxamide F NH N O 35 N// O N O Oxalylchloride (7.41 mL, 0.086 mol) was added slowly to a stirring solution of methyl 1-methylpyrrolecarboxylate (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 temperature for 18 hours. Methyl 4-(2-chlorooxo-acetyl)methyl-pyrrolecarboxylate (1.45 g) was filtered off, washed with dichloroethane (2x), and used as such. Methyl 4-(2-chlorooxo-acetyl)methyl- pyrrolecarboxylate (1.45 g, 6.32 mmol) was added portionwise to a stirring solution of 3-methyloxetanamine (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 ature for 1 hour. The volatiles were evaporated. The residue was stirred in H20 (15 mL), filtered off, washed with H20 (3x), and dried at 50°C, resulting in methyl 1-methyl[2-[(3-methyloxetanyl)- amino]oxo-acetyl]pyrrolecarboxylate (839 mg). LC method A; Rt: 1.29 min. m/z : 278.9 (M-H)" Exact mass:.280.1. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.56 (s, 3 H), 3.78 (s, 3 H), 3.93 (s, 3 H), 4.34 (d, J=6.6 Hz, 2 H), 4.70 (d, J=6.4 Hz, 2 H), 7.37 (d, J=2.0 Hz, 1 H), 8.20 (d, J=1.3 Hz, 1 H), 9.25 (s, 1 H). NaOH (1M in H20, 6.6 mL) was added to a stirring mixture of methyl 1-methyl[2-[(3 -methyloxetanyl)amino]—2-oxo-acetyl]- pyrrolecarboxylate (939 mg, 2.99 mmol) in MeOH (10 mL). The reaction mixture was stirred at room temperature for 5 h. HCl 1N (7 mL) was added slowly, and itation occurred. After stirring for 10 minutes, the mixture was left standing for 16 hours, filtered off, washed with HzO-MeOH 3/1 (2x), and dried at 50°C in vacuo resulting in 1-methyl [2-[(3-methyloxetanyl)amino]oxo-acetyl]pyrrolecarboxylic acid (0.66 g). 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.56 (s, 3 H), 3.92 (s, 3 H), 4.34 (d, J=6.6 Hz, 2 H), 4.70 (d, J=6.4 Hz, 2 H), 7.31 (d, J=1.8 Hz, 1 H), 8.15 (d, J=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 ng mixture of 1-methyl [2-[(3-methyloxetanyl)amino]oxo-acetyl]pyrrolecarboxylic acid (0.322 g, 1.21 mrnol ), and CH3CN (dried on molecular sieves, 7.5 mL ) under Nz-atm. To the resulting solution was added 5-aminofluorobenzonitrile (0.187 g, 1.33 mmol) then HATU (0.483 g, 1.27 mmol ). The reaction mixture was d at 50°C for 18 hours. The reaction mixture was allowed to reach room temperature, and poured slowly into stirring H20 (25 mL). After stirring for 10 minutes, the product was filtered off, washed with H20 (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. 1H NMR (400 MHZ, DMSO-d6) 8 ppm 1.58 (s, 3 H), 3.96 (s, 3 H), 4.35 (d, J=6.6 Hz, 2 H), 4.72 (d, J=6.4 Hz, 2 H), 7.53 (dd, J=9.1 Hz, 1 H), 7.71 (d, J=1.8 Hz, 1 H), 8.04 (ddd, J=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).

Com ound 17: N— 3 -Chloro-4 5-difluoro hen lmeth l 3-meth loxetan l - amino oxo ace 1 -1H- rrolecarboxamide CI H 0 6 N o Compound 17 (251 mg) was prepared similarly as described for compound 16 using 3-chloro-4,5-difluoro-aniline instead of ofluorobenzonitrile. LC method B; Rt: 1.06 min. m/z : 410.2 (M-H)" Exact mass: 411.1. 1H NMR (400 MHz, 6) 8 ppm 1.58 (s, 3 H), 3.95 (s, 3 H), 4.35 (d, J=6.6 Hz, 2 H), 4.72 (d, J=6.4 Hz, 2 H), 7.70 (d, J=1.5 Hz, 1 H), 7.79 - 7.88 (m, 2 H), 8.22 (d, J=1.3 Hz, 1 H), 9.28 (s, 1 H), 10.34 (s, 1 H).

Com ound 18: N— 3-Chloro-4 5-difluoro hen l meth l oxo 1R -2 2 2-trifluoro meth leth lamino acet l-1H- olecarboxamide o F / F Ethyl 2-chlorooxo-acetate (12.3 g, 89.8 mmol) was dissolved in CH2C12 (70 mL), and the mixture was cooled on ice / N2. AlC13 (14.4 g, 108 mmol) was added. A on of methyl 1-methylpyrrolecarboxylate (5 g, 35.9 mmol) in CH2C12 (30 mL) was added dropwise over 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-ethoxyoxo-acetyl)methyl-pyrrolecarboxylate (6.1 g), ning 2-(5-methoxycarbonylmethyl-pyrrolyl )oxo-acetic acid as a white powder.1H NMR (400 MHz, DMSO-d6) 8 ppm 1.31 (t, J=7.2 Hz, 3 H), 3.79 (s, 3 H), 3.94 (s, 3 H), 4.33 (q, J=7.2 Hz, 2 H), 7.30 (d, J=2.0 Hz, 1 H), 8.06 (d, J=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-ethoxyoxo-acetyl)methyl-pyrrole carboxylate (6.1 g) was ded in EtOH (40 mL) and the mixture was cooled on ice.

NaOH (1M, 24.5 mL), and H20 was added (30 mL), and the mixture was stirred at 0°C for minutes. 1N 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 methyl-pyrrolyl)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-methoxycarbonylmethyl-pyrrolyl) oxo-acetic acid (2.48 g, 11.6 mmol) (2R)-1,1,1-trifluoropropanamine (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 filrther stirred at room temperature. After 4 hours the reaction e was filtered off, the precipitate was washed with EtOAc, and dried in vacuo, ing in methyl 1-methyl [2-oxo[[(1R)-2,2,2-trifluoromethylethyl]amino]acetyl]pyrrolecarboxylate as a white powder (1.4 g). 1H NMR (400 MHz, 6) 8 ppm 1.34 (d, J=7.0 Hz, 3 H), 3.78 (s, 3 H), 3.93 (s, 3 H), 4.51 - 4.85 (m, 1 H), 7.35 (d, J=1.8 Hz, 1 H), 8.10-8.15 (1 H), 9.32 (d, J=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 1N HCl, NaHCOg, and brine, and evaporated to dryness, resulting in a white powder (2.3 g). Methyl 1-methyl[2-oxo [[(1R)-2,2,2-trifluoromethyl-ethyl]amino]acetyl]pyrrolecarboxylate (3.7 g) was mixed with MeOH (35 mL). To the ing suspension, NaOH (1M, 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 1-methyl[2-oxo [[(1R)-2,2,2-trifluoromethyl-ethyl]amino]acetyl]pyrrolecarboxylic acid (2.94 g) as an off-white powder. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.34 (d, J=7.0 Hz, 3 H), 3.92 (s, 3 H), 4.51 - 4.86 (m, 1 H), 7.29 (d, J=2.0 Hz, 1 H), 8.07 (d, J=1.3 Hz, 1 H), 9.29 (d, J=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 . 1-methyl [2-oxo[[( 1 R)-2,2,2-trifluoromethylethyl]amino] acetyl]pyrrole carboxylic 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 temperature for 15 s, and next at 50-60°C. After 2 hour and 15 minutes at 50-60°C, 1 equiv. more 3-chloro-4,5-difluoro-aniline hydro- chloride was added and the e was stirred at 50°C overweekend. EtOAc (100 mL) was added and the mixture was washed with 1N HCl, NaHC03 and brine. After concentration in vacuo, the obtained residue was d by preperative HPLC (Stationary phase: Uptisphere C18 ODB — 10 um), Mobile phase: 0.25% NH4HC03 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: 437.1.1H NMR (400 MHz, DMSO-d6) 8 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, J=1.8 Hz, 1 H), 7.75 - 7.89 (m, 2 H), 8.14 (d, J=1.5 Hz, 1 H), 9.33 (br. s., 1 H), 10.30 (br. s., 1 H).

Com ound 19: 4- tert-But lamino oxo acet l -N- 3-c anofluoro hen l -1 3 5- trimeth l-1H- rrolecarboxamide O n NH N, o K Ethyl 1,3,5-trimethylpyrrolecarboxylate (2 g, 11.0 mmol) was dissolved inCH2C12 (30 mL) and cooled on ice. A solution of ethyl 2-chlorooxo-acetate (3.8 g, 27.6 mmol) in CH2C12 (10 mL) was added dropwise, followed by A1C13 (4.4 g, 33.1 mmol) in portions. The mixture was fithher stirred at 0°C. After 2.5 hours, the mixture was poured out into ice water (150 mL) and extracted with EtOAc (2x). The ed organic layers were washed with water and brine, dried (Na2SO4) and evaporated to dryness, resulting in crude ethyl thoxyoxo-acetyl)-1,3,5-trimethyl-pyrrolecarboxylate 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 oxo-acetyl)-1,3,5-trimethyl-pyrrolecarboxylate (4.6 g) was taken up in EtOH (30 mL), NaOH was added (33.1 mL, 1M) was added and the mixture was stirred for 10 minutes at room temperature. The mixture was cooled on ice and 1N 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-1,2,4-trimethyl-pyrrolyl)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: 253.1.1H NMR (400 MHz, 6) 8 ppm 1.30 (t, J=7.2 Hz, 3 H), 2.39 (s, 3 H), 2.42 (s, 3 H), 3.73 (s, 3 H), 4.27 (q, J=7.0 Hz, 2 H). 2-(5-ethoxycarbonyl-1,2,4-trimethyl-pyrrolyl)oxo-acetic acid (930 mg, 3.5 mmol), 2-methylpropanamine (258 mg, 3.5 mmol) and DIPEA (1.4 g, .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 e was stirred at room temperature.

After 3 hours, EtOAc (150 mL) was added and the mixture was washed with 1N HCl, NaHC03 and brine. After drying over Na2SO4 the mixture was concentrated to dryness, resulting in crude ethyl 4-[2-(tert-butylamino)oxo-acetyl]-1,3,5-trimethyl-pyrrole carboxylate (1.52 g). Crude ethyl 4-[2-(tert-butylamino)oxo-acetyl]-1,3,5-trimethylpyrrolecarboxylatewas dissolved in EtOH (20 mL), NaOH (1M, 10.6 mL) was added and the mixture was stirred at room temperature overnight. While cooling on ice, 1M HCl was added until pH=1 and the formed white precipitate was collected by filtration and dried in vacuo, resulting in 4-[2-(tert-butylamino)oxo-acetyl]-1,3,5-trimethyl-pyrrolecarboxylic acid (760 mg). LC method B; Rt: 0.45 min. m/z ; 279.1 (M-H)‘ Exact mass: 280.1. 1H NMR (400 MHz, DMSO-d6) 8 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)oxo-acetyl]-1,3,5-trimethyl-pyrrolecarboxylic acid (250 mg, 0.89 mmol), 5-aminofluoro-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 temperature in a closed vessel for 3 hours at room temperature and further at 50-60°C for 3 hours. 5 equiv. more ofluoro-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 fiarther stirred overnight. The reaction was quenched with a small amount of MeOH, EtOAc was added, the mixture was washed with 1N HCl, NaHC03 and brine, and concentrated in vacuo, resulting an oil (450 mg) which was purified by preperative HPLC onary phase: RP Vydac Denali C18 - 10um, 200g, 5cm), Mobile phase: 0.25% NH4HC03 solution in water, , resulting in compound 19 (150 mg) as an ite powder. LC method A; Rt: 1.76 min. m/z: 397.0 (M-H)" Exact mass: 398.2. 1H NMR (400 MHz, DMSO-d6) 8 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 metry: From 30 to 300 0C at 10°C/min: Peak: 188.7 0C.

Com ound 20: 4- tert-But lamino oxo acet l -N- 3 4-difluoro hen l -1 3 5-trimeth l-1H- pmolecarboxamide F©\NHo H o 7< / Compound 20 (126 mg) was prepared similarly as described for compound 19, using 3,4-difluoroaniline instead of ofluoro-benzonitrile. LC method A; Rt: 1.84 min. m/z: 390.0 (M-H)" Exact mass: 391.2. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.34 (s, 9 H), WO 11281 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, 1H), 10.37 (s, 1 H).

Com ound 21: 4- tert—Bu lamino oxo ace 1 -N- 3 4-difiuoro hen l -1 3-dimeth l-1H- pmolecarboxamide F\©\NH0%"/N] o 7< Ethyl 1,3-dimethylpyrrolecarboxylate (2 g, 11.72 mmol) was dissolved in CH2C12 (40 mL) under N2-atmosphere. The mixture was cooled to 0°C and ethyl 2-chlorooxo- acetate (1.5 mL) dissolved in CH2C12 (10 mL) was added dropwise. AlC13 (3.1 g, 23.4 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 CH2C12. The organic fractions were combined, dried (MgSO4), filtered and concentrated in vacuo to ing in crude ethyl 4-(2-ethoxyoxo-acetyl)-1,3-dimethyl-pyrrolecarboxylate. Crude Ethyl 4-(2-ethoxy oxo-acetyl)-1,3-dimethyl-pyrrolecarboxylate was dissolved in EtOH (20 mL) and NaOH (23.4 mL, 1 M) was added. The mixture was stirred at room temperature for 10 minutes.The mixture was cooled on a ice bath and HCl (1M in H20, 23.4 mL, 1 M) was added se.

A precipitate was . water (20 mL) was added and the precipitate was filtered off, washed with water and diisopropylether and dried in vacuo, resulting in 2-(5-ethoxy- carbonyl-1,4-dimethyl-pyrrolyl)oxo-acetic acid (1.8 g) as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 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-1,4-dimethyl-pyrrol- 3-yl)oxo-acetic acid (1.8 g, 7.524 mmol), 2-methylpropanamine (877 uL, 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 d at 5°C for 1 h. The mixture was poured out in EtOAc (200 mL) and washed with 1N HCl solution, sat. NaHC03 on and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo ing in an oil which was purified by silica gel column chromatography by eluding with CH2C12. The product fractions were collected and concentrated in vacuo resulting in ethyl 4-[2-(tert-butylamino)oxo-acetyl]-1,3-dimethyl- pyrrolecarboxylate (1.8 g) which fied on standing. LC method B; Rt: 1.16 min. m/z: 293.1 (M-H)‘ Exact mass: 294.2.

Ethyl 4-[2-(tert-butylamino)oxo-acetyl]-1,3-dimethyl-pyrrolecarboxylate (1.8 g, 6.1 mmol) was dissolved in 1,4-dioxane (22.5 mL, 264.1 mmol) and lithium hydroxide drate (513 mg, 12.2 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was trated in vacuo. The residue was ved in water and neutralized with HCl (1M in H20) (11.7 mL, 1 M, 11.7 mmol). The precipitate was filtered off, washed with water and dried in vacuo resulting in 4-[2-(tert-butylamino)oxo- acetyl]-1,3-dimethyl-pyrrolecarboxylic acid (1.3 g) as a white solid. 4-[2-(tert-butylamino )oxo-acetyl]-1,3-dimethyl-pyrrolecarboxylic acid (600 mg, 2.253 mmol), 3,4-difiuoroaniline (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 anol/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. 1H NMR (400 MHz, DMSO-d6) 8 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).

Com ound 22: 4- tert-But lamino oxo acet l-N- 3-c anofiuoro hen l -1 3-dimeth l- olecarboxamide \ O NH OWWKI N O Compound 22 was prepared similarly as bed for compound 21, using of 5-amino fiuoro-benzonitrile instead of 3,4-difiuoroaniline. LC method B; Rt: 1.07 min. m/z: 383.2 (M-H)" Exact mass: 384.2. 1H NMR (400 MHz, DMSO-ds) 8 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).

Com ound 23: 4- tert-But lamino oxo acet lchloro-N- 3-c anofiuoro hen l meth l-1H- rrolecarboxamide 8m"(x CI 0 0 N / r Sodium hydride (1.37 g, 34.3 mmol) was added portionwise over a period of 10 s to a e of methyl 3-chloro-1H-pyrrolecarboxylate (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 temperature and stirred for 1 hour. The reaction mixture was acidified with 1M HCl (8 mL) and evaporated to dryness. The residue was dissolved in CH2C12 (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 methyl-pyrrolecarboxylate (4.2 g). Methyl romethyl-pyrrolecarboxylate (2 g, 11.5 mmol) was dissolved in CH2C12 (40 mL) under N2 atmosphere. The mixture was cooled to 0°C and ethyl 2-chlorooxo-acetate (2.6 mL, 23.0 mmol) dissolved in CH2C12 (10 mL) was added dropwise. AlC13 (6.15 g, 46.1 mmol) was added in ns to the on 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 CH2C12. The c fractions were combined, dried (MgSO4), filtered and concentrated in vacuo resulting in crude methyl 3-chloro(2-ethoxyoxo-acetyl)methyl-pyrrole ylate as an oil. This crude methyl 3-chloro(2-ethoxyoxo-acetyl)methylpyrrolecarboxylate was dissolved in EtOH (30 mL) and NaOH (34.6 mL, 1 M, 34.6 mmol) was added. The mixture was stirred room temperature for 10 minutes. The mixture was cooled on an ice bath and HCl (1M in H20) was added dropwise till pH~4. A precipitate was formed. Water (20 mL) was added and the t was filtered off, washed with water and diisopropylether and dried in vacuo resulting in 2-(4-chloromethoxy- carbonylmethyl-pyrrolyl)oxo-acetic acid (1.93 g) as a white solid. 2-(4-chloro methoxycarbonylmethyl-pyrrolyl)oxo-acetic acid (1 g, 4.07 mmol), 2-methyl- propanamine (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 c layer was separated, dried (MgSO4), filtered and concentrated in vacuo resulting in an oil. The product was d by silica gel chromatography by elution with CH2C12. The product fractions were collected and concentrated in vacuo resulting in methyl 4-[2-(tert-butylamino)oxo- acetyl]chloromethyl-pyrrolecarboxylate (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-butyl- amino)oxo-acetyl]chloromethyl-pyrrolecarboxylate (100 mg, 0.333 mmol) was dissolved in dry tetrahydrofuran (1 mL). To this was added 5-aminofluorobenzonitrile (58.3 mg, 0.416 mmol) and the mixture was cooled in an ice water bath and purged with nitrogen. Lithium bis(trimethylsilyl)amide (1M in toluene, 0.67 mL, 1 M, 0.67 mmol) was added se under cooling over a period of 2 minutes. The resulting mixture was stirred for 1 hour while cooling was continued, then the mixture was r stirred at room temperature for 16 hours. The mixture was quenched with sat. NH4Cl-sol. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The product was purified by silica gel column chromatography using gradient n with Heptane-EtOAc; 100-0 -> 50-50. The product fractions were collected and trated in vacuo. The product was triturated in diisopropylether, d 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. 1H NMR (400 MHz, 6) 8 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).

Com ound 24: 3-chloro-N— 3-c anofiuoro- hen l meth l 2-oxo 1R -2 2 2- trifiuoro-l-meth l-eth lamino acet l rrolecarboxamide 2-(4-chloromethoxycarbonylmethyl-pyrrolyl)oxo-acetic acid (1 g, 4.071 mmol), 1,1-trifiuoropropylamine (582 mg, 4.89 mmol), 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 ature for 16 hours. The e was poured out in EtOAc (200 mL) and washed with 1N HCl solution, sat. NaHC03 solution and brine. The organic layer was dried (MgSO4), 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 -chloromethyl[2-oxo[[(1R)-2,2,2-trifiuoromethyl- ethyl]amino]acetyl]pyrrolecarboxylate (657 mg) as a fluffy solid. Methyl 3-chloro methyl [2-oxo[[( 1 R)-2,2,2-trifiuoromethyl-ethyl]amino] acetyl]pyrrolecarboxylate (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 temperature for 16 hours. The mixture was concentrated in vacuo. The residue was dissolved in water and neutralized with HCl (1M in H20) (3.86 mL, 1 M, 3.86 mmol). The mixture was extracted with CH2C12 and the organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was porated with diisopropylether, resulting in 3-chloromethyl[2-oxo[[(1R)-2,2,2-trifiuoromethylethyl ]amino]acetyl]pyrrolecarboxylic acid (450 mg) as a white solid.3-chloromethyl [2-oxo[[(1R)—2,2,2-trifiuoromethyl-ethyl]amino]acetyl]pyrrolecarboxylic acid WO 11281 (450 mg, 1.38 mmol, 5-aminofluorobenzonitrile (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 t was crystallized from CH3CN, filtered off and dried in vacuo, resulting in compound 24 (246 mg) as a fluffy white solid. 1H NMR (400 MHz, DMSO-d6) 8 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, 1H) 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.

Com ound 64: N— 3-c anofluoro- hen l meth l 2-oxo 1R -2 2 2-trifluoro meth l-eth lamino acet l olecarboxamide o F H F N// O /N Methyl[2-oxo[[(1R)-2,2,2-trifluoromethyl-ethyl]amino]acetyl]pyrrolecarboxylic 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-aminofluorobenzonitrile (1584 mg, 11.6 mmol).The reaction mixture was stirred at room temperature for 2 hours. Then this mixture was ed ly onto a silica plug. The mixture was ed 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. 1H NMR (400 MHz, DMSO-d6) 8 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) Com ound 25 : 5-bromo-N— 3-c anofluoro- hen l meth l 2-oxo 1R -2 2 2- trifluoro-l-meth l-eth lamino acet l rrolecarboxamide O F H F F NH N// O N Com ound 26: 3-bromo-N— 3-c fluoro- hen l meth l 2-oxo 1R -2 2 2- trifluoro-l-meth l-eth lamino acet l rrolecarboxamide F NHm F N" O N Com ound 27: 3 5-dibromo-N— 3-c anofluoro- hen l meth l 2-oxo 1R - 2 2 2-trifluorometh l-eth 1 amino acet l rrolecarboxamide F NHW F N" O N Br re 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) nwise while stirring.The resulting mixture was d at room temperature for 2 hours. The resulting 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 - 10um, 200g, 5cm, Mobile phase: 0.25% NH4HC03 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). nd 25: 1H NMR (400 MHz, DMSO- d6) 8 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, J=9.1 Hz, 1H), 7.81 (s, 1 H), 7.98 - 8.05 (m, 1 H), 8.20 (dd, J=5.8, 2.8 Hz, 1 H), 9.23 - 9.58 (m, 1 H), .58 (br. s., 1 H). LC method B; Rt: 1.13 min. m/z: 487.0 (M-H)— Exact mass: 488.0.

Compound 26: 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.35 (d, J=7.0 Hz, 3 H), 3.81 (s, 3 H), 4.60 - 4.76 (m, 1 H), 7.57 (t, J=9.1 Hz, 1 H), 7.95 - 8.02 (m, 1 H), 8.17 (s, 1 H), 8.21 (dd, J=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: 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.35 (d, J=7.0 Hz, 3 H), 3.74 (s, 3 H), 4.59 - 4.80 (m, 1 H), 7.57 (t, J=9.1 Hz, 1 H), 7.91 - 8.01 (m, 1 H), 8.20 (dd, J=5.7, 2.6 Hz, 1 H), 9.50 (d, J=6.4 Hz, 1 H), 10.96 (br. s., 1 H). LC method B; Rt: 1.06 min. m/z: 566.9 (M-H)— Exact mass: 567.9.

Com ound 28 :N— 3-c anofiuoro- hen l -1 5-dimeth l 2-oxo 1R -2 2 2- trifluoro-l-meth l-eth lamino acet l rrolecarboxamide O F H F F NH N" O N 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 s.

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 ave irradiation. The reaction mixture was trated and the obtained residue was purified by silica gel column chromatography ent 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. 1H NMR (400 MHz, DMSO-d6) 8 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) Com ound 29: 5-bromochloro-N— 3-c anofiuoro- hen l meth l 2-oxo 1R - 2 2 2-trifluorometh l-eth 1 amino acet l rrolecarboxamide F NHW F O N Br0 N" / Methyl 3 -chloromethyl[2-oxo[[(1R)-2,2,2-trifluoromethyl-ethyl]amino]acetyl]- pyrrolecarboxylate (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 temperature 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 d 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 ochloromethyl[2-oxo -2,2,2-trifluoromethyl-ethyl]amino]acetyl]pyrrolecarboxylate (1.75 g) as a pale yellow solid. Methyl 5 -bromochloro-1 -methyl[2-oxo[[(1R)-2,2,2-trifluoro methyl-ethyl]amino]acetyl]pyrrolecarboxylate (1 g, 2.383 mmol) was dissolved in 1,4-dioxane (9 mL) and water (2 mL). Lithium hydroxide monohydrate (200 mg, 4.77 mmol) was added and the mixture was stirred at room temperature for 16 hour. The mixture was concentrated in vacuo and the residue dissolved in water. HCl (1M in H20) (4.767 mL, 1 M, 4.767 mmol) was added and a precipitate was formed. After stirring for 5 minutes the product was d off and dried under vacuum resulting in 5-bromochloro- 1-methyl[2-oxo[[(1R)-2,2,2-trifluoromethyl-ethyl]amino]acetyl]pyrrole carboxylic acid (856 mg) as a white solid. Eth (0.88 mL, 6.33 mmol) was added to -bromochloro- 1 l[2-oxo [ [( 1 R)-2,2,2-trifluoromethyl-ethyl]amino] acetyl] - ecarboxylic acid (856 mg, 2.111 mmol), HATU (1003 mg, 2.64 mmol), 5-amino 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 temperature and poured out in ice water. The mixture was extracted with EtOAc and the organic layer was separated, dried (MgSO4), d and concentrated in vacuo. A purification was performed via Preperative HPLC (Stationary phase: Uptisphere C18 ODB - 10um, 200g, 5cm, Mobile phase: 0.25% NH4HC03 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. 1H NMR (400 MHz, DMSO- d6) 8 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, J=9.1 Hz, 1 H) 7.97 (ddd, J=9.2, 4.8, 2.9 Hz, 1 H) 8.20 (dd, J=5.7, 2.6 Hz, 1 H) 9.32 - 9.65 (m, 1 H) 10.30 - 11.17 (m, 1 H).

Com ound 30: 3-chloro-N— 3-c anofiuoro- hen l -1 5-dimeth 1 2- 1R -2 2 2- trifluoro-l-meth l-eth lamino acet l rrolecarboxamide F NHm F N" O N A microwave vial was charged with methyl 5 -bromochloromethyl[2-oxo[[(1R)- trifluoromethyl-ethyl]amino]acetyl]pyrrolecarboxylate (200 mg, 0.477 mmol) and tetramethyltin (139.0 uL, 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 purified by silica gel chromatography (using gradient eluent e-EtOAc; 100-0 to 50-50. The product fractions were collected and concentrated in vacuo resulting in methyl 3-chloro-1,5- dimethyl[2-oxo[[(1R)-2,2,2-trifluoromethyl-ethyl]amino]acetyl]pyrrole carboxylate (94 mg) as a white solid. Methyl 3-chloro-1,5-dimethyl[2-oxo[[(1R)-2,2,2- trifluoromethyl-ethyl]amino]acetyl]pyrrolecarboxylate (94 mg, 0.265 mmol) was W0 2015/011281 dissolved 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 temperature for 16 hours. The mixture was concentrated in vacuo and then dissolved in water. HCl (1M in H20) (0.53 mL, 1 M, 0.53 mmol) was added and the e was d for 5 minutes at room temperature The mixture was extracted with Me-THF and the organic layer was dried (MgSO4), filtered and concentrated in vacuo resulting in ro-1,5- yl[2-oxo[[(1R)-2,2,2-trifiuoromethyl-ethyl]amino]acetyl]pyrrole carboxylic acid (85 mg) as a solid. 3-chloro-1,5-dimethyl[2-oxo[[(1R)-2,2,2-trifiuoro- 1-methyl-ethyl]amino]acetyl]pyrrolecarboxylic acid (85 mg, 0.249 mmol), 5-amino fiuorobenzonitrile (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 d at 50°C for 16 hour. The mixture was concentrated in vacuo. The residue was partioned between water and EtOAc. The organic layer was ted, dried (MgSO4), filtered and concentrated in vacuo. A purification was performed via preperative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10um,30x150 mm, Mobile phase: 0.25% NH4HC03 solution in water, CH3CN) resulting in 3-chloro-N-(3-cyanofiuoro-phenyl)- 1 ,5 -dimethyl [2-oxo[[( 1 R)-2,2,2-trifiuoromethyl-ethyl] amino]acetyl]pyrrole carboxamide (40 mg) as a white solid. LC method B; Rt: 1.03 min. m/z: 457.0 (M-H)" Exact mass: 458.1. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.32 (d, J=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, J=9.1 Hz, 1 H) 7.95 - 8.02 (m, 1 H) 8.21 (dd, J=5.8, 2.5 Hz, 1 H) 9.37 (d, J=8.8 Hz, 1 H) 10.75 (s, 1 H).

Com ound 31 : 3-chloro-N— 3-c fiuoro- hen lc clo ro lmeth l 2-oxo 1R -2 2 2-trifiuorometh l-eth 1 amino acet l olecarboxamide F NH F /| O N" O N A microwave vial was charged with methyl 5 -bromochloromethyl[2-oxo[[(1R)- 2,2,2-trifiuoromethyl-ethyl]amino]acetyl]pyrrolecarboxylate (150 mg, 0.36 mmol), potassium cyclopropyltrifiuoroborate (79.4 mg, 0.54 mmol), CS2C03 (349 mg, 1.07 mmol), DME (4 mL) and water (0.4 mL). The mixture was purged with N2 for 5 minutes.

Tetrakis(triphenylphosphine)palladium(0) (82.6 mg, 0.072 mmol) was added and the vial was capped. The mixture was d at 110°C for 16 hours. The mixture was cooled and the residue partioned between sat. NH4Cl-sol and Me-THF. The organic layer was ted, dried (MgSO4), filtered and concentrated in vacuo. The product was purified by silica gel WO 11281 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 rocyclopropylmethyl[2-oxo[[(1R)-2,2,2-trifluoromethyl-ethyl]amino]acetyl]- pyrrolecarboxylate (114 mg) as a solid. 3-chloro-N-(3-cyanofluoro-phenyl)cyclopropylmethyl [2-oxo[[( 1 R)-2,2,2-trifluoromethyl-ethyl]amino] acetyl]pyrrole carboxamide (22 mg) was synthesized similarly as described for compound 30 using methyl 3 -chloro-5 -cyclopropylmethyl[2-oxo[[(1R)-2,2,2-trifluoromethyl-ethyl]- amino]acetyl]pyrrolecarboxylate instead of methyl 3-chloro-1,5-dimethyl[2-oxo [[(1R)-2,2,2-trifluoromethyl-ethyl]amino]acetyl]pyrrolecarboxylate.LC method C; Rt: 1.99 min. m/z: 483.0 (M-H)- Exact mass: 484.0. 1H NMR (400 MHz, 6) 8 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, 3 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, J=5.7, 2.6 Hz, 1 H) 9.32 (d, J=9.0 Hz, 1 H) 10.75 (br. s., 1 H) Com ound 32: 4- 2- tert-but lamino oxo-acet l chloro-N- 3-c anofluoro- hen l - 15-dimeth l- rrolecarboxamide CI H F NH / I N74 N" o N Compound 32 (81 mg) was synthesized similarly as bed for compound 30, using methyl o[2-(tert-butylamino)oxo-acetyl] -3 -chloromethyl-pyrrole carboxylate instead of methyl 5-bromochloromethyl[2-oxo[[(1R)-2,2,2-trifluoro- 1-methyl-ethyl]amino]acetyl]pyrrolecarboxylate. LC method B; Rt: 1.03 min. m/z: 417.1 (M-H)‘ Exact mass: 418.1. 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.34 (s, 9 H) 2.46 (s, 3 H) 3.65 (s, 3 H) 7.55 (t, J=9.1 Hz, 1 H) 7.94 - 8.04 (m, 1 H) 8.21 (dd, J=5.7, 2.6 Hz, 1 H) 8.27 (s, 1 H) 10.70 (s, 1 H).

Com ound 33: 4- 2- tert-but lamino -acet l chloro-N- 3-c anofluoro- hen l - 1-meth l trifluorometh l olecarboxamide 0 H CI F >9 W 0 NH N// O N / CF3 Compound 50 (100 mg, 0.207 mmol) was dissolved in DMF (2 mL). 4-methylmorpholine (45.5 uL, 0.413 mmol), copper (I) iodide (19.7 mg, 0.103 mmol) and fluorosulfonyl- W0 2015/011281 (difluoro)acetic acid methyl ester (78.1 uL, 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 on mixture. Then this was extracted using EtOAc (3 x 15mL). The combined extracts were dried (MgSO4), d and concentrated in vacuo. The obtained residue was purified using column chromatography on silica (gradient elution: cetate: heptane from 0 to 100%). The product fractions were collected and concentrated in vacuo ing in compound 33 (60 mg) as a white fluffy solid. LC method C; Rt: 2.16 min. m/z: 471.1 (M-H)" Exact mass: 472.1. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.33 (s, 9 H) 3.84 (s, 3 H) 7.59 (t, J=9.13 Hz, 1 H) 7.93 - 8.02 (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.

Com ound 34: 4- 2- tert-but lamino oxo-acet l -N- 3-c anofluoro- hen l fluoro- 1-meth l- olecarboxamide F H F NH / I N74 N" O N Sodium hydride (5.3 g, 138.7 mrnpol, 60%) was added portionwise to ethyl 3-fluoro-1H- pyrrolecarboxylate (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 temperature. The reaction mixture was acidified with 1M HCl and concentrated. The ed residue was dissolved in EtOAc. The organic layer was dried over Na2SO4, 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 tography using a gradient from 10 till 25% EtOAc in heptane. The product ons were concentrated ng ethyl omethyl-pyrrolecarboxylate as a clear oil (10.7 g). More ethyl 3-fluoromethyl-pyrrolecarboxylate (1.7 g) was recuperated from the evaporated solvent. Ethyl omethyl-pyrrolecarboxylate (1.96 g, 11.5 mmol), ethyl 2-chlorooxo-acetate (1.99 mL, 17.46 mmol) was dissolved in DCM (100 mL) and cooled in an ice bath. AlC13 (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 temperature. 1 extra eq ofAlC13 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 1M. The organic layer was dried over magnesium sulphate filtered and concentrated, resulting in crude ethyl 4-(2-ethoxyoxo-acetyl)fluoromethyl-pyrrolecarboxylate (3.29 g). The residue was dissolved in EtOH (20 mL), NaOH (1M in H20) (11.5 mL, 1 M, 11.5 mmol) was added and the reaction mixture was stirred for 10 minutes. The reaction e was neutralised with HCl (1M in H20) (11.5 mL, 1 M, 11.5 mmol), partially concentrated and extracted with EtOAc/water. The organic layer was dried over magnesium sulphate, filtered and concentrated. The residue was purified by silica gel column tography using a gradient from 10 till 100% EtOAc in e. The fractions were concentrated yielding 2-(5-ethoxycarbonylfluoromethyl-pyrrolyl)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 thoxycarbonyl fluoro-l-methyl-pyrrolyl)oxo-acetic acid (596 mg, 2.45 mmol), 2-methylpropan amine (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)oxo-acetyl]fluoromethyl-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. Amixture of ethyl 4-[2-(tert-butylamino)- 2-oxo-acetyl]fluoromethyl-pyrrolecarboxylate (204 mg, 0.684 mmol), LiOH (49.1 mg, 2.05 mmol) water (10 mL,) and THE (20 mL) was stirred overnight. HCl (1M, 2.1 mL) was added and the THF was distilled off. The formed white precipitate was d off and dried in vacuo at 50°C overnight, ing in 4-[2-(tert-butylamino)oxo-acetyl]- 3-fiuoromethyl-pyrrolecarboxylic acid (121 mg) as a white powder. LC method C; Rt: 1.03 min. m/z: 269.3 (M-H)" Exact mass: 270.1. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.34 (s, 9 H), 3.86 (s, 3 H), 7.97 (d, J=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)oxo-acetyl]fluoromethyl- pyrrolecarboxylic acid (115.9 mg, 0.43 mmol), HATU (203.8 mg, 0.54 mmol), 5-amino- 2-fluoro-benzonitrile (116.76 mg, 0.86 mmol) ved 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 overnight in vacuo at 50°C. LC method C; Rt: 2.03 min. m/z: 387.1 (M-H)‘ Exact mass: 388.1. Differential scanning metry: From 30 to 300 °C at 10°C/min: Peak: 179.2 °C. 1H NMR (360 MHz, DMSO-d6) 8 ppm 1.35 (s, 9 H), 3.85 (s, 3 H), 7.54 (t, J=9.1 Hz, 1 H), 7.93 - 7.99 (m, 1 H), 8.04 (d, J=4.4 Hz, 1 H), 8.12 (s, 1 H), 8.18 (dd, J=5.7, 2.7 Hz, 1 H), 10.37 (s, 1 H).

Com ound 35: N— 3-c anofluoro- hen 1 2- 3 3-difluorometh l-c clobut l- amino oxo-acet l fluorometh l- olecarboxamide F H F NH / I O Né N// O N F F Compound 35 was prepared similarly as bed for nd 34, using 4-[2-[(3,3-di- fluoromethyl-cyclobutyl)amino]oxo-acetyl] romethyl-pyrrolecarboxylic acid instead of 4-[2-(tert-butylamino)oxo-acetyl]fluoromethyl-pyrrolecarboxylic acid. Compound 35 (345 mg) was crystallised by addition of water to a MeOH solution. 4-[2- [(3 ,3 romethyl-cyclobutyl)amino]oxo-acetyl]fluoromethyl-pyrrole carboxylic acid was prepared similarly as described for 4-[2-(tert-butylamino)oxo- acetyl]fluoromethyl-pyrrolecarboxylic acid using 3,3-difluoromethylcyclobutan- amine hydrochloride (commercial from Pharmablock PBN2012lOl9) instead of 2-methyl- propanamine. LC method C; Rt: 1.99 min. m/z: 435.4 (M-H)" Exact mass: 436.1.

Differential scanning calorimetry: From 30 to 300 CC at 10°C/min: Peak: 195.0 °C. 1H NMR (400 MHz, DMSO-d6) 5 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).

Com ound 36 : 4- 2- tert-but lamino oxo-acet l -N- 3-c anofluoro- hen l fluoro- eth l- rrolecarboxamide F H F NH / I N74 N" o N Ethyl 4-[2-(tert-butylamino)oxo-acetyl] fluoromethyl-pyrrolecarboxylate (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 overnight. 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 t fractions were concentrated yielding ethyl 5-bromo[2-(tert-butylamino)oxo-acetyl]fluoro methyl-pyrrolecarboxylate (255 mg) as a clear oil. 1H NMR (360 MHZ, 6) 8 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)palladium(0) (65.9 mg, 0.057 mmol) was added to ethyl -bromo[2-(tert-butylamino)oxo-acetyl] fiuoromethyl-pyrrolecarboxylate (215 mg, 0.57 mmol) and tetramethyltin (214.6 mg, 1.14 mmol) dissolved in DMF (3 mL) and the on 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)oxo-acetyl] fiuoro-l,5-dimethyl-pyrrolecarboxylate (149 mg) as a clear colorless resin . 1H NMR (400 MHz, DMSO-d6) 8 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). Amixture of ethyl 4-[2-(tert-butylamino)oxo- acetyl]fiuoro-1,5-dimethyl-pyrrolecarboxylate (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 ght.

HCl (1M in H20 (1.4 mL, 1 M, 1.40 mmol) was added and THF distilled off. The formed white itate was filtered off and dried in vacuo at 50°C resulting in 4-[2-(tert- mino)oxo-acetyl]fluoro-1,5-dimethyl-pyrrolecarboxylic acid (95 mg) as a white powder. LC method C; Rt: 0.93 min. m/z: 283.1 (M-H)‘ Exact mass: 284.1. 1H NMR (360 MHz, DMSO-d6) 5 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) oxo-acetyl]fluoro-1,5-dimethyl-pyrrolecarboxylic acid (92 mg, 0.32 mmol), HATU (153.8 mg, 0.41 mmol) and 5-aminofiuoro-benzonitrile (88.1 mg, 0.65 mmol) in DMF (1 mL) and the mixture was stirred overnight at 40°C. The reacton mixture was purified directly by silica gel chromatography using a gradient from 10 t0100% EtOAc in e.

The t fractions were concentrated. The residue was ved in methanol (10 mL).

The product crystallised upon addition of water. The white crystals were filtered off and dried overnight 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 metry: From 30 to 300 °C at 10°C/min: Peak: 153.4 °C. 1H NMR (400 MHz, DMSO-d6) 8 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).

Com ound 37: N— 3-c anofiuoro- hen l 2- 3 3-difiuorometh l-c clobut 1- amino oxo-acet l fiuoro-1 5-dimeth l- rrolecarboxamide F on F NH N// ON / FF 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 W0 2015/011281 2014/066093 silica gel column chromatography using a gradient from 10 till 100% EtOAc in heptane. The product fractions were concentrated and the residue crystallised from ol (20 mL) upon addition of water. The white powder, crude 5-bromo-N-(3-cyanofluoro-phenyl)—4- [2- [(3 ,3 -difluoromethyl-cyclobutyl)amino]oxo-acetyl]fluoromethyl-pyrrole carboxamide (154 mg) was filtered 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. en was bubbled through a solution of crude 5-bromo-N-(3 -cyanofluoro-phenyl)—4- [2-[(3 ,3-difluoromethyl-cyclobutyl)- amino]—2-oxo-acetyl] fluoromethyl-pyrrolecarboxamide (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 nt 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. 1H NMR (400 MHz, DMSO-d6) 8 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, J=9.1 Hz, 1 H), 7.96 (ddd, J=9.2, 4.9, 2.6 Hz, 1 H), 8.16 (dd, J=5.7, 2.6 Hz, 1 H), 9.14 (s, 1 H), 10.40 (s, 1 H).

Com ound 38: 3-chloro-N— 3-c anofluoro- hen l meth l 2-oxo 1R trifluorometh l ro lamino acet l rrolecarboxamide Compound 38 (91 mg) was synthesized similarly as described for compound 40 using 1,1-trifluorobutylamine instead of 3,3-difluoromethylcyclobutanamine hloride. LC method C; Rt: 2.08 min. m/z: 457.0 (M-H)- Exact mass: 458.1. 1H NMR (400 MHz, DMSO-d6) 8 ppm 0.92 (t, J=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, J=9.1 Hz, 1 H) 7.98 (ddd, J=9.2, 4.8, 2.9 Hz, 1 H) 8.14 (s, 1 H) 8.21 (dd, J=5.7, 2.6 Hz, 1 H) 9.31 (d, J=9.2 Hz, 1 H) 10.74 (s, 1 H). Differential scanning calorimetry: From 30 to 300 0C at 10°C/min: Peak: 248.53 0C.

W0 2015/011281 Com ound 39: 3-chloro-N- 3-c anofluoro- hen l meth l 2-oxo 1- tri- fluorometh l c clobut 1 amino acet l olecarboxamide F 9 mNH F N// O N Compound 39 (152 mg) was synthesized similarly as described for compound 40 using 1-(trifluoromethyl)cyclobutanamine d of 3,3-difluoromethylcyclobutanamine hydrochloride. LC method C; Rt: 2.08 min. m/z: 469.1 (M-H)‘ Exact mass: 470.1. 1H NMR (400 MHz, 6) 8 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’C.

Com ound 40: 3-chloro-N- 3-c anofluoro- hen l 2- 3 3-difluorometh l- c clobut lamino oxo-acet lmeth l- carboxamide CI H F NH N// 0 N / F F Methyl 3-chloromethyl-pyrrolecarboxylate (6.2 g, 35.7 mmol) and 5-amino fluorobenzonitrile (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 on mixture at room temperature. After 2 hours the mixture was poured out in sat.

NH4Cl-sol. The mixture was extracted with Me-THF. The organic layer was separated, dried (MgSO4), 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 ro-N-(3-cyanofluoro-phenyl)methyl-pyrrolecarboxamide (5.8 g) as a pale pink solid. 3-chloro-N-(3-cyanofluoro-phenyl)methyl-pyrrolecarboxamide (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. Aluminium(III) chloride (7.24 g, 54.31mmol) was added portionwise. At 0-5°C ethyl oxoacetate (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 temperature. The mixture was further d at room temperature for 32 hours. The mixture was fully converted to 2-[4-chloro[(3-cyanofluoro-phenyl)- carbamoyl]methyl-pyrrolyl]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 (MgSO4), filtered and concentrated in vacuo. The residue was d with 1 N NaOH on and the water layer was washed with Me-THF. The water layer was acidified with 1N HCl solution. The water layer was extracted with Me- THF (2x) and the organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo resulting in 2-[4-chloro[(3-cyanofluoro-phenyl)carbamoyl]methyl-pyrrol- 3-yl]oxo-acetic acid (3 g) as a white solid. Eth (0.238 mL, 0.728 g/mL, 1.716 mmol) was added to a on of 2-[4-chloro[(3-cyanofiuoro-phenyl)carbamoyl]methyl- pyrrolyl]—2-oxo-acetic acid (150 mg, 0.429 mmol), 3,3-difiuoromethylcyclobutan- amine 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 fluffy solid. LC method C; Rt: 2.02 min. m/z: 451.3 (M-H)" Exact mass: 452.1. 1H NMR (400 MHz, DMSO- d6) 8 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) .71 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: Peak: 222.1 °C.

Sflthesis of 3-1trifluoromethyl)tetrahydrofiuranamine hydrochloride: A mixture of 3-oxotetrahydrofuran (30 g, 348.5 mmol), benzylamine (39.2 g, 365.8 mmol), MgSO4 (21 g, 174.5 mmol) and CH2C12 (200 mL) was stirred at 28°C for 24 hours. The mixture was filtrated. The e 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). Trifiuoroacetic acid (45 g, 394 mmol), potassium hydrogenfiuoride (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. (trifiuoromethyl)trimethylsilane (77 g, 541 mmol) was added to the on mixture and the e was stirred at ambient temperature for 12 h. Saturated aqueous Na2C03 (200 mL) was added and the mixture was stirred for 5 min. The mixture was diluted with water (500 mL), and ted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated under d pressure. The obtained residue was dissolved in 2M HCl/MeOH and the solvent was evaporated. The resulting hydrochloride salt was llized from CH3CN to provide N—benzyl-3 -(trifluoromethyl)tetrahydrofuran-3 -amine (30.5 g). A mixture of N—benzyl(trifluoromethyl)tetrahydrofuran-3 -amine (30.5 g), palladium on a (1.5 g) and MeOH was stirred under H2 (20 psi) atmosphere at 28 °C for 12 hours.

W0 2015/011281 The mixture was filtered and the filtrate was concentrated in vacuo resulting in 3-(trifluoromethyl)tetrahydrofuranamine hydrochloride (20.5 g). 1H NMR (400 MHz, DMSO-d6) 8 ppm 2.21 - 2.43 (m, 2 H) 3.83 - 4.16 (m, 4 H) 9.68 (br. s., 3 H).

Com ound 41: 3-chloro-N— 3-c anofluoro- hen l -1 5-dimeth 1 2-oxo 3- tri- fluorometh ltetrah drofuran 1 amino acet l olecarboxamide F NH N" 0 N 0 3 o-N-(3-cyanofluoro-phenyl)- 1 ,5 -dimethyl [2-oxo[[3 -(trifluoromethyl)- tetrahydrofuranyl]amino]acetyl]pyrrolecarboxamide (58 mg) was sized similarly as described for compound 43 using racemic 3-(trifluoromethyl)tetrahydrofilran- e instead of 1-(trifluoromethyl)cyclobutanamine. LC method B; Rt: 0.98 min. m/z: 499.0 (M-H)- Exact mass: 500.1. 1H NMR (400 MHz, DMSO-d6) 8 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, J=9.1 Hz, 1 H) 7.99 (ddd, J=9.2, 4.8, 2.9 Hz, 1 H) 8.21 (dd, J=5.7, 2.6 Hz, 1 H) 9.39 (s, 1 H) 10.75 (s, 1 H).

Com ound 42: 3-chloro-N— 3-c anofluoro- hen l -1 5-dimeth 1 2-oxo 1R trifluorometh l ro lamino acet l rrolecarboxamide 3 -chloro-N-(3-cyanofluoro-phenyl)- 1 ,5 -dimethyl [[( 1 R)(trifluoro- methyl)propyl]amino]acetyl]pyrrolecarboxamide (5 mg) was synthesized similarly as bed for compound 43 using (R)-1,1,1-trifluorobutylamine instead of 1-(trifluoromethyl)cyclobutanamine. LC method C; Rt: 1.97 min. m/z: 471.1 (M-H)- Exact mass: 472.1. 1H NMR (400 MHz, DMSO-ds) 8 ppm 0.97 (t, J=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, J=9.1Hz, 1 H) 7.93 - 8.03 (m, 1 H) 8.21 (dd, J=5.7, 2.6 Hz, 1 H) 9.29 (d, J=8.8 Hz, 1 H) .75 (s, 1 H).

Com ound 43: 3-chloro-N- 3-c anofiuoro- hen l -l 5-dimeth l 2-oxo l- tri- fiuorometh l c clobut 1 amino acet l olecarboxamide F Q m3?NH N" 0 N 3-chloro-N-(3-cyanofluoro-phenyl)-l-methyl-pyrrolecarboxamide (4 g, 14.405 mmol) was ved 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 e was stirred for 30 minutes at 0-5°C and was then d to rise to room temperature. The mixture was stirred at room temperature 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 temperature 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 (MgSO4), filtered and trated in vacuo. The residue was ded in little Me-THF and the t was filtered off resulting in ethyl 2-[4-chloro[(3-cyano fiuoro-phenyl)carbamoyl]-l-methyl-pyrrolyl]oxo-acetate (l .8 g) as a white solid. Ethyl 2-[2-bromochloro-5 - [(3-cyanofluoro-phenyl)carbamoyl] - l -methyl-pyrrol-3 -yl] oxo- acetate (1 .8 g) was synthesized similarly as described for 2-[2-bromochloro[(3 -cyano- 4-fluoro-phenyl)carbamoyl]-l-methyl-pyrrolyl]oxo-acetic acid in the synthesis of compound 47 using ethyl 2-[4-chloro[(3 -cyanofiuoro-phenyl)carbamoyl]-l-methyl- pyrrolyl]oxo-acetate instead of hloro[(3 -cyanofluoro-phenyl)carbamoyl]- l-methyl-pyrrolyl]oxo-acetic acid. Ethyl 2-[4-chloro[(3-cyanofiuoro-phenyl)- carbamoyl]-l,2-dimethyl-pyrrolyl]oxo-acetate (700 mg) was synthesized similarly as described for 2-[4-chloro[(3-cyanofluoro-phenyl)carbamoyl]-l ethyl-pyrrol- 3-yl]oxo-acetic acid in the synthesis of compound 47 using ethyl romochloro [(3-cyanofluoro-phenyl)carbamoyl]-l-methyl-pyrrolyl]oxo-acetate (l g) instead of 2-[2-bromochloro-5 - [(3-cyanofluoro-phenyl)carbamoyl] - l -methyl-pyrrol-3 -yl] oxo- acetic acid. Ethyl 2-[4-chloro[(3-cyanofluoro-phenyl)carbamoyl]-l,2-dimethyl-pyrrol- 3-yl]oxo-acetate (700 mg, 1.787 mmol) was dissolved in l,4-dioxane (6.6 mL, 77.2 mmol) and water (1 .5 mL). Lithium hydroxide drate (150 mg, 3.57 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the residue dissolved in water. HCl (lM in H20) (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[(3-cyanofiuoro-phenyl)carbamoyl]-l ,2- dimethyl-pyrrolyl]oxo-acetic acid (400 mg) as a white solid. Compound 43 (33 mg) was synthesized similarly as described for nd 47 starting from 2-[4-chloro[(3- cyanofluoro-phenyl)carbamoyl]-1,2-dimethyl-pyrrolyl]oxo-acetic acid using 1-(trifluoromethyl)cyclobutanamine instead of 3,3-difluoromethylcyclobutanamine hydrochloride. LC method C; Rt: 1.97 min. m/z: 483.1 (M-H)‘ Exact mass: 484.1. 1H NMR (400 MHz, 6) 8 ppm 1.81 - 2.10 (m, 2 H) 2.42 - 2.57 (m, 7 H) 3.66 (s, 3 H) 7.55 (t, J=9.1 Hz, 1 H) 7.99 (ddd, J=9.1, 4.8, 2.8 Hz, 1 H) 8.21 (dd, J=5.7, 2.6 Hz, 1 H) 9.28 (s, 1 H) .75 (s, 1 H). ential scanning calorimetry: From 30 to 300 CC at in: Peak: 218.9 °C.

Com ound 44: 3-chloro-N- 3-c anofluoro- hen ldimeth l 2- 3-meth loxetan- 3- 1 amino oxo-acet l olecarboxamide CI H F NH / I O 0 N// o N Compound 44 (60 mg) was synthesized rly as described for compound 47 using 3-methyloxetanamine instead of 3,3-difluoromethylcyclobutanamine hydrochloride.

LC method C; Rt: 1.60 min. m/z: 431.1 (M-H)" Exact mass: 432.1. 1H NMR (400 MHz, DMSO-ds) 5 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, J=6.4 Hz, 2 H) 7.55 (t, J=9.1 Hz, 1 H) 7.99 (ddd, J=9.2, 4.8, 2.6 Hz, 1 H) 8.21 (dd, J=5.7, 2.6 Hz, 1 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 0C.

Com ound 45: 3-chloro-N- 3-c anofluoro- hen l 2- iso ro lamino oxo-acet l - -dimeth l- rrolecarboxamide CI H F NH / I Nf N// o N Compound 45 (59 mg) was synthesized similarly as described for compound 47 using isopropylamine instead of 3,3-difluoromethylcyclobutanamine hydrochloride. LC method C; Rt: 1.76 min. m/z: 403.1 (M-H)" Exact mass: 404.1. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.14 (d, J=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, J=9.1 Hz, 1 H) 7.98 (ddd, J=9.2, 4.8, 2.8 Hz, 1 H) 8.21 (dd, J=5.7, 2.6 Hz, 1 H) 8.58 (d, J=7.7 Hz, 1 H) 10.71 (s, 1 H). Differential scanning calorimetry: From 30 to 300 °C at 10°C/min: Peak: 238.3 c’C.

Com ound 46: 3-chloro-N- 3-c fluoro- hen l 2- 1R -2 2-difluorometh l- ro 1 amino oxo-acet l -1 5-dimeth l- olecarboxamide o F ‘3' H F NH F / I MlX N" o N nd 46 (64 mg) was synthesized similarly as described for compound 47 using (2R)- 3,3-difluorobutanamine instead of 3,3-difluoromethylcyclobutanamine hydrochloride.

LC method C; Rt: 1.85 min. m/z: 453.1 (M-H)- Exact mass: 4541. 1H NMR (400 MHz, 6) 5 ppm 1.21 (d, J=6.8 Hz, 3 H) 1.62 (t, J=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, J=9.1 Hz, 1 H) 7.93 - 8.02 (m, 1 H) 8.21 (dd, J=5.7, .6 Hz, 1 H) 9.03 (d, J=9.0 Hz, 1 H) 10.74 (s, 1 H) ential scanning calorimetry: From 30 to 300 CC at 10°C/min: Peak: 240.5 0C.

Com ound 47: 3-chloro-N- 3-c anofluoro- hen 1 2- 3 3-difluorometh l-c clo- but 1 amino oxo-acet l -1 5-dimeth l- rrolecarboxamide CI H F4mm;NH N// 0 N / F F 2-[4-chloro-5 - [(3 -cyanofluoro-phenyl)carbamoyl]methyl-pyrrol-3 -yl] 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 temperature 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-bromochloro-5 - [(3-cyanofluoro-phenyl)carbamoyl]methyl-pyrrol-3 -yl]oxo- acetic acid (306 mg). A solution of 2-[2-bromochloro[(3-cyanofluoro-phenyl)- carbamoyl]methyl-pyrrolyl]oxo-acetic acid (306 mg, 0.714 mmol), tetramethyltin (0.208 mL, ol) 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 on mixture was heated at 140°C during 30 min by microwave irradiation. The reaction mixture was concentrated resulting in 2-[4-chloro[(3-cyanofluoro-phenyl)carbamoyl]-1,2- dimethyl-pyrrolyl]oxo-acetic acid (260 mg) and used as such in the next step. Eth (0.397 mL, 2.9 mmol) was added to a solution of 2-[4-chloro[(3-cyanofluoro-phenyl)- carbamoyl]-1,2-dimethyl-pyrrolyl]oxo-acetic acid (260 mg, 0.715 mmol), 3,3-difluoromethylcyclobutanamine 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 e Prep C18 OBD-10um,30x150mm, Mobile phase: 0.25% NH4HC03 solution in water, CH3CN) ing in compound 47 (68 mg) as a white fluffy solid. LC method D; Rt: .74 min. m/z: 465.0 (M-H)- Exact mass: 466.1.1H NMR (400 MHz, DMSO-d6) 8 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, J=9.1Hz, 1 H) 7.95 - 8.04 (m, 1 H) 8.21 (dd, J=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.

Com ound 48 : 4- 2- tert-but lamino oxo-acet l chloro-N- 3-c fluoro- hen l - -c clo ro lmeth l- rrolecarboxamide HN 0 0 \ \ F N HN Compound 48 (54 mg) was sized similarly as described for compound 31 using tert- Butylamine instead of (2R)-1,1,1-trifluoropropanamine. LC method C; Rt: 2.04 min. m/z: 443.1 (M-H)" Exact mass: 444.1. 1H NMR (400 MHZ, DMSO-d6) 8 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, J=9.13 Hz, 1 H) 7.93 - 8.02 (m, 1 H) 8.13 (s, 1 H) 8.20 (dd, J=5.72, 2.64 Hz, 1 H) 10.68 (s, 1 H). ential scanning calorimetry: From 30 to 300 °C at 10°C/min: Peak: 198.8 °C.

Com ound 49: 4- 2- ut lamino oxo-acet 1 chloroc ano-N- 3-c anofluoro- phenyl )methyl-pyrrolecarboxamide Cl H F NH / | N74 N// O N / \\N Amicrowave 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 (MgSO4), filtered and concentrated in vacuo. The obtained residue was purified using column chromatography on silica ent 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 ing 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. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.32 - 1.38 (m, 9 H) 3.92 (s, 3 H) 7.60 (t, J=9.2 Hz, 1 H) 7.94 - 8.02 (m, 1 H) 8.21 (dd, J=5.9, 2.6 Hz, 1 H) 8.59 (s, 1 H) 11.16 (s, 1 H).

S thesis of meth l4- 2- tert-but lamino oxo-acet l chlorometh l- ole carboxylate Et3N (5.09 mL, 36.6 mmol) was added to a on of 2-(4-chloromethoxycarbonyl methyl-pyrrolyl)oxo-acetic acid (3 g, 12.21 mmol), 2-methylpropanamine (1.62 mL, 15.27 mmol), HATU (5.81 g, 15.27 mmol) in DMF (14.96 mL, 193.26 mmol) and d 30 minutes at 65°C. The solution was ted 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)oxo-acetyl]chloromethyl- pyrrolecarboxylate (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.

Com ound 50: 5-bromo 2- tert-but lamino oxo-acet l chloro-N- 3-c anofiuoro- phenyl )methyl-pyrrolecarboxamide CI H F NH / | O N// O N Compound 50 (500 mg) was synthesized similarly as described for nd 29 using methyl 4-[2-(tert-butylamino)oxo-acetyl] -3 -chloromethyl-pyrrolecarboxylate instead of methyl 3 -chloromethyl[2-oxo[[(1R)-2,2,2-trifiuoromethyl-ethyl]- amino]acetyl]pyrrolecarboxylate. LC method B; Rt: 1.06 min. m/z: 481.0 (M-H)" Exact mass: 482.0. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.35 (s, 9 H) 3.75 (s, 3 H) 7.57 (t, J=9.13 Hz, 1 H) 7.94 - 8.03 (m, 1 H) 8.20 (dd, J=5.72, 2.64 Hz, 1 H) 8.38 (s, 1-H) 10.88 (s, 1 H).Differential ng calorimetry: From 30 to 300 CC at 10°C/min: Peak: 204.4 °C.

WO 11281 2014/066093 Com ound 51: N— 3-c anofluoro- hen l meth l 2-oxo 1S -2 2 uoro meth l-eth lamino acet l olecarboxamide O F H F F NH "IMF / I 1: N// o N A solution of 2-(5-methoxycarbonylmethyl-pyrrolyl)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, .36 mmol) and (S)-1,1,1-trifluoropropylamine (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 precipitation was formed which was collected on a filter and rinsed with water. Then it was dried in a vacuum oven at 55°C for 24 hours resulting in methyl 1-methyl[2-oxo[[(1S)-2,2,2-trifluoro methyl-ethyl]amino]acetyl]pyrrolecarboxylate (872 mg) as a beige solid. Methyl 1-methyl [2-oxo[[(1 S)-2,2,2-trifluoromethyl-ethyl]amino] acetyl]pyrrole carboxylate (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 all the reactants.The mixture was d overnight at room temperature and next concentrated in vacuo untill only water remained. HCl (1M in H20) (11.4 mL, 1 M, 11.4 mmol) was added and this was extracted using Me-THF (3 X 10 mL). The combined extracts were washed with brine (20 mL), dried on , filtered, and concentrated in vacuo yielding 1-methyl- 4-[2-oxo[[(1S)—2,2,2-trifluoromethyl-ethyl]amino]acetyl]pyrrolecarboxylic 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[2-oxo[[(1S)—2,2,2-trifluoromethyl-ethyl]amino]acetyl]- pyrrolecarboxylic 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 temperature for 30 minutes. Then 5-aminofluorobenzonitrile (209.6 mg, 1.54 mmol) was added and the resulting e was stirred for 2 hours at room temperature. The mixture was injected as such on a silicaplug and purified using silica gel column tography (gradient elution: 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. 1H NMR (400 MHz, DMSO- d6) 8 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, J=9.1 Hz, 1 H), 7.69 (d, J=1.8 Hz, 1 H), 8.03 (ddd, J=9.2, 4.9, 2.6 Hz, 1 H), 8.14 (d, J=1.3 Hz, 1 H), 8.23 (dd, J=5.8, 2.8 Hz, 1 H), 9.34 (d, J=8.1 Hz, 1 H), 10.42 (br. s., 1 H) WO 11281 Com ound 52: N— 3-c anofiuoro- hen l 2- iso ro lamino oxo-acet l -1 5- dimeth l- rrolecarboxamide QWTN F NH N" ON NaH (60% dispersion in mineral oil, 5875 mg, 147 mmol) was added portionwise to a solution of ethyl 5-methyl-1H-pyrrolecarboxylate (15000 mg, 97.92 mmol) and iodomethane (7.3 mL, 117.5 mmol) in DMF (40 mL). The on was stirred for 1 hour.

HCl (1M in H20) (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 1,5-dimethylpyrrole ylate (8.56 g) as a yellow powder which was used as such. Crude ethyl 1,5-dimethylpyrrolecarboxylate (8560 mg) was dissolved in THF (dried on molecular ) (144 mL) and 5-aminofiuorobenzonitrile (7666 mg, 56.3 mmol) was added.This mixture was cooled in an ice bath. Lithium bis(trimethylsilyl)amide (1M 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 temperature.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 trated in vacuo. The obtained residue was d by column chromato- graphy using nt elution from e to EtOAc (100:0 to 0:100). The desired fractions were collected and concentrated in vacuo yielding N-(3-cyanofiuoro-phenyl)-1,5- dimethyl-pyrrolecarboxamide (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 fiuorophenyl)-1,5-dimethyl-pyrrolecarboxamide (5000 mg, 19.44 mmol) was dissolved in DCM (50 mL) and cooled on ice under nitrogen. A solution of ethyl 2-chlorooxo-acetate (3.3 mL) in DCM (10 mL) was added dropwise and the mixture was stirred for 15 minutes.

AlC13 (5183 mg, 38.9 mmol) was added in portions. The mixture was stirred at 0°C under N2 for 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 (Na2SO4) and evaporated to dryness, resulting in crude ethyl 2-[5-[(3-cyanofiuoro-phenyl)carbamoyl]-1,2- dimethyl-pyrrolyl]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-cyano- 4-fluoro-phenyl)carbamoyl]-1,2-dimethyl-pyrrolyl]oxo-acetate (9.4 g, 26.4 mmol) was dissolved in THE (200 mL) and to this was added NaOH (1M in H20, 39.6 mL). The resulting e was stirred at room temperature for 30 minutes and next concentrated in vacuo until only water remained. Then HCl (aq/ 1M / 40 mL) was added and this was extracted using Me-THF (3 X 100 mL). The combined extracts were washed with brine, dried on Na2SO4, filtered and trated in vacuo, resulting in crude 2-[5-[(3 -cyano fluoro-phenyl)carbamoyl]-1,2-dimethyl-pyrrolyl]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-cyanofluoro-phenyl)carbamoyl]-1,2-dimethyl-pyrroly1]oxo- acetic 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 temperature for minutes. Then isopropylamine (18.09 mg, 0.31 mmol) was added and the ing mixture was stirred for 2 hours at room temperature and next at 50°C for 2 hours. The mixture was injected as such on a silicaplug and purified using silica gel column chromato- graphy (gradient elution: EtOAc-heptane 0:100 to 100:0). And filrther by Preperative HPLC (RP SunFire Prep C18 OBD-10um, mm). Mobile phase (0.25% NH4HC03 solution in water, MeOH). The desired fractions were concentrated under reduced pressure and co- ated twice (2 x 15 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. 1H NMR (400 MHz, 6) 8 ppm 1.15 (d, J=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, J=9.1 Hz, 1 H), 7.72 (s, 1 H), 8.02 (ddd, J=9.2, 5.0, 2.8 Hz, 1 H), 8.22 (dd, J=5.7, 2.6 Hz, 1 H), 8.51 (d, J=7.9 Hz, 1 H), 10.42 (s, 1 H).

Com ound 53:N— 3-c anofluoro- hen 1-1 5-dimeth 1 2- 1R meth 1 ro 1- amino oxo-acet l rrolecarboxamide O H O N N" Compound 53 was prepared similarly as described for compound 52, using (R)-(-)aminobutane instead of isopropylamine. LC method B; Rt: 1.06 min. m/z: 383.1 (M-H)‘ Exact mass: 384.2. 1H NMR (400 MHz, DMSO-d6) 8 0.86 (t, J=7.3 Hz, 3 H), 1.12 (d, J=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, J=9.2 Hz, 1 H), 7.73 (s, 1 H), 8.02 (ddd, J=9.2, 5.0, 2.8 Hz, 1 H), 8.22 (dd, J=5.7, 2.6 Hz, 1 H), 8.45 (d, J=8.4 Hz, 1 H), 10.43 (s, 1 H).

Sflthesis of 12R )—3 ,3 -difluorobutanamine (R)((tert-butoxycarbonyl)amino)propanoic acid (30 g, 159 mmol), N,O-dimethyl- hydroxylamine 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 temperature for 15 hours. The reaction mixture was concentrated under vacuum and the residue was dissolved in CH2C12 (500 mL) and washed with brine (3 x 200 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The e was purified via silica gel chromatography using petroleum ether: EtOAc 2:1 as eluent yielding utyl N-[(1R)[methoxy(methyl)amino]methyloxo-ethyl]carbamate (28.9 g). Tert-butyl N—[(1R)[methoxy(methyl)amino]methyloxo-ethyl]carbamate was dissolved in THF (300 mL) and cooled to 0°C. Methylmagnesium bromide 3.0 m in diethyl ether (85 mL, 255 mmol) was added se and the reaction mixture was stirred 15 hours at room temperature. The reaction mixture was quenched with sat. NH4Cl and extracted with CH2C12 (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. The obtained residue was d via silica gel chromatography yielding tert-butyl N—[(1R)methyloxo-propyl]carbamate (18.9 g). To a cooled (-78°C) solution of tert-butyl N-[(1R)methyloxo-propyl]carbamate (10 g, 53.4 mmol) in CH2C12 (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 e was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with sat. NaHC03 and ted with EtOAc. The ed 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 eum ether to petroleum ether:EtOAc 1:1 yielding tert-butyl N-[(1R)-2,2-difiuoromethyl-propyl]carbamate (6.77 g). utyl N-[(1R)-2,2-difiuoromethyl-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 temperature. The formed precipitate was filtered off and dried under high vacuum yielding (2R)-3,3-difiuorobutanamine hydrochloride (3.5 g).

Com ound 54:N— 3-c anofiuoro- hen l 2- 1R -2 2-difiuorometh l- ro l - amino oxo-acet l -1 5-dimeth l- olecarboxamide F NH N" ON A vial was loaded with crude 2-[5-[(3-cyanofiuoro-phenyl)carbamoyl]-1,2-dimethyl- pyrrolyl]oxo-acetic acid (250 mg,), HATU 4 mg, 0.7 mmol), (2R)-3,3-difiuoro- butanamine hydrochloride (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 temperature and injected directly onto a silica plug and purified using silica gel column chromatography (gradient elution: EtOAc- heptane 0:100to . 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 18 hours yielding nd 54 (124 mg) as white powder. LC method B; Rt: 1.06 min. m/z: 419.1 (M-H)" Exact mass: 420.1. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.23 (d, J=6.8 Hz, 3 H), 1.62 (t, J=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, J=9.1 Hz, 1 H), 7.65 (s, 1 H), 7.98 - 8.05 (m, 1 H), 8.21 (dd, J=5.7, 2.6 Hz, 1 H), 8.92 (d, J=9.2 Hz, 1 H), 10.44 (s, 1 H).

Sflthesis of 12S1-3,3-difiuorobutanamine hydrochloride (S)((tert-butoxycarbonyl)amino)propanoic acid (39 g, 206 mmol), N,O-dimethyl- ylamine 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 temperature for 16 hours. The reaction mixture was poured into water (500 mL) and the formed precipitate was filtered off. The filter cake was washed with water (1 L) and dried to give tert-butyl N-[(1S)[methoxy(methyl)amino]methyloxo- ethyl]carbamate (36 g) as a white powder. tert-butyl )—2-[methoxy(methyl)amino] oxo-ethyl]carbamate (35 g, 151 mmol) was dissolved in THF (500 mL) and cooled to 0°C. Methylmagnesium bromide (3.0 M in diethyl ether, 140 mL) was added and the on mixture was d 16 hours at room temperature. 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, filtered and evaporated to dryness yielding tert-butyl N-[(1S)methyloxo-propyl]carbamate (22 g) as a white powder. To a cooled (-78°C) solution of tert-butyl N-[(1S)methyloxo-propyl]carbamate (12 g, 64.1 mmol) in CH2C12 (200 mL) bis(2-methoxyethyl)aminosulfi1rtrifiuoride (18.9 g, 117.5 mmol) was added. The reaction mixture was allowed to warm to room ature and stirred overnight. The reaction e was poored into water and extracted with CH2C12. The organic layer was washed with water, dried over Na2SO4, filtered and evaporated to dryness.

The obtained residue was purified by silica gel chromatography yielding tert-butyl N—[(1S)—2,2-difiuoromethyl-propyl]carbamate (5.8 g) as a pale yellow solid. Tert-butyl N-[(1S)—2,2-difiuoromethyl-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-difiuorobutanamine hydrochloride (3.8 g) 1H NMR (400MHz, DMSO-d6) 5 ppm 8.69 (br. s., 3H), 3.76 — 3.63 (m, 1H), 1.72 (t, J=19.7 Hz, 3H), 1.28 (d, J=6.8 Hz, 3H).

Com ound 55:N- 3-c anofluoro- hen l 2- 1S -2 2-difluorometh l- ro l- amino oxo-acet l -1 5-dimeth l- olecarboxamide F NH s. F / I 1: N" O N Compound 55 (130 mg) was prepared similarly as described for compound 54, using (2S)-3,3-difluorobutanamine hydrochloride d of ,3-difluorobutanamine hydrochloride. LC method B; Rt: 1.06 min. m/z: 419.1 (M-H)‘ Exact mass: 420.1. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.23 (d, J=6.8 Hz, 3 H), 1.62 (t, J=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, J=9.1 Hz, 1 H), 7.65 (s, 1 H), 7.98 - 8.05 (m, 1 H), 8.21 (dd, J=5.7, 2.6 Hz, 1 H), 8.92 (d, J=9.2 Hz, 1 H), 10.44 (s, 1 H).

Com ound 56 :N- 3-c anofluoro- hen l 2- 3 orometh l-c clobut l- amino oxo-acet l -1 5-dimeth l- olecarboxamide 0 H F9W3?NH N// O N F F Compound 56 (147 mg) was ed similarly as described for compound 54, using 3,3-difluoromethyl-cyclobutanamine hydrochloride instead of (2R)-3,3-difluorobutan- 2-amine hydrochloride. LC method B; Rt: 1.08 min. m/z: 431.1 (M-H)" Exact mass: 432.1. 1H NMR (400 MHz, DMSO-d6) 8 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, J=9.1 Hz, 1 H), 7.73 (s, 1 H), 7.99 - 8.06 (m, 1 H), 8.22 (dd, J=5.8, 2.8 Hz, 1 H), 9.10 (s, 1 H), 10.45 (s, 1 H).

Com ound 57: N- 3-c anofluoro- hen l -1 5-dimeth l 2-oxo 1- trifluorometh l - c clo ro lamino acet l olecarboxamide 0 HF F F Q W76NH N" O N WO 11281 Compound 57 (138 mg) was prepared similarly as described for nd 54, using 1-trifluoromethylcyclopropylamine instead of (2R)-3,3-difluorobutanamine hydrochloride. LC method B; Rt: 1.07 min. m/z: 435.1 (M-H)" Exact mass: 436.1. 1H NMR (400 MHz, DMSO-d6) 8 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, J=5.7, 2.6 Hz, 1 H), 9.49 (s, 1 H), 10.46 (s, 1 H).

Com ound 58: N— 3-c anofluoro- hen l -1 5-dimeth l 2-oxo 2 2 2-trifluoro-1 1- dimeth l-eth lamino acet l rrolecarboxamide O H F NH / I NflF O F // O N N / Compound 58 (129 mg) was prepared similarly as bed for nd 54, using 2,2,2-trifluoro-1,1-dimethyl-ethylamine instead of (2R)-3,3-difluorobutanamine hydrochloride. LC method B; Rt: 1.14 min. m/z: 437.1 (M-H)" Exact mass: 438.1. 1H NMR (400 MHz, DMSO-d6) 8 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, J=5.8, 2.8 Hz, 1 H), 8.62 (s, 1 H), 10.48 (s, 1 H) Com ound 59: 4- 2- tert-but lamino oxo-acet l -N- 3-c anofluoro- hen l -1 5- dimeth l- rrolecarboxamide F QWCNH N" ON Compound 59 (54 mg) was prepared similarly as described for compound 54, using tertbutylamine instead of (2R)-3,3-difluorobutanamine hydrochloride. LC method B; Rt: 1.10 min. m/z: 383.1 (M-H)" Exact mass: 384.2. 1H NMR (400 MHZ, DMSO-d6) 8 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) 2014/066093 Com ound 60:N— 3-c anofluoro- hen ldimeth l 2- 3-meth loxetan l - amino oxo-acet l rrolecarboxamide Compound 60 (149 mg) was ed similarly as described for compound 54, using 3-methyloxetanamine instead of ,3-difluorobutanamine hydrochloride. LC method B; Rt: 0.90 min. m/z: 397.1 (M-H)" Exact mass: 398.1. 1H NMR (400 MHz, DMSO- d6) 8 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, J=6.4 Hz, 2 H), 7.52 (t, J=9.1 Hz, 1 H), 7.77 (s, 1 H), 7.98 - 8.06 (m, 1 H), 8.21 (dd, J=5.8, 2.8 Hz, 1 H), 9.22 (s, 1 H), 10.45 (s, 1 H).

Com ound 61:N— 3-c anofluoro- hen lc clo ro lmeth l 2-oxo 1R - 2 2 2-trifluorometh l-eth 1 amino acet l rrolecarboxamide O F H F F4/< >7NH NR /| (fig: N" 0 N A microwave Vial was charged with compound 25 (100 mg, 0.2 mmol), potassium cyclo- propyltrifluoroborate (45mg, 0.31 mmol), CS2C03 (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)palladium(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. NH4Cl-sol and Me-THF. The organic layer was separated, dried (MgSO4), d and concentrated in vacuo. The crude was purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0: 100 to 100:0) and filrther by preparative HPLC (RP SunFire Prep C18 OBD-10um, 30x150mm). Mobile phase (0.25% NH4HC03 solution in water, MeOH), nd 61 (16 mg) as a white powder.

LC method B; Rt: 1.11 min. m/z: 449.1 (M-H)" Exact mass: 450.1. 1H NMR (400 MHz, DMSO-d6) 5 ppm 0.61 - 0.70 (m, 2 H), 1.02 - 1.13 (m, 2 H), 1.34 (d, J=7.0 Hz, 3 H), 1.76 - 1.90 (m, 1 H), 3.96 (s, 3 H), 4.70 (dq, J=15.5, 7.7 Hz, 1 H), 7.52 (t, J=9.2 Hz, 1 H), 7.56 (s, 1 H), 7.96 - 8.06 (m, 1 H), 8.21 (dd, J=5.8, 2.8 Hz, 1 H), 9.25 (d, J=8.8 Hz, 1 H), 10.42 (s, 1 H).

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

Com ound 62:N— 3-c anofluoro- hen l 2- 3R 4S h drox h l i erid 1 amino oxo-acet l -1 5-dimeth l- olecarboxamide O H H? N,,,,, F NH (g) / | o N\ // O N N / (3R,4S)aminomethylpiperidinol was used as amine, resulting in compound 62 (40.3 mg). 1H NMR (400 MHz, DMSO-d6) 8 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.

Com ound 63: N— 3-c anofluoro- hen l 2- 1S h drox eth 1 en lamino - 2-oxo-acet ldimeth l- rrolecarboxamide (S)—(+)—2-aminohexanol was used as amine, ing in compound 63 (33.7 mg). 1H NMR (400 MHz, DMSO-d6) 8 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, J=9.2, 4.8, 2.6 Hz, 1 H), 8.22 (dd, J=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.

Com ound 65: N— 3-c anofluoro- hen 1 2- 1S 2S h drox c clo ent lamino - 2-oxo-acet ldimeth l- rrolecarboxamide 0 H 0.: F NH N,,;s' Om b // N N / (1 S,2S)-transaminocyclopentanol hydrochloride was used as amine, ing in compound 65 (27.1 mg). 1H NMR (400 MHz, DMSO-d6) 8 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, J=4.0 Hz, 1 H), 7.52 (t, J=9.1 Hz, 1 H), 7.71 (s, 1 H), 8.02 (ddd, J=9.2, 4.9, 2.6 Hz, 1 H), 8.22 (dd, J=5.7, 2.6 Hz, 1 H), 8.54 (d, J=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.

Com ound 66 :N— 3-c anofluoro- hen l 2- 1S 2R 5R h drox meth l- c clo ent lamino oxo-acet ldimeth l- rrolecarboxamide O H Nflgs'9(2) F NH - // om 13N (R) N / (1R,2S,3R)aminomethyl-cyclopentanol hloride was used as amine, resulting in compound 66 (38.2 mg). 1H NMR (400 MHz, DMSO-d6) 8 ppm 0.98 (d, J=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, J=4.2 Hz, 1 H), 7.52 (t, J=9.1 Hz, 1 H), 7.92 (s, 1 H), 7.96 - 8.06 (m, 2 H), 8.22 (dd, J=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.

Com ound 67 :N— 3-c fluoro- hen l 2- 1S 2S h drox c clohex 1 amino - 2-oxo-acet ldimeth l- rrolecarboxamide o H F NH N" O N Trans-(1S,2S)- 2-aminocyclohexanol hydrochloride was used as amine, resulting in compound 67 (42.5 mg). 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.19 - 1.35 (m, 4 H), 1.51 - 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, J=4.8 Hz, 1 H), 7.52 (t, J=9.1 Hz, 1 H), 7.79 (s, 1 H), 8.02 (ddd, J=9.2, 4.9, 2.6 Hz, 1 H), 8.22 (dd, J=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.

Com ound 68:N— 3-c anofluoro- hen 1 2- 1S h drox eth 1meth 1- ro 1 amino oxo-acet 1 -1 5-dimeth 1- olecarboxamide O H o N OHO N// / (S)-(+)aminomethy1butanol was used as amine, resulting in nd 68 (43.9 mg). 1H NMR (400 MHz, DMSO-d6) 8 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, J=5.2 Hz, 1 H), 7.52 (t, J=9.1 Hz, 1 H), 7.78 (s, 1 H), 8.02 (ddd, J=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.

Com ound 69 :N— 3-c anofluoro- hen 1 2- 1S 2S h drox eth 1 h 1- but 1 amino oxo-acet 1 -1 5-dimeth 1- rrolecarboxamide O H OHO O N N// / L-isoleucinol was used as amine, resulting in compound 69 (34.8 mg). 1H NMR (400 MHz, DMSO-d6) 8 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, J=9.1 Hz, 1 H), 7.79 (s, 1 H), 8.03 (ddd, J=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.

W0 2015/011281 Com ound 70:N— 3-c anofluoro- hen l 2- 3-h drox methox eth l meth l- ro lamino oxo-acet ldimeth l- rrolecarboxamide \\ O O N / O/ F I NH N O omethoxymethylbutanol was used as amine, resulting in compound 70 (13.5 mg). 1H NMR (400 MHz, DMSO-d6) 8 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, J=9.1 Hz, 4 H), 3.83 (s, 3 H), 4.54 - 4.70 (m, 1 H), 7.52 (t, J=9.1 Hz, 1 H), 7.80 (s, 1 H), 8.03 (ddd, J=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.

Com ound 71 :N— 3-c fluoro- hen l 2- 3- h drox meth loxetan 1 amino - 2-oxo-acet ldimeth l- rrolecarboxamide F gmfloNH 0H N" N (3-aminooxetanyl)methanol was used as amine, resulting in compound 71 (36.4 mg). 1H NMR (400 MHz, DMSO-d6) 5 ppm 2.58 (s, 3 H), 3.66 - 3.74 (m, 2 H), 3.85 (s, 3 H), 4.54 (d, J=6.6 Hz, 2 H), 4.66 (d, J=6.6 Hz, 2 H), 5.14 - 5.31 (m, 1 H), 7.52 (t, J=9.1 Hz, 1 H), 7.77 (s, 1 H), 7.98 - 8.07 (m, 1 H), 8.22 (dd, J=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.

Com ound 72:N— 3-c anofluoro- hen l 2- 2-h drox dimeth l- ro lamino - 2-oxo-acet ldimeth l- rrolecarboxamide O H F NH O N N" 3-aminomethylbutanol was used as amine, resulting in compound 72 (6.3 mg). 1H NMR (400 MHz, DMSO-d6) 8 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, J=9.1 Hz, 1 H), 7.79 (s, 1 H), 8.02 (ddd, W0 2015/011281 2014/066093 J=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.

Com ound 73:N— 3-c anofluoro- hen l 2- l- h drox eth lc clo ro lamino - 2-oxo-acet ldimeth l- 2-carboxamide 0 H F NH OH Om7? // N N / To a Vial containing (1-aminocyclopropyl)methanol (32 mg, 0.37 mmol), HATU (128.03 mg, 0.34 mmol) was added followed by 2-[5-[(3 -cyanofluoro-phenyl)- carbamoyl]-1,2-dimethyl-pyrrolyl]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 ing mixture was stirred for 5 hours at room temperature. Then water (5 mL) was added and the mixture was extracted using CH2C12 (2 x 5 mL). The combined organics were concentrated and the mixture purified Via preperative HPLC (Stationary phase: RP XBridge Prep C18 OBD- 10um,30xl50mm, Mobile phase: 0.25% NH4HC03 on in water, MeOH) and fiarther 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). 1H NMR (400 MHz, DMSO-d6) 8 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, l H), 7.52 (t, J=9.2 Hz, 1 H), 7.71 (s, l H), 8.02 (ddd, J=9.3, 4.9, 2.8 Hz, 1 H), 8.22 (dd, J=5.8, 2.8 Hz, 1 H), 8.78 (s, l H), 10.46 (s, l H). LC method B; Rt: 0.80 min. m/z: 397.1 (M-H)‘ Exact mass: 398.1.

Com ound 74:N— 3-c anofluoro- hen l 2- l-c clo ro lh drox - ro l- amino oxo-acet l -1 5-dimeth l- olecarboxamide 0 H F NH / 0 N N/ / OH ocyclopropyl-propanol was used as amine, resulting in compound 74 (40 mg). 1H NMR (400 MHz, DMSO-d6) 8 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, J=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, J=9.2 Hz, 1 H), 7.75 (s, 1 H), 8.02 (ddd, J=9.2, 4.9, 2.9 Hz, 1 H), 8.22 (dd, J=5.8, 2.8 Hz, 1 H), 8.54 (d, J=8.8 Hz, 1 H), 10.46 (s, 1 H). LC method C; Rt: 1.75 min. m/z: 425.2 (M-H)‘ Exact mass: 426.2 Com ound 75:N- 3-c anofluoro- hen l 2- 1R h drox eth l ent lamino - 2-oxo-acet ldimeth l- rrolecarboxamide \\ O O Na; F I NH N 0 WA )aminohexanol was used as amine, resulting in compound 75 (22 mg). 1H NMR (400 MHz, DMSO-d6) 5 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, J=9.1 Hz, 1 H), 7.77 (s, 1 H), 8.03 (ddd, J=9.2, 5.0, 2.8 Hz, 1 H), 8.22 (dd, J=5.8, 2.8 Hz, 1 H), 8.28 (d, J=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 Com ound 76:N- 3-c fluoro- hen l 2- 1- h drox eth lmeth l- ro l- amino oxo-acet l -1 5-dimeth l- olecarboxamide 0 " OH F NH N// 0 N 2-aminomethylbutanol was used as amine, resulting in compound 76 (26 mg). 1H NMR (400 MHz, DMSO-d6) 8 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, J=9.1 Hz, 1 H), 7.76 (s, 1 H), 7.80 (s, 1 H), 8.03 (ddd, J=9.2, 5.0, 2.8 Hz, 1 H), 8.22 (dd, J=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 Com ound 77: N- 3-c anofluoro- hen l 2- 1-c clo ro lh drox meth l- eth 1 amino oxo-acet l -1 5-dimeth l- rrolecarboxamide 0 H F NH /I O (4V N" 0 N OH 2-aminocyclopropylpropanol was used as amine, resulting in compound 77 (24 mg).

W0 2015/011281 1H NMR (400 MHz, DMSO-d6) 8 ppm 0.28 - 0.41 (m, 3 H), 0.42 - 0.51 (m, 1 H), 1.10 (s, 3 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, J=9.2 Hz, 1 H), 7.75 (s, 1 H), 7.82 (s, 1 H), 8.03 (ddd, J=9.1, 5.0, 2.6 Hz, 1 H), 8.22 (dd, J=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.

Com ound 78: N— 3-c anofluoro- hen 1dimeth 1 2- 3-meth h dro an- 3- 1 amino oxo-acet 1 olecarboxamide 0 H FQmoNH N" o N 3-methyloxanamine was used as amine, resulting in compound 78 (15 mg). 1H NMR (400 MHz, 6) 8 ppm 1.31 (s, 3 H), 1.40 - 1.70 (m, 3 H), 2.24 (m, J=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, J=9.1 Hz, 1 H), 7.73 (s, 1 H), 7.97 - 8.07 (m, 2 H), 8.22 (dd, J=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.

Com ound 79 :N— 3-c anofluoro- hen 1 2- 2-methox -1 1-dimeth 1-eth 1amino - 2-oxo-acet 1dimeth 1- rrolecarboxamide \\ 0H NHNIOKN / / o 1-methoxyaminomethy1propane was used as amine, resulting in compound 79 (31 mg). 1H NMR (400 MHz, DMSO-d6) 8 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, J=9.1 Hz, 1 H), 7.70 (s, 1 H), 7.95 - 8.08 (m, 2 H), 8.22 (dd, J=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.

Com ound 80: N— 3-c anofluoro- hen l -l 5-dimeth l 2-oxo 2 2 uoro-l- methox eth lmeth l-eth lamino acet l rrolecarboxamide \\ O o N / O/ F I NH N O F F / F l,l,l-trifluoromethoxymethylpropanamine hydrochloride was used as amine, resulting in compound 80 (52 mg). 1H NMR (400 MHZ, DMSO-ds) 8 ppm 1.60 (s, 3 H), 2.57 (s, 3 H), 3.34 (s, 3 H), 3.67 (d, J=9.7 Hz, 1 H), 3.84 (s, 3 H), 3.96 (d, J=9.7 Hz, 1 H), 7.52 (t, J=9.1 Hz, 1 H), 7.63 (s, l H), 8.01 (ddd, J=9.2, 5.0, 2.8 Hz, 1 H), 8.22 (dd, J=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.

Com ound 81:N— 3-c anofluoro- hen l 2- 3-h drox -l l-dimeth l- ro lamino - 2-oxo-acet ldimeth l- rrolecarboxamide 0 H F Q m 74m)"NH N// 0 N 3-aminomethylbutanol was used as amine, resulting in compound 81 (24 mg).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.38 (s, 6 H), 1.84 (t, J=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, J=9.2, 4.9, 2.6 Hz, 1 H), 8.22 (dd, J=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.

Com ound 82: N— 3-c anofluoro- hen l 2- 4-h drox -l- trifluorometh lc clo- hex 1 amino oxo-acet l -1 5-dimeth l- carboxamide O F H F F NHW F // O N /N OH o(trifluoromethyl)cyclohexanol was used as amine, resulting in compound 82 (10 mg). 1H NMR (400 MHz, DMSO-d6) 8 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, J=9.1 Hz, WO 11281 1 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, 1 H), 10.52 (br. s., 1 H). LC method B; Rt: 1.00 min. m/z: 493.1 (M-H)" Exact mass: 494.2.

Com ound 83:N— 3-c fluoro- hen lfluorometh l 2-oxo 3- trifluoro- meth ltetrah drofuran 1 amino acet l olecarboxamide F Q m{éNH o N 0 N" / Compound 83 was prepared similarly as described for compound 34, using 3-(trifluoromethyl )tetrahydrofuranamine hydrochloride instead of 2-methylpropanamine. 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. 1H NMR (400 MHz, DMSO-d6) 8 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, J=10.6 Hz, 1 H) 4.27 (d, J=10.6 Hz, 1 H) 7.54 (t, J=9.0 Hz, 1 H) 7.92 - 8.04 (m, 2 H) 8.18 (dd, J=5.7, 2.6 Hz, 1 H) 9.40 (s, l H) 10.37 (s, l H).

Com ound 84: N— 3-c anofluoro- hen lfluorometh l 2- 1- trifluoro- meth lc clobut lamino acet l rrolecarboxamide F Q m 5:NH N// O N Compound 84 was prepared similarly as described for compound 34, using 1-(trifluoro- methyl)cyclobutan-l-amine instead of 2-methylpropanamine. 1H NMR (400 MHz, 6) 8 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, J=9.1 Hz, 1 H) 7.97 (ddd, J=9.2, 4.9, 2.6 Hz, 1 H) 8.04 (d, J=4.4 Hz, 1 H) 8.18 (dd, J=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 °C/min: Peak: 194.7 0C.

Com ound 85:N— 3-c anofluoro- hen lfluorometh l 2-oxo 1R - 2,2,2-trifluoromethyl-ethyl |amino |acetyl |pyrrolecarboxamide F O F F :N N \N O N\ Compound 85 was prepared rly as described for compound 34, using (R)-1,1,1-trifluoropropylamine d of 2-methylpropanamine. LC method C; Rt: 1.95 min. m/z: 427.2 (M-H)" Exact mass: 428.1. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.35 (d, J=7.0 Hz, 3 H) 3.86 (s, 3 H) 4.58 - 4.75 (m, 1 H) 7.54 (t, J=9.1 Hz, 1 H) 7.97 (ddd, J=9.2, 4.8, 2.9 Hz, 1 H) 8.04 (d, J=4.4 Hz, 1 H) 8.18 (dd, J=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 in: Peak: 197.1 °C.

Com ound 86 : 3 5-dichloro-N- 3-c anofluoro- hen l meth l 2-oxo 1R - 2 2 2-trifluorometh l-eth 1 amino acet l rrolecarboxamide F NHW F N// O N 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 temperature and next heated at 40°C overnight. 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. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.33 (d, J=7.0 Hz, 3 H), 3.75 (s, 3 H), 4.70 (dq, J=15.5, 7.6 Hz, 1 H), 7.57 (t, J=9.1 Hz, 1 H), 7.92 - 8.01 (m, 1 H), 8.20 (dd, J=5.7, 2.6 Hz, 1 H), 9.50 (d, J=8.8 Hz, 1 H), 10.91 (br. s., 1 H).

Com ound 87: ro-N- 3-c anofluoro- hen l meth l 2-oxo 1R -2 2 2- trifluoro-l-meth l-eth lamino acet l rrolecarboxamide O F H F F >C WY:NH N// 0 N 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 uL, 0.11 mmol). The 2014/066093 resulting mixture was stirred at room temperature for 18 hours. Then it was poured into water and extracted using CH2C12 (3 X 15 mL). The combined extracts were washed with NaHC03 (20 mL, aq / sat), dried on Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by Preperative HPLC on (RP SunFire Prep C18 um, 30x150mm). Mobile phase (0.25% NH4HC03 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. 1H NMR (600 MHz, CHLOROFORM-d) 8 ppm 1.44 (d, J=6.9 Hz, 3 H), 4.02 (s, 3 H), 4.65 (dquin, J=9.8, 7.0, 7.0, 7.0, 7.0 Hz, 1 H), 7.22 (t, J=8.7 Hz, 1 H), 7.45 (d, J=9.7 Hz, 1 H), 7.71 (ddd, J=9.1, 4.5, 2.8 Hz, 1 H), 7.96 (s, 1 H), 8.06 (dd, J=5.4, 2.8 Hz, 1 H), 8.11 (s, 1 H).

Com ound 88: ro-N— 3-c anofiuoro- hen l meth 1 2-oxo 1S -2 2 2- trifluoro-l-meth l-eth lamino acet l rrolecarboxamide O F "IMFH F F NH / I i N// O N Compound 88 was prepared similarly as described for compound 87 (stirring at room ature for 6 hours instead of 18 hours), ng from compound 51 d of compound 64. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.35 (d, J=7.0 Hz, 3 H), 3.93 (s, 3 H), 4.62 - 4.79 (m, 1 H), 7.54 (t, J=9.1 Hz, 1 H), 7.79 (s, 1 H), 8.01 (ddd, J=9.2, 4.8, 2.9 Hz, 1 H), 8.21 (dd, J=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.

Com ound 89 : 5-chloro-N— 3-c anofiuoro- hen l fiuorometh 1 2-oxo- 2- 3- trifluorometh ltetrah drofuran lamino acet l olecarboxamide F NH N// 0 N 0 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 temperature and was then heated at 55°C for 16 hour. Purification was performed Via Preperative HPLC (Stationary phase: RP e Prep C18 ODB- 5um, 30x250mm, Mobile phase: 0.25% NH4HC03 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. 1H NMR (400 MHz, 6) 8 ppm 2.28 - 2.42 (m, 1 H) 2.45- 2.59 (m, l H) 3.75 - 3.84 (m, 4 H) 3.85 - 3.97 (m, l H) 4.10 (d, J=10.3 Hz, 1 H) 4.23 (d, J=10.6 Hz, 1 H) 7.55 (t, J=9.1 Hz, 1 H) 7.96 (ddd, J=9.2, 4.8, 2.9 Hz, 1 H) 8.16 (dd, J=5.7, 2.9 Hz, 1 H) 9.54 (s, l H) 10.61 (s, l H).

Com ound 90: 5-chloro-N- 3-c fluoro- hen l rometh l 2-oxo 1- trifluorometh l c clobut 1 amino acet l olecarboxamide F Q W 6KNH N// 0 N 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’C. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.84 - 2.08 (m, 2 H) 2.40 - 2.57 (m, 4 H) 3.81 (s, 3 H) 7.56 (s, l H) 7.91 - 8.00 (m, l H) 8.16 (dd, J=5.8, 2.8 Hz, 1 H) 9.41 (s, l H) 10.60 (br. s, l H).

Com ound 91 : 5-chloro-N- 3-c anofluoro- hen l fluorometh l 2-oxo 1R - 2 2 2-trifluoro-l-meth l-eth 1 amino acet l rrolecarboxamide F NH / | "Mfg N// o N 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. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.32 (d, J=7.0 Hz, 3 H) 3.80 (s, 3 H) 4.60 - 4.77 (m, l H) 7.55 (s, l H) 7.95 (ddd, J=9.2, 4.8, 2.9 Hz, 1 H) 8.16 (dd, J=5.8, 2.8 Hz, 1 H) 9.48 (d, J=8.6 Hz, 1 H) 10.58 (br. s., l H).

Com ound 92: ro-N- 3-c anofluoro- hen l 2- 2-h drox -1 1-dimeth l- eth 1 amino -acet l h l- olecarboxamide m7LCI H F NH OH // O N N / Et3N (0.18 mL, 1.287 mmol) was added to a solution of 2-[4-chloro[(3 -cyanofluoro- phenyl)carbamoyl]methyl-pyrrolyl]oxo-acetic acid (150 mg, 0.429 mmol), HATU (204 mg, 0.536 mmol), 2-aminomethylpropanol (0.051 mL, 0.536 mmol) in DMF (1.1 mL) and stirred 30 minutes at room temperature. The solution was purified 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 temperature.

The mixture was concentrated in vacuo and the residue partioned between water and CH2C12. The organic layer was separated and trated 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. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.29 (s, 6 H) 3.45 (d, J=5.7 Hz, 2 H) 3.82 (s, 3 H) 4.99 (t, J=5.8 Hz, 1 H) 7.56 (t, J=9.1 Hz, 1 H) 7.90 (s, 1 H) 7.98 (ddd, J=9.2, 4.9, 2.6 Hz, 1 H) 8.21 (dd, J=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.

Com ound 93: N— 3-c anofluoro- hen l 2- 1R -2 2-difluorometh l ro l- amino oxo-acet l fluorometh l- olecarboxamide H O N \\ II F nd 93 (130 mg) was prepared similarly as described for compound 34, using (2R)- 3,3-difluorobutanamine hydrochloride instead of 2-methylpropanamine. LC method C; Rt: 1.97 min. m/z: 423.4 (M-H)" Exact mass: 424.1. ential scanning calorimetry: From 30 to 300 CC at 10°C/min: Peak: 206.8 c’C. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.23 (d, J=7.0 Hz, 3 H), 1.61 (t, J=19.3 Hz, 3 H), 3.86 (s, 3 H), 4.25 - 4.40 (m, 1 H), 7.54 (t, J=9.1 Hz, 1 H), 7.97 (ddd, J=9.1, 5.0, 2.6 Hz, 1 H), 8.02 (d, J=4.2 Hz, 1 H), 8.18 (dd, J=5.7, 2.6 Hz, 1 H), 8.97 (d, J=9.2 Hz, 1 H), 10.35 (br. s., 1 H).

Com ound 94: N— 3-c anofluoro- hen l 2- 2-h drox -1 1-dimeth l-eth lamino oxo-acet l -1 5-dimeth l- olecarboxamide F 9m*0 NH 0H N" N Compound 94 (46 mg) was prepared similarly as bed for compound 73, using 2-aminomethylpropanol instead of (1-aminocyclopropyl) methanol. LC method C; Rt: 1.72 min. m/z: 399.2 (M-H)" Exact mass: 400.2. 1H NMR (400 MHz, DMSO-d6) 8 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, J=5.7 Hz, 1 H) 7.52 (t, J=9.1 Hz, 1 H) 7.80 (s, 1 H) 7.89 (s, 1 H) 8.03 (ddd, J=9.2, 5.0, 2.8 Hz, 1 H) 8.22 (dd, J=5.9, 2.6 Hz, 1 H) 10.45 (s, 1 H) Com ound 95: N— 3-c anofluoro- hen lfluoro 2- 1R h drox meth l- eth 1 amino oxo-acet l meth l- olecarboxamide F NH N // O NTR)\/OH N F o H Compound 95 (28 mg) was prepared similarly as described for compound 34, using D-alaninol instead of 2-methylpropanamine. LC method C; Rt: 1.54 min. m/z: 389.2 (M-H)‘ Exact mass: 390.1. Differential ng calorimetry: From 30 to 300 °C at in: Peak: 191.8 c’C. 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.10 (d, J=6.8 Hz, 3 H) 3.32 - 3.46 (m, 2 H) 3.81 - 3.92 (m, 4 H) 4.76 (t, J=5.6 Hz, 1 H) 7.54 (t, J=9.1 Hz, 1 H) 7.97 (ddd, J=9.1, 4.8, 2.8 Hz, 1 H) 8.12 (d, J=4.4 Hz, 1 H) 8.18 (dd, J=5.7, 2.6 Hz, 1 H) 8.42 (d, J=8.4 Hz, 1 H) 10.34 (s, 1 H).

Com ound 96: N— 3-c anofluoro- hen lfluoro 2- 2-methox -1 1-dimeth l- eth 1 amino oxo-acet l meth l- olecarboxamide F NH \N // O N F NXO/ O H Compound 96 (145 mg) was prepared similarly as described for compound 34, using 1-methoxymethylpropanamine d of 2-methylpropanamine. LC method C; Rt: 1.98 min. m/z: 417.2 (M-H)" Exact mass: 418.1. 1H NMR (400 MHz, FORM- d) 8 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, J=9.1, 4.5, 2.8 Hz, 1 H) 7.87 - 7.97 (m, 1 H) 8.05 (dd, J=5.5, 2.6 Hz, 1 H) 8.24 (d, J=4.6 Hz, 1 H).

Com ound 97: 5-chloro-N- 4-fluorometh l- hen l meth l 2-oxo 1S -2 2 2- ro-l-meth l-eth lamino acet l rrolecarboxamide F$\\S\ F (SI-1N F 2-(5 -(4-fluoromethylphenylcarbamoyl)methyl-1H-pyrrolyl)oxoacetic acid (500 mg, 1.64 mmol) was dissolved in HOAc (25 mL). Trifluoromethanesulfonic acid (218 uL) was added, followed by NCS (219 mg, 1.64 mmol) in portions. This was stirred for 4 hours at room temperature. The mixture was poured into water (20 mL) and then extracted using dichloromethane (3 x 25 mL). The combined extracts were washed with NaHC03 (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 to- graphy (gradient elution: EtOAc-heptane 0:100 to 100:0) yielding 2-[2-chloro[(4-fluoro- 3-methyl-phenyl)carbamoyl]methyl-pyrrolyl]oxo-acetic acid (109 mg) as an oil wich was used as such. A vial was d with 2-[2-chloro[(4-fluoromethyl- phenyl)carbamoyl]methyl-pyrrolyl]oxo-acetic acid (109.4 mg, 0.32 mmol), (S)-1,1,1-trifiuoropropylamine (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 temperature. Water (5 mL) was added and the e was extracted using CH2C12 (2 X 15 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. 1H NMR (400 MHZ, DMSO-d6) 8 ppm 1.34 (d, J=7.0 Hz, 3 H), 2.23 (d, J=1.8 Hz, 3 H), 3.92 (s, 3 H), 4.63 - 4.79 (m, 1 H), 7.11 (t, J=9.2 Hz, 1 H), 7.48 - 7.56 (m, 1 H), 7.63 (dd, J=7.0, 2.2 Hz, 1 H), 7.73 (s, 1 H), 9.42 (d, J=7.9 Hz, 1 H), 10.24 (s, 1 H).

Com ound 98: 4- 2- tert-but lamino oxo-acet l chloro-N- 3-c anofiuoro- hen l - 1-meth l- olecarboxamide 0 H F NH // O /N CI Compound 98 (17 mg) was prepared similarly as described for nd 87 (stirring at room temperature for 5 hours instead of 18 hours), starting from nd 15 instead of compound 64. The obtained crude was purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0:100 to . 1H NMR (400 MHZ, FORM-d) 8 ppm 1.37 (s, 9 H), 3.92 (s, 3 H), 7.53 (t, J=9.1 Hz, 1 H), 7.76 (s, 1 H), 8.02 (ddd, J=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.

Com ound 99:N— 3-c anofiuoro- hen lfiuoro 2- 2-h drox -1 1-dimeth l- eth 1 amino oxo-acet l meth l- olecarboxamide H F N /N o / HO%m N\ HN F Ethyl 3 -fluoro [2- [(2-hydroxy- 1 ,1-dimethyl-ethyl)amino]oxo-acetyl]methyl-pyrrole- 2-carboxylate was prepared similarly as described for ethyl 4-[2-(tert-butylamino)oxo- acetyl] -3 -fluoromethyl-pyrrolecarboxylate, using 2-aminomethyl- 1 nol instead of 2-methylpropanamine and stirring 2 hours at room temperature instead of minutes at 65°C. Compound 99 (5 mg) was ed similarly as described for compound 34, using ethyl 3 -fiuoro [2-[(2-hydroxy-1 , 1 -dimethyl-ethyl)amino]oxo- acetyl]methyl-pyrrolecarboxylateinstead of ethyl 4-[2-(tert-butylamino)oxo-acetyl]- 3-fiuoromethyl-pyrrolecarboxylate. 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: RP XBridge Prep C18 OBD-10um,30x150mm, Mobile phase: 0.25% NH4HC03 on in water, CH3CN). LC method B; Rt: 0.90 min. m/z: 403.2 (M-H)‘ Exact mass: 404.1. 1H NMR (400 MHz, CHLOROFORM-d) 8 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, J=5.4, 2.8 Hz, 1 H) 8.23 (d, J=4.6 Hz, 1 H) WO 11281 Com ound 100: 5-chloro-N- 3-c anofluoro- hen lmeth l 2- 3-meth loxetan- 3- 1 amino oxo-acet l olecarboxamide Compound 100 (12.8 mg) was prepared similarly as described for compound 87 (stirring at room temperature for 5 hours instead of 18 hours, using DMF (4,84 mL) d of HOAc), starting from compound 16 instead of compound 64. The obtained crude was purified using silica gel column chromatography (gradient n: EtOAc-heptane 0: 100 to 100:0). LC method B; Rt: 0.94 min. m/z: 417.1 (M-H)" Exact mass: 418.08. 1H NMR (400 MHz, 6) 8 ppm 1.60 (s, 3 H), 3.93 (s, 3 H), 4.37 (d, J=6.6 Hz, 2 H), 4.73 (d, J=6.4 Hz, 2 H), 7.53 (t, J=9.1 Hz, 1 H), 7.90 (s, 1 H), 8.02 (ddd, J=9.2, 4.9, 2.6 Hz, 1 H), 8.21 (dd, J=5.7, 2.6 Hz, 1 H), 9.34 (s, 1 H), 10.58 (br. s., 1 H).

Com ound 101:N— 3-c anofluoro- hen lfluorometh l 2-oxo 1- trifluoro- meth lc clo ro lamino acet l rrolecarboxamide FH F o F o F N \ N \ \ H \N o N Compound 101 (17 mg) was prepared similarly as described for compound 34 using 1-trifluoromethylcyclopropylamine instead of 2-methylpropanamine. LC method B; Rt: 1.05 min. m/z: 439.1 (M-H)" Exact mass: 440.09. 1H NMR (400 MHZ, DMSO-d6) 8 ppm 1.07 - 1.20 (m, 2 H), 1.26 - 1.37 (m, 2 H), 3.85 (s, 3 H), 7.53 (t, J=9.1 Hz, 1 H), 7.96 (ddd, J=9.2, 4.8, 2.9 Hz, 1 H), 8.04 (d, J=4.4 Hz, 1 H), 8.18 (dd, J=5.8, 2.8 Hz, 1 H), 9.57 (s, 1 H), 10.37 (br. s., 1 H).

WO 11281 Com ound 102: N— 3-c anofluoro- hen lfluoro 2- l- h drox eth lc clo- ro 1 amino oxo-acet l -l-meth l- olecarboxamide HOLP F OF 0 \ N \ \ H \N o N Compound 102 (37.7 mg) was prepared rly as described for compound 34 using l-amino-cyclopropanemethanol instead of 2-methylpropanamine. LC method B; Rt: 0.81 min. m/z: 401.2 (M-H)" Exact mass: 402.11. 1H NMR (400 MHz, DMSO-d6) 8 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, l H), 7.98 - 8.05 (m, l H), 8.08 (s, l H), 8.22 (dd, J=5.7, 2.6 Hz, 1 H), 10.46 (s, l H) Biological examples — anti-HBV activity of compounds of a (IA) The anti-HBV activity was ed using a stable transfected cell line, HepG2.2.l5. This cell line was described to secrete relatively consistent high levels of HBV virion particles, which have 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 d 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 me PCR and an HBV specific primer set and probe.

The anti HBV activity was also measured using the HepG2. l 17 cell line, a , inducibly HBV producing cell line, which replicates HBV in the absence of doxicycline (Tet-off system). For the antiviral assay, HBV replication was d, followed 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 c 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.

Results are displayed in Table l.

WO 11281 Table 1.

HepG HepG2 HepG2 HepG HepG2 HepG2 C0. 2.2.15 117 4days C0. 2.2.15 117 4days H 0.10 ->25 \DOOQON D—t O WO 11281 HepG HepGZ HepGZ C0. 2.2.15 117 4 days No. ECSO EC50 CC50 (PM) (PM) (PM) 63 0.21 >25 64 0.066 >25 65 0.16 >25 66 0.11 >25 94 0.004 95 0.065 96 0.006

Claims (12)

Claims

1. l. A compound of Formula (IA) R6’N O *er fifRZ I 0 R4 R3 (IA) 5 or a stereoisomer or tautomeric form thereof, n: Each X independently represents CR7; R1, R2 and R3 are independently selected from the group consisting of Hydrogen, , Chloro, Bromo, -CHF2, -CH2F, -CF3, -CN, C1-C3alkyl or C3-C4cycloalkyl; R4 is Hydrogen C1-C3alkyl or C3-C4cycloalkyl; 10 R5 is Hydrogen; R6 is selected from the group consisting of C1-C6alkyl and a 3-7 membered saturated ring ally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such C1-C6alkyl or 3-7 membered saturated ring optionally substituted with one or more substituents ed from the group 15 consisting of Fluoro, C3-C4cycloalkyl, -OR8 ,oxo, -CN, -C(=O)-OR8, -C(=O)-N(R8)2 or C1-C3alkyl optionally tuted with one or more Fluoro; Each R7 independently represents hydrogen, C3-C4cycloalkyl, -CN, Fluoro, Chloro, Bromo or C1-C3alkyl optionally substituted with one or more Fluoro; R8 represents hydrogen or C1-C3alkyl; 20 or a pharmaceutically acceptable salt or a solvate thereof.

2. A compound according to claim 1, wherein R1 is selected from hydrogen, Fluoro, Chloro, -CHF2, -CN, -CF3 or .

3. A nd according to claim 1 or 2 wherein R4 is methyl.

4. A compound according to any one of the previous claims wherein R6 is a 3-7 membered ted ring optionally containing one oxygen, such 3-7 membered saturated ring ally substituted with one or more substituents selected from Fluoro or lkyl optionally substituted with one or more Fluoro.

5. A compound according to any one of the previous claims wherein R6 is a 4 or 5 membered saturated ring ally containing one oxygen, such 4 or 5 membered saturated ring optionally substituted with one or more substituents selected from C1- C3alkyl optionally substituted with one or more Fluoro.

6. A nd according to any one of claims 1 to 3, wherein R6 is a branched lkyl optionally substituted with one or more Fluoro.

7. A compound according to any one of the previous claims with Formula (Ia). R6 N O O H N R2 R4 O 15 R3 (Ia)

8. A compound according to any one of the previous claims with Formula (Ib). R6 N O O H R1 N R2 (Ib)

9. A compound according to any one of the previous claims for use in the prevention or treatment of an HBV infection in a mammal.

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

11. A product containing (a) a nd of Formula (IA) as defined in any one of claims 1 to 8, and (b) another HBV inhibitor, as a combined preparation for simultaneous, separate or sequential use in the treatment of HBV infections. 5

12. The compound according to claim 1, substantially as herein bed with reference to any one of the Examples thereof.