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1. WO2020109224 - FURTHER HETEROAROMATIC COMPOUNDS HAVING ACTIVITY AGAINST RSV

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WO 2020/109224 PCT/EP2019/082404

- 1 -

FURTHER HETERO AROMATIC COMPOUNDS HAVING ACTIVITY AGAINST RSV

Field of the Invention

The invention concerns compounds having antiviral activity, in particular having an inhibitory activity on the replication of the respiratory syncytial virus (RSV). The invention further concerns pharmaceutical compositions comprising these compounds and the compounds for use in the treatment or prevention of respiratory syncytial virus infection.

Background

Human RSV or Respiratory Syncytial Virus is a large RNA virus, member of the family of Pneumoviridae, genus Orthopneumovirus together with bovine RSV virus. Human RSV is responsible for a spectrum of respiratory tract diseases in people of all ages throughout the world. It is the major cause of lower respiratory tract illness during infancy and childhood. Over half of all infants encounter RSV in their first year of life, and almost all within their first two years. The infection in young children can cause lung damage that persists for years and may contribute to chronic lung disease in later life (chronic wheezing, asthma). Older children and adults often suffer from a (bad) common cold upon RSV infection. In old age, susceptibility again increases, and RSV has been implicated in a number of outbreaks of pneumonia in the aged resulting in significant mortality.

Infection with a virus from a given subgroup does not protect against a subsequent infection with an RSV isolate from the same subgroup in the following winter season. Re-infection with RSV is thus common, despite the existence of only two subtypes, A and B.

Today only three drugs have been approved for use against RSV infection. A first one is ribavirin, a nucleoside analogue that provides an aerosol treatment for serious RSV infection in hospitalized children. The aerosol route of administration, the toxicity (risk of teratogenicity), the cost and the highly variable efficacy limit its use. Synagis® (palivizumab a monoclonal antibody, is used for passive immunoprophylaxis . Athough the benefit of Synagis® has been demonstrated, the treatment is expensive, requires parenteral administration and is restricted to children at risk for developing severe pathology.

Clearly there is a need for an efficacious non-toxic and easy to administer drug against RSV replication. It would be particularly preferred to provide drugs against RSV replication that could be administered perorally.

Compounds that exhibit anti-RSV activity are disclosed in WO-2016/174079.

Detailed description of the Invention

The present invention relates to compounds of formula (I)


including any stereochemically isomeric form thereof, wherein


wherein each CH is optionally substituted with halo or

C^alkyl;

Y1 and Y2 are each independently selected from CH, CF and N;

R1 is CH3 or CH2CH3;

R2 is hydrogen, halo or C| -4alkyl;

R12 is C^alkyl;

R13 and R14 are each independently selected from C^alkyl;

R15 is hydrogen or C| -4alkyl;

R3 is halo;

R4 is C| -6alkyl; C3_6cycloalkyl; di(C| -4alkyl)amino, pyrrolidinyl, Heteroaryl1; phenyl; phenyl substituted with 1, 2 or 3 substituents each individually selected from halo, hydroxy, cyano, C^alkyl, polyhaloC| -4alkyl, and C| -4alkyloxy;

R6 is a substituent selected from substituent (a), (b), (c), (d) or (e); wherein

(a) is -(CO)-OH, -(CO)-NR7R8, or -NR7R8;

(b) is Heteroaryl2;

(c) is C2-6alkenyl substituted with one or two substituents selected from C| -6alkyl, -(CO)-OH or -(CO)-NR8R9; or

(d) is -NR8-(CO)-Heterocycle wherein said Heterocycle is substituted with one, two or three substituents each independently selected from halo, hydroxy, C| -4alkyl of

Ci_4alkyloxy; or

(e) is C3_6cycloalkyl or Heterocycle, wherein said C3_6cycloalkyl and Heterocycle is substituted with one, two or three substituents each independently selected from

C^alkyl;

C| -6alkyl substituted with one, two or three substituents each independently selected from halo, hydroxy, hydroxycarbonyl, and aminocarbonyl;

hydroxy;

halo;

-(CO)-OH;

-(CO)-NR10R11;

-(C0)-NR8-S02-R9;

-NR8R9;

-NR8-(CO)-C i _4alkyl;

-NR8-(CO)-C3_6cycloalkyl;

-NR8-S02-R9;

-S02-NR10R11; or

-S02-NR8-(C0)-R9;

wherein

R7 is hydrogen, C | _4alky 1 , hydroxyC| -4alkyl or dihydroxyC| -4alkyl;

each R8 is independently selected from hydrogen, C| -4alkyl, or hydroxyC| -4alkyl;

R9 is C | -4alkyl, polyhaloC | -4alkyl, or C3_6cycloalkyl;

R10 and R1 1 are each indepently selected from hydrogen; C | -4alkyl;

polyhaloC | -4alkyl; C3_6cycloalkyl; C3_6cycloalkyl substituted with

C I _4alky 1 ; or C | -4alkyl substituted with hydroxy or cyano;

Heterocycle is azetidinyl, pyrrolodinyl, piperidinyl, or homopiperidinyl;

Heteroaryl1 is thienyl, pyridinyl or pyrimidinyl, wherein each Heteroaryl1 is optionally

substituted with one or two substituents each independently selected from C | -4alkyl, halo, amino, and aminocarbonyl;

Heteroaryl2 is pyrrolyl, pyrazolyl or thiazolyl; wherein each Heteroaryl2 is optionally substituted with one or two substituents each independently selected from C | -4alkyl, halo, -(CO)-OR7 or -(CO)-NR8R9;

or a pharmaceutically acceptable acid addition salt thereof.

As used in the foregoing definitions:

- halo is generic to fluoro, chloro, bromo and iodo;

- C I _4alky 1 defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methyl- propyl and the like;

- C I _6alky 1 is meant to include C | -4alkyl and the higher homologues thereof having 5 or 6 carbon atoms, such as, for example, 2 methylbutyl, pentyl, hexyl and the like;

- C^.^alkcnyl defines bivalent straight or branched chain hydrocarbon radicals containing from 2 to 6 carbon atoms such as, for example, 1 ,2-ethanediyl, 1,3-propanediyl, 1 ,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl, and the branched isomers thereof;

- C3_6cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

- polyhaloC | -4alkyl is defined as polyhalosubstituted C | _4alky 1 , in particular C | -4alkyl (as hereinabove defined) substituted with 2 to 6 halogen atoms such as difluoromethyl, trifluoromethyl, trifluoroethyl, and the like;

- -(CO)- or (CO) means carbonyl.

The term“compounds of the invention” as used herein, is meant to include the compounds of formula (I), and the salts and solvates thereof.

As used herein, any chemical formula with bonds shown only as solid lines and not as solid wedged or hashed wedged bonds, or otherwise indicated as having a particular configuration (e.g. R, S) around one or more atoms, contemplates each possible stereoisomer, or mixture of two or more stereoisomers.

Hereinbefore and hereinafter, the terms“compound of formula (I)” and“intermediates of synthesis of formula (I)” are meant to include the stereoisomers thereof and the tautomeric forms thereof

The terms“stereoisomers”,“stereoisomeric forms” or“stereochemically isomeric forms” hereinbefore or hereinafter are used interchangeably.

The invention includes all stereoisomers of the compounds of the invention either as a pure stereoisomer or as a mixture of two or more stereoisomers. Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a racemate or racemic mixture. Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration. Substituents on bivalent cyclic

(partially) saturated radicals may have either the cis- or trans-configuration; for example, if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration.

The term“stereoisomers” also includes any rotamers, also called conformational isomers, the compounds of formula (I) may form.

Therefore, the invention includes enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, rotamers, and mixtures thereof, whenever chemically possible.

The meaning of all those terms, i.e. enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof are known to the skilled person.

The absolute configuration is specified according to the Cahn-Ingold-Prelog system. The configuration at an asymmetric atom is specified by either R or S. Resolved stereoisomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light. For instance, resolved enantiomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.

When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other stereoisomers. Thus, when a compound of formula (I) is for instance specified as (R), this means that the compound is substantially free of the (S) isomer; when a compound of formula (I) is for instance specified as E, this means that the compound is substantially free of the Z isomer; when a compound of formula (I) is for instance specified as cis, this means that the compound is substantially free of the trans isomer.

Some of the compounds according to formula (I) may also exist in their tautomeric form. Such forms in so far as they may exist, although not explicitly indicated in the above formula (I) are intended to be included within the scope of the present invention.

It follows that a single compound may exist in both stereoiso meric and tautomeric form.

Atropisomers (or atropoisomers) are stereoisomers which have a particular spatial configuration, resulting from a restricted rotation about a single bond, due to large steric hindrance. All atropisomeric forms of the compounds of Formula (I) are intended to be included within the scope of the present invention.

The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms that the compounds of formula (I) are able to form. These pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

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

The compounds of formula (I) may exist in both unsolvated and solvated forms. The term ‘solvate’ is used herein to describe a molecular association comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, e.g. water or ethanol. The term‘hydrate’ is used when said solvent is water.

For the avoidance of doubt, compounds of formula (I) may contain the stated atoms in any of their natural or non-natural isotopic forms. In this respect, embodiments of the invention that may be mentioned include those in which (a) the compound of formula (I) is not isotopically enriched or labelled with respect to any atoms of the compound; and (b) the compound of formula (I) is isotopically enriched or labelled with respect to one or more atoms of the compound. Compounds of formula (I) that are isotopically enriched or labelled (with respect to one or more atoms of the compound) with one or more stable isotopes include, for example, compounds of formula (I) that are isotopically enriched or labelled with one or more atoms such as deuterium, 13C, 14C, 14N, 150 or the like.

A first group of compounds are compounds of formula (I) wherein radical A is of formula (a-1).

A second group of compounds are compounds of formula (I) wherein radical A is of formula (a-2).

A third group of compounds are compounds of formula (I) wherein radical A is of formula (a-5).

A fourth group of compounds are compounds of formula (I) wherein R5 is of formula (b-1) wherein Y1 and Y2 are CH.

A fifth group of compounds are compounds of formula (I) wherein R5 is of formula (b-2).

A sixth group of compounds are compounds of formula (I) wherein R5 is of formula (b-3).

A seventh group of compounds are compounds of formula (I) R1 is CH3.

An eight group of compounds are compounds of formula (I) wherein radical A is of formula (a-2)·

A ninth group of compounds are compounds of formula (I) wherein R4 is C3-6cycloalkyl.

A 10th group of compounds are compounds of formula (I) wherein R6 is Heterocycle having one, two or three substituents as defined in (e).

A 11th group of compounds are compounds of formula (I) wherein X | is N, X2 is CH, and X3 is CH.

A 12th group of compounds are compounds of formula (I) wherein X | is N, X2 is N, and X3 is CH.

A 13th group of compounds are compounds of formula (I) wherein X | is N, X2 is CH, and X3 is

N.

Interesting compounds of formula (I) are those compounds of formula (I) wherein one or more of the following restrictions apply :

a) A is a radical of formula (a-1) wherein R1 is CH3; or

b) A is a radical of formula (a-2) wherein R1 is CH3; or

c) A is a radical of formula (a-5) wherein R1 is CH3; or

d) R2 is hydrogen; or

e) R3 is fluoro; or

f) R4 is C3-6cycloalkyl, in particular cyclopropyl; or

g) R4 is C I _4alky 1 , in particular ethyl; or

h) R4 is Heteroaryl1 wherein Heteroaryl1 is pyridinyl; or

i) R5 is of formula (b-1) wherein Y1 and Y2 are CH and R3 is halo, in particular R3 is fluoro; and

j) R6 is C3-6cycloalkyl or pyrrolidinyl, wherein said C3-6cycloalkyl or pyrrolidinyl are

substituted with one or two substituents each independently selected from OH, -(CO)-OH or -(CO)-NR10R11.

In general compounds of formula (I) can be prepared by reacting an intermediate of formula (II) with an alkylboronate intermediate of formula (III) in at least one reaction-inert solvent and optionally in the presence of at least one transition metal coupling reagent and/or at least one suitable ligand, the said process further optionally comprising converting a compound of formula (I) into an addition salt thereof. Suitable metal coupling reagents and/or suitable ligands for this reaction are, e.g. palladium compounds such as palladium tetra(triphenylphosphine),

tris(dibenzylidene-acetone dipalladium, 2,2’-bis(diphenylphosphino)-l, -binaphtyl and the like.


Compounds of formula (I-a), defined as compounds of formula (I) wherein R5 is of formula (b-1), can also be prepared by reacting an intermediate of formula (IV) with either an

intermediate of formula (V), (VI) or (VII) in a reaction- inert solvent and optionally in the presence of at least one transition metal coupling reagent and/or at least one suitable ligand, the said process further optionally comprising converting a compound of formula (I) into an addition salt thereof.

Other synthetic pathways for preparing compounds of formula (I) have been described in the experimental party as general methods of preparation and specific working examples.

The compounds of formula (I) may further be prepared by converting compounds of formula (I) into each other according to art-known group transformation reactions.

The starting materials and some of the intermediates are known compounds and are

commercially available or may be prepared according to conventional reaction procedures generally known in the art.

The compounds of formula (I) as prepared in the hereinabove described processes may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. Those compounds of formula (I) that are obtained in racemic form may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. 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 desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

The compounds of formula (I) show antiviral properties. Viral infections treatable using the compounds and methods of the present invention include those infections brought on by ortho-and paramyxoviruses and in particular by human and bovine respiratory syncytial virus (RSV).

A number of the compounds of this invention moreover are active against mutated strains of RSV. Additionally, many of the compounds of this invention show a favorable pharmacokinetic profile and have attractive properties in terms of bioavailabilty, including an acceptable half-life, AUC and peak values and lacking unfavourable phenomena such as insufficient quick onset and tissue retention.

The in vitro antiviral activity against RSV of the present compounds was tested in a test as described in the experimental part of the description, and may also be demonstrated in a virus yield reduction assay. The in vivo antiviral activity against RSV of the present compounds may be demonstrated in a test model using cotton rats as described in Wyde et al. in Antiviral Research, 38, p. 31 - 42 (1998).

The compounds of formula (I) show antiviral properties. Viral infections preventable or treatable using the compounds and methods of the present invention include those infections brought on by Pneumoviridae and in particular by human and bovine respiratory syncytial virus (RSV).

Therefore the present compounds of formula (I), or a pharmaceutically acceptable acid addition salt thereof, may be used as a medicine, in particular may be used as a medicine for the treatment or prevention of infections brought on by Pneumoviridae and in particular by human and bovine respiratory syncytial virus (RSV).

The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of infections brought on by Pneumoviridae and in particular by human and bovine respiratory syncytial virus (RSV).

In other aspects, provided are methods of treating a respiratory syncytial virus (RSV) infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of formula (I) provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the individual has one or more symptoms of an RSV infection. In some embodiments, the RSV is RSV Type A. In some embodiments, the RSV is RSV Type B.

Also provided are methods of ameliorating one or more symptoms of an RSV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of formula (I) provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the symptom is one or more of : coughing, sneezing, runny nose, sore throat, fever, decrease of appetite, irritability, decreased activity, apnea, and wheezing. In some embodiments, the individual has a lower respiratory tract infection. In some embodiments, the individual has bronchiolitis, pneumonia, or croup. In some embodiments, the individual has been diagnosed with an RSV infection. In some embodiments, the RSV is RSV Type A. In some embodiments, the RSV is RSV Type B. In some embodiments, the RSV infection has been confirmed by a laboratory test. In some embodiments, the method further comprises obtaining the results of an RSV detecting laboratory test. In some embodiments, the laboratory test comprises detecting RSV in a nasal sample.

Also provided are methods of preventing an RSV infection in an individual at risk of developing an RSV infection comprising administering to the individual a prophylactically effective amount of a compound of formula (I) provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a prophylactically effective amount of a compound of formula (I) provided herein, or a pharmaceutically acceptable salt thereof In some

embodiments, the individual is between 0 and about 2 years of age. In some embodiments, the individual was bom prematurely. In other embodiments, the individual is greater than 65 years of age. In some embodiments, the individual is immunocompromised.

As used herein,“treatment” or“treating” is an approach for obtaining beneficial or desired results including clinical results. For example, beneficial or desired results in treating a viral infection include, but are not limited to, one or more of the following: eliminating or lessening the severity of one or more symptoms resulting from the viral infection (such as but not limited to coughing, sneezing, runny nose, sore throat, fever, decrease of appetite, irritability, decreased activity, apnea, and wheezing), increasing the quality of life of those suffering from the viral infection, decreasing the dose of other medications required to treat the viral infection, delaying the progression of the viral infection, and/or prolonging survival of an individual.

As used herein,“preventing” a viral infection is an approach for eliminating or reducing the risk of developing a viral infection or delaying the onset of a viral infection, including biochemical, histological and/or behavioral symptoms of a viral infection. Prevention may be in the context of an individual at risk of developing the viral infection, such as where the“at risk” individual does not develop the viral infection over a period of time, such as during a viral season or during a period of exposure to the virus, which may be days to weeks to months. An individual“at risk” of developing a viral infection is an individual with one or more risk factors for developing the viral infection but who has not been diagnosed with and does not display symptoms consistent with a viral infection. Risk factors for developing an RSV infection include but are not limited to an individual’s age (young children under age 5 such as children between about 0 and about 2 years of age, including infants, and individuals greater than 65 years of age), premature birth, co-morbidities associated with RSV and individuals who are immune-compromised.

As used herein, a“therapeutically effective dosage” or“therapeutically effective amount” of compound or salt thereof or pharmaceutical composition is an amount sufficient to produce a desired therapeutic outcome. A therapeutically effective amount or a therapeutically effective dosage can be administered in one or more administrations. A therapeutically effective amount or dosage may be considered in the context of administering one or more therapeutic agents (e.g., a compound, or pharmaceutically acceptable salt thereof), and a single agent may be

considered to be given in a therapeutically effective amount if, in conjunction with one or more other agents, a desired therapeutic outcome is achieved. Suitable doses of any of the co administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.

As used herein, a“prophylactically effective dosage” or“prophylactically effective amount” is an amount sufficient to effect the preventative result of eliminating or reducing the risk of developing a viral infection or delaying the onset of a viral infection, including biochemical, histological and/or behavioral symptoms of a viral infection. A prophylactically effective amount or a prophylactically effective dosage can be administered in one or more administrations and over a period of time in which such prevention is desired. Additionally, the present invention provides pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I).

Also provided are pharmaceutical compositions comprising a pharmaceutically acceptable carrier, a therapeutically active amount of a compound of formula (I), and another antiviral agent, in particular an RSV inhibiting compound.

Also, the combination of another antiviral agent and a compound of formula (I) can be used as a medicine. Thus, the present invention also relates to a product containing (a) a compound of formula (I), and (b) another antiviral compound, as a combined preparation for simultaneous, separate or sequential use in antiviral treatment. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers. Other antiviral compounds (b) to be combined with a compound of formula (I) for use in the treatment of RSV are RSV fusion inhibitors or RSV polymerase inhibitors.

In order to prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in free base form or acid addition salt form, as the active ingredient is combined in intimate admixture with at least one pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for oral administration, rectal administration, percutaneous administration, parenteral or intramuscular injection.

For example in preparing the compositions in oral dosage form, any of the usual liquid pharmaceutical carriers may be employed, such as for instance water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid pharmaceutical carriers such as starches, sugars, kaolin, lubricants, binders,

disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their easy administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral injection compositions, the pharmaceutical carrier will mainly comprise sterile water, although other ingredients may be included in order to improve solubility of the active ingredient.

Injectable solutions may be prepared for instance by using a pharmaceutical carrier comprising a saline solution, a glucose solution or a mixture of both. Injectable suspensions may also be prepared by using appropriate liquid carriers, suspending agents and the like. In compositions suitable for percutaneous administration, the pharmaceutical carrier may optionally comprise a penetration enhancing agent and/or a suitable wetting agent, optionally combined with minor proportions of suitable additives which do not cause a significant deleterious effect to the skin. Said additives may be selected in order to facilitate administration of the active ingredient to the skin and/or be helpful for preparing the desired compositions. These topical compositions may be administered in various ways, e.g., as a transdermal patch, a spot-on or an ointment. Addition salts of the compounds of formula (I), due to their increased water solubility over the

corresponding base form, are obviously more suitable in the preparation of aqueous

compositions.

It is especially advantageous to formulate the pharmaceutical compositions of the invention in dosage unit form for ease of administration and uniformity of dosage. "Dosage unit form" as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.

For oral administration, the pharmaceutical compositions of the present invention may take the form of solid dose forms, for example, tablets (both swallowable and chewable forms), capsules or gelcaps, prepared by conventional means with pharmaceutically acceptable excipients and carriers such as binding agents, fillers, lubricants, disintegrating agents, wetting agents and the like. Such tablets may also be coated by methods well known in the art.

Liquid preparations for oral administration may take the form of e.g. solutions, syrups or suspensions, or they may be formulated as a dry product for admixture with water and/or another suitable liquid carrier before use. Such liquid preparations may be prepared by conventional means, optionally with other pharmaceutically acceptable additives such as suspending agents,

emulsifying agents, non-aqueous carriers, sweeteners, flavours, masking agents and preservatives.

The compounds of formula (I) may be formulated for parenteral administration by injection, conveniently intravenous, intramuscular or subcutaneous injection, for example by bolus injection or continuous intravenous infusion. Formulations for injection may be presented in unit dosage form, e.g. in ampoules or multi-dose containers, including an added preservative. They may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as isotonizing, suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be present in powder form for mixing with a suitable vehicle, e.g. sterile pyrogen free water, before use.

The compounds of formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter and/or other glycerides.

In general, it is contemplated that an antivirally effective daily amount would be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from 0.1 mg/kg to 50 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines.

Also, the combination of another antiviral agent and a compound of formula (I) can be used as a medicine. Thus, the present invention also relates to a product containing (a) a compound of formula (I), and (b) another antiviral compound, as a combined preparation for simultaneous, separate or sequential use in antiviral treatment. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers. For instance, the compounds of the present invention may be combined with interferon-beta or tumor necrosis

factor-alpha in order to treat or prevent RSV infections. Other antiviral compounds (b) to be combined with a compound of formula (I) for use in the treatment of RSV are RSV fusion inhibitors or RSV polymerase inhibitors. Specific antiviral compounds for combination with any of the compounds of formula (I) that are useful in the treatment of RSV are the RSV inhibiting compounds selected from ribavirin, lumicitabine, presatovir, nirsevimab, sisunatovir, ziresovir, ALX-0171 , MDT-637, BTA-9881 , BMS-433771 , YM-543403, A-60444, TMC-353121 , RFI-641 , CL-387626, MBX-300, EDP-938, 3-( j 5-chloro- 1 -[3-(mcthyl-sulfonyl)propyl]- 1 H-benzimidazol-2-yl}methyl)-l -cyclopropyl- l ,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one, 3-[[7-chloro-3-(2-ethylsulfonyl-ethyl)imidazo[ 1 ,2-a]pyridin-2-yl]methyl]- 1 -cyclopropyl- imidazo[4, 5-c]pyridin-2-one, and 3-( j 5-chloro- 1 -[3-(mcthyl-sulfonyl)propyl]- 1 //- i ndo 1-2-y 1 [ methyl)- 1 - (2,2,2-trifluoroethyl)-l ,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one.

Experimental part

A. Abbreviations



The stereochemical configuration for some compounds has been designated as R* or S* (or *R or *S) when the absolute stereochemistry is undetermined (even if the bonds are drawn

stereospecifically) although the compound itself has been isolated as a single stereoisomer and is enantiomerically pure. This means that the absolute stereoconfiguration of the stereocentre indicated by * is undetermined (even if the bonds are drawn stereospecifically) although the compound is enantiomerically pure at the indicated centre.

B. Compound synthesis

Part 1 : Imidazofl,2-alnyridines

Synthesis of Intermediates A3 and A6:


Intermediate L1

Methyl 6-amino-5-cyclopropylpyridine-3-carboxylate


A1

A mixture of methyl 6-amino-5-bromonicotinate [180340-70-9] (6.00 g, 26.0 mmol), cyclopropylboronic acid [411235-57-9] (3.35 g, 39.0 mmol) and potassium phosphate tribasic (18.7 g, 88.3 mmol) in toluene (56 mL) and H2O (10 mL) was purged with nitrogen for 5 min. Tricyclohexylphosphine (728 mg, 2.60 mmol) and palladium acetate (583 mg, 2.60 mmol) were added and the mixture was purged with nitrogen for 2 min. The reaction mixture was heated at 120°C using a single mode microwave (Biotage® Initiator EXP 60) with a power output ranging from 0 to 400 W for 40 min. The reaction mixture was filtered through a pad of Celite® and washed with EtOAc and EEO. The layers were separated, and the aqueous phase was extracted

with EtOAc. The combined organic extracts were washed with brine, dried over MgSCfi, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 120 g, 30 pm, liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90: 10 to 60:40) to afford intermediate A1 (3.3 g, 66%) as a yellow solid.

Intermediate L2

Methyl 2-(4-bromo-2-fluorophenyl)-8-cyclopropylimidazo[ 1 ,2-a]pyridine-6-carboxylate


A mixture of intermediate A1 (1.00 g, 5.20 mmol) and 4-bromo-2-fluorophenacyl bromide

[869569-77-7] (1.85 g, 6.24 mmol) in MeCN (15 mL) was heated at 120°C using a single mode microwave (Anton Paar Monowave® 300) with a power output ranging from 0 to 850 W for 40 min. The mixture was cooled to 0°C. The solid was filtered off and dried under vacuum to afford intermediate A2 (1.38 g, 68%) as a beige solid.

Intermediate A3

Potassium 2-(4-bromo-2-fluorophenyl)-8-cyclopropylimidazo[ 1 ,2-a]pyridine-6-carboxylate


A mixture of intermediate A2 (1.00 g, 2.57 mmol) and potassium hydroxide (577 mg, 10.3 mmol) in EtOH (40 mL) was stirred at 80°C for 5 h. The mixture was cooled to 0°C. The precipitate was filtered off and dried under vacuum to afford intermediate A3 (0.85 g, 80%) as a beige solid.

Synthesis of Intermediate A6 :

Intermediate L4

Methyl 6-amino-5-phenylpyridine-3-carboxylate

A4

A mixture of methyl 6-amino-5-bromonicotinate [180340-70-9] (1.50 g, 6.49 mmol), phenylboronic acid [98-80-6] (871 mg, 7.14 mmol) and potassium phosphate tribasic (4.69 g, 22.1 mmol) in toluene (14 mL) and ELO (2.5 mL) was purged with nitrogen for 5 min.

Tricyclohexylphosphine (182 mg, 0.65 mmol) and palladium acetate (146 mg, 0.65 mmol) were added. The reaction mixture was purged with nitrogen for 2 min and heated at 120°C using a single mode microwave (Anton Paar Monowave® 300) with a power output ranging from 0 to 850 W for 40 min. The reaction mixture was filtered through a pad of Celite® and washed with EtOAc and LfiO. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSCL, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 40 g, 30 pm, liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90:10 to 70:30) to afford intermediate A4 (1.3 g, 88%) as a yellow solid.

Intermediate AS

Methyl 2-(4-bromo-2-fluorophenyl)-8-phenylimidazo [ 1 ,2-a]pyridine-6-carboxylate


A mixture of intermediate A4 (1.10 g, 4.82 mmol) and 4-bromo-2-fluorophenacyl bromide

[869569-77-7] (1.71 g, 5.78 mmol) in MeCN (15 mL) was heated at 120°C using a single mode microwave (Anton Paar Monowave® 300) with a power output ranging from 0 to 850 W for 40 min. The mixture was cooled to 0°C. The solid was filtered off and dried under vacuum to afford intermediate A5 (0.9 g, 44%) as a white solid.

Intermediate L6

Potassium 2-(4-bromo-2-fluorophenyl)-8-phenylimidazo[l,2-a]pyridine-6-carboxylate

A mixture of intermediate A5 (0.90 g, 2.12 mmol) and potassium hydroxide (475 mg, 8.47 mmol) in EtOH (30 mL) was stirred at 80°C for 5 h. The mixture was cooled to 0°C. The precipitate was filtered off and dried under vacuum to afford intermediate A6 (578 mg, 61%) as a white solid.

Synthesis of Intermediate A9


Intermediate II

4-Bromo- 1 -(2-bromo- 1 , 1 -dimethoxyethyl)-2-fluorobenzene


11

A mixture of 4-bromo-2-fluorophenacyl bromide [869569-77-7] (1.50 g, 5.07 mmol), trimethyl orthoformate (1.11 mL, 10.1 mmol) and /;-tolucncsulfonic acid monohydrate (48.3 mg, 0.25 mmol) in MeOH (45 mL) was stirred under reflux overnight. The solvent was evaporated in vacuo. The residue was diluted with DCM and H2O. The organic phase was separated

(hydrophobic frit) and evaporated to dryness to afford intermediate II (1.14 g, 98%) as a colorless oil.

Intermediate A 7

Methyl 6-amino-5 -(pyridin-3 -yl)pyridine-3 -carboxylate


A mixture of methyl 6-amino 5-bromonicotinate [180340-70-9] (1.00 g, 4.33 mmol), 3-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine [329214-79-1] (1.33 g, 6.49 mmol) and potassium carbonate (2.0 M in H2O, 6.50 mL, 13.0 mmol) was purged with nitrogen for 5 min. [I,G-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II), dichloromethane complex (353 mg, 0.43 mmol) was added and the reaction mixture was purged again with nitrogen for 2 min. The reaction mixture was heated at 120°C using a single mode microwave (Anton Paar Monowave® 300) with a power output ranging from 0 to 850 W for 40 min. The reaction mixture was filtered through a pad of Celite® and washed with EtOAc and H2O. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 40 g, 30 pm, dry loading (Celite®), mobile phase gradient: DCM / MeOH from 100:0 to 97:3) to afford intermediate A7 (0.75 g, 76%) as a grey solid.

Intermediate L8

Methyl 2-(4-bromo-2-fluorophenyl)-8-(pyridin-3-yl)imidazo[l,2-a]pyridine-6-carboxylate


A mixture of intermediate A7 (0.34 g, 1.48 mmol), intermediate II (609 mg, 1.78 mmol) and scandium trifluoromethanesulfonate (36.5 mg, 74.2 pmol) in MeCN (7.4 mL) was heated at 140°C using a single mode microwave (Anton Paar Monowave® 300) with a power output ranging from 0 to 850 W for 30 min. The solid was filtered off, washed with EtOAc and dried under vacuum. The residue was purified by flash chromatography over silica gel (Puriflash Interchim® 24 g, 30 pm, dry loading (Celite®), mobile phase gradient: DCM / MeOH from 100:0 to 98:2) to afford intermediate A8 (0.18 g, 28%) as a beige solid.

Intermediate L9

Potassium 2-(4-bromo-2-fluorophenyl)-8-(pyridin-3-yl)imidazo[l,2-a]pyridine-6-carboxylate


A mixture of intermediate A8 (0.60 g, 1.41 mmol) and potassium hydroxide (316 mg, 5.63 mmol) in MeOH (20 mL) was stirred under reflux for 5 h. The mixture was acidified with acetic acid until pH 5. The precipitate was filtered off, washed with MeOH and ¾0 and dried under vacuum to afford intermediate A9 (0.35 g, 55%) as a beige solid.

Synthesis of Intermediate A13:


A10

A mixture of 2,6-difluropyridine [1513-65-1] (1 mL, 11.0 mmol), (S)-mcthyl pyrrolidinc-3-carboxylate hydrochloride [1099646-61-3] (2.00 g, 12.1 mmol) and potassium carbonate (4.57 g, 33.1 mmol) in NMP (50 mL) was stirred at 80°C for 18 h. The reaction mixture was diluted with EtOAc and ELO. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with ELO (4 times), dried over MgSCE, filtered and evaporated to dryness to afford intermediate A10 (2.22 g, 90%) as a colorless oil.

Intermediate All

Methyl (35)- 1 -(5-bromo-6-fluoropyridin-2-yl)pyrrolidine-3-carboxylate


A mixture of intermediate A10 (2.20 g, 9.81 mmol) and NBS (2.10 g, 11.8 mmol) in MeCN (49 mL) was stirred at rt for 18 h. The reaction was quenched with a saturated aqueous solution of Na2S2C>3. The mixture was extracted with DCM. The combined organic extracts were washed with brine, dried over MgSC>4, filtered and concentrated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 40 g, 30 pm, liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 100:0 to 80:20) to give intermediate All (2.1 g, 71%) as a white solid.

Intermediate A12

Methyl (35)- 1 -(5-acetyl-6-fluoropyridin-2-yl)pyrrolidine-3-carboxylate


A solution of intermediate All (1.00 g, 3.30 mmol) in THF (14 mL) was purged with nitrogen for 10 min. Tributyl(l-ethoxyvinyl)tin (2.23 mL, 6.60 mmol) and

bis(triphenylphosphine)palladium(II) dichloride (232 mg, 0.33 mmol) were added. The reaction mixture was heated at 120°C using a single mode microwave (Anton Paar Monowave® 300) with a power output ranging from 0 to 850 W for 20 min. A 3N aqueous solution of HC1 (15 mL) was added and the resulting mixture was stirred at rt for 15 min. The layers were separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with LLO and brine, dried over MgS04, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 40 g, 30 pm, dry loading

(Celite®), mobile phase gradient: heptane / EtOAc from 100:0 to 70:30) to afford intermediate A12 (0.71 g, 80%) as a yellow oil.

Intermediate A13

Methyl (3S)-l-[5-(2-bromoacetyl)-6-fluoropyridin-2-yl]pyrrolidine-3-carboxylate


To a solution of copper(II) bromide (1.18 g, 5.27 mmol) in EtOAc (7 mL) was added a solution of intermediate A12 (0.70 g, 2.64 mmol) in EtOAc (3 mL) dropwise. The reaction mixture was stirred under reflux for lh. The solid was filtered out. The filtrate was washed with a saturated aqueous solution of NaHCOs and brine. The organic phase was dried over MgS04, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 40 g, 30 pm, mobile phase gradient: heptane / EtOAc from 90:10 to 60:40) to afford intermediate A13 (0.68 g, 75%) as a yellow oil.

Intermediate B1

(17?)-2-[2-(4-Bromo-2-fluorophenyl)-8-cyclopropylimidazo[l,2-a]pyridine-6-carbonyl]-l-methyl- 1 ,2,3 ,4-tetrahydroisoquino line


To a mixture of intermediate A3 (0.77 g, 1.86 mmol) and (17?)- 1 -methyl- 1, 2,3,4-tetrahydroisoquinoline [84010-66-2] (329 mg, 2.24 mmol) in DMF (21.5 mL) were added DIPEA (0.98 mL, 5.59 mmol) and HATU (921 mg, 2.42 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was poured out slowly into water and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04, filtered and evaporated to dryness. The crude mixture was purified by flash

chromatography over silica gel (Puriflash Interchim® 80 g, 30 pm, mobile phase gradient: heptane / EtOAc, from 90:10 to 70:30) to afford intermediate B1 (0.63 g, 67%) as a white solid.

Intermediate B2

2-(4-Bromo-2-fluorophenyl)-8-cyclopropyl-6-[(47?*)-4-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]imidazo[ 1 ,2-a]pyridine


To a mixture of intermediate A3 (0.27 g, 0.72 mmol) and 4-(7? *)-methyl-4, 5,6,7-tetrahydrothieno[3,2-c]pyridine [92503-61-2] (0.13 g, 0.86 mmol) in DMF (5 mL) were added DIPEA (0.38 mL, 2.16 mmol) and HATU (0.36 g, 0.94 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was poured out slowly into water and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 25 g, 30 pm, mobile phase gradient: heptane / EtOAc from 100:0 to 80:20). The good fractions were collected and the solvent was evaporated to afford intermediate

B2 (0.26 g, 71%) as a beige solid.

Intermediate B3

(27?)- 1 -[2-(4-Bromo-2-fluorophenyl)-8-cyclopropylimidazo[ 1 ,2-a]pyridine-6-carbonyl]-2-methylazepane


To a mixture of intermediate A3 (1.00 g, 2.42 mmol) and (27?)-2-methylhexahydroazepine hydrochloride [331994-00-4] (435 mg, 2.90 mmol) in DMF (30 mL) were added DIPEA (2.11 mL, 12.1 mmol) and HATU (1.20 g, 3.15 mmol). The reaction mixture was stirred at rt for 2 h.

The mixture was poured out slowly into water and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 40 g, 30 pm, mobile phase gradient: heptane / EtOAc from 100:0 to 70:30) to afford intermediate B3 (0.62 g, 54%) as a beige solid.

Intermediate B4

(17?)-2-[2-(4-Bromo-2-fluorophenyl)-8-phenylimidazo[l,2-a]pyridine-6-carbonyl]-l -methyl-1 ,2,3 ,4-tetrahydroisoquinoline


To a mixture of intermediate A6 (0.57 g, 1.27 mmol) and ( 17?)- 1 -methyl- 1,2, 3,4-tetrahydroisoquinoline [84010-66-2] (224 mg, 1.52 mmol) in DMF (20 mL) were added DIPEA (0.67 mL, 3.81 mmol) and HATU (627 mg, 1.65 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was poured out slowly into water and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 40 g, 30 pm, mobile phase gradient: heptane / EtOAc from 90:10 to 70:30) to afford intermediate B4 (0.62 g, 90%) as a beige solid.

Intermediate B5

(17?)-2-[2-(4-Bromo-2-fluorophenyl)-8-(pyridin-3-yl)imidazo[l,2-a]pyridine-6-carbonyl]-l-methyl- 1 ,2,3 ,4-tetrahydroisoquinoline

To a solution of intermediate A9 (0.25 g, 606 pmol) and ( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [84010-66-2] (107 mg, 728 pmol) in DMF (6 mL) were added DIPEA (0.42 mL, 2.43 mmol) and HATU (0.30 g, 0.79 mmol). The reaction mixture was stirred at rt for

2 h. The mixture was poured out slowly into water. The aqueous phase was extracted with DCM. The combined organic extracts were washed with brine, dried over MgS04, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 24 g, 30 pm, mobile phase gradient: heptane / EtOAc from 100:0 to 60:40) to afford intermediate B5 (0.27 mg, 82%) as a beige solid.

Intermediate B6

3-[2-(4-Bromo-2-fluorophenyl)-6-[(47?*)-4-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]imidazo[l,2-a]pyridin-8-yl]pyridine


To a solution of intermediate A9 (0.11 g, 244 pmol) and 4-(*7?)-methyl-4, 5,6,7-tetrahydrothieno[3,2-c]pyridine [92503-61-2] (44.9 mg, 293 pmol) in DMF (2.5 mL) were added DIPEA (0.13 mL, 0.73 mmol) and HATU (111 mg, 0.29 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was poured out slowly into water and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04, filtered and evaporated to dryness. The crude mixture was purified by flash

chromatography over silica gel (Puriflash Interchim® 12 g, 30 pm, liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90:10 to 50:50) to afford intermediate B6 (0.13 g, 96%) as a beige solid.


Intermediate Cl

6- Amino-5 -bromopyridine-3 -carboxylic acid


C1

A mixture of methyl 6-amino-5-bromonicotinate [180340-70-9] (1.00 g, 4.33 mmol) and potassium hydroxide (971 mg, 17.3 mmol) in MeOH (25 mL) was stirred under reflux for 5 h. The reaction mixture was acidified with a solution of acetic acid until pH 5. The precipitate was filtered off, washed with MeOH and ¾0 and dried under vacuum to afford intermediate Cl (0.65 g, 69%) as a white solid.

Intermediate C2

3-Bromo-5-[(17?)- 1 -methyl- 1,2, 3, 4-tetrahydroisoquinoline-2-carbonyl]pyridin-2-amine


To a mixture of intermediate Cl (0.65 g, 3.00 mmol) and (17?)- 1 -methyl- 1, 2,3,4-tetrahydroisoquinoline [84010-66-2] (0.53 g, 3.59 mmol) in DMF (15 mL) were added DIPEA (2.1 mL, 12.0 mmol) and HATU (1.48 g, 3.89 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was poured out slowly into water and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSCL, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 24 g, 30 pm, mobile phase gradient: heptane / EtOAc from 100:0 to 60:40) to afford intermediate C2 (0.46 g, 44%) as a beige solid.

Intermediate C5


Intermediate C3

Methyl 6-amino-5-cyclopropylpyridine-3-carboxylate


C3

A mixture of methyl 6-amino-5-bromonicotinate [180340-70-9] (6.00 g, 26.0 mmol), cyclopropylboronic acid [411235-57-9] (3.35 g, 39.0 mmol) and potassium phosphate tribasic (18.7 g, 88.3 mmol) in toluene (56 mL) and H2O (10 mL) was purged with nitrogen for 5 min. Tricyclohexylphosphine (728 mg, 2.60 mmol) and palladium acetate (583 mg, 2.60 mmol) were added. The reaction mixture was purged again with nitrogen for 2 min and heated at 120°C using a single mode microwave (Biotage® Initiator EXP 60) with a power output ranging from 0 to 400 W for 40 min. The reaction mixture was filtered through a pad of Celite® and washed with EtOAc and EEO. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSCE, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 120 g, 30 pm, mobile phase gradient: heptane / EtOAc from 90: 10 to 60:40) to afford intermediate C3 (3.35 g, 67%) as a yellow solid.

Intermediate C4

6-Amino-5-cyclopropylpyridine-3-carboxylic acid


C4

A mixture of intermediate C3 (2.00 g, 10.4 mmol) and potassium hydroxide (2.34 g, 41.6 mmol) in MeOH (50 mL) was stirred under reflux for 5 h. The reaction mixture was acidified with a solution of acetic acid until pH 5. The precipitate was filtered off, washed with MeOH and ¾0 and dried under vacuum to afford intermediate C4 (1.5 g, 81%) as a beige solid.

Intermediate C5

3-Cyclopropyl-5-[(17?)- 1 -methyl- 1,2, 3, 4-tetrahydroisoquinoline-2-carbonyl]pyridin-2-amine


To a mixture of intermediate C4 (1.42 g, 7.97 mmol) and ( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [84010-66-2] (1.41 g, 9.56 mmol) in DMF (24 mL) were added DIPEA (5.57 mL, 31.9 mmol) and HATU (3.94 g, 10.4 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was poured out slowly into water and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 40 g, 30 pm, mobile phase gradient: heptane / EtOAc from 100:0 to 70:30) to afford intermediate C5 (2.2 g, 90%) as a beige solid.

Intermediate C6

3-Cyclopropyl-5-[(47?*)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl]pyridin-2-amine


To a solution of intermediate C4 (0.85 g, 4.74 mmol) and (4*7?)-4-methyl-4, 5,6,7-tetrahydrothieno[3,2-c]pyridine [30433-78-7] (0.87 g, 5.69 mmol) in DMF (25 mL) were added DIPEA (3.31 mL, 19.0 mmol) and HATU (2.34 g, 6.17 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was poured out slowly into water and the aqueous phase was extracted with EtOAc. The combined organic extracts were was washed with brine, dried over MgSCU, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 40 g, 30 pm, mobile phase gradient: DCM / MeOH from 100:0 to 97:3) to afford intermediate C6 (1.10 g, 74%) as a beige solid.


Intermediate D1

3-N,N-Dimcthyl-5-[( I R)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2-carbonyl]pyridinc-2,3-diamine

A mixture of intermediate C2 (0.60 g, 1.73 mmol) and RuPhos (80.9 mg, 173 mhioΐ) in THF (9 mL) was purged with nitrogen for 5 min. Dimethylamine hydrochloride [506-59-2] (0.17 g, 2.08 mmol) was added followed by LiHMDS (1.5 M in THF, 4.6 mL, 6.90 mmol). The reaction mixture was stirred at 65 °C for 16 h. The reaction was quenched by the addition of a saturated aqueous solution of NH4CI and diluted with EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS04, filtered and the solvent was evaporated in vacuo. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 25 g, 30 pm, mobile phase gradient: DCM / MeOH from 100:0 to 98:2) to afford intermediate D1 (0.22 g, 41%) as a beige solid.

Intermediate D2

2-(4-Bromo-2-fluorophenyl)-N ,N-dimethyl-6-[(17?)-l -methyl- 1,2,3, 4-tetrahydroisoquinoline-2-carbonyl] imidazo[ 1 ,2-a]pyridin-8-amine


A mixture of intermediate D1 (0.22 g, 709 pmol) and 4-bromo-2-fluorophenacyl bromide

[869569-77-7] (252 mg, 851 pmol) in MeCN (4 mL) was heated at 100°C using a single mode microwave (Anton Paar Monowave® 300) with a power output ranging from 0 to 850 W for 30 min. The mixture was evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 25 g, 30 pm, mobile phase gradient: heptane / EtOAc from 100:0 to 70:30) to afford intermediate D2 (0.12 g, 33%) as a beige solid.

Synthesis of Intermediate D4


Intermediate D3

5 - [( 17?)- 1 -Methyl- 1 ,2,3 ,4-tetrahydroisoquino line-2 -carbonyl] -3 -(pyrrolidin- 1 -yl)pyridin-2-amine


A mixture of intermediate C2 (0.60 g, 1.73 mmol) and RuPhos (80.9 mg, 173 pmol) in THF (9 mL) was purged with nitrogen for 5 min. Pyrrolidine [123-75-1] (0.17 mL, 2.08 mmol) was added followed by LiHMDS (1.5 M in THF, 3.5 mL, 5.25 mmol). The reaction mixture was stirred at 65°C for 16 h. The reaction was quenched by the addition of H2O and diluted with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgSCE, filtered and the solvent was evaporated in vacuo. The residue was taken up in DCM, the mixture was cooled to 0°C and a precipitate was formed. The solid was filtered off and dried under vacuum to afford intermediate D3 (0.43 g, 74%) as a beige solid.

Intermediate D4

(17?)-2-[2-(4-Bromo-2-fluorophenyl)-8-(pyrrolidin-l-yl)imidazo[l,2-a]pyridine-6-carbonyl]-l-methyl- 1 ,2,3 ,4-tetrahydroisoquino line

A mixture of intermediate D3 (0.43 g, 1.28 mmol) and 4-bromo-2-fluorophenacyl bromide

[869569-77-7] (454 mg, 1.53 mmol) in MeCN (6 mL) was heated at 100°C using a single mode microwave (Anton Paar Monowave® 300) with a power output ranging from 0 to 850 W for 40 min. The mixture was evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 25 g, 30 pm, mobile phase gradient:

heptane / EtOAc, from 100:0 to 70:30) to afford intermediate D4 (0.30 g, 44%) as a green solid.

Intermediate D5


Intermediate 12

2-Bromo- 1 -(4-bromo-2-fluorophenyl)propan- 1 -one


[259750-61 -3] [4207-56-1 ] 12

A mixture of l-(4-bromo-2-fluorophenyl)propan-l-one [259750-61-3] (0.70 g, 3.03 mmol) and PTAT (1.14 g, 3.03 mmol) in THF (15 mL) was stirred under nitrogen atmosphere for 72 h at rt. The reaction mixture was filtered, and the filter cake was washed with THF several times. The filtrate was concentrated in vacuo. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 24 g, 30 pm, dry loading (Celite®), mobile phase gradient:

heptane / EtOAc from 100:0 to 90:10) to afford intermediate 12 (0.72 g, 77%) as a yellow oil.

Intermediate D5

(li?)-2-[2-(4-Bromo-2-fluorophenyl)-8-cyclopropyl-3-methylimidazo[l,2-a]pyridine-6-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline


A mixture of intermediate C5 (0.45 g, 1.46 mmol) and intermediate 12 (0.50 g, 1.61 mmol) in MeCN (9 mL) was heated at 135°C using a single mode microwave (Anton Paar Monowave® 300) with a power output ranging from 0 to 850 W for 40 min. The reaction mixture was diluted with EtOAc and H2O. The layers were separated, and the aqueous phase was extracted with

EtOAc. The combined organic extracts were washed with brine, dried over MgSC>4, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 25 g, 30 pm, dry loading (Celite®), mobile phase gradient: heptane / EtOAc from 100:0 to 85:15) to afford intermediate D5 (0.31 g, 41%) as a brown solid.

Synthesis of Intermediate D6

Intermediate 13

(n-Bu)3SiT JLiDEt


14

A mixture of 4-bromo-3-fluoro-2-hydroxybenzaldehyde [1427373-29-2] (1.00 g, 4.57 mmol), methyl acrylate (2.9 mL, 32.0 mmol) and triethylenediamine [280-57-9] (102 mg, 0.91 mmol) were heated at 150°C using a single mode microwave (Anton Paar Monowave® 300) with a power output ranging from 0 to 850 W for 50 min. The mixture was poured out into a solution of water and DCM. The layers were separated (hydrophobic frit) and the organic phase was evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 40 g, 30 pm, mobile phase gradient: heptane / EtOAc from 100:0 to 80:20) to afford intermediate 14 (0.49 g, 37%) as a white solid.

Intermediate 15

Methyl 7-acetyl-8-fluoro-2H-chromene-3-carboxylate


15

A solution of intermediate 14 (0.43 g, 1.39 mmol) in THF (1.5 mL) was purged with nitrogen for 10 min. Tributyl(l-ethoxyvinyl)tin (1.0 mL, 3.00 mmol) and bis(triphenylphosphine)palladium dichloride (105 mg, 0.15 mmol) were added. The mixture was heated at 120°C using a single mode microwave (Anton Paar Monowave® 300) with a power output ranging from 0 to 850 W for 20 min. A 3N aqueous solution of HC1 (1 mL) was added and the resulting mixture was stirred at rt for 30 min. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with ELO and brine and dried over MgSCL, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 25 g, 30 pm, dry loading (Celite®), mobile phase gradient:

heptane / EtOAc from 100:0 to 80:20). The residue (0.23 g) was hydrolysed with a 3N aqueous solution of HC1 for 30 min at rt. The mixture was extracted with EtOAc. The combined organic extracts were dried over MgS04, filtered and evaporated to dryness to afford intermediate 15 (0.13 g, 35%) as a yellow solid.

Intermediate 13

Methyl 7-(2-bromoacetyl)-8-fluoro-2H-chromene-3-carboxylate


13

To a solution of copper bromide (1.27 g, 5.68 mmol) in EtOAc (4 mL) was added a solution of intermediate 15 (0.71 g, 2.84 mmol) in EtOAc (3 mL). The reaction mixture was stirred under reflux for 1 h. The solid was filtered off. The filtrate was washed with a saturated aqueous solution of NaHC03 and brine, dried over MgS04, filtered and concentrated in vacuo to give intermediate 13 (0.56 g, 60%) as a beige solid.

Intermediate D6

Methyl 6- {8-cyclopropyl-6-[(17?)-l-methyl-l, 2,3, 4-tetrahydroisoquino line-2-

carbonyl]imidazo[l,2-a]pyridin-2-yl}-7-fluoro-2H-chromene-3-carboxylate


A mixture of intermediate C5 (132 mg, 0.43 mmol) and intermediate 13 (0.17 g, 517 iirnol) in MeCN (2.5 mL) was heated at 120°C using a single mode microwave (Anton Paar Monowave® 300) with a power output ranging from 0 to 850 W for 30 min. The mixture was concentrated in vacuo. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 25 g, 30 pm, mobile phase gradient: heptane / EtOAc from 90:10 to 70:30) to afford intermediate D6 (135 mg, 58%) as a yellow solid.

Compound 1

4- (8-Cyc lopropyl-6-[( 1 /?)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2-carbonyl]imidazo[l ,2-a]pyridin-2-yl} -3-fluorobenzoic acid


In autoclave, N2 was bubbled into a solution of intermediate B1 (0.50 g, 991 pmol) in H2O (0.72 mL) and NMP (3.5 mL) for 10 min. Palladium acetate (11.1 mg, 49.6 inriol), 1,3-bis(diphenylphosphino)propane (20.4 mg, 49.6 pmol) and potassium carbonate (164 mg, 1.19 mmol) were added. The autoclave was purged with nitrogen and with CO (3 times). The autoclave was pressurized with CO (7 bars) and heated at 120°C overnight. The reaction mixture was filtered through a pad of Celite®. The filtrate was acidified with a IN aqueous solution of HC1. The organic phase was washed with water and brine, dried over MgS04 and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash

Interchim® 40 g, 30 mhi, mobile phase gradient: DCM / MeOH from 100:0 to 96:4) to afford compound 1 (0.38 g, 82%) as a beige solid.

Compound 2

4- { 8-Cyc lopropyl-6-[( 1 ?)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2-carbonyl]imidazo[l ,2-a]pyridin-2-yl} -3-fluorobenzamide


A mixture of compound 1 (0.32 g, 0.68 mmol), HATU (311 mg, 0.82 mmol) and DIPEA (0.35 mL, 2.05 mmol) in DMF (7 mL) was stirred at rt for 15 min. Ammonia (30% in H2O, 77 pL, 4.09 mmol) was added. The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with H2O and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with H2O (3 times) and brine, dried over MgS04, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 25 g, 30 pm, mobile phase gradient: DCM / MeOH from 100:0 to 98:2). The residue (0.11 g) was taken up in DIPE. The solid was filtered off and dried under vacuum to give compound 2 (0.1 g, 31%) as a beige solid.

Compound 3

4- { 8-Cyc lopropyl-6-[( 1 ?)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2-carbonyl]imidazo[l ,2-a]pyridin-2-yl} -3-fluoroaniline


In a sealed tube a mixture of intermediate B1 (0.50 g, 0.99 mmol), benzophenone imine (0.25 mL, L49 mmol) and cesium carbonate (646 mg, 1.98 mmol) in 1,4-dioxane (5 mL) was purged with nitrogen. BINAP (30.9 mg, 49.6 pmol) and palladium acetate (11.1 mg, 49.6 pmol) were added. The reaction mixture was purged with nitrogen and stirred at 100°C for 18 h.

The reaction mixture was diluted with FLO and EtOH. The mixture was filtered through a pad of Celite® and washed with EtOAc. The layers were separated. The organic phase was washed with brine, dried over MgS04, filtered and evaporated to dryness. The residue was dissolved in THF (10 mL) and HC1 (3.0 M in FLO, 0.89 mL, 2.68 mmol) was added dropwise at 0°C. The mixture was stirred at rt for 2 h. A 10% aqueous solution of K2CO3 was added and the mixture was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS04, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 40 g, 30pm, dry loading (Celite®), mobile phase gradient: heptane / EtOAc from 100:0 to 60:40. The residue (0.28 g) was triturated in DCM and the solid was filtered off to give compound 3 (0.25 g, 57%) as a brown powder.

Compound 4

(3S)-N-(4- j 8-Cyclopropyl-6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2-carbonyl]imidazo[l,2-a]pyridin-2-yl}-3-fluorophenyl)-3-hydroxypyrrolidine-l -carboxamide


To a mixture of compound 3 (0.19 g, 0.43 mmol) in DMF (4.0 mL) was added CDI (175 mg,

1.08 mmol). The reaction mixture was stirred at rt for 15 h and a solution of (5)-3-hydroxypyrrolidine (113 mg, 1.29 mmol) in DMF (0.6 mL) was added. The reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with FLO and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with FLO and brine, dried over MgS04, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim®

25 g, 30 pm, mobile phase gradient: DCM / MeOH from 100:0 to 97:3). The residue (0.13 g) was taken up in Et20. The solid was filtered off and dried under vacuum to give compound 4 (0.11 g 46%) as a yellow solid.

Synthesis of Compound 5


Intermediate 129

(37?)-3 -hydroxypyrro lidine- 1 -carboxamide


Trimethylsilyl isocyanate (8.0 mL, 64.3 mmol) was added dropwise to a solution of (R)-3-hydroxypyrrolidine [2799-21-5] (4.00 g, 45.9 mmol) in z-PrOH (110 mL). The reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrate in vacuo (~ half of the solvent) until precipitation was observed. The solid was filtered off, washed with z-PrOH and dried to afford intermediate 129 (4.6 g, 77%) as a white solid.

Compound 5

(37?)-N-(4- (8-Cyclopropyl-6-[(l R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]imidazo[l,2-a]pyridin-2-yl}-3-fluorophenyl)-3-hydroxypyrrolidine-l -carboxamide


A mixture of intermediate B1 (0.28 g, 0.56 mmol), intermediate 129 (108 mg, 0.83 mmol), cesium carbonate (0.90 g, 2.78 mmol) and XantPhos (32.1 mg, 55.5 pmol) in 1,4-dioxane (11.6 mL) was purged with nitrogen. Palladium acetate (12.5 mg, 55.5 mhioΐ) was added and the mixture was purged again with nitrogen. The reaction mixture was stirred at 100°C for 15 h. The reaction mixture was diluted with EtOAc and LEO. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with LEO, dried over MgS04, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 25 g, 30 pm, mobile phase gradient: DCM / MeOH from 100:0 to 96:4). The residue (0.21 g) was taken up in Et20. The solid was filtered off and dried under vacuum to give compound 5 (0.19 g, 62%) as a brown solid.

Compound 6


Intermediate 16

Ethyl (2E)-3-(4- (8-cyclopropyl-6-[(li?)-l-methyl- 1,2,3, 4-tetrahydroisoquinoline-2-carbonyl]imidazo[l,2-a]pyridin-2-yl}-3-fluorophenyl)prop-2-enoate


A solution of intermediate B1 (0.43 g, 852 pmol) in MeCN (7.5 mL) was purged with nitrogen for 5 min. Ethyl acrylate (0.46 mL, 4.26 mmol), EhN (0.36 mL, 2.56 mmol), tri(o-

tolyl)phosphine (51.9 mg, 0.17 mmol) and palladium acetate (19.1 mg, 85.3 prnol) were added. The reaction mixture was purged again with nitrogen for 2 min and heated at 120°C using a single mode microwave (Anton Paar Monowave® 300) with a power output ranging from 0 to 850 W for 20 min. The mixture was poured out into a solution of water and DCM. The layers were separated (hydrophobic frit) and the organic phase was evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 40 g, 30 pm, mobile phase gradient: heptane / EtOAc from 90:10 to 60:40) to afford intermediate 16 (0.36 g, 81%) as a beige solid.

Intermediate 17

Ethyl trans -2-(4- j 8-cyclopropyl-6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2-carbonyl]imidazo[l,2-a]pyridin-2-yl}-3-fluorophenyl)cyclopropane-l-carboxylate


A mixture of trimethylsulfoxonium iodide (166 mg, 756 gmol) and potassium /e/V-butoxidc (84.9 mg, 756 prnol) in DMSO (4.6 mL) was stirred at rt for 1 h. A solution of intermediate 16 (0.36 g, 688 prnol) in DMSO (3 mL) was added dropwise. The reaction mixture was stirred at 60°C for 1 h. The mixture was poured out into water and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with ELO and brine, dried over MgS04, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 24 g, 30 pm, mobile phase gradient: heptane / EtOAc from 90:10 to 60:40) to afford intermediate 17 (125 mg, 34%).

Compound 6

Trans 2-(4- j 8-Cyclopropyl-6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2-carbonyl]imidazo[l,2-a]pyridin-2-yl}-3-fluorophenyl)cyclopropane-l -carboxylic acid

A mixture of intermediate 17 (0.12 g, 223 pmol) and lithium hydroxide monohydrate (65.6 mg, 1.56 mmol) in THF (3.5 mL) and H2O (1 mL) was stirred at 70°C overnight. An aqueous solution of citric acid (300 mg in 5 mL of LEO) was added. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04, filtered and concentrated in vacuo. The residue was taken up in EtOAc and pentane (5:95). The solid was filtered off and dried under vacuum to give compound 6 (98 mg, 86%) as a yellow solid.

Compound 7

Trans 2-(4- j 8-Cyclopropyl-6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2-carbonyl]imidazo[l,2-a]pyridin-2-yl}-3-fluorophenyl)cyclopropane-l -carboxamide


To a mixture of compound 6 (52.0 mg, 102 gmol) in DMF (2 mL) were added HATU (58.2 mg, 153 prnol) and DIPEA (53.0 pL, 306 prnol). The reaction mixture was stirred at rt for 15 min. Ammonia (30% in H2O, 38.6 pL, 0.61 mmol) was added and the reaction mixture was stirred at rt for 4 h. The reaction mixture was diluted with H2O and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H2O and brine, dried over MgSC>4, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 4 g, 30 pm, mobile phase gradient: DCM / MeOH from 100:0 to 97:3). The residue (50 mg) was taken up in DIPE. The precipitate was filtered off and dried under vacuum to give compound 7 (38 mg, 73%) as a yellow solid.

Compound 8

Trans 2-(4- j 8-Cyclopropyl-6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2-carbonyl]imidazo[l,2-a]pyridin-2-yl}-3-fluorophenyl)-N-methanesulfonylcyclopropane-l-carboxamide


A mixture of compound 6 (0.10 g, 196 pmol) and CDI (38.2 mg, 0.24 mmol) in MeCN (2 mL) was stirred at rt for 2 h. Methanesulfonamide (28.0 mg, 0.29 mmol) and DBU (44.0 LIL, 0.29 mmol) were added. The reaction mixture was stirred at 80°C for 16 h. A IN aqueous solution of HC1 and DCM were added. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were washed with brine, dried over MgSC>4, filtered and evaporated in vacuo. The residue was taken up in Et20. The solid was filtered off and dried under vacuum to give compound 8 (55 mg, 48%).

Synthesis of Compound 9


Intermediate 18

Methyl (35*)- 1 -(4- j 8-cyclopropyl-6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2-carbonyljimidazo [ 1 ,2-a]pyridin-2-yl} -3 -fluorophenyl)pyrro lidine-3 -carboxylate


A mixture of intermediate B1 (0.50 g, 0.99 mmol), (5)-methyl pyrrolidine-3 -carboxylate hydrochloride [1099646-61-3] (197 mg, 1.19 mmol), cesium carbonate (969 mg, 2.97 mmol) and XantPhos (57.4 mg, 99.9 pmol) was purged with nitrogen. 1,4-Dioxane (12 mL) was added and the mixture was purged again with nitrogen. Palladium acetate (22.3 mg, 99.9 inriol) was added. The reaction mixture was purged with nitrogen and stirred at 100°C for 5 h. The reaction mixture was diluted with EtOAc and H2O. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS04, filtered and the solvent was evaporated in vacuo. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 80 g, 30 pm, mobile phase gradient: heptane / EtOAc from 90:10 to 60:40) to afford intermediate 18 (188 mg, 34%) as a beige solid.

Compound 9

(35)- 1 -(4- (8-Cyclopropyl-6-[(17?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyljimidazo [ 1 ,2-a]pyridin-2-yl} -3 -fluorophenyl)pyrro lidine-3 -carboxylic acid


A mixture of intermediate 18 (188 mg, 0.34 mmol) and lithium hydroxide monohydrate (100 mg, 2.38 mmol) in THF (8 mL) and H2O (2.5 mL) was stirred at rt overnight. An aqueous solution of citric acid (457 mg in 8 mL of H2O) was added. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04, filtered and evaporated to dryness. The residue was taken up in DIPE. The solid was filtered off and dried at 25°C under vacuum to give compound 9 (125 mg, 68%) as an orange solid.

Compound 10

(3 S)- 1 -(4- j 8-Cyclopropyl-6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyljimidazo [ 1 ,2-a]pyridin-2-yl} -3 -fluorophenyl)pyrro lidine-3 -carboxamide


To a mixture of compound 9 (78.0 mg, 145 pmol) in DMF (2.5 mL) were added DIPEA (75 mL, 0.43 mmol) and HATU (82.6 mg, 217 mhioΐ). The reaction mixture was stirred at rt for 15 min. Ammonia (30% in LEO, 16.4 pL, 0.87 mmol) was added dropwise. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with LEO and EtOAc. The layers were separated and the organic phase was washed with EEO and brine (3 times), dried over MgS04, filtered and evaporated to dryness. The residue was taken up with EEO. The solid was filtered off and dried under vacuum to give compound 10 (60 mg, 77%) as a beige solid.

Compound 11

(3 S)- 1 -(4- j 8-Cyclopropyl-6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]imidazo[l,2-a]pyridin-2-yl}-3-fluorophenyl)-N-methylpyrrolidine-3-carboxamide


To a mixture of compound 9 (90.0 mg, 167 pmol) in DMF (2.5 mL) were added DIPEA (86.4 pL, 0.50 mmol) and HATU (95.3 mg, 0.25 mmol). The reaction mixture was stirred at rt for 15 min. Methylamine (47.5 pL, 1.00 mmol) was added dropwise. The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with H2O and EtOAc. The layers were separated and the organic phase was washed with H2O and brine (3 times), dried over MgSC>4, filtered and evaporated to dryness. The residue was taken up in Et20. The solid was filtered off and dried under vacuum to give compound 11 (60 mg, 65%) as a brown solid.

Compound 12

(3 S)- 1 -(4- j 8-Cyclopropyl-6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]imidazo[ 1 ,2-a]pyridin-2-yl} -3-fluorophenyl)pyrrolidin-3-ol


A mixture of intermediate B1 (0.10 g, 198 pmol), S)-3-hydroxypyrrolidine [100243-39-8] (43.2 mg, 496 pmol), cesium carbonate (258 mg, 0.79 mmol) and XantPhos (13.8 mg, 23.8 pmol) was purged with nitrogen. 1 ,4-Dioxane (2 mL) was added and the mixture was purged again with nitrogen. Palladium acetate (5.34 mg, 23.8 pmol) was added. The reaction mixture was purged with nitrogen and stirred at 100°C for 15 h. The reaction mixture was diluted with H2O and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with H2O and brine, dried over MgS04, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 12 g, 30 pm, mobile phase gradient: DCM / MeOH from 100:0 to 97:3) to afford compound 12 (70 mg, 69%) as a brown solid.

Synthesis of compound 13


Intermediate 19

Methyl (35)-l-(4-{8-cyclopropyl-6-[(4*i?)-4-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-5-carbonyljimidazo [ 1 ,2-a]pyridin-2-yl} -3 -fluorophenyl)pyrro lidine-3 -carboxylate


A mixture of intermediate B2 (0.88 g, 1.72 mmol), (S)-mcthyl pyrrolidine-3 -carboxylate hydrochloride [1099646-61-3] (371 mg, 2.24 mmol), cesium carbonate (1.69 g, 5.17 mmol) and XantPhos (lOOmg, 0.17 mmol) was purged with nitrogen. 1,4-Dioxane (15 mL) was added and the mixture was purged again with nitrogen. Palladium acetate (38.7 mg, 0.17 mmol) was added. The reaction mixture was purged with nitrogen and stirred at 100°C for 5 h. The reaction mixture was diluted with EtOAc and EEO. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS04, filtered and the solvent was evaporated in vacuo. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 40 g, 30 pm, mobile phase gradient: heptane / EtOAc from 90:10 to 60:40) to afford intermediate 19 (384 mg, 40%) as a yellow solid.

Intermediate IIP

(35)-l-(4-{8-Cyclopropyl-6-[(4*i?)-4-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-5-carbonyl] imidazo [ 1 ,2-a]pyridin-2-yl} -3 -fluorophenyl)pyrro lidine-3 -carboxylic acid


A mixture of intermediate 19 (0.38 g, 0.68 mmol) and lithium hydroxide monohydrate (171 mg, 4.08 mmol) in THF (12 mL) and H2O (3 mL) was stirred at rt overnight. An aqueous solution of citric acid (784 mg in 20 mL of H2O) was added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04, filtered and evaporated to dryness to afford intermediate 110 (0.3 g, 81%) as a yellow solid.

Compound 13

(35)-l-(4-{8-Cyclopropyl-6-[(4*7?)-4-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-5-carbonyl] imidazo [ 1 ,2-a]pyridin-2-yl} -3 -fluorophenyl)pyrro lidine-3 -carboxamide


To a mixture of intermediate 110 (287 mg, 527 mhioΐ) in DMF (4 mL) were added DIPEA (0.27 mL, 1.58 mmol) and HATU (301 mg, 0.79 mmol). The reaction mixture was stirred at rt for 15 min. Ammonia (30% in H2O, 60 pL, 3.16 mmol) was added and the reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with H2O and EtOAc. The layers were separated and the organic phase was washed with H2O and brine (3 times), dried over MgSC>4, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 4 g, 30 pm, mobile phase gradient: DCM / MeOH from 100:0 to 98:2). The residue (120 mg) was taken up in Et20. The solid was filtered off and dried under vacuum to give compound 13 (0.1 g, 35%) as a beige solid.

Compound 14

(35)-l-(4-{8-Cyclopropyl-6-[(4*i?)-4-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]imidazo[l,2-a]pyridin-2-yl}-3-fluorophenyl)-N-methylpyrrolidine-3-carboxamide


To a solution of intermediate 110 (0.15 g, 275 gmol) in DMF (4 mL) were added DIPEA (0.14 mL, 0.83 mmol) and HATU (157 mg, 0.41 mmol). The reaction mixture was stirred at rt for 15 min. Methylamine(40% in water, 57 pL, 1.65 mmol) was added dropwise. The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with H2O and EtOAc. The layers were separated and the organic phase was washed with H2O and brine (3 times), dried over MgS04, filtered and evaporated to dryness to give compound 14 (0.1 g, 65%) as a brown solid.

Synthesis of compound 15


Intermediate Ill

Methyl (35)- 1 -(4- {8-cyclopropyl-6-[(27?)-2-methylazepane- 1 -carbonyl]imidazo[l ,2-a]pyridin-2-yl}-3-fluorophenyl)pyrrolidine-3-carboxylate


A mixture of intermediate B3 (0.60 g, 1.28 mmol), (5)-mcthyl pyrrolidine-3 -carboxylate hydrochloride [1099646-61-3] (275 mg, 1.66 mmol), cesium carbonate (1.25 g, 3.83 mmol) and XantPhos (73.8 mg, 128 mhioΐ) was purged with nitrogen. 1,4-Dioxane (13 mL) was added and the mixture was purged again with nitrogen. Palladium acetate (28.6 mg, 0.13 mmol) was added. The reaction mixture was purged with nitrogen and stirred at 100°C for 5 h. The reaction mixture was diluted with EtOAc and LEO. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS04, filtered and the solvent was evaporated in vacuo. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 40 g, 30 pm, mobile phase gradient: heptane / EtOAc from 90: 10 to 60:40) to afford intermediate Ill (231 mg, 35%) as a brown solid.

Intermediate 112

(35)- 1 -(4- {8-Cyclopropyl-6-[(27?)-2-methylazepane- 1 -carbonyl]imidazo[l ,2-a]pyridin-2-yl} -3-fluorophenyl)pyrrolidine-3 -carboxylic acid


112

A mixture of intermediate Ill (231 mg, 445 pmol) and lithium hydroxide monohydrate (112 mg, 2.67 mmol) in THF (8 mL) and LEO (2 mL) was stirred at rt overnight. An aqueous solution of citric acid (513 mg in 15 mL of LEO) was added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04, filtered and evaporated to dryness to afford intermediate 112 (212 mg, 94%) as a yellow solid.

Compound 15

(35)- 1 -(4- (8-Cyclopropyl-6-[(2i?)-2-methylazepane- 1 -carbonyl]imidazo[l ,2-a]pyridin-2-yl} -3-fluorophenyl)pyrrolidine-3-carboxamide


To a solution of intermediate 112 (0.20 g, 396 pmol) in DMF (4 mL) were added DIPEA (0.21 mL, 1.19 mmol) and HATU (226 mg, 0.60 mmol). The reaction mixture was stirred at rt for 15 min. Ammonia (30% in H2O, 45 pL, 2.38 mmol) was added and the reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with H2O and EtOAc. The layers were separated and the organic phase was washed with H2O and brine (3 times), dried over MgSC>4, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 12 g, 30 pm, mobile phase gradient: DCM / MeOH from 100:0 to 98:2) to give compound 15 (80 mg, 40%) as a beige solid.

Synthesis of compound 16


Intermediate 113

Methyl (35)- 1 -(3-fluoro-4- {6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]-8-phenylimidazo [ 1 ,2-a]pyridin-2-yl} phenyl)pyrrolidine-3 -carboxylate


A mixture of intermediate B4 (0.61 g, 1.13 mmol), (5)- methyl pyrrolidine-3 -carboxylate hydrochloride [1099646-61-3] (243 mg, 1.47 mmol), cesium carbonate (1.10 g, 3.39 mmol) and XantPhos (65.3 mg, 0.11 mmol) was purged with nitrogen. 1,4-Dioxane (14 mL) was added and the mixture was purged again with nitrogen. Palladium acetate (25.3 mg, 0.11 mmol) was added.

The reaction mixture was purged with nitrogen and stirred at 100°C for 5 h. The reaction mixture was diluted with EtOAc and EEO. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS04, filtered and the solvent was evaporated in vacuo. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 40 g, 30 pm, mobile phase gradient: heptane / EtOAc from 90:10 to 60:40) to afford intermediate 113 (0.16 g, 24%) as a brown solid.

Intermediate 114

(3 S)- 1 -(3-Fluoro-4- {6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]-8-phenylimidazo[l,2-a]pyridin-2-yl}phenyl)pyrrolidine-3-carboxylic acid


A mixture of intermediate 113 (151 mg, 257 pmol) and lithium hydroxide monohydrate (64.6 mg, 1.54 mmol) in THF (4 mL) and H2O (1 mL) was stirred at rt overnight. An aqueous solution of citric acid (296 mg in 10 mL of H2O) was added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSCL, filtered and evaporated to dryness to afford intermediate 114 (147 mg, 99%) as a yellow solid.

Compound 16

(3 S)- 1 -(3-Fluoro-4- {6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]-8-phenyhmidazo[l,2-a]pyridin-2-yl}phenyl)pyrrolidine-3-carboxamide


To a solution of intermediate 114 (136 mg, 237 pmol) in DMF (3.5 mL) were added DIPEA (0.12 mL, 0.71 mmol) and HATU (135 mg, 0.36 mmol). The reaction mixture was stirred at rt for 15 min. Ammonia (30% in FLO, 26.9 pL, 1.42 mmol) was added dropwise. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with FLO and EtOAc. The layers were separated and the organic phase was washed with FLO and brine (3 times), dried over MgS04, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 4 g, 30 pm, mobile phase gradient: DCM / MeOH from 100:0 to 98:2) to give compound 16 (75 mg, 59%) as a beige solid.

Synthesis of compound 17


Intermediate 115

Methyl (3 S)- 1 -(3-fluoro-4- {6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]-8-(pyridin-3 -yl)imidazo [ 1 ,2-a]pyridin-2-yl} phenyl)pyrrolidine-3 -carboxylate


A mixture of intermediate B5 (0.26 g, 0.48 mmol), (S)-mcthyl pyrrolidine-3 -carboxylate hydrochloride (111 mg, 0.67 mmol), cesium carbonate (0.63 g, 1.92 mmol) and XantPhos (33.3 mg, 57.6 LHTiol) was purged with nitrogen. 1,4-Dioxane (5 mL) was added and the mixture was purged again with nitrogen. Palladium acetate (12.9 mg, 57.6 inriol) was added. The reaction mixture was purged with nitrogen and stirred at 100°C for 12 h. The mixture was diluted with EtOAc and EEO. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgSCE, filtered and the solvent was evaporated in vacuo. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 25 g, 30 pm, mobile phase gradient: DCM / MeOH from 100:0 to 98:2) to afford intermediate 115 (0.19 g, 67%) as a yellow solid.

Intermediate 116

(3 S)- 1 -(3-Fluoro-4- {6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]-8-(pyridin-3-yl)imidazo[l,2-a]pyridin-2-yl}phenyl)pyrrolidine-3-carboxylic acid


A mixture of intermediate 115 (0.18 g, 305 iirnol) and lithium hydroxide monohydrate (76.9 mg, 1.83 mmol) in THF (8 mL) and FLO (2 mL) was stirred at rt overnight. An aqueous solution of citric acid (352 mg) was added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04, filtered and evaporated to dryness to afford intermediate 116 (0.15 g, 85%) as an orange solid.

Compound 17

(3 S)- 1 -(3-Fluoro-4- {6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]-8-(pyridin-3-yl)imidazo [ 1 ,2-a]pyridin-2-yl} phenyl)pyrro lidine-3 -carboxamide


To a mixture of intermediate 116 (0.14 g, 243 mhioΐ) in DMF (4 mL) were added DIPEA (0.13 mL, 0.73 mmol) and HATU (111 mg, 0.29 mmol). The reaction mixture was stirred at rt for 15 min. Ammonia (30% in FLO, 28 iiL 1.46 mmol) was added dropwise. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with FLO and EtOAc. The layers were separated and the organic phase was washed with FLO (3 times) and brine, dried over MgS04, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over

silica gel (Puriflash Interchim® 12 g, 30 pm, mobile phase gradient: DCM / MeOH from 100:0 to 98:2). The residue (0.11 g) was diluted with EtOAc and the mixture was stirred at rt for 1 h. The solid was filtered off and dried under vacuum to give compound 17 (0.06 g, 43%) as a brown solid.

Synthesis of compound 18


Intermediate II 7

Methyl (35)-l-(3-fluoro-4-{6-[(4*i?)-4-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-5-carbonyl] -8-(pyridin-3 -yl)imidazo [ 1 ,2-a]pyridin-2-yl} phenyl)pyrrolidine-3 -carboxylate


A mixture of intermediate B6 (0.12 g, 219 iirnol), (S)-mcthyl pyrrolidine-3 -carboxylate hydrochloride [1099646-61-3] (50.8 mg, 307 pmol), cesium carbonate (286 mg, 0.88 mmol) and XantPhos (15.2 mg, 26.3 pmol) was purged with nitrogen. 1,4-Dioxane (3 mL) was added and the mixture was purged again with nitrogen. Palladium acetate (5.91 mg, 26.3 pmol) was added. The reaction mixture was purged with nitrogen and stirred at 100°C for 12 h. The reaction

mixture was diluted with EtOAc and H2O. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS04, filtered and the solvent was evaporated in vacuo. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 25 g, 30 pm, mobile phase gradient: DCM / MeOH from 100:0 to 98:2) to afford intermediate 117 (0.10 g, 77%) as a yellow solid.

Intermediate 118

(35)-l-(3-Fluoro-4-{6-[(4*i?)-4-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]-8-(pyridin-3-yl)imidazo[l,2-a]pyridin-2-yl}phenyl)pyrrolidine-3-carboxylic acid


A mixture of intermediate 117 (0.1 g, 168 pmol) and lithium hydroxide monohydrate (42.3 mg, 1.00 mmol) in THF (6 mL) and H2O (1.5 mL) was stirred at rt overnight. An aqueous solution of citric acid (193 mg) was added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04, filtered and evaporated to dryness to afford intermediate 118 (97 mg, quant.,) as a yellow solid.

Compound 18

(35)-l-(3-Fluoro-4-{6-[(4*7?)-4-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]-8-(pyridin-3 -yl)imidazo [ 1 ,2-a]pyridin-2-yl} phenyl)pyrrolidine-3 -carboxamide


A mixture of intermediate 118 (97.0 mg, 167 pmol) in DMF (2 mL) were added DIPEA (86.2 pL, 0.50 mmol) and HATU (76.1 mg, 0.20 mmol). The reaction mixture was stirred at rt for 15 min. Ammonia (30% in H2O, 19 pL, 1.00 mmol) was added dropwise. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with H2O and EtOAc. The layers were separated and the organic phase was washed with H2O (3 times) and brine, dried over MgSC>4, filtered and evaporated to dryness. The crude residue was diluted with EtOAc. The solid was filtered off and dried in vacuo. The residue (0.05 g) was taken up in DIPE. The solid was filtered off and dried under vacuum to give compound 18 (25 mg, 26%, 20% over 3 steps) as a brown solid.

Synthesis of compound 19


Intermediate 119

Methyl (35)- 1- {4-[8-(dimethylamino)-6-[(17?)- 1-methyl- 1,2,3, 4-tetrahydroisoquinoline-2-carbonyljimidazo [ 1 ,2-a]pyridin-2-yl] -3 -fluorophenyl} pyrrolidine-3 -carboxylate


A mixture of intermediate D2 (0.11 g, 217 pmol), (S)-mcthyl pyrrolidine-3 -carboxy late hydrochloride [1099646-61-3] (50.3 mg, 304 mhioΐ), cesium carbonate (283 mg, 0.87 mmol) and XantPhos (15.0 mg, 26.0 mhioΐ) was purged with nitrogen. 1,4-Dioxane (4 mL) was added and the mixture was purged again with nitrogen. Palladium acetate (5.84 mg, 26.0 mhioΐ) was added. The reaction mixture was purged with nitrogen and stirred at 100°C for 12 h. The reaction mixture was diluted with EtOAc and EEO. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS04, filtered and the solvent was evaporated in vacuo. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 25 g, 30 pm, mobile phase gradient: heptane / EtOAc from 100:0 to 70:30) to afford intermediate 119 (80 mg, 66%) as a brown solid.

Intermediate 120

(3 S)- 1 - (4-[8-(Dimethylamino)-6-[( 17?)- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinoline-2-carbonyl]imidazo[ 1 ,2-a]pyridin-2-yl]-3-fluorophenyl}pyrrolidine-3-carboxylic acid


A mixture of intermediate 119 (80.0 mg, 144 mhioΐ) and lithium hydroxide monohydrate (36.3 mg, 0.86 mmol) in THF (5 mL) and EEO (1 mL) was stirred at rt overnight. An aqueous solution of citric acid (166 mg) was added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04, filtered and evaporated to dryness to afford intermediate 120 (75 mg, 96%) as an orange solid.

Compound 19

(3 S)- 1 - (4-[8-(Dimethylamino)-6-[( 17?)- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinoline-2-carbonyljimidazo [ 1 ,2-a]pyridin-2-yl] -3 -fluorophenyl} pyrrolidine-3 -carboxylamide

To a solution of intermediate 120 (75.0 mg, 138 gmol) in DMF (2 mL) were added DIPEA (72 pL, 415 pmol) and HATU (57.9 mg, 152 pmol). The reaction mixture was stirred at rt for 15 min. Ammonia (30% in H2O, 15.7 pL, 0.83 mmol) was added dropwise. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with H2O and EtOAc. The layers were separated and the organic phase was washed with H2O (3 times) and brine, dried over MgSC>4, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 12 g, 30 pm, mobile phase gradient: DCM / MeOH from 100:0 to 98:2). The residue (45 mg) was taken up in Et20. The solid was filtered off and dried under vacuum to give compound 19 (34 mg, 45%) as a grey solid.

Synthesis of Compound 20


Intermediate 121

Methyl (35)- 1 -(3-fluoro-4- (6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]-8-(pyrrolidin- 1 -yl)imidazo [ 1 ,2-a]pyridin-2-yl} phenyl)pyrrolidine-3 -carboxylate

A mixture of intermediate D4 (0.29 g, 544 pmol), (S)-mcthyl pyrrolidine-3 -carboxy late hydrochloride [1099646-61-3] (126 mg, 0.76 mmol), cesium carbonate (709 mg, 2.18 mmol) and XantPhos (37.7 mg, 65.2 prnol) was purged with nitrogen. 1,4-Dioxane (4 mL) was added and the mixture was purged again with nitrogen. Palladium acetate (14.6 mg, 65.2 prnol) was added. The reaction mixture was purged with nitrogen and stirred at 100°C for 12 h. The reaction mixture was diluted with EtOAc and H2O. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS04, filtered and the solvent was evaporated in vacuo. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 25 g, 30 pm, mobile phase gradient: heptane / EtOAc from 100:0 to 70:30) to afford intermediate 121 (0.21 g, 66%) as a beige solid.

Intermediate 122

(3 S)- 1 -(3-Fluoro-4- {6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tefrahydroisoquinoline-2-carbonyl]-8-(pyrrolidin-l-yl)imidazo[l,2-a]pyridin-2-yl}phenyl)pyrrolidine-3-carboxylic acid


A mixture of intermediate 121 (0.19 g, 327 pmol) and lithium hydroxide monohydrate (82.2 mg, 1.96 mmol) in THF (8 mL) and H2O (2 mL) was stirred at rt overnight. An aqueous solution of citric acid (377 mg) was added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSC>4, filtered and evaporated to dryness to afford intermediate 122 (188 mg, quant.) as an orange solid.

Compound 20

(3 S)- 1 -(3-Fluoro-4- {6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]-8-(pyrrolidin-l-yl)imidazo[l,2-a]pyridin-2-yl}phenyl)pyrrolidine-3-carboxamide


To a solution of intermediate 122 (0.15 g, 264 gmol) in DMF (4 mL) were added DIPEA (0.14 mL, 0.79 mmol) and HATU (121 mg, 0.32 mmol). The reaction mixture was stirred at rt for 15 min. Ammonia (30% in H2O, 30 pL, 1.59 mmol) was added dropwise. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with H2O and EtOAc. The layers were separated and the organic phase was washed with H2O (3 times) and brine, dried over MgSC>4, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 12 g, 30 pm, mobile phase gradient: DCM / MeOH from 100:0 to 98:2). The residue (0.12 g) was taken up in Et20. The solid was filtered off and dried under vacuum to give compound 20 (94 mg, 63%) as a grey solid.

Synthesis of compound 21


Intermediate 123

Methyl (35)- 1 -(4- {8-cyclopropyl-3-methyl-6-[(17?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyljimidazo [ 1 ,2-a]pyridin-2-yl} -3 -fluorophenyl)pyrro lidine-3 -carboxylate


A mixture of intermediate D5 (0.31 g,598 iirnol), (5)-methyl pyrrolidine-3 -carboxylate hydrochloride [1099646-61-3] (139 mg, 0.84 mmol), cesium carbonate (0.78 g, 2.39 mmol) and XantPhos (41.5 mg, 71.8 pmol) was purged with nitrogen. 1,4-Dioxane (6 mL) was added and the mixture was purged again with nitrogen. Palladium acetate (16.1 mg, 71.8 inriol) was added. The reaction mixture was purged with nitrogen and stirred at 100°C for 5 h. The reaction mixture was diluted with EtOAc and EEO. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS04, filtered and the solvent was evaporated in vacuo. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 25 g, 30 pm, mobile phase gradient: heptane / EtOAc from 90: 10 to 50:50) to afford intermediate 123 (0.22 g, 65%) as a yellow solid.

Intermediate 124

(35)- 1 -(4- {8-Cyclopropyl-3-methyl-6-[(17?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyljimidazo [ 1 ,2-a]pyridin-2-yl} -3 -fluorophenyl)pyrro lidine-3 -carboxylic acid


A mixture of intermediate 123 (215 mg, 0.38 mmol) and lithium hydroxide monohydrate (95.5 mg, 2.28 mmol) in THF (6 mL) and EEO (3 mL) was stirred at rt overnight. An aqueous solution of citric acid (438 mg in 10 mL of LEO) was added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04, filtered and evaporated to dryness to afford intermediate 124 (0.21 g, quant.) as an orange solid.

Compound 21

(3 S)- 1 -(4- j 8-Cyclopropyl-3-mcthyl-6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl] imidazo [ 1 ,2-a]pyridin-2-yl} -3 -fluorophenyl)pyrro lidine-3 -carboxamide


To a solution of intermediate 124 (0.21 g, 0.38 mmol) in DMF (5 mL) were added DIPEA (0.20 mL, 1.14 mmol) and HATU (217 mg, 0.57 mmol). The reaction mixture was stirred at rt for 15 min. Ammonia (30% in LEO, 43.1 pL, 2.28 mmol) was added dropwise. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with LEO and EtOAc. The layers were separated and the organic phase was washed with EEO (3 times) and brine, dried over MgSCE, filtered and evaporated to dryness to give compound 21 (0.15 g, 72%) as a brown solid.

Synthesis of compound 22

Intermediate 130

Methyl (35)-l-(5-{8-cyclopropyl-6-[(17?)-l-methyl-l,2,3,4-tetrahydroisoquino line-2-carbonyl]imidazo[l,2-a]pyridin-2-yl}-6-fluoropyridin-2-yl)pyrrolidine-3-carboxylate


A mixture of intermediate C5 (0.13 g, 0.42 mmol) and intermediate A13 (175 mg, 0.51 mmol) in MeCN (2 mL) was heated at 120°C using a single mode microwave (Anton Paar Monowave® 300) with a power output ranging from 0 to 850 W for 40 min. The reaction mixture was concentrated in vacuo. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 25 g, 30 pm, mobile phase gradient: heptane / EtOAc from 90:10 to 60:40 to afford intermediate 130 (0.173 g, 74%) as a yellow solid.

Intermediate 130

(35)- 1 -(5- (8-Cyclopropyl-6-[(17?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]imidazo[l,2-a]pyridin-2-yl}-6-fluoropyridin-2-yl)pyrrolidine-3-carboxylic acid


131

A mixture of intermediate 130 (0.17 g, 0.31 mmol) and lithium hydroxide monohydrate (91.8 mg, 2.19 mmol) in THF (6 mL) and H2O (2.5 mL) was stirred at rt overnight. An aqueous solution of citric acid (420 mg in 10 mL of H2O) was added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSCL, filtered and evaporated to dryness to afford intermediate 131 (0.168 g, quant.) as a beige solid.

Compound 22

(3 S)- 1 -(5- j 8-Cyclopropyl-6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]imidazo[l,2-a]pyridin-2-yl}-6-fluoropyridin-2-yl)pyrrolidine-3-carboxamide


To a solution of intermediate 131 (168 mg, 0.31 mmol) in DMF (4 mL) were added DIPEA (0.16 mL, 0.93 mmol) and HATU (0.18 g, 0.47 mmol). The reaction mixture was stirred at rt for 15 min and ammonia (30% in H2O, 35 pL, 1.87 mmol) was added dropwise. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with H2O and EtOAc. The layers were separated and the organic phase was washed with water (3 times) and brine, dried over MgS04, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 12 g, 30 pm, mobile phase gradient: DCM / MeOH from 100:0 to 95:5) to afford give compound 22 (0.085 g, 51%) as a brown solid.

Synthesis of compound 23


Intermediate 132

Methyl (35)-l-(5-{8-Cyclopropyl-6-[(4*i?)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl]imidazo[l,2-a]pyridin-2-yl}-6-fluoropyridin-2-yl)pyrrolidine-3-carboxylate


A mixture of intermediate C6 (0.25 g, 0.80 mmol) and intermediate A13 (0.33 g, 0.96 mmol) in MeCN (4 mL) was heated at 120°C using a single mode microwave (Anton Paar Monowave® 300) with a power output ranging from 0 to 850 W for 40 min. The reaction mixture was concentrated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 12 g, 30 mM, mobile phase gradient: heptane / EtOAc from 100:0 to 60:40) to afford intermediate 132 (0.20 g, 45%) as a brown solid.

Intermediate 133

(35)-l-(5-{8-Cyclopropyl-6-[(4*i?)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl]imidazo[l,2-a]pyridin-2-yl}-6-fluoropyridin-2-yl)pyrrolidine-3-carboxylic acid


133

A mixture of intermediate 132 (189 mg, 0.34 mmol) and lithium hydroxide monohydrate (85 mg, 2.03 mmol) in THF (5 mL) and H2O (1.5 mL) was stirred under reflux for 6 h. An aqueous solution of citric acid (390 mg in 5 mL of H2O) was added. The precipitate was filtered off, washed with H2O and Et20 and dried under vacuum to afford intermediate 133 (0.18 g, 99%) as a yellow solid.

Compound 23

(35)-l-(5-{8-cyclopropyl-6-[(4*7?)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl]imidazo[l,2-a]pyridin-2-yl}-6-fluoropyridin-2-yl)pyrrolidine-3-carboxamide


To a solution of intermediate 133 (183 mg, 0.34 mmol) in DMF (5 mL) were added DIPEA (0.17 mL, 1.01 mmol) and HATU (0.19 g, 0.50 mmol). The reaction mixture was stirred at rt for 15 min and ammonia (30% in H2O, 38 pL, 2.01 mmol) was added dropwise. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with H2O and EtOAc. The layers were separated and the organic phase was washed with H2O (3 times) and brine, dried over MgSC>4, filtered and evaporated to dryness to give compound 23 (0.15 g, 82%) as a brown solid.

Synthesis of compound 24

Intermediate 125

6- { 8-Cyc lopropyl-6-[( 1 /?)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2-carbonyl]imidazo[l ,2-a]pyridin-2-yl}-7-fluoro-2H-chromene-3-carboxylic acid


A mixture of intermediate D6 (127 mg, 236 pmol) and lithium hydroxide monohydrate (69.4 mg, 1.65 mmol) in THF (5 mL) and H2O (1.5 mL) was stirred at rt for 15 h. An aqueous solution of citric acid (317 mg in 5 mL of H2O) was added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSCL, filtered and evaporated to dryness to afford intermediate 125 (0.10 g, 81%) as a beige solid.

Compound 24

6- j 8-Cyc lopropyl-6-[( 1 /?)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2-carbonyl]imidazo[l ,2-a]pyridin-2-yl}-7-fluoro-2H-chromene-3-carboxamide


To a solution of intermediate 125 (0.16 g, 306 mhioΐ) in DMF (4 mL) were added DIPEA (0.16 mL, 0.92 mmol) and HATU (174 mg, 0.46 mmol). The reaction mixture was stirred at rt for 15 min. Ammonia (30% in EEO, 35 pL, 1.83 mmol) was added dropwise. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with H2O (3 times) and EtOAc. The layers were separated and the organic phase was washed with H2O and brine (3 times), dried over MgS04, filtered and evaporated to dryness. The crude mixture was purified by flash

chromatography over silica gel (Puriflash Interchim® 12 g, 30 pm, mobile phase gradient: DCM / MeOH from 100:0 to 97:3) to give compound 24 (52 mg, 33%) as an orange solid.

Synthesis of compound 25


Intermediate 126

Ethyl 1 -(4- j 8-cyclopropyl-6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2-carbonyl]imidazo[l,2-a]pyridin-2-yl}-3-fluorophenyl)-lH-pyrazole-4-carboxylate


A mixture of intermediate B1 (0.50 g, 0.99 mmol), ethyl 4-pyrazolecarboxylate [37622-90-5] (0.34 g, 2.38 mmol), copper iodide (189 mg, 0.99 mmol), (17?,27?)-N,N’-dimethylcyclohexane-1, 2-diamine (0.16 mL, 0.99 mmol) and potassium carbonate (0.41 g, 2.97 mmol) was purged with nitrogen for 5 min. DMF (8.5 mL) was added and the reaction mixture was stirred at 100°C for 18 h. The mixture was poured out into a solution of EtOAc and a saturated aqueous solution of NH4CI. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with a saturated aqueous solution of NH4CI, H2O and brine, dried over MgS04, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 40 g, 30 pm, mobile phase gradient: heptane / EtOAc from 100:0 to 60:40) to afford intermediate 126 (0.25 g, 45%) as a yellow solid.

Compound 25

1 -(4- j 8-Cyclopropyl-6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2-carbonyl]imidazo[ 1 ,2-a]pyridin-2-yl}-3-fluorophenyl)-lH-pyrazole-4-carboxylic acid


A mixture of intermediate 126 (135 mg, 0.24 mmol) and lithium hydroxide monohydrate (70.4 mg, 1.68 mmol) in THF (5 mL) and H2O (1 mL) was stirred at rt overnight. An aqueous solution of citric acid (322 mg in 5 mL of H2O) was added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 25 g, 30 pm, mobile phase gradient: DCM / MeOH from 100:0 to 98:2) to give compound 25 (51 mg, 40%) as a beige solid.

Compound 26

1 -(4- j 8-Cyclopropyl-6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2-carbonyl]imidazo[ 1 ,2- a]pyridin-2-yl} -3 -fluorophenyl)- 1 H-pyrazo le-4-carboxamide


To a solution of compound 25 (61.0 mg, 114 pmol) in DMF (2 mL) were added HATU (65.0 mg, 0.17 mmol) and DIPEA (59 pL, 0.34 mmol). The reaction mixture was stirred at rt for 15 min. Ammonia (30% in EEO, 43 pL, 0.68 mmol) was added. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with EEO and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with EEO and brine, dried over MgS04, filtered and evaporated to dryness. The residue was taken up in EEO. The solid was filtered off and dried under vacuum. The residue was purified by flash chromatography over silica gel (Puriflash Interchim® 4 g, 30 pm, mobile phase gradient: DCM / MeOH from 100:0 to 98:2) to give compound 26 (17 mg, 28%) as a beige solid.

Compound 27

1 -(4- j 8-Cyclopropyl-6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2-carbonyl]imidazo[ 1 ,2-a]pyridin-2-yl} -3 -fluorophenyl)azetidin-3 -o 1


A mixture of intermediate B1 (0.15 g, 297 pmol), (3)-hydroxyazetidine hydrochloride [18621-18-6] (65.2 mg, 595 pmol), cesium carbonate (388 mg, 1.19 mmol) and XantPhos (20.6 mg, 35.7 pmol) was purged with nitrogen. 1,4-Dioxane (3 mL) was added and the mixture was purged again with nitrogen. Palladium acetate (8.01 mg, 35.7 pmol) was added. The reaction mixture was purged with nitrogen and stirred at 100°C for 20 h. The mixture was diluted with H2O and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The

combined organic extracts were washed with H2O and brine, dried over MgSC>4, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 25 g, 30 pm, mobile phase gradient: DCM / MeOH from 100:0 to 97:3). The residue (0.11 g) was taken up in DIPE. The solid was filtered off and dried in vacuo to give compound 27 (0.09 g, 61%) as an orange solid.

Compound 28


Intermediate 127

Methyl 1 -(4- (8-cyclopropyl-6-[( 17?)- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinoline-2-carbonyl]imidazo[l,2-a]pyridin-2-yl}-3-fluorophenyl)azetidine-3-carboxylate


A mixture of intermediate B1 (0.20 g, 397 innol), methyl azetidine-3-carboxylate hydrochloride [100202-39-9] (90.2 mg, 595 pmol), cesium carbonate (517 mg, 1.59 mmol) and XantPhos (27.5 mg, 47.6 Lunol) was purged with nitrogen. 1,4-Dioxane (4 mL) was added and the mixture was purged again with nitrogen. Palladium acetate (10.7 mg, 47.6 pmol) was added. The reaction mixture was purged with nitrogen and stirred at 100°C for 15 h. The mixture was diluted with H2O and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with H2O and brine, dried over MgS04, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 25 g, 30 pm, mobile phase gradient: heptane / EtOAc from 100:0 to 60:40) to afford intermediate 127 (0.16 g, 75%) as a beige solid.

Intermediate 128

1 -(4- j 8-Cyclopropyl-6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2-carbonyl]imidazo[ 1 ,2-a]pyridin-2-yl} -3-fluorophenyl)azetidine-3-carboxylic acid


A mixture of intermediate 127 (0.15 g, 278 iimol) and lithium hydroxide monohydrate (70.1 mg, 1.67 mmol) in THF (8 mL) and H2O (2 mL) was stirred at rt overnight. An aqueous solution of citric acid (321 mg) was added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSC>4, filtered and evaporated to dryness to afford intermediate 128 (0.15 g, quant.) as a yellow solid.

Compound 28

1 -(4- j 8-Cyclopropyl-6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2-carbonyl]imidazo[ 1 ,2-a]pyridin-2-yl}-3-fluorophenyl)-N-methanesulfonylazetidine-3-carboxamide


A mixture of intermediate 128 (0.14 g, 267 gmol) and CDI (51.9 mg, 0.32 mmol) in MeCN (3 mL) was stirred at rt for 2 h. Methanesulfonamide (38.1 mg, 0.40 mmol) and DBU (59.8 pL, 0.40 mmol) were added. The reaction mixture was stirred at 80°C for 16 h. A IN aqueous solution of HCI and DCM were added. A yellow precipitate was formed. The solid was filtered off and dried in vacuo. The yellow solid was purified by flash chromatography over silica gel

(Puriflash Interchim® 25 g, 30 pm, mobile phase gradient: DCM / MeOH from 100:0 to 96:4). The residue (80 mg) was taken up in DIPE. The solid was filtered off and dried in vacuo to give compound 28 (0.06 g, 37%) as a beige solid.

Synthesis of compound 29


Intermediate HI

3-bromo-2-fluoro-6-hydroxybenzaldehyde


To a solution of 3-bromo-2-fluoro-6-methoxybenzaldehyde (3.0 g, 12.9 mmol) in DCM (25 mL) at -10°C was added dropwise of boron tribromide (38.6 mL, 1 M, 36.6 mmol). The resulting mixture was allowed to warm up to rt and stirred at rt for 1.5 h. The reaction mixture was quenched with ice water and extracted with DCM (twice). The combined organic extracts were washed with a saturated aqueous solution of NaHCCb, brine and dried over MgS04, filtered and evaporated to dryness to afford intermediate HI (2.8 g, 99%) as a beige solid.

Intermediate H2

Methyl 6-bromo-5-fluoro-2H-chromene-3-carboxylate


A mixture of intermediate HI (1.48 g, 6.76 mmol), methyl acrylate (4.48 mL, 50.00 mmol) and l,4-diazabicyclo[2.2.2]octane (0.15 g, 1.35 mmol) were heated at 150°C using a single mode microwave (Anton Paar Monowave® 300) with a power output ranging from 0 to 850 W for 45 min. The mixture was concentrated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 40 g, 30 pm, dry loading (celite®), mobile phase gradient: heptane / EtOAc from 100:0 to 80:20) to afford intermediate H2 (0.60 g, 31%) as a white solid.

Intermediate H3

Methyl 6-acetyl-5-fluoro-2H-chromene-3-carboxylate


H3

A solution of intermediate H2 (0.38 g, 1.32 mmol) in THF (7.5 mL) was purged with nitrogen for 10 min. Tributyl(l-ethoxyvinyl)tin (0.90 mL, 2.65 mmol) and

bis(triphenylphosphine)palladium dichloride (93 mg, 0.13 mmol) were added. The mixture was heated at 120°C using a single mode microwave (Anton Paar Monowave® 300) with a power output ranging from 0 to 850 W for 20 min. The mixture was poured into the solution of KF (2 g in 50 mL of H2O) and stirred for 10 min at rt then filtered through a short pad of celite® and rinsed with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H2O and brine and dried over MgS04, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 40 g, 30 mhi, dry loading (Celite®), mobile phase gradient: heptane / EtOAc from 100:0 to 80:20) to afford intermediate H3 (0.24 g, 72%) as a white solid.

Intermediate H4

Methyl 6-(2-bromoacetyl)-5-fluoro-2H-chromene-3-carboxylate


To a solution of intermediate H3 (0.23 g, 0.92 mmol) in EtOAc (7 mL) at rt, was added copper (II) bromide (0.41 g, 1.84 mmol). The reaction mixture was stirred under reflux for 5 h. The solid was filtered off. The filtrate was washed with a saturated aqueous solution of NaHCOs and brine, dried over MgS04, filtered and concentrated in vacuo to give intermediate H4 (0.30 g, 99%) as a white solid.

Intermediate H5

Methyl (R)-6-(8-cyclopropyl-6-( 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinoline-2-carbonyl)imidazo[l,2-a]pyridin-2-yl)-5-fluoro-2H-chromene-3-carboxylate


A mixture of intermediate C5 (60 mg, 0.20 mmol) and intermediate H4 (77 mg, 0.23 mmol) in MeCN (2.0 mL) was heated at 120°C using a single mode microwave (Anton Paar Monowave® 300) with a power output ranging from 0 to 850 W for 40 min. The mixture was concentrated in vacuo. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 12 g, 30 pm, mobile phase gradient: heptane / EtOAc from 90:10 to 70:30) to afford intermediate H5 (30 mg, 29%) as a yellow solid.

Compound 29

(R)-6-(8-cyclopropyl-6-(l-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)imidazo[l,2-a]pyridin-2-yl)-5-fluoro-2H-chromene-3-carboxylic acid


A mixture of intermediate H5 (30 mg, 60 mhioΐ) and lithium hydroxide monohydrate (16 mg, 0.39 mmol) in THF (2 mL) and LEO (0.5 mL) was stirred at rt for 15 h. An aqueous solution of citric acid (75 mg in 2 mL of H2O) was added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04, filtered and evaporated to dryness to afford compound 29 (28 mg, 95%) as a beige foam.

Compound 30

(R)-N-(4-(8-cyclopropyl-6-(l-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)imidazo[l,2-a]pyridin-2-yl)-3 -fluorophenyl)-3 -hydroxyazetidine- 1 -carboxamide


A mixture of intermediate B1 (0.3 g, 0.60 mmol), 3 -hydroxyazetidine-1 -carboxamide (0.14 g, 1.19 mmol), cesium carbonate (0.78 g, 2.38 mmol) and XantPhos (34 mg, 60 pmol) in 1,4-dioxane (6 mL) was purged with nitrogen. Palladium acetate (13 mg, 0.06 mmol) was added.

The reaction mixture was purged again with nitrogen and stirred at 100°C for 15 h. The reaction mixture was diluted with EtOAc and ELO then filtered through a short pad of celite®. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS04, filtered and the solvent was evaporated in vacuo. The crude mixture was purified by flash chromatography over silica gel (Puriflash

Interchim® 40 g, 30 mhi, mobile phase gradient: DCM/MeOH, from 100:0 to 97:03) to afford compound 30 (0.11 g, yield 34%) as a yellow solid.

Compound 31

(R),(E)-3-(4-(8-cyclopropyl-6-( 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinoline-2-carbonyl)imidazo[ 1 ,2-a]pyridin-2-yl)-3-fluorophenyl)acrylic acid


A mixture of intermediate 16 (0.10 g, 0.19 mmol) and lithium hydroxide monohydrate (64 mg, 1.53 mmol) in THF (5.5 mL) and H2O (1 mL) was stirred at rt for 15 h. An aqueous solution of citric acid (294 mg in 5 mL of H2O) was added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSCE, filtered and concentrated in vacuo. The residue was taken up in EtOAc and stirred at rt for 5 min. The solid was filtered off and dried under vacuum to give compound 31 (65 mg, 69%) as a beige solid.

Part 2: Tmidazofd-blpyridazines

Synthesis of Intermediate 135

Intermediate 134

Ethyl ( I S, 2A)-2-(4-acctyl-3-fluorophcnyl [cyclopropane- 1 -carboxylatc


134

To a degassed mixture of ethyl (lS,2S)-2-(4-bromo-3-fluorophenyl)cyclopropane-l-carboxylate [2035422-08-1] (5.00 g, 17.0 mmol, 95% purity) and 1 -ethoxy- l-(tributylstannyl)ethylene

[97674-02-7] (6.1 mL, 18.2 mmol) in toluene (95 mL) was added [I,G-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (605 mg, 827 gmol). The reaction mixture was stirred at 100°C for 24 h. The reaction mixture was evaporated to dryness. The crude mixture was purified by preparative LC (regular SiOH, 30 pm, 220 g Interchim®, dry loading (Celite®), mobile phase gradient: heptane / EtOAc from 100:0 to 80:20) to give intermediate 134 (1.3 g, 31%) and a fraction containing impurities (2.8 g). The latter was hydrolyzed with a IN aqueous solution of HC1 (50 mL) in THF (50 mL) for 1 h. The reaction mixture was diluted with LLO and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgS04, filtered and the solvent was evaporated in vacuo. The residue was purified by preparative LC (regular SiOH, 30 pm, mobile phase gradient: heptane / EtOAc from 100:0 to 80:20) to afford intermediate 134 (1.2 g, 29%).

Intermediate 135

Ethyl ( l S,2S)-2-[4-(2-bromoacctyl)-3-fluorophcnyl]cyclopropanc- 1 -carboxylatc


135

Bromine (0.27 mL, 5.19 mmol) was added dropwise to a solution of intermediate 134 (1.30 g, 5.19 mmol) in acetic acid (26 mL). The reaction mixture was stirred at rt for 16 h. The reaction mixture was evaporated to dryness and azeotroped with toluene to give intermediate 135 (1.6 g, 94%).

Intermediate El

Ethyl (15',25)-2-(4-{8-bromo-6-chloroimidazo[l,2-b]pyridazin-2-yl}-3-fluorophenyl)-cyclopropane- 1 -carboxylate


A mixture of intermediate 135 (1.20 g, 3.65 mmol) and 3-amino-4-bromo-6-chloropyridazine [446273-59-2] (912 mg, 4.38 mmol) in EtOH (34 mL) was stirred at 90°C for 24 h. The reaction mixture was cooled to 0°C. The precipitate was filtered off and dried to afford a first crop of intermediate El (421 mg, 26%). Mother liquor was evaporated to dryness. The residue was taken up in EtOH. The solid was filtered off and dried. The residue, mother liquor and another batch (208 mg, 0.63 mmol) were combined and purified by preparative LC (regular SiOH, 30 pm, 80 g Interchim®, dry loading (Celite®), mobile phase gradient: heptane / EtOAc from 100:0 to 60:40). The residue (580 mg) was triturated in EtOH and the solid was filtered off and dried to afford a 2nd crop of intermediate El (157 mg).

Intermediate E2

Ethyl (15',25)-2-(4-{6-chloro-8-cyclopropylimidazo[l,2-b]pyridazin-2-yl}-3-fluorophenyl)-cyclopropane- 1 -carboxylate


To a degassed mixture of intermediate El (578 mg, 1.32 mmol), cesium carbonate (1.29 g, 3.95 mmol) and cyclopropylboronic acid [411235-57-9] (113 mg, 1.32 mmol) in H2O (2.8 mL) and 1,4-dioxane (28 mL) was added [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (98.3 mg, 0.13 mmol). The reaction mixture was stirred at 100°C for 48 h. The reaction mixture was diluted with EtOAc and H2O. The layers were separated and the aqueous layers was extracted with EtOAc (once). The combined organic extracts were dried over MgS04, filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (regular SiOH, 30 pm, 40 g Interchim®, mobile phase gradient: heptane / EtOAc from 100:0 to 60:40) to afford intermediate E2 (400 mg, 76%).

Intermediate E3

8-Cyclopropyl-2- {4-[( 1 S,2S)-2-(cthoxycarbonyl)cyclopropyl]-2-fluorophcnyl [ imidazo[ 1 ,2-b]pyridazine-6-carboxylic acid


A degassed mixture of intermediate E2 (580 mg, 1.45 mmol), potassium carbonate (241 mg,

1.74 mmol), palladium acetate (32.6 mg, 145 mhioΐ) and cataCXium® A (104 mg, 0.29 mmol) in NMP (14.5 mL) and H2O (1 mL) was stirred under 3 bars of carbon monoxide at 130°C for 3 h. Additional amount of palladium acetate (32.6 mg, 145 iirnol) and cataCXium® A (104 mg, 0.29 mmol) were added and the reaction mixture was stirred under 3 bars of carbon monoxide at 130°C for another 24 h. The reaction mixture was diluted with H2O and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (once). The combined organic extracts were washed with brine (3 times), dried over MgS04, filtered and evaporated in vacuo.

The crude mixture was purified by preparative LC (regular SiOH, 30 pm, 80 g Interchim®, mobile phase gradient: heptane / EtOAc from 100:0 to 0:100 then EtOAc / MeOH from 100:0 to 95:5 and (EtOAc / AcOH 97.5 / 2.5) / MeOH from 95:5 to 85:15) to afford intermediate E3 (0.41 g, 40%, 58% purity).

S



Intermediate F2

Methyl 6-amino-5-ethylpyridazine-3-carboxylate


In a stainless-steel bomb, to a degassed mixture of 6-chloro-4-ethylpyridazin-3-amine [933035-42-8] (1.78 g; 11.3 mmol) and TEA (3.84 mL; 27.6 mmol) in MeOH (77 mL) was added PdCl2(dppf) (603 mg; 0.824 mmol). The resulting mixture stirred 3 h at 130°C under 10 bars of CO. The mixture was cooled to rt, filtered and evaporated to dryness to give intermediate F2 (3.7 g, 99%) as a brownish gum.

Intermediate F3

Methyl 2-(4-bromo-2-fluorophenyl)-8-ethylimidazo[l,2-b]pyridazine-6-carboxylate

A mixture of 4-Bromo-2-fluorophenacyl bromide (3.30 g, 11.1 mmol), intermediate F2 (3.65 g, 11.1 mmol) and NaHCCb (0.931 g, 11.08 mmol) in acetone (87 mL) was stirred at 60°C for 16 h. The mixture was cooled to rt. The filtrate was evaporated to dryness and the residue was taken-up with MeCN. The solid was filtered off to give intermediate F3 (1.9 g, 47%) as a yellow solid. The filtrate was evaporated under vacuum and purified by preparative LC (irregular SiOH, 15-40 pm, 120 g Grace Resolv™, solid loading (Celite®), mobile phase gradient: from Heptane 100%, EtOAc 0% to heptane 70%, EtOAc 30%). The fractions containing product were evaporated under vacuum to give a residue. The residue was taken-up in MeCN and the solid was filtered to give intermediate F3 (276 mg, 7%) as a yellow solid. (Global yield 54%)

Intermediate F4

Potassium 2-(4-bromo-2-fluorophenyl)-8-ethylimidazo[ 1 ,2-b]pyridazine-6-carboxylate


KOH (1.18 g; 17.9 mmol) was dissolved in EtOH (47 mL) then intermediate F3 (2.26 g; 5.98 mmol) was added portionwise and the suspension was stirred at reflux for 18 h. The solid was filtered, washed with EtOH (once), then with Et20 (4 times) and dried over frit to give intermediate F4 (2.2 g, 92%) as a white solid.

Intermediate F6

(R)-(2-(4-bromo-2-fluorophenyl)-8-ethylimidazo[l,2-b]pyridazin-6-yl)(l -methyl-3, 4-dihydroisoquino lin-2( 1 H)-yl)methanone


A mixture of intermediate F4 (1.0 g; 2.49 mmol), (R)-l -methyl- 1,2, 3, 4-tetrahydroisoquino line [84010-66-2] (659 mg; 4.48 mmol) and DIPEA (2.14 mL; 12.4 mmol) in DCM (6.4 mL) was stirred at 0°C. 1-Propanephosphonic anhydride (50% in EtOAc; 3.7 mL; 6.2 mmol) was added slowly (over 5 min.) at 0°C. The mixture was stirred at 0°C for 10 min then at rt for 18 h. Brine, EtOAc and a sat. aq. solution of NaHCOs were added to the reaction mixture, the aqueous layer was extracted with EtOAc (twice). The combined organic layers were washed with a brine and a sat. aq. solution of NaHC03 (4 times), dried over MgS04 and evaporated in vacuo to give intermediate F6 (1.31 g, 99%) as an orange foam.

Synthesis of intermediate F20


Intermediate F5

(R)-N-(4-acetyl-3-fluorophenyl)-3-hydroxypyrrolidine-l -carboxamide


F5

To a degassed mixture of 4-bromo-2-fluoroacetophenone (6.17 g; 28.4 mmol), (3R)-3-hydroxypyrrolidine-1 -carboxamide (4.77 g; 34.1 mmol) and CS2CO3 (27.8 g; 85.2 mmol) in dioxane (118 mL) was added Pd(OAc)2 (638 mg; 2.84 mmol) and XantPhos (1.65 g; 2.84 mmol). The resulting mixture was stirred at 100°C for 16 h. Water and EtOAc were added. The

layers were separated and the aqueous layer was extracted with EtOAc (once). The combined organic layers were washed with brine, dried over MgS04, filtered and the solvent was removed in vacuo to give 9.0 g of crude which was purified by preparative LC (regular SiOH, 30 pm, 330 g Interchim®, mobile phase gradient: from heptane/EtOAc 60/40 to 0/100 then EtOAc/MeOH 100/0 to 85/15) to give intermediate F5 (4.6 g, 61%).

Intermediate F20

(R)- 1 -((4-(2-bromoacetyl)-3-fluorophenyl)carbamoyl)pyrrolidin-3-yl acetate


A mixture of intermediate F5 (4.6 g; 17 mmol) and pyridine hydrobromide perbromide (5.5 g; 17 mmol) in AcOH (92 mL) was stirred at rt for 16 h. The mixture was evaporated to dryness and the residue was azeotroped with toluene (twice) then the residue was purified by preparative LC (regular SiOH, 30 pm, 220 g Interchim®, mobile phase gradient: from heptane/EtOAc 70/30 to 0/100 then EtOAc/MeOH 100/0 to 90/10) to give intermediate F20 (5.5 g, 82%).

Synthesis of intermediate F24


Oct

F23

Intermediate F21

(R)-l-((4-(8-bromo-6-chloroimidazo[l,2-b]pyridazin-2-yl)-3-fluorophenyl)carbamoyl)-pyrrolidin-3-yl acetate


A mixture of intermediate F20 (1.15 g; 2.97 mmol), 3-amino-4-bromo-6-chloropyridazine (619 mg; 2.97 mmol) and NaHCCL (249 mg; 2.97 mmol) in acetone (15 mL) was stirred at 110°C for 16 h in a pressure vessel reactor. The mixture was evaporated to dryness. The residue was taken-up with DCM and the solid was filtered and dried over frit. The solid was triturated in water, filtered and dried over frit to give intermediate F21 (699 mg, 47%). The mother liquor was purified by preparative LC (regular SiOH, 30 pm, 40 g Interchim®, dry loading (celite®), mobile phase gradient: from DCM/iPrOH 100/0 to 90/10) the fraction containing product was collected and evaporated to dryness then the residue was taken-up with DCM and the solid was filtered and dried over frit to give intermediate F21 (93 mg, 6%). The mother liquor was purified by preparative LC (regular SiOH, 30 pm, Interchim® 40 g, mobile phase gradient: from heptane/EtOAc 70/30 to 0/100 then EtOAc/MeOH 100/0 to 85/15)) the fraction containing product was collected and evaporated to dryness then the residue was taken-up with DCM and the solid was filtered and dried over frit to give intermediate F21 (76 mg, 5%). Global yield (868 mg, 58%).

Intermediate F22

(R)- 1 -((4-(6-chloro-8-cyclopropylimidazo[ 1 ,2-b]pyridazin-2-yl)-3-fluorophenyl)carbamoyl)-pyrrolidin-3-yl acetate


In a microwave vial, PdCbdppf (95 mg; 0.13 mmol) was added to a degassed solution of intermediate 21 (646 mg; 1.30 mmol), cPrB(OH)2 (106 mg; 1.24 mmol) and CS2CO3 (1.75 g; 5.36 mmol) in dioxane (10 mL) and water (2 mL) at rt. The resulting mixture was heated at 100°C using one single mode microwave (biotage®) with a power output ranging from 0 to 400 W for 1 h. Water and EtOAc were added and the layers were separated. The aqueous layer was

extracted with EtOAc (once). The combined organic layer were dried over MgS04, filtered and the solvent was removed in vacuo. The residue was purified by preparative LC (regular SiOH, 30 pm, Interchim® 40 g, mobile phase gradient: from hcptanc/'PrOH 90/10 to 40/60) to give intermediate F22 (0.31 g, 52%).

Intermediate F23

Ethyl (R)-2-(4-(3-acetoxypyrrolidine- 1 -carboxamido)-2-fluorophenyl)-8-cyclopropyl-imidazo[l,2-b]pyridazine-6-carboxylate


To a degassed mixture of intermediate F22 (0.37 g; 0.808 mmol) and NaOAc (132 mg; 1.61 mmol) in EtOH (4.9 mL) and DMF (2 mL) was added PdCbdppf (60 mg; 81 gmol) then the resulting mixture was stirred under 7 bar of CO in a pressure vessel reactor. The resulting mixture was stirred at 70°C for 16 h. water and EtOAc were added. The layers were separared and the aqueous layer was extracted with EtOAc (once). The combined organic layers were washed with brine, dried over MgS04, filtered and the solvent was removed in vacuo. The residue was purified by preparative LC (regular SiOH, 30 pm, Interchim® 25 g, mobile phase gradient: from heptane/iPrOH 90/10 to 30/70) to give intermediate F23 (263 mg, 66%).

Intermediate F24

(R)-8-cyclopropyl-2-(2-fluoro-4-(3-hydroxypyrrolidine-l-carboxamido)phenyl)imidazo[l,2-b]pyridazine-6-carboxylic acid


A mixture of intermediate F23 (263 mg; 0.531 mmol) and KOH (66 mg; 1.17 mmol) in EtOH (4.6 mL) was stirred at rt for 16 h. The precipitate was filtered and dried over frit then the solid was dried by azeotrope with toluene (twice) to give 55 mg of intermediate F24 as potassium salt. The mother liquor was evaporated to dryness and the residue was taken-up with THF and aqueous HC1 IN was added. The mixture was evaporated to dryness and the residue was dried by

azeotrope with toluene (twice) to give intermediate F24 as acid form (185 mg, purity 90%). Global yield 96%

Synthesis of Intermediate F30


Intermediate F28

(R)- 1 -((4-(6-chloro-8-ethylimidazo[ 1 ,2-b]pyridazin-2-yl)-3-fluorophenyl)carbamoyl)pyrrolidin-3-yl acetate


A mixture of 6-chloro-4-ethylpyridazin-3-amine [933035-42-8] (0.52 g; 3.30 mmol), intermediate F20 (1.28 g; 3.30 mmol) and NaHCCh (278 mg; 3.30 mmol) in acetone (26 mL) was stirred at relux for 36 h. The mixture was evaporated to dryness and the residue was taken-up with DCM then the solid was filtered off and the mother liquor was evaporated to dryness. The residue was purified by preparative LC (regular SiOH, 30 pm, 40 g Interchim®, mobile phase gradient: from hcptanc/'PrOH 98/2 to 60/40) to give intermediate F28 (1.0 g, 68%).

Intermediate F29

Ethyl (R)-2-(4-(3-acetoxypyrrolidine-l-carboxamido)-2-fluorophenyl)-8-ethylimidazo[l,2-b]pyridazine-6-carboxylate


To a degassed mixture of intermediate F28 (753 mg; 1.69 mmol) and NaOAc (202 mg; 3.38 mmol) in EtOH (10 mF) and DMF (4.4 mF) was added PdCl2(dppf) (123 mg; 0.166 mmol) then the resulting mixture was stirred under 7 bar of CO at 70°C for 16 h. Water and EtOAc were added. The layers were separated and the aqueous layer was extracted with EtOAc (once). The combined organic layers were washed with brine, dried over MgS04, filtered and the solvent was removed in vacuo. The residue was purified by preparative EC (regular SiOH, 30 pm, 40 g Interchim®, mobile phase gradient: from hcptanc/'PrOH 90/10 to 30/70) to give intermediate F29 (0.50 g, 61%).

Intermediate F30

(R)-8-ethyl-2-(2-fluoro-4-(3-hydroxypyrrolidine-l-carboxamido)phenyl)imidazo[l,2-b]-pyridazine-6-carboxylic acid


A mixture of intermediate F29 (0.48 g; 0.993 mmol) and KOH (123 mg; 2.18 mmol) in EtOH (8.6 mL) was stirred at rt for 16 h. The mixture was evaporated to dryness. The residue was dried by azeotrope with toluene (twice) then aqueous HC1 IN and THF were added. The mixture was stirred for 5 min then was evaporated to dryness. The residue was dried by azeotrope with toluene (twice) to give 0.56 g of intermediate F30 (0.56 g, quant, 73% purity).

Synthesis of Intermediate F45

Intermediate F44

6-amino-5-ethylpyridazine-3-carboxylic acid hydrochloride


A mixture of intermediate F2 (708 mg, 3.91 mmol) and KOH (438 mg, 7.82 mmol) in EtOH (58 mL) and water (5.8 mL) was stirred at rt for 3 h. The mixture was evaporated under vacuum then aqueous HC1 IN and THF were added. The mixture was stirred for 5 min then was evaporated to dryness to give intermediate F44 (1.1 g, quant, 73% purity).

Intermediate F45

(R)-(6-amino-5 -ethylpyridazin-3 -yl)( 1 -methyl-3 ,4-dihydroisoquino lin-2( 1 H)-yl)methanone


A mixture of intermediate F44 (1.05 g, 3.77 mmol), 73% purity), ( 17?)- 1 -methyl- 1,2, 3,4-tetrahydroisoquinoline [84010-66-2] (666 mg, 4.52 mmol), HATU (2.1 g, 5.65 mmol) and DiPEA (2.0 mL) in DMF (25 mL) was stirred at rt for 1 h. Brine and EtOAc were added to the reaction mixture. The layers were separated. The aqueous layer was extracted with EtOAc (twice). The combined organic layers were washed with brine (3 times), dried over MgS04 and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 pm, 80 g Grace Resolv™, dry loading (celite®), mobile phase gradient: from DCM/MeOH 100/00 to 95/05). The fraction containing product was collected and evaporated to dryness. The residue was triturated in MeCN, filtered and dried over frit to give intermediate F45 (587 mg, 52%) as a white solid. The filtrate was evaporated to dryness and the residue was purified by reverse phase (spherical C18, 25 pm, 40 g YMC-ODS-25, dry loading (Celite®), mobile phase gradient: from (aq. NH4HC03 0.2%)/MeCN 85/15 to 45/55%). The fraction containing pure product was collected and evaporated to dryness to give intermediate F45 (133 mg, 8%) as a white solid. Global yield (720 mg, 64%)


Intermediate E4

Ethyl ( 1 S,2S)-2-(4- i 8-cyclopropyl-6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2-carbonyl]imidazo[l,2-b]pyridazin-2-yl}-3-fluorophenyl)cyclopropane-l-carboxylate


To a mixture of intermediate E3 (0.19 g, 269 pmol, 58% purity), DIPEA (19 pL, 1.08 mmol) and ( 1 R)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc [84010-66-2] (43.6 mg, 296 pmol) in DCM (2.8 mL) was added HATU (153 mg, 404 pmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was purified by preparative LC (regular SiOH, 30 pm, 12 g Interchim®, mobile phase gradient: heptane / EtOAc from 100:0 to 40:60) to afford intermediate E4 (74 mg, 51%).

Compound 32

( 1 S,2S)-2-(4- j 8-Cyclopropyl-6-[( 1 R)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2-carbonyl]imidazo[l,2-b]pyridazin-2-yl}-3-fluorophenyl)cyclopropane-l -carboxylic acid


A mixture of intermediate E4 (74.0 mg, 137 pmol) and lithium hydroxide monohydrate (8.65 mg, 206 Luriol) in THF (1 mL) and H2O (0.5 mL) was stirred at rt for 16 h. The reaction mixture was combined with another batch (71 mg, 132 pmol) and diluted with EtOAc and an aqueous solution of AcOH (10% v/v). The layers were separated and the aqueous phase was extracted with EtOAc (once). The combined organic extracts were dried over MgS04, filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (regular SiOH, 30 pm, 12 g Interchim®, mobile phase gradient: heptane / (EtOAc/ AcOH 97.5:2.5) from 95:5 to 50:50) to give compound 32 (52 mg, 74%). The product was combined with another fraction of compound 32 (58 mg). The residue was solubilized in EtOAc and heptane was added until precipitation. The solid was filtered off and dried under high vacuum at 60°C for 16 h to give compound 32 (70 mg).

Synthesis of compound 33

Ethyl ( 1 S,2S)-2-(4- j 8-cyclopropyl-6-[(2 ?)-2-mcthylazcpanc- 1 -carbonyl]imidazo[ 1 ,2-b]pyridazin-2-yl} -3-fluorophenyl)cyclopropane- 1 -carboxylate


To a mixture of intermediate E3 (170 mg, 241 pmol, 58% purity), DIPEA (0.16 mL, 0.96 mmol) and (27?)-2-methylazepane hydrochloride [331994-00-4] (39.6 mg, 0.27 mmol) in DCM (2.5 mL) was added HATU (137 mg, 0.36 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was purified by preparative LC (regular SiOH, 30 pm, 25 g Interchim®, mobile phase gradient: heptane / EtOAc from 80:20 to 0:100) to afford intermediate E5 (60 mg, 49%).

Compound 33

{\S,2S)-2-{4- {8-Cyclopropyl-6-[(27?)-2-methylazepane- 1 -carbonyl]imidazo[ 1 ,2-b]pyridazin-2-yl} -3-fluorophenyl)cyclopropane- 1 -carboxylic acid


A mixture of intermediate E5 (60.0 mg, 119 iimol) and lithium hydroxide monohydrate (7.49 mg, 0.18 mmol) in THF (0.9 mL) and H2O (0.5 mL) was stirred at rt for 16 h. the reaction mixture was diluted with EtOAc and an aqueous solution of AcOH (10% v/v) was added. The

layers were separated and the aqueous phase was extracted with EtOAc (once). The combined organic extracts were dried over MgS04, filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (regular SiOH, 30 pm, 12 g Interchim®, mobile phase gradient: heptane / (EtOAc + 2.5% AcOH) from 100:0 to 50:50). The residue (52 mg) was solubilized in EtOAc and heptane was added until precipitation. The solid was filtered off and dried under high vacuum at 60°C for 16 h to give compound 33 (30 mg, 53%) as a white solid.

Compound 34

(2-(4-((3 S,4S)-3 ,4-dihydroxypyrrolidin- 1 -yl)-2-fluorophenyl)-8-ethylimidazo[ 1 ,2-b]pyridazin-6-yl)((R)- 1 -methyl-3 ,4-dihydroisoquino lin-2( 1 H)-yl)methanone


In a sealed tube, a mixture of F6 (300 mg, 0.608 mmol), NaCfBu (129 mg, 1.34 mmol) and (3S, 4S)-Dihydroxypyrrolidine (75 mg, 0.73 mmol) in THF (7.2 mL) was degazed with N2 for 10 min. RuPhos Pd G3 (51 mg, 0.061 mmol) and RuPhos (28 mg, 0.061 mmol) were added and the reaction mixture was purged with N2. The mixture was heated at 100°C using a single mode microwave (Biotage initiator60®) with a power output ranging from 0 to 400 W for 30 min. Water and EtOAc were added to the reaction mixture. The layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgS04 and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH 15-40 pm, 24 g Grace Resolv™, mobile phase gradient: from DCM 99%, PrOH 1% to DCM 85%, PrOH 15%). The fractions containing product were evaporated under vacuum to give a residue which was taken-up in MeCN and evaporated under vacuum twice, then it was suspended in MeCN (~2 mL in total) and heated at reflux until complete solubilization (oil bath 85°C). Then the heating source was stopped (the flask was kept in the oil bath during the crystallization with a gentle stirring allowing slow cooling) for 4 h. The suspension was cooled down to rt, filtered over glass frit, washed with MeCN (2 x 2 mL), dried over glass frit. The solid was dried under vacuum at 50°C for 18 h to give compound 34 (68 mg, 22%).

Compound 35

(R)-(8-ethyl-2-(2-fluoro-4-(3-hydroxyazetidin-l-yl)phenyl)imidazo[l,2-b]pyridazin-6-yl)(l-methyl-3 ,4-dihydroisoquino lin-2( 1 H)-yl)methanone


A mixture of intermediate F6 (200 mg, 0.405 mmol) 3 -Hydroxy azetidine hydrochloride (53 mg, 0.49 mmol) and CS2CO3 (396 mg, 1.22 mmol) was charged in a sealed tube and purged with N2. Dioxane (8.4 mL) was added and the mixture was degased with N2, then Pd(OAc)2 (9.1 mg,

0.041 mmol) and Xantphos (23 mg, 0.041 mmol) were added. The reaction mixture was stirred and heated at 100°C for 18 h. Water and EtOAc were added to the reaction mixture. The layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgS04 and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH 15-40 pm, 24 g Grace Resolv™, mobile phase gradient: from heptane 60%, EtOAc 40% to Heptane 0%, EtOAc 100%). The fractions containing product were evaporated under vacuum to give a residue. The residue was taken-up in MeCN and evaporated under vacuum twice and the sample was dried under vacuum at 50°C for 16 h to give compound 35 (140 mg, 71%).

Compound 36

(R,E)-3-(4-(8-ethyl-6-(l-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)imidazo[l,2-b]pyridazin-2-yl)-3-fluorophenyl)acrylic acid


In a sealed tube, a mixture of intermediate F6 (150 mg, 0.304 mmol), Acrylic acid (20.8 pL, 0.304 mmol) and TEA (127 pL, 0.912 mmol) in DMF (3.6 mL) was degazed with N2 for 10 min.

Pd(OAc)2 (14 mg, 0.061 mmol) and dppf (34 mg, 0.061 mmol) were added and the reaction mixture was purged with N2. The mixture was heated at 100°C for 16 h. Water and EtOAc were added to the reaction mixture. The layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgS04 and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH 15-40 pm, 24 g Grace Resolv™, mobile phase gradient: from heptane 75%, EtOAc 25% to Heptane 25%, EtOAc 75%). The fractions containing product were evaporated under vacuum. The residue was taken-up in MeCN and evaporated under vacuum twice, then it was suspended in MeCN (~2 mL in total) and heated at reflux until complete solubilization (oil bath 85°C). Then the heating source was stopped (the flask was kept in the oil bath during the crystallization with a gentle stirring allowing slow cooling) for 4 h. The suspension was cooled down to rt, filtered over glass frit, washed with MeCN (2 x 2 mL), dried over glass frit. The solid was dried under vacuum at 50°C for 18 h to give compound 36 (52 mg, 35%).

Compound 37

(R)-N-(4-(8-cyclopropyl-6-((R)- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinoline-2-carbonyl)imidazo [ 1 ,2-b]pyridazin-2-yl)-3 -fluorophenyl)-3 -hydroxypyrrolidine- 1 -carboxamide


To a mixture of intermediate F24 (149 mg; 0.315 mmol, 90% purity), ( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [84010-66-2] (58 pL; 0.38 mmol), DiPEA (0.27 mL; 1.6 mmol) in Me-THF (2 mL), DCM (1 mL) then DMF (1 mL) was added HATU (180 mg; 0.473 mmol) at rt. The resulting mixture was stirred at rt for 2h30. Water and EtOAc were added. The layers were separated and the aqueous layer was extracted with EtOAc (once). The combined organic layers were washed with brine, dried over MgS04, filtered and the solvent was removed in vacuo. The residue was purified by preparative LC (regular SiOH, 30 pm, Interchim® 12 g, mobile phase gradient: from hcptanc/'PrOH 90/10 to 20/80). The pure fraction was collected and evaporated to dryness. The residue was taken-up with MeCN then the solid crystallized after few minutes. The solid was filtered and dried under high vacuum for 3 h at 50°C to give compound 37 (75 mg, 43%) as an off- white solid.

Compound 38

(R)-N-(4-(8-cyclopropyl-6-((R*)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl)imidazo [ 1 ,2-b]pyridazin-2-yl)-3 -fluorophenyl)-3 -hydroxypyrrolidine- 1 -carboxamide


To a mixture of intermediate F24 (48 mg; 0.102 mmol), intermediate F24 as potassium salt (55 mg; 0.119 mmol), DiPEA (0.191 mL; 1.11 mmol), 4-(*7?)-methyl-4,5,6,7-tetrahydrothieno[3,2-cjpyridine [92503-61-2] (41 mg; 0.27 mmol) in DMF (2 mL) was added HATU (126 mg; 0.331 mmol) at rt. The resulting mixture was stirred at rt for 72 h. Water and EtOAc were added. The layers were separated and the aqueous layer was extracted with EtOAc (once). The combined organic layers were washed with brine, dried over MgS04, filtered and the solvent was removed in vacuo. The residue was purified by preparative LC (regular SiOH, 30 pm, Interchim® 12 g, mobile phase gradient: from hcptanc/ PrOH 75/25 to 20/80). The pure fraction was collected and evaporated to dryness. The residue was taken-up with MeCN then the solid crystallized after few minutes. The solid was filtered and dried over frit then under high vacuum for 3 h at 50°C to give compound 38 (54 mg, 44%) as an off-white solid.

Compound 39

(R)-N-(4-(8-ethyl-6-((R)-l-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)imidazo[l,2-b]pyridazin-2-yl)-3 -fluorophenyl)-3 -hydroxypyrrolidine- 1 -carboxamide


To a mixture of intermediate F30 (100 mg; 0.177 mmol), ( 17?)- 1 -methyl- 1,2,3, 4-tetrahydro-isoquinoline [84010-66-2] (32 pL; 0.21 mmol), DiPEA (152 pL; 0.883 mmol) in DMF (1 mL) was added HATU (101 mg; 0.265 mmol) at rt. The resulting mixture was stirred at rt for 2h30. Water and EtOAc were added. The layers were separated and the aqueous layer was extracted with EtOAc (once). The combined organic layers were washed with brine, dried over MgS04, filtered and the solvent was removed in vacuo. The residue was purified by preparative LC (regular SiOH, 30 pm, Interchim® 12 g, mobile phase gradient: from hcptanc/'PrOH 90/10 to 20/80). The pure fraction was collected and evaporated to dryness. The residue was taken-up with MeCN then the solid crystallized after few minutes. The solid was filtered off and dried over frit then under high vacuum for 72 h at 50°C to give compound 39 as a yellow solid (41 mg, 43%).

Compound 40

(R)-N-(4-(8-ethyl-6-((R*)-2-fluoro-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl)imidazo [ 1 ,2-b]pyridazin-2-yl)-3 -fluorophenyl)-3 -hydroxypyrrolidine- 1 -carboxamide


To a mixture of intermediate F30 (110 mg; 0.194 mmol), DiPEA (0.167 mL; 0.971 mmol) and (R*)-2-fluoro-4-mcthyl-4,5,6,7-tctrahydrothicno[3,2-c] pyridine (44 mg; 0.214 mmol) in DMF (2 mL) was added HATU (111 mg; 0.291 mmol) at rt. The resulting mixture was stirred at rt for 16 h. Water and EtOAc were added. The layers were separated and the aqueous layer was extracted with EtOAc (once). The combined organic layers were washed with brine, dried over MgS04, filtered and the solvent was removed in vacuo. The residue was purified by preparative LC (regular SiOH, 30 pm, Interchim® 12 g, mobile phase gradient: from hcptanc/'PrOH 80/20 to 20/80) The pure fraction was collected and evaporated to dryness. The residue was taken-up with MeCN then the solid was crystallized after few minutes. The solid was filtered and dried over frit then under high vacuum for 16 h at 50°C to give compound 40 as a yellow solid (45 mg, 41%).

Compound 41

(R)-N-(4-(8-cthyl-6-((R*)-7-fluoro- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2-carbonyl)-imidazo [ 1 ,2-b]pyridazin-2-yl)-3 -fluorophenyl)-3 -hydroxypyrrolidine- 1 -carboxamide


To a mixture of intermediate F30 (103 mg; 0.182 mmol), DiPEA (157 iiL; 0.909 mmol) and (R*)-7-fluoro- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc (43 mg; 0.21 mmol) in DMF (2 mL) was added HATU (104 mg; 0.273 mmol) at rt. The resulting mixture was stirred at rt for 2h30. Water and EtOAc were added. The layers were separated and the aqueous layer was extracted with EtOAc (once). The combined organic layers were washed with brine, dried over MgS04, filtered and the solvent was removed in vacuo. The residue was purified by preparative LC (regular SiOH, 30 pm, Interchim® 12 g, mobile phase gradient: from hcptanc/'PrOH 90/10 to 20/80) The pure fraction was collected and evaporated to dryness. The residue was purified via Reverse phase (Stationary phase: YMC-actus Triart Cl 8 lOpm 30* 150mm, Mobile phase: Gradient from 65% aq. NH4HCO3 0.2%, 35% MeCN to 45% aq. NH4HCO3 0.2%, 55% MeCN). The pure fraction was collected and evaporated to dryness. The residue was crystallized from MeCN. The solid was filtered and dried over frit then under high vacuum at 60°C for 16 h to give compound 41 (16 mg, 16%).

Compound 42

N,8-diethyl-2-(2-fluoro-4-((R)-3-hydroxypyrrolidine-l-carboxamido)phenyl)-N-(3-methylbutan- 2-yl)imidazo[l,2-b]pyridazine-6-carboxamide


To a mixture of intermediate F30 (105 mg; 0.185 mmol), DiPEA (0.16 mL; 0.93 mmol), N-ethyl-3-methylbutan-2-amine [2738-06-9] (31 pL; 0.20 mmol) in DMF (2 mL) was added HATU (106 mg; 0.278 mmol) at rt. The resulting mixture was stirred at rt for 16 h. Water and EtOAc were added. The layers were separated and the aqueous layer was extracted with EtOAc (once). The combined organic layers were washed with brine, dried over MgSC>4, filtered and the solvent was removed in vacuo. The residue was purified by preparative LC (regular SiOH, 30 pm, Interchim® 12 g, mobile phase gradient: from hcptanc/'PrOH 80/20 to 20/80. The pure fraction was collected and evaporated to dryness. The residue was purified again by preparative LC (regular SiOH, 30 pm, 4 g Interchim®, mobile phase gradient: from D C M /( D C M/' P rO H 60/40) 99/1 to 50/50). The pure fraction was collected and evaporated to dryness. The residue was taken-up with MeCN (twice) and evaporated to dryness to give compound 42 (25 mg, 26%).

Synthesis of compound 43


Intermediate F38

6-chloro-4-(3-fluorophenyl)pyridazin-3-amine

F38

To a degassed mixture of 3-amino-4-bromo-6-chloropyridazine (500 mg, 2.40 mmol), 3-fluorophenylboronic acid pinacol ester (586 mg, 2.64 mmol) and K2CO3 (663 mg, 4.80 mmol) in water (3 mL) and dioxane (30 mL) was added Pd(PPh3)4 (277 mg, 0.240 mmol), and the mixture was stirred at 100°C for 18 h. EtOAc and water were added. The layers were separated and the aqueous layer was extracted with EtOAc (once). The combined organic layers were dried over MgS04, filtered and the solvent was removed in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 pm, 24 g Grace Resolv™, dry loading (celite®), mobile phase gradient: from Heptane/EtOAc 90/10 to 50/50). The pure fraction was collected and evaporated to dryness to give intermediate F38 (338 mg, 63%).

Intermediate F39

Methyl 6-amino-5 -(3 -fluorophenyl)pyridazine-3 -carboxylate


F39

In a stainless-steel bomb, to a degassed mixture of intermediate F38 (1.44 g; 6.44 mmol) and TEA (2.2 mL; 15.8 mmol) in MeOH (40 mL) was added PdCkdppf (344 mg; 0.470 mmol). The resulting mixture was stirred under 10 bars of CO for 18 h at 90°C. The mixture was cooled to rt and evaporated to dryness to give a purple residue which was triturated with MeOH, filtered off and dried on frit to afford intermediate F39 as a grey solid (1.06 g, 67%).

Intermediate F40

Methyl 2-(4-bromo-2-fluorophenyl)-8-(3-fluorophenyl)imidazo[ 1 ,2-b]pyridazine-6-carboxylate A mixture of intermediate F39 (954 mg; 3.86 mmol), 4-bromo-2-fluorophenacyl bromide

[869569-77-7] (1.14 g; 3.86 mmol) and NaHCCb (324 mg; 3.86 mmol) in acetone (30 mL) was stirred at 60°C for 18 h. The mixture was filtered and the resulting solid was dried on frit to give intermediate F40 as a yellow solid (1.8 g, Quant.).

Intermediate F41

Potassium 2-(4-bromo-2-fluorophenyl)-8-(3-fluorophenyl)imidazo[l,2-b]pyridazine-6-carboxylate


A solution of intermediate F40 (1.8 g; 4.1 mmol) and KOH (682 mg; 12.2 mmol) in EtOH (50 mL) was stirred at rt for 2 h. The mixture was filtered, and the solid was washed with Et20 and MeOH. The solid was dried on frit to give intermediate F41 as a yellow solid (1.6 g, 84%).

Intermediate F42

(R)-(2-(4-bromo-2-fluorophenyl)-8-(3-fluorophenyl)imidazo[l,2-b]pyridazin-6-yl)(l -methyl-3 , 4-dihydro isoquinolin-2( 1 H)-yl)methanone


A mixture of intermediate F41 (250 mg; 0.534 mmol), 2-bromo-l-(4-bromo-2-fluorophenyl)ethan-l-one [84010-66-2] (94 mg; 0.64 mmol), HATU (304 mg; 0.801 mmol) and DiPEA (0.28 mL; 1.6 mmol) in DMF (6.5 mL) was stirred at rt for 20 h. Brine and EtOAc were added to the reaction mixture. The layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine (3 times), dried over MgS04 and evaporated in vacuo. The residue was purified by preparative LC (regular SiOH, 15-40 pm, Grace Resolv™ 12 g, mobile phase gradient: from heptane/EtO Ac 90/10 to 70/30) to give intermediate F42 as a yellow foam (237 mg, 79%).

Compound 43

(R)-N-(3-fhioro-4-(8-(3-fhrorophenyl)-6-((R)-l-methyl-l,2,3,4-tetrahydroisoquino line-2-carbonyl)imidazo [ 1 ,2-b]pyridazin-2-yl)phenyl)-3 -hydroxypyrrolidine- 1 -carboxamide


In a schlenk tube, a mixture of intermediate F42 (217 mg; 0.388 mmol), (37?)-3-hydroxypyrrolidine-1 -carboxamide (136 mg; 0.970 mmol), CS2CO3 (632 mg; 1.94 mmol) was purged with N2. 1,4 dioxane (7.9 mL) was added and the mixture was degassed with N2, then Pd(OAc)2 (9 mg; 0.04 mmol) and XantPhos (22 mg; 0.039 mmol) were added. The reaction mixture was stirred and heated at 100°C for 20 h. The reaction mixture was poured out into water and extracted with EtOAc (twice). The combined organic layers were dried over MgS04, filtered and evaporated till dryness. The residue was purified by preparative LC (irregular SiOH 15-40 pm, 12 g Grace Resolv™, mobile phase gradient: from DCM/MeOH 100/0 to 95/5) to give a yellow gum which was crystallized with MeOH, filtered and dried under high vacuum at 50°C for 20 h to give compound 43 as a yellow solid (145 mg, 61%).

Synthesis of Compound 44


Intermediate F46

Methyl (S)- 1 -(4-fluoropyridin-2-yl)pyrrolidine-3-carboxylate


A mixture of 2-bromo-4-fluoropyridine (900 mg; 5.12 mmol), methyl (S)-pyrrodine-3-carboxylate (846 mg; 5.12 mmol) and CS2CO3 (5.0 g; 15.3 mmol) was charged in a sealed tube and purged with N2. Dioxane (36 mL) was added and the mixture was degassed with N2, then Pd(OAc)2 (104 mg; 0.52 mmol) and XantPhos (296 mg; 0.52 mmol) were added. The reaction mixture was stirred and heated at 100°C for 18 h. The reaction mixture was poured out into water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSC>4 and evaporated till dryness. The residue was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g Grace Resolv™, mobile phase gradient: from heptane/EtOAc 90/10 to 40/60). The fraction containing pure product was collected and evaporated to dryness to give intermediate F46 as a colorless oil (340 mg, 40%).

Intermediate F47

Methyl (S)- 1 -(5-bromo-4-fluoropyridin-2-yl)pyrrolidine-3-carboxylate

Intermediate F46 (340 mg, 1.52 mmol) and NBS (270 mg, 1.52 mmol) were stirred in MeCN (15 mL) at rt for 18 h. The solvent was removed under vacuo then the residue was purified by preparative LC (irregular SiOH 15-40 pm, 12 g Grace Resolv™, mobile phase gradient: from heptane / EtOAc from 99:1 to 60:40). The fraction containing pure product was collected and evaporated to dryness to give intermediate F47 as a white solid (446 mg, 97%).

Intermediate F48

Methyl (35)- 1 - [5 -( 1 -ethoxy ethenyl)-4-fluoropyridin-2-yl]pyrro lidine-3 -carboxylate


A solution of intermediate F47 (0.45 g, 1.5 mmol) in THF (10 mL) was purged under N2 for 10 min. To the solution tributyl(l-ethoxyvinyl)tin (1.0 mL, 2.9 mmol) and PdCl2(PPli3)2 (0.10 g, 0.15 mmol) were added. The mixture was heated at 120°C using a singlemode microwave (Anton Paar Monowave® 300) with a power output ranging from 0 to 850 W for 20 min. The mixture was evaporated to dryness and the residue was purified by preparative LC (irregular SiOH 15-40 pm, 24 g Grace Resolv™, mobile phase gradient: from heptane / EtOAc from 99:1 to 60:40). The fraction containing pure product was collected and evaporated to dryness to give intermediate F48 as a yellow oil (270 mg, 62%).

Intermediate F49

Methyl (35)- 1 -[5-(bromoacetyl)-4-fluoropyridin-2-yl]pyrrolidine-3-carboxylate


A mixture of intermediate F48 (0.27 g; 0.92 mmol) and NBS (0.16 g; 0.92 mmol) in THF (4.4 mL) and water (0.9 mL) were stirred at 0°C for 2 h. EtOAc was added. The organic layer was washed with water and brine (twice), dried over MgSC>4, concentrated under reduce pressure. The residue was purified by preparative LC (irregular SiOH 15-40 pm, 24 g Grace Resolv™, mobile phase gradient: from heptane / EtOAc from 99:1 to 60:4). The fraction containing pure product was collected and evaporated to dryness to give intermediate F49 as a yellow oil (47 mg, 15%).

Intermediate F50

Methyl (3S)- 1 -(5- j 8-cthyl-6-[( 1 R)- 1 -mcthyl-3,4-dihydroisoquinolinc-2( 1 H)-carbonyl] imidazo [ 1 ,2-h]pyridazin-2-yl} -4-fluoropyridin-2-yl)pyrrolidine-3 -carboxylate


A mixture of intermediate F45 (40 mg, 0.14 mmol), F49 (47 mg, 0.14 mmol) and NaHC03 (11 mg, 0.14 mmol) in acetone (1.0 mL) was stirred at reflux for 16 h. The mixture was evaporated to dryness. The residue was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g Grace Resolv™, mobile phase gradient: from heptane/EtOAc 50/50 to 0/100). The fraction containing pure product was collected and evaporated to dryness to give intermediate F50 as a yellow oil (60 mg, 81%).

Intermediate F51

63 A)- 1 -(5- j 8-cthyl-6-[( 1 R)- 1 -mcthyl-3,4-dihydroisoquinolinc-2( 1 /7)-carbonyl]imidazo[ 1 ,2-h]pyridazin-2-yl}-4-fluoropyridin-2-yl)pyrrolidine-3-carboxylic acid


- I l l -

LiOEEEEO (14 mg; 0.33 mmol) was added to a solution of intermediate F50 (60 mg; 0.11 mmol) in THF (0.9 mL) and water (0.4 mL) and the reaction mixture was stirred at rt for 16 h. Aqueous sat. NaCl solution and an aqueous solution of KHSO4 10% were added. The aqueous layer was extracted (twice) with EtOAc and the combined organic layers were washed with water, dried over MgSC>4, filtered and concentrated to give intermediate F51 as a yellowish gum (58 mg, 99%).

Compound 44

63 A)- 1 -(5- j 8-cthyl-6-[( 1 R)- 1 -mcthyl-3,4-dihydroisoquinolinc-2( 1 //)-carbonyl]imidazo[ 1 ,2-6]pyridazin-2-yl }-4-fl uoropyridi n-2-yl )-/V-mcthyl pyrrol idinc-3-carboxamidc


A mixture of intermediate F51 (58 mg; 110 gmol), HATU (63 mg; 165 gmol) and DiPEA (57 qL; 0.33 mmol) in DMF (3 mL) was stirred at rt for 1 h. Methylamine 40% in water (47 qL; 0.55 mmol) was then added and the reaction mixture was stirred at rt for 18 h. Water and EtOAc were added to the reaction mixture. The layers were separated. The organic layer was washed (twice) with aq NaHC03 (1%), dried over MgS04 and evaporated in vacuo. The residue was purified by preparative LC (Irregular SiOH, 15-40 qm, 40 g Grace Resolv™, mobile phase gradient: from DCM/ PrOH 100/0 to 75/25). The fractions containing product were evaporated under vacuum. The residue was crystallized from MeCN (2 mL) at rt and the suspension was filtered and dried over frit then under high vacuum (60°C, 16 h) to give compound 44 as yellow solid (27 mg, 45%).

Synthesis of compound 45


Intermediate F56

Methyl (R)-6-(8-ethyl-6-(l -methyl- 1,2,3, 4-tetrahydroisoquinoline-2-carbonyl)imidazo[l, 2-b]pyridazin-2-yl)-5-fluoro-2H-chromene-3-carboxylate


A mixture of intermediate F45 (276 mg, 0.93 mmol), intermediate H4 (340 mg, 0.93 mmol) and NaHCCL (78 mg, 0.93 mmol) in acetone (7.3 mL) was stirred at reflux for 16 h. The mixture was evaporated to dryness and the residue was taken-up with MeCN then the solid was filtered off to give intermediate F56 (534 mg, 90%).

Intermediate F57

(R)-6-(8-ethyl-6-(l -methyl- 1,2,3, 4-tetrahydroisoquinoline-2-carbonyl)imidazo[l,2-b]pyridazin- 2-yl)-5-fluoro-2H-chromene-3-carboxylic acid


LiOH'TkO (232 mg, 5.53 mmol) was added to a solution of intermediate F56 (534 mg, 1.00 mmol) in THF (29 mL) and water (7.3 mL) and the reaction mixture was stirred at rt for 3 h. An aqueous solution of KHSO4 10% was added until pH=3 and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSCE, filtered and evaporated to give intermediate F57 as a yellow solid (380 mg, 72%).

Compound 45

(R)-6-(8-ethyl-6-(l -methyl- 1,2, 3, 4-tetrahydroisoquinoline-2-carbonyl)imidazo[l,2-b]pyridazin-2-yl)-5-fluoro-2H-chromene-3-carboxamide


A mixture of intermediate F57 (100 mg, 0.191 mmol), ammonium chloride (12 mg, 0.23 mmol), EDCEHCl (36 mg, 0.19 mmol) and ElOBfrEEO (44 mg, 0.29 mmol) in DMF (9.5 mL) was stirred at 0°C. DiPEA (165 pL, 0.956 mmol) was added slowly at 0°C. The mixture was stirred at rt for 18 h. Brine and EtOAc were added. The layers were separated. The organic layer was dried over MgS04 and evaporated to dryness. The residue was purified by preparative LC (irregular SiOH 15-40 pm, 4 g Grace Resolv™, mobile phase gradient: from DCM/MeOH 100/00 to 90/10). The fractions containing pure product were evaporated under vacuum. The residue was triturated in MeCN, filtered over frit and dried to give compound 45 (26 mg, 27%).

Synthesis of compound 46


Intermediate F62

Methyl (R)-7-(8-ethyl-6-(l -methyl- 1,2,3, 4-tetrahydroisoquinoline-2-carbonyl)imidazo[l, 2-b]pyridazin-2-yl)-8-fluoro-2H-chromene-3-carboxylate


A mixture of intermediate F45 (294 mg, 0.991 mmol), intermediate 13 (326 mg, 0.991 mmol) and NaHCCL (83 mg, 0.99 mmol) in acetone (7.8 mL) was stirred at reflux for 16 h. The mixture was evaporated to dryness and the residue was taken-up with MeCN then the solid was filtered off to give intermediate F62 (452 mg, 72%).

Intermediate F63

(R)-7-(8-ethyl-6-(l -methyl- 1,2,3, 4-tetrahydroisoquinoline-2-carbonyl)imidazo[l,2-b]pyridazin- 2-yl)-8-fluoro-2H-chromene-3-carboxylic acid


LiOLLLLO (198 mg, 4.73 mmol) was added to a solution of intermediate F62 (452 mg, 0.858 mmol) in THF (25 mL) and water (6.2 mL) and the reaction mixture was stirred at rt for 3 h. An aqueous solution of KHSCL 10% was added until pH=3 and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSCE, filtered and evaporated to give intermediate F63 as a yellow solid (319 mg, 71%).

Compound 46

(R)-7-(8-ethyl-6-(l-methyl-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)imidazo[l,2-b]pyridazin-2-yl)-8-fluoro-2H-chromene-3-carboxamide


A mixture of intermediate F63 (100 mg, 0.191 mmol), ammonium chloride (12 mg, 0.23 mmol), EDCEHCl (36 mg, 0.19 mmol) and EIOBEEEO (44 mg, 0.29 mmol) in DMF (9.5 mL) was stirred at 0°C. DiPEA (165 pL, 0.956 mmol) was added slowly at 0°C. The mixture was stirred at rt for 18 h. Brine and EtOAc were added. The layers were separated. The organic layer was dried over MgS04 and evaporated. The residue was purified by preparative LC (irregular SiOH 15-40 pm, 4 g Grace Resolv™, mobile phase gradient: from DCM/MeOH 100/00 to 90/10). The fractions containing pure product were evaporated under vacuum. The residue was triturated in MeCN, the solid was filtered off and dried to give compound 46 (39 mg, 40%).

Synthesis of compound 51


Intermediate K1

(R)-(2-(4-bromo-2-fluorophenyl)-8-cyclopropylimidazo[l,2-b]pyridazin-6-yl)(l -methyl-3, 4-dihydroisoquino lin-2( 1 H)-yl)methanone

A mixture of intermediate H4 (1.1 g, 3.57 mmol), acetone (28 mL), 4-bromo-2-fluorophenacyl bromide (1.06 g, 3.57 mmol) and NaHCCb (300 mg, 3.57 mmol) was stirred at 60 °C for 16 h. The mixture was evaporated under vacuum and purified by preparative LC (irregular SiOH, 15-40 pm, 80 g GraceResolv®, solid loading (celite®), mobile phase gradient: from Heptane / EtOAc 100:0 to 70:30) to give intermediate K1 as a pink foam (1.53 g, 85%).

Compound 51:

(8-cyclopropyl-2-(4-((3 S,4S)-3 ,4-dihydroxypyrrolidin- 1 -yl)-2-fluorophenyl)imidazo[ 1 ,2-b]pyridazin-6-yl)((R)- 1 -methyl-3 , 4-dihydro isoquinolin-2( 1 H)-yl)methanone


Under N2, a mixture of intermediate K1 (1.53 g, 3.03 mmol), (3S,4S)-pyrrolidine-3,4-diol (437 mg, 4.24 mmol) and K2CO3 (1.46 g, 10.6 mmol) in THF (28 mL) was degassed with N2 for 10 min. DavePhos (119 mg, 0.303 mmol) and Pd2dba3 (277 mg, 0.303 mmol) were added and the reaction mixture was purged with N2. The mixture was heated at reflux (80 °C) for 20 h. Water and EtOAc were added. The aqueous layer was extracted with EtOAc (twice), the combined organic layers were dried over MgS04, filtered, concentrated in vacuo and purified by preparative LC (irregular SiOH 15-40 pm, 120 g Grace Resolv®, mobile phase gradient: from DCM/MeOH 100/0 to 90/10) to give 1.03 g of a solid as a yellow foam. The solid and

SiliaMetS® Thiol (0.27 g; 0.362 mmol) in THF (23 mL) was stirred at rt for 3 h, then filtered over celite and the filtrate was evaporated to dryness to give 1.05 g of a solid as yellow foam. The solid was purified by preparative LC (spherical Cl 8, 25 pm, 120 g YMC-ODS-25, mobile phase gradient 0.2% aq. NH4HCO3 / MeCN from 65:35 to 25:75), the fraction containing product was extracted with EtOAc and water. The organic layer was dried (MgSOr), filtered and evaporated to give 896 mg of a residue which was taken-up with MeCN and evaporated to dryness to give compound 51 as a solid (725 mg, 42%).

Part 3 : imidazo[l,2-alpyrazine

Synthesis of intermediate G4


Intermediate G1

Methyl 5-amino-6-cyclopropylpyrazine-2-carboxylate


A mixture of methyl 5-amino-6-bromopyrazine-2-carboxylate (0.35 g, 1.51 mmol),

cyclopropylboronic acid (0.19 g, 2.26 mmol) and potassium carbonate (0.83 g, 6.03 mmol) in THF (14 mL) was purged under nitrogen for 5 min. PdCl2(dppf).DCM (0.12 g, 0.15 mmol) was added and the mixture was purged again under nitrogen. The mixture was heated at 120°C using a single mode microwave (Anton Paar Monowave® 300) with a power output ranging from 0 to 850 W for 45 min. The reaction mixture was diluted with ¾0 and EtOAc. The mixture was filtered through a pad of Celite® and washed with EtOAc. The layers were separated and the organic phase was washed with LLO, brine, dried over MgSCL, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 25 g, 30 pm, Mobile phase gradient: heptane/EtOAc from 100:0 to 40:60) to afford intermediate G1 (0.28 g, 96%) as a yellow solid.

Intermediate G2

Methyl 2-(4-bromo-2-fluorophenyl)-8-cyclopropylimidazo[ 1 ,2-a]pyrazine-6-carboxylate


A mixture of intermediate G1 (0.38 g, 1.97 mmol) and 4-bromo-2-fluorophenacyl bromide (0.82 g, 2.75 mmol) in ACN (17 mL) was heated at 120°C using a single mode microwave (Anton Paar Monowave® 300) with a power output ranging from 0 to 850 W for 60 min. The solid was filtered off and rinsed with ACN (x3). The residue obtained was taken up in ACN (15 mL) and refluxed for 2 h. After cooled down to rt, the white precipitate was filtered off and dried in vacuum to afford intermediate G2 (0.26 g, 33%) as a white solid.

Intermediate G3

Potassium 2-(4-bromo-2-fluorophenyl)-8-cyclopropylimidazo[ 1 ,2-a]pyrazine-6-carboxylate


A mixture of intermediate G2 (0.40 g, 1.03 mmol) and potassium hydroxide (0.23 g, 4.10 mmol) in MeOH (15 mL) were stirred at reflux for 6 h. The white precipitate was filtered off and dried in vacuum to afford intermediate G3 (0.24 g, 57%) as a white solid.

Intermediate G4

(R)-(2-(4-bromo-2-fluorophenyl)-8-cyclopropylimidazo[l,2-a]pyrazin-6-yl)(l -methyl-3, 4-dihydroisoquino lin-2( 1 H)-yl)methanone


To a mixture of intermediate G3 (0.22 g, 0.53 mmol), ( 17?)- 1 -methyl- 1,2, 3,4-tetrahydroisoquinoline (94 mg, 0.64 mmol) and DIPEA (0.37 mL, 2.12 mmol) in DMF (9 mL) was added HATU (0.26 g, 0.69 mmol). The reaction mixture was stirred at rt for 2h. The mixture was poured slowly out into water and the aqueous phase was extracted with DCM. The combined organic extracts were dried over MgS04, filtered and evaporated till dryness. The crude residue was taken up in EtOAc and the slurry obtained was stirred for 10 min at rt. The white precipitate was filtered off and dried in vacuum to afford intermediate G4 (0.22 g, 82%) as a white solid.

Compound 47

(R)-N-(4-(8-cyclopropyl-6-((R)- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinoline-2-carbonyl)imidazo [ 1 ,2-a]pyrazin-2-yl)-3 -fluorophenyl)-3 -hydroxypyrrolidine- 1 -carboxamide


A mixture of intermediate G4 (0.16 g, 0.32 mmol), (R)-3-hydroxypyrrolidine-l -carboxamide (82.40 mg, 0.63 mmol), cesium carbonate (0.41 g, 1.27 mmol) and XantPhos (18.3 mg, 0.03 mmol) in 1,4-dioxane (6.2 mL) was purged with nitrogen. Palladium acetate (7.1 mg, 0.03 mmol) was added. The reaction mixture was purged again with nitrogen and stirred at 100°C for 15 h. The reaction mixture was diluted with EtOAc and LEO then filtered through a short pad of celite®. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS04, filtered and the solvent was evaporated in vacuo. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 25 g, 30 pm, mobile phase gradient: DCM/MeOH, from 100:0 to 97:03) to afford compound 47 (76 mg, yield 56%) as a brown solid.

Compound 48

(8-cyclopropyl-2-(4-((3 S,4S)-3 ,4-dihydroxypyrrolidin- 1 -yl)-2-fluorophenyl)imidazo[ 1 ,2-a]pyrazin-6-yl)((R)- 1 -methyl-3 ,4-dihydroisoquinolin-2( 1 H)-yl)methanone


A mixture of intermediate G4 (0.10 g, 0.20 mmol), (3S,4S)-pyrrolidine-3,4-diol (51 mg, 0.50 mmol) and potassium carbonate (0.11 g, 0.79 mmol) in THF (2.3 mL) was stirred and purged with nitrogen for 5 min. DavePhos (12.0 mg, 0.03 mmol) and Pd2(dba)3 (27.0 mg, 0.03 mmol) were added. The reaction mixture was purged again with nitrogen for 2 min and heated at 80°C for 20 h. The reaction mixture was diluted with EtOAc and ThO. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS04, filtered and the solvent was evaporated in vacuo. The crude mixture was purified by flash chromatography over silica gel (Puriflash Interchim® 12 g, 30 pm, mobile phase gradient: DCM/MeOH, from 100:0 to 98:02) to afford compound 48 (67 mg, 64%) as a brown solid.

Part 4: nyrrolol 1,2-blnyridazine

Synthesis of compound 49


L1

A mixture of 3-amino-4-bromo-6-chloropyridazine (10 g; 48.0 mmol), cesium carbonate (47 g; 144 mmol) and cyclopropylboronic acid (12 g; 144 mmol) in H2O (70 mL) and 1,4-dioxane (200 mL) was purged with N2 then PdCl2(dppf) (3.5 g; 4.80 mmol) was added and the mixture was purged with N2 again. The resulting mixture was stirred at 100 °C for 3 h. Water and EtOAc were added. The aqueous layer was extracted with EtOAc (twice), the combined organic layers were dried over MgS04, filtered, concentrated in vacuo and purified by preparative LC (irregular SiOH 15-40 pm, 330 g GraceResolv®, dry loading (celite®), mobile phase gradient: from DCM/MeOH 100:0 to 90:10) to give intermediate LI as a black solid (7.24 g, 89%).

Intermediate L2

methyl 6-amino-5-cyclopropylpyridazine-3-carboxylate

In a pressure vessel reactor, to a degassed mixture of intermediate LI (7.24 g; 42.7 mmol) and TEA (15.9 mL; 115 mmol) in MeOH (100 mL) was added PdCl2(dppf) (2.66 mg; 3.63 mmol). The resulting mixture was stirred under 5 bars of CO for 18 h at 130 °C. The mixture was evaporated and purified by preparative LC (irregular SiOH 15-40 pm, 330 g GraceResolv®, mobile phase gradient: DCM / MeOH from 100:0 to 90:10) to give intermediate L2 as brown solid (1.58 g, 19%).


L3

A mixture of intermediate L2 (1.0 g; 5.18 mmol) and KOH (581 mg; 10.4 mmol) in EtOH (51 mL) and ¾0 (3.6 mL) was stirred at rt for 18 h. The mixture was evaporated under vacuum and coevaporated (3 times) with THF to give crude intermediate L3 (1.52 g, quant., estimated purity 61%).

Intermediate L4

(R)-(6-amino-5 -eye lopropylpyridazin-3 -yl)( 1 -methyl-3 ,4-dihydroisoquino lin-2( 1 H)-yl)methanone


A mixture of intermediate L3 (1.52 g; 5.18 mmol; purity 61%), lR-methyl-1,2,3,4-tetrahydroisoquinoline (0.91 g; 6.21 mmol), HATU (2.95 g; 7.76 mmol), DiPEA (2.7 mL; 15.5 mmol) and DMF (26 mL) was stirred at rt for 2 days. EtOAc and water were added. The organic layer was separated, washed with brine, dried (MgSCL) and purified by preparative LC (irregular SiOH 15-40 mhi, 120 g GraceResolv®, mobile phase gradient: DCM / MeOH from 100:0 to 95:5) to give intermediate L4 (1.05 g, 66%).

Intermediate L5

(R)-(5 -cyclopropyl-6-iodopyridazin-3 -yl)( 1 -methyl-3 ,4-dihydroisoquino lin-2( 1 H)-yl)methanone


Isoamylnitrite (1.09 mL; 8.11 mmol) was added to a solution of intermediate L4 (1 g; 3.24 mmol) and Cul (1.96 g; 10.3 mmol) in MeCN (23 mL). The solution was heated at 85°C for 24 h. EtOAc and water were added. A filtration over celite was performed. The organic layer was separated, washed with brine, dried (MgS04), evaporated and purified by preparative LC (irregular SiOH 15-40 pm, 80 g GraceResolv®, mobile phase gradient: Heptane / EtOAc from 75:25 to 10:90) to give intermediate L5 as yellow solid (509 mg, 37%).

Intermediate L6

(R)-(5 -cyclopropyl-6-methylpyridazin-3 -yl)( 1 -methyl-3 ,4-dihydroisoquino lin-2( 1 H)-yl)methanone


MeZnCl (1.2 mL; 2.43 mmol, 2M in THF) was added to a solution of intermediate L5 (509 mg; 1.21 mmol) in THF (10 mL). The mixture was purged with N2. Pd2dba3 (111 mg; 0.121 mmol) and JohnPhos (72 mg; 0.243 mmol) was added. The mixture was purged with N2 and stirred at 90 °C for 18 h. EtOAc and water were added. The organic layer was separated, washed with brine, dried (MgSCL), evaporated and purified by preparative LC (irregular SiOH 15-40 pm, 40 g GraceResolv®, mobile phase gradient: Heptane / EtOAc from 100:0 to 0: 100) to give intermediate L6 as brown gum (343 mg, 92%).

Intermediate L7

(R)- 1 -((4-(4-cyclopropyl-2-((R)- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinoline-2-carbonyl)pyrrolo[ 1 ,2-b]pyridazin-6-yl)-3-fluorophenyl)carbamoyl)pyrrolidin-3-yl acetate


A mixture of intermediate L6 (242 mg; 1.12 mmol), intermediate F20 (432 mg; 1.12 mmol) and MeCN (5 mL) was stirred at 70°C for 18 h then TEA (0.465 mL; 3.35 mmol) was added and the mixture was stirred at 70 °C for 6 h. Water and EtOAc were added and an extraction was performed. The organic layer was washed with brine, dried (MgSCL), filtered, evaporated and purified by preparative LC (spherical C18 25 pm, 40 g YMC-ODS-25, mobile phase gradient 0.2% aq. NH4+HC03_ / MeCN from 70:30 to 30:70) the fractions containing product were freeze-dried to give compound 49 as white solid (67 mg, 11%, -90% purity) and intermediate L7 as white solid (26 mg, 4%).

Compound 49

(R)-N-(4-(4-cyclopropyl-2-((R)- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinoline-2-carbonyl)pyrrolo[ 1 ,2-b]pyridazin-6-yl)-3 -fluorophenyl)-3 -hydroxypyrrolidine- 1 -carboxamide


A mixture of intermediate L7 (26 mg; 0.0436 mmol), K2CO3 (30.2 mg; 0.218 mmol) and MeOH (1.25 mL) was stirred at rt for 18 h. The mixture was evaporated and combined with previous isolated impure batch of compound 49. The resulting compound was purified by preparative LC (irregular SiOH 15-40 pm, 12 g Buchi®, mobile phase gradient: DCM/MeOH: 99: 1 to 95:5, then DCM/MeOH:95/5) the fractions containing product were evaporated to dryness then diluted with MeCN, extended with water and freeze-dried to give compound 49 (47 mg).

Part 5: indolizine

Synthesis of compound 50

ZnEt2 in toluene, CO (5-10 bars), 1.Li0H*H20, THF/H20 2 PdCI2(PPh3)2 PdCI2(dppf)

- ►


fY— h· 1 8 H

CI^N THF, rt, 2 days TEA, MeOH, 130 °C, 18 h Me02C

J1 J2

2.HATU, DiPEA, rt, 18 h


Intermediate J1

5 -chloro-3 -ethyl-2-methylpyridine


Diethylzinc (15 mL; 16.5 mmol, 1.1 M in toluene) was added to a solution of 3-bromo-5-chloro-2-methylpyridine (3.36 g; 16.3 mmol) in THF (100 mL). The mixture was purged with N2. PdCl2(PPli3)2 (1.14 g; 1.63 mmol) was added. The mixture was purged again with N2 and stirred at rt for 2 days. EtOAc and water were added and the mixture was filtered on a celite® pad then the organic layer was washed with brine, dried (MgSCL), filtered, evaporated and purified by preparative LC (irregular SiOH 15-40 pm, 120 g GraceResolv®, mobile phase gradient:

heptane/EtOAc from 100:0 to 60:40) to give intermediate J1 as a colorless oil (1.35 g, 53%).

Intermediate 32

methyl 5-ethyl-6-methylnicotinate


In a pressure vessel reactor, to a degassed mixture of intermediate J1 (1.25 g; 8.03 mmol) and TEA (3 ml) in MeOH (50 mL) was added PdCl2(dppf) (500 mg; 0.683 mmol). The resulting mixture was stirred under 5 bars of CO for 18 h at 130 °C. The mixture was evaporated and purified by preparative LC (irregular SiOH 15-40 pm, 80 g GraceResolv®, mobile phase gradient: heptane / EtOAc from 100:0 to 50:50) to give intermediate J2 as colorless oil (936 mg, 65%).

Intermediate J3

(R)-(5 -ethyl-6-methylpyridin-3 -yl)( 1 -methyl-3 ,4-dihydroisoquino lin-2( 1 H)-yl)methanone


A mixture of intermediate J2 (920 mg; 5.13 mmol), LiOH»H20 (1.19 g; 28.3 mmol), THF (30 mL) and ¾0 (5 mL) was stirred at rt for 18 h. EtOAc and 10% aq. KHSO4 were added to the mixture and an extraction was performed. The organic layer was dried (MgS04), evaporated to give 50 mg of acid intermediate as white solid. The aqueous layer was freeze-dried to give 2 g of acid intermediate (~40% purity). The 50 mg batch (pure) and the 2 g batch (~40% purity) were combined and were solubilized in DMF (33 mL) then lR-methyl-l,2,3,4-tetrahydroisoquinoline (909 mg, 6.17 mmol), HATU (2.93 g, 7.71 mmol) and DiPEA (2.70 mL; 15.4 mmol) were added and the resulting mixture was stirred at rt for 18 h. Brine and EtOAc were added to the reaction mixture. The layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine (3 times), dried over MgS04, evaporated and purified by preparative LC (irregular SiOH 15-40 pm, 80 g GraceResolv®, mobile phase

gradient: from Heptane /EtOAc 80/20 to 0/100) to give 530 mg as colorless gum. This fraction was purified by preparative LC (spherical Cl 8 25 pm, 40 g YMC-ODS-25, mobile phase gradient 0.2% aq. NH4HCO3 / MeCN from 75:25 to 0: 100) the fraction containing product was extracted with EtOAc and water. The organic layer was washed with brine, dried (MgS04), evaporated to give intermediate J3 (265 mg, 18%).

Intermediate J4

(R)- 1 -((4-(8-ethyl-6-((R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl)indolizin-2-yl)-3-fluorophenyl)carbamoyl)pyrrolidin-3 -yl acetate


A mixture of intermediate J3 (255 mg; 0.866 mmol), intermediate F20 (335 mg; 0.866 mmol) and MeCN (4 mL) was stirred at 70°C for 18 h then TEA (0.361 mL; 2.60 mmol) was added and the mixture was stirred at 70 °C for 6 h. Water and EtOAc were added and an extraction was performed. The organic layer was washed with brine, dried (MgS04), filtered, evaporated and purified by preparative LC (irregular SiOH 15-40 pm, 40 g GraceResolv®, mobile phase gradient: DCM/MeOH from 100:0 to 90: 10) to give 246 mg of intermediate J4 as pale yellow solid and 61 mg of impure compound 50 as yellow solid.

Compound 50

(R)-N-(4-(8-ethyl-6-((R)-l -methyl- 1,2, 3, 4-tetrahydroisoquinoline-2-carbonyl)indolizin-2-yl)-3-fluorophenyl)-3-hydroxypyrrolidine- 1 -carboxamide


A mixture of intermediate J4 (235 mg; 0.403 mmol), K2CO3 (278 mg; 2.02 mmol) and MeOH (5 mL) was stirred at rt for 18 h. The mixture was evaporated then combined with impure

compound 50 (batch isolated during intermediate J4 synthesis). The resulting mixture was purified by preparative LC (spherical C18 25 pm, 40 g YMC-ODS-25, mobile phase gradient 0.2% aq. MHHCCE/MeCN from 70/30 to 30:70) the fractions containing product were extracted with EtOAc and water. The organic layer was washed with brine, dried (MgS04) and evaporated to give 164 mg as yellow solid which was purified again by Reverse phase (Stationary phase: YMC-actus Triart® Cl 8 lOpm 30* 150mm, Mobile phase gradient 0.2% aq. NH4HCO3 / MeCN from 55:45 to 35:65). The fractions containing product were evaporated, solubilized with MeCN and extended with water then freeze-dried to give 67 mg of compound 50 as pale yellow solid.

C. Compound identification

!H-NMR

1 H-NMR spectra were recorded on a Bruker Avance DRX 400 spectrometer using internal deuterium lock and equipped with reverse double-resonance (' H, 13C, SEI) probe head with z gradients and operating at 400 MHz for proton and 100 MHz for carbon and a Bruker Avance 500 MHz spectrometer equipped with a Bruker 5mm BBFO probe head with z gradients and operating at 500 MHz for proton and 125 MHz for carbon.

NMR spectra were recorded at ambient temperature unless otherwise stated.

Data are reported as follow: chemical shift in parts per million (ppm) relative to TMS (5 = 0 ppm) which was used as internal standard, integration, multiplicity (s = singulet, d = doublet, t = triplet, q = quartet, quin = quintuplet, sex = sextuplet, m = multiplet, b = broad, or a combination of these), coupling constant(s) J in Hertz (Hz).

Compound 1

Major rotamer (65%)

Ή NMR (500 MHz, DMSO-de) 5 ppm 13.15 (br s, 1H), 8.64 (s, 1H), 8.48 (d, J= 4.1 Hz, 1H), 8.43 (t, J=1.9 Hz, 1H), 7.91 (d, J=1.9 Hz, 1H), 7.78 (d, 7=12.0 Hz, 1H), 7.17 (br s, 4H), 6.88 (br s, 1H), 5.22 - 5.81 (m, 1H), 3.40 - 3.43, (m, 1H), 3.23 (br s, 1H), 3.05 - 2.99 (m, 1H), 2.78 (br d, 7=16.4 Hz, 1H), 2.54 - 2.66 (m, 1H), 1.52 (d, J=6.6 Hz, 3H), 0.91 - 1.24 (m, 4H)

Minor rotamer (35%)

Ή NMR (500 MHz, DMSO-76) 5 ppm 13.15 (br s, 1H), 8.64 (s, 1H), 8.48 (d, 7=4.1 Hz, 1H), 8.43 (t, J=1.9 Hz, 1H), 7.91 (d, J=1.9 Hz, 1H), 7.78 (d, 7=12.0 Hz, 1H), 7.17 (br s, 4H), 6.88 (br s, 1H), 4.20 - 4.97 (m, 1H), 3.75 - 3.95 (m, 1H), 3.40 - 3.43, (m, 1H), 3.05 - 2.99 (m, 1H), 2.78 (br d, .7=16.4 Hz, 1H), 2.54 - 2.66 (m, 1H), 1.52 (d, 7=6.6 Hz, 3H), 0.91 - 1.24 (m, 4H)

Compound 2

Major rotamer (75%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.65 (s, 1H), 8.47 (d, J= 4.1 Hz, 1H), 8.38 (t, J=1.9 Hz, 1H), 8.11 (s, 1H), 7.87 (dd, =8.2, 1.6 Hz, 1H), 7.82 (dd, =12.3, 1.3 Hz, 1H), 7.55 (s, 1H), 7.30 (br s, 1H), 7.08 - 7.25 (m, 3H), 6.89 (br s, 1H), 5.55 (br s, 1H), 3.83 (br s, 1H), 3.48 (br s, 1H), 3.05 (br s, 1H), 2.77 (br d, =15.1 Hz, 1H), 2.56 - 2.63 (m, 1H), 1.99 (s, 1H), 1.52 (d, J= 6.9 Hz, 3H), 1.06 - 1.15 (m, 3H).

Minor rotamer (25%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.65 (s, 1H), 8.47 (d, J= 4.1 Hz, 1H), 8.38 (t, J=1.9 Hz, 1H), 8.11 (s, 1H), 7.87 (dd, =8.2, 1.6 Hz, 1H), 7.82 (dd, =12.3, 1.3 Hz, 1H), 7.55 (s, 1H), 7.08

- 7.25 (m, 4H), 6.89 (br s, 1H), 4.96 (br s, 1H), 4.51 (br s, 1H), 3.20 - 3.30 (m, 1H), 3.05 (br s, 1H), 2.77 (br d, =15.1 Hz, 1H), 2.56 - 2.63 (m, 1H), 1.91 (s, 1H), 1.52 (d, =6.9 Hz, 3H), 1.06 -1.15 (m, 3H).

Compound 3

Major rotamer (75%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.57 (s, 1H), 8.10 (d, J= 4.1 Hz, 1H), 7.94 (t, =8.7 Hz, 1H), 7.09 - 7.37 (m, 4H), 6.78 (br s, 1H), 6.51 (dd, =8.5, 1.9 Hz, 1H), 6.42 (dd, =14.0, 2.0 Hz, 1H), 5.62 (s, 2H), 5.44 - 5.58 (m, 1H), 3.81 (br d, J= 3.8 Hz, 1H), 3.38 - 3.61 (m, 1H), 3.03 (br s, 1H), 2.77 (br d, =16.1 Hz, 1H), 2.51 - 2.60 (m, 1H), 1.51 (br d, J= 6.6 Hz, 3H), 1.00 - 1.13 (m, 4H)

Minor rotamer (25%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.57 (s, 1H), 8.10 (d, J= 4.1 Hz, 1H), 7.94 (t, =8.7 Hz, 1H), 7.09 - 7.37 (m, 4H), 6.78 (br s, 1H), 6.51 (dd, =8.5, 1.9 Hz, 1H), 6.42 (dd, =14.0, 2.0 Hz, 1H), 5.62 (s, 2H), 4.77 - 5.07 (m, 1H), 4.28 - 4.68 (m, 1H), 3.38 - 3.61 (m, 1H), 3.03 (br s, 1H), 2.77 (br d, =16.1 Hz, 1H), 2.51 - 2.60 (m, 1H), 1.51 (br d, J=6.6 Hz, 3H), 1.00 - 1.13 (m, 4H)

Compound 4

Major rotamer (70%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.61 (s, 1H), 8.47 (s, 1H), 8.26 (d, J=4A Hz, 1H), 8.14 (t, J= 8.8 Hz, 1H), 7.70 (dd, =14.5, 1.9 Hz, 1H), 7.43 (dd, =8.7, 2.0 Hz, 1H), 7.05 - 7.34 (m, 4H), 6.83 (br s, 1H), 5.54 (br s, 1H), 5.00 (d, J= 3.5 Hz, 1H), 4.31 (br s, 1H), 3.75 - 3.82 (m, 1H), 3.47

- 3.49 (m, 4H), 3.3 l(s, 1H), 3.04 (br s, 1H), 2.77 (br d, J=15A Hz, 1H), 2.53 - 2.61 (m, 1H), 1.73

- 1.98 (m, 2H), 1.52 (br d, J= 6.6 Hz, 3H), 1.09 (m, 4H)

Minor rotamer (30%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.61 (s, 1H), 8.47 (s, 1H), 8.26 (d, J= 4.1 Hz, 1H), 8.14 (t, J= 8.8 Hz, 1H), 7.70 (dd, =14.5, 1.9 Hz, 1H), 7.43 (dd, =8.7, 2.0 Hz, 1H), 7.05 - 7.34 (m, 4H), 6.83 (br s, 1H), 5.00 (d, J= 3.5 Hz, 1H), 4.85 - 4.90 (m, 1H), 4.40 - 4.58 (m, 1H), 4.31 (br s, 1H),

3.47 - 3.49 (m, 4H), 3.3 l(s, 1H), 3.04 (br s, 1H), 2.77 (br d, J=15A Hz, 1H), 2.53 - 2.61 (m, 1H), 1.73 - 1.98 (m, 2H), 1.52 (br d, J= 6.6 Hz, 3H), 1.09 (m, 4H)

Compound 5

Major rotamer (75%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.62 (s, 1H), 8.47 (s, 1H), 8.26 (d, J= 4.1 Hz, 1H), 8.14 (t, =8.7 Hz, 1H), 7.70 (dd, =14.7, 1.7 Hz, 1H), 7.43 (dd, J= 8.5, 1.9 Hz, 1H), 7.06 - 7.35 (m, 4H), 6.83 (br s, 1H), 5.54 (br d, J= 1.6 Hz, 1H), 5.00 (d, J=3.5 Hz, 1H), 4.32 (br s, 1H), 3.71 - 3.92 (m, 1H), 3.40 - 3.55 (m, 4H), 3.32 (s, 1H), 3.04 - 3.06 (m, 1H), 2.77 (br d, =15.1 Hz, 1H), 2.54 -2.64 (m, 1H), 1.75 - 1.99 (m, 2H), 1.52 (br d, J=6.6 Hz, 3H), 1.08 - 1.10 (m, 4H)

Minor rotamer (25%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.62 (s, 1H), 8.47 (s, 1H), 8.26 (d, J=4A Hz, 1H), 8.14 (t, =8.7 Hz, 1H), 7.70 (dd, =14.7, 1.7 Hz, 1H), 7.43 (dd, =8.5, 1.9 Hz, 1H), 7.06 - 7.35 (m, 4H), 6.83 (br s, 1H), 5.00 (d, J= 3.5 Hz, 1H), 4.81 - 4.98 (m, 1H), 4.41 - 4.58 (m, 1H), 4.32 (br s, 1H), 3.40 - 3.55 (m, 4H), 3.32 (s, 1H), 3.04 - 3.06 (m, 1H), 2.77 (br d, J=15A Hz, 1H), 2.54 - 2.64 (m, 1H), 1.75 - 1.99 (m, 2H), 1.52 (br d, J=6.6 Hz, 3H), 1.08 - 1.10 (m, 4H)

Compound 6

Major rotamer (70%)

Ή NMR (500 MHz, DMSO-de) d ppm 12.39 (br s, 1H), 8.62 (s, 1H), 8.34 (d, J=4A Hz, 1H), 8.19 (t, J= 8.2 Hz, 1H), 7.30 (br s, 1H), 7.05 - 7.25 (m, 5H), 6.85 (br s, 1H), 5.54 (br s, 1H), 3.82 (br s, 1H), 3.46 (br s, 1H), 3.05 (br s, 1H), 2.77 (br d, =14.8 Hz, 1H), 2.53 - 2.62 (m, 1H), 2.44 - 2.48 (m, 1H), 1.86 - 1.96 (m, 1H), 1.52 (br d, J=6.6 Hz, 3H), 1.40 - 1.50 (m, 2H), 1.04 - 1.16 (m, 4H).

Minor rotamer (30%)

Ή NMR (500 MHz, DMSO-de) d ppm 12.39 (br s, 1H), 8.62 (s, 1H), 8.34 (d, J=4A Hz, 1H), 8.19 (t, J= 8.2 Hz, 1H), 7.05 - 7.25 (m, 6H), 6.85 (br s, 1H), 4.96 (br s, 1H), 4.51 (br s, 1H), 3.46 (br s, 1H), 3.05 (br s, 1H), 2.77 (br d, =14.8 Hz, 1H), 2.53 - 2.62 (m, 1H), 2.44 - 2.48 (m, 1H), 1.86 - 1.96 (m, 1H), 1.52 (br d, J=6.6 Hz, 3H), 1.40 - 1.50 (m, 2H), 1.04 - 1.16 (m, 4H).

Compound 7

Ή NMR (500 MHz, DMSO-de, 77°C) d ppm 8.55 (s, 1 H), 8.27 (d, J= 3.8 Hz, 1H), 8.17 (br t, =8.0 Hz, 1H), 7.24 - 7.57 (br s, 1H), 7.13 - 7.23 (m, 4H), 7.10 (br d, J=1.9 Hz, 1H), 7.06 (br d, J=12.9 Hz, 1H), 6.81 (s, 1H), 6.46 - 6.86 (br s, 1H), 5.36 (br s, 1H), 3.42 (br t, J=\ 1.7 Hz, 1H), 2.94 - 3.04 (m, 1H), 2.78 (br d, =15.8 Hz, 1H), 2.52 - 2.58 (m, 1H), 2.27 - 2.34 (m, 1H), 1.97 (s, 1H), 1.90 - 1.96 (m, 1H), 1.51 (br d, J=6.6 Hz, 3H), 1.39 (dt, =8.7, 4.5 Hz, 1H), 1.20 - 1.26 (m, 1H), 1.10 - 1.15 (m, 2H), 1.02 - 1.10 (m, 2H).

Compound 8

Ή NMR (500 MHz, DMSO-de, 77°C) d ppm 11.75 (br s, 1H), 8.56 (d, J= 1.3 Hz, 1H), 8.29 (d, J=4.1 Hz, 1H), 8.20 (t, =8.2 Hz, 1H), 7.14 - 7.23 (m, 5H), 7.13 (d, J=1.6 Hz, 1H), 6.82 (s, 1H), 5.36 (br s, 1H), 4.04 (br s, 1H), 3.42 - 3.47 (m, 1H), 3.24 (s, 3H), 2.95 - 3.03 (m, 1H), 2.78 (br d, J=16.1 Hz, 1H), 2.50 - 2.59 (m, 2H), 2.13 - 2.19 (m, 1H), 1.55 (dt, =9.3, 4.8 Hz, 1H), 1.51 (d, J= 6.9 Hz, 3H), 1.45 - 1.50 (m, 1H), 1.10 - 1.15 (m, 2H), 1.05 - 1.10 (m, 2H).

Compound 9

Major rotamer (75%)

Ή NMR (500 MHz, DMSO-de) d ppm 12.51 (br s, 1H), 8.58 (br s, 1H), 8.15 (br d, J= 3.5 Hz, 1H), 8.08 (br t, J= 8.8 Hz, 1H), 7.29 (br s, 1H), 7.09 - 7.39 (m, 3H), 6.79 (br s, 1H), 6.53 (br d,

J= 8.2 Hz, 1H), 6.46 (br d, J=14.5 Hz, 1H), 5.53 (br s, 1H), 3.82 (br s, 1H), 3.42 - 3.56 (m, 3H),

3.29 - 3.42 (m, 2H), 3.17 - 3.26 (m, 1H), 3.03 (br s, 1H), 2.77 (br d, J=15A Hz, 1H), 2.54 - 2.61 (m, 1H), 2.12 - 2.29 (m, 2H), 1.51 (br d, =6.3 Hz, 3H), 0.99 - 1.13 (m, 4H).

Minor rotamer (25%)

Ή NMR (500 MHz, DMSO-de) d ppm 12.51 (br s, 1H), 8.58 (br s, 1H), 8.15 (br d, J= 3.5 Hz, 1H), 8.08 (br t, J= 8.8 Hz, 1H), 7.09 - 7.39 (m, 4H), 6.79 (br s, 1H), 6.53 (br d, J= 8.2 Hz, 1H), 6.46 (br d, J=14.5 Hz, 1H), 4.95 (br s, 1H), 4.50 (br s, 1H), 3.42 - 3.56 (m, 2H), 3.29 - 3.42 (m, 3H), 3.17 - 3.26 (m, 1H), 3.03 (br s, 1H), 2.77 (br d, =15.4 Hz, 1H), 2.54 - 2.61 (m, 1H), 2.12 - 2.29 (m, 2H), 1.51 (br d, J= 6.3 Hz, 3H), 0.99 - 1.13 (m, 4H).

Compound 10

Major rotamer (75%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.58 (s, 1H), 8.15 (d, J=4A Hz, 1H), 8.08 (t, J= 8.8 Hz, 1H), 7.50 (br s, 1H), 7.29 (br s, 1H), 7.09 - 7.24 (m, 3H), 7.00 (br s, 1H), 6.78 (br s, 1H), 6.51 (dd, J=8.5, 1.6 Hz, 1H), 6.43 (dd, =14.5, 1.3 Hz, 1H), 5.53 (br s, 1H), 3.82 (br s, 1H), 3.43 -3.52 (m, 1H), 3.27 - 3.43 (m, 5H), 3.04 - 3.12 (m, 1H), 2.77 (br d, =15.8 Hz, 1H), 2.53 - 2.60 (m, 1H), 2.15 - 2.24 (m, 1H), 2.03 - 2.14 (m, 1H), 1.51 (br d, =6.3 Hz, 3H), 1.09 (br s, 4H).

Minor rotamer (25%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.58 (s, 1H), 8.15 (d, J= 4.1 Hz, 1H), 8.08 (t, J= 8.8 Hz, 1H), 7.50 (br s, 1H), 7.09 - 7.24 (m, 4H), 7.00 (br s, 1H), 6.78 (br s, 1H), 6.51 (dd, J= 8.5, 1.6 Hz, 1H), 6.43 (dd, =14.5, 1.3 Hz, 1H), 4.95 (br s, 1H), 4.49 (br s, 1H), 3.43 - 3.52 (m, 1H), 3.27 - 3.43 (m, 5H), 3.04 - 3.12 (m, 1H), 2.77 (br d, =15.8 Hz, 1H), 2.53 - 2.60 (m, 1H), 2.15 - 2.24 (m, 1H), 2.03 - 2.14 (m, 1H), 1.51 (br d, =6.3 Hz, 3H), 1.09 (br s, 4H).

Compound 11

Major rotamer (80%)

Ή NMR (400 MHz, DMSO-de) d ppm 8.57 (s, 1H), 8.15 (d, J= 4.0 Hz, 1H), 8.07 (t, J= 8.8 Hz, 1H), 7.98 (br q, J= 4.5 Hz, 1H), 7.28 (br s, 1H), 7.17 (br s, 3H), 6.78 (br s, 1H), 6.50 (br d, J=9A Hz, 1H), 6.42 (br d, =14.7 Hz, 1H), 5.53 (br s, 1H), 3.82 (br s, 1H), 3.44 - 3.54 (m, 1H), 3.25 -3.44 (m, 4H), 2.97 - 3.13 (m, 2H), 2.77 (br d, J=15J Hz, 1H), 2.62 (d, J= 4.5 Hz, 3H), 2.56 (t,

J= 6.3 Hz, 1H), 2.04 - 2.23 (m, 2H), 1.51 (br d, J= 6.6 Hz, 3H), 1.09 (br t, J=1.1 Hz, 4H).

Minor rotamer (20%)

Ή NMR (400 MHz, DMSO-de) d ppm 8.57 (s, 1H), 8.15 (d, J= 4.0 Hz, 1H), 8.07 (t, J= 8.8 Hz, 1H), 7.98 (br q, J= 4.5 Hz, 1H), 7.17 (br s, 4H), 6.78 (br s, 1H), 6.50 (br d, J=9A Hz, 1H), 6.42 (br d, J=14.7 Hz, 1H), 4.97 (br s, 1H), 4.49 (br s, 1H), 3.44 - 3.54 (m, 1H), 3.25 - 3.44 (m, 4H), 2.97 - 3.13 (m, 2H), 2.77 (br d, J=15J Hz, 1H), 2.62 (d, J= 4.5 Hz, 3H), 2.56 (t, J= 6.3 Hz, 1H), 2.04 - 2.23 (m, 2H), 1.51 (br d, J= 6.6 Hz, 3H), 1.09 (br t, J=1.1 Hz, 4H).

Compound 12

Ή NMR (500 MHz, DMSO-de) d ppm 8.57 (s, 1H), 8.14 (d, J=4A Hz, 1H), 8.07 (t, J= 8.8 Hz, 1H), 7.27 (br s, 1H), 7.17 (br s, 3H), 6.78 (br s, 1H), 6.49 (dd, =8.7, 1.7 Hz, 1H), 6.41 (br d, J=14.8 Hz, 1H), 5.53 (br s, 1H), 4.99 (d, J= 3.5 Hz, 1H), 4.42 (br s, 1H), 3.83 (br s, 1H), 3.46 (br dd, =10.1, 4.7 Hz, 1H), 3.32 - 3.54 (m, 3H), 3.14 (br d, =9.8 Hz, 1H), 3.03 (br s, 1H), 2.77 (br d, J=15.8 Hz, 1H), 2.52 - 2.60 (m, 1H), 2.01 - 2.11 (m, 1H), 1.87 - 1.96 (m, 1H), 1.51 (br d,

J= 6.6 Hz, 3H), 1.03 - 1.15 (m, 4H).

Compound 13

Ή NMR (500 MHz, DMSO-de) d ppm 8.57 (d, J= 1.3 Hz, 1H), 8.15 (d, J=4A Hz, 1H), 8.07 (t, J= 8.8 Hz, 1H), 7.49 (br s, 1H), 7.35 (br s, 1H), 6.89 - 7.10 (m, 2H), 6.78 (s, 1H), 6.51 (dd, =8.7, 2.0 Hz, 1H), 6.42 (dd, =14.8, 1.9 Hz, 1H), 5.45 (br s, 1H), 3.94 (br s, 1H), 3.48 (t, J= 8.7 Hz, 1H), 3.26 - 3.43 (m, 4H), 3.08 (quin, J= 7.6 Hz, 1H), 3.00 (br s, 1H), 2.80 (br d, J=15A Hz, 1H), 2.53 - 2.60 (m, 1H), 2.15 - 2.25 (m, 1H), 2.04 - 2.14 (m, 1H), 1.46 (br d, =6.3 Hz, 3H), 1.03 -1.15 (m, 4H).

Compound 14

Ή NMR (500 MHz, DMSO-de, 77°C) d ppm 8.51 (s, 1H), 8.10 (d, J= 4.1 Hz, 1H), 8.05 (t, J= 8.8 Hz, 1H), 7.69 (br d, J= 3.8 Hz, 1H), 7.29 (d, J=5A Hz, 1H), 6.91 (d, J= 5.0 Hz, 1H), 6.76 (s, 1H),

6.50 (dd, J=8.7, 2.0 Hz, 1H), 6.39 (dd, =14.5, 1.9 Hz, 1H), 5.31 (br s, 1H), 4.16 (br s, 1H), 3.49 (t, =8.8 Hz, 1H), 3.28 - 3.44 (m, 4H), 3.06 - 3.11 (m, 1H), 2.91 - 3.00 (m, 1H), 2.80 (dd, =16.1, 3.2 Hz, 1H), 2.63 (d, J=4A Hz, 3H), 2.51 - 2.57 (m, 1H), 2.08 - 2.22 (m, 2H), 1.46 (d, J= 6.6 Hz, 3H), 1.10 - 1.15 (m, 2H), 1.04 - 1.09 (m, 2H).

Compound 15

Major rotamer (65%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.44 (br s, 1H), 8.12 (br s, 1H), 8.06 (t, J= 8.8 Hz, 1H),

7.50 (br s, 1H), 6.98 (br s, 1H), 6.68 (br s, 1H), 6.50 (dd, =8.8, 1.9 Hz, 1H), 6.42 (dd, =14.5,

1.6 Hz, 1H), 3.99 (br d, =12.3 Hz, 1H), 3.68 (br s, 1H), 3.48 (t, =8.7 Hz, 1H), 3.26 - 3.44 (m, 4H), 3.03 - 3.11 (m, 1H), 2.85 (br t, J=l 1.8 Hz, 1H), 2.52 - 2.58 (m, 1H), 2.15 - 2.23 (m, 1H), 2.05 - 2.14 (m, 1H), 1.88 - 2.04 (m, 1H), 1.51 - 1.84 (m, 4H), 1.18 - 1.33 (m, 3H), 1.10 - 1.16 (m, 2H), 1.04 - 1.10 (m, 4H).

Minor rotamer (35%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.48 (br s, 1H), 8.12 (br s, 1H), 8.06 (t, J= 8.8 Hz, 1H),

7.50 (br s, 1H), 6.98 (br s, 1H), 6.68 (br s, 1H), 6.50 (dd, =8.8, 1.9 Hz, 1H), 6.42 (dd, =14.5,

1.6 Hz, 1H), 4.43 (br s, 1H), 3.48 (t, =8.7 Hz, 2H), 3.26 - 3.44 (m, 4H), 3.03 - 3.11 (m, 1H),

2.85 (br t, J=11.8 Hz, 1H), 2.52 - 2.58 (m, 1H), 2.15 - 2.23 (m, 1H), 2.05 - 2.14 (m, 1H), 1.88 -2.04 (m, 1H), 1.51 - 1.84 (m, 4H), 1.18 - 1.33 (m, 3H), 1.10 - 1.16 (m, 2H), 1.04 - 1.10 (m, 4H).

Compound 16

Major rotamer (80%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.81 (s, 1H), 8.21 - 8.31 (m, 3H), 8.07 (t, J= 8.8 Hz, 1H), 7.52 - 7.58 (m, 2H), 7.42 - 7.51 (m, 3H), 7.31 (br s, 1H), 7.10 - 7.26 (m, 3H), 6.99 (br s, 1H),

6.51 (dd, J=8.7, 2.0 Hz, 1H), 6.44 (dd, =14.7, 1.7 Hz, 1H), 5.59 (br s, 1H), 3.96 (br s, 1H), 3.53 (br s, 1H), 3.49 (br t, =8.7 Hz, 1H), 3.35 - 3.43 (m, 2H), 3.26 - 3.32 (m, 1H), 3.08 (br dt,

J=15A, 7.6 Hz, 2H), 2.79 (br d, J=15A Hz, 1H), 2.15 - 2.24 (m, 1H), 2.05 - 2.15 (m, 1H), 1.55 (br d, J= 6.3 Hz, 3H).

Minor rotamer (20%)

'H NMR (500 MHz, DMSO-de) d ppm 8.81 (s, 1H), 8.21 - 8.31 (m, 3H), 8.07 (t, =8.8 Hz, 1H),

7.52 - 7.58 (m, 2H), 7.42 - 7.51 (m, 3H), 7.10 - 7.26 (m, 4H), 6.99 (br s, 1H), 6.51 (dd, =8.7, 2.0 Hz, 1H), 6.44 (dd, J=14.7, 1.7 Hz, 1H), 5.12 (br s, 1H), 4.54 (br s, 1H), 3.49 (br t, =8.7 Hz, 1H), 3.35 - 3.43 (m, 3H), 3.26 - 3.32 (m, 1H), 3.08 (br dt, =15.1, 7.6 Hz, 2H), 2.79 (br d, =15.4 Hz, 1H), 2.15 - 2.24 (m, 1H), 2.05 - 2.15 (m, 1H), 1.55 (br d, =6.3 Hz, 3H).

Compound 17

Ή NMR (500 MHz, DMSO-de, 37°C) d ppm 9.37 (br s, 1H), 8.77 (s, 1H), 8.53 - 8.64 (m, 2H), 8.20 (d, J= 3.8 Hz, 1H), 7.99 (t, J= 8.8 Hz, 1H), 7.53 (br s, 1H), 7.50 (dd, J=1.7 , 4.9 Hz, 1H), 7.36 (br s, 1H), 7.19 (br s, 1H), 7.11 (br s, 3H), 6.83 (br s, 1H), 6.45 (dd, =8.7, 1.4 Hz, 1H), 6.36 (br d, =14.5 Hz, 1H), 5.49 (br s, 1H), 3.93 (br s, 1H), 3.42 (t, J= 8.8 Hz, 1H), 3.36 - 3.58 (m, 1H), 3.28 - 3.37 (m, 2H), 3.20 - 3.27 (m, 1H), 3.01 (br quin, J=1.5 Hz, 2H), 2.73 (br d, J=\6A Hz,

1H), 2.08 - 2.17 (m, 1H), 1.98 - 2.08 (m, 1H), 1.49 (br d, J= 6.6 Hz, 3H).

Compound 18

Ή NMR (500 MHz, DMSO-de, 23°C) d ppm 9.44 (d, J= 1.3 Hz, 1H), 8.85 (d, J= 1.3 Hz, 1H), 8.63 - 8.71 (m, 2H), 8.29 (d, J=4A Hz, 1H), 8.06 (t, J= 8.8 Hz, 1H), 7.62 (s, 1H), 7.58 (dd, J=1.9, 4.7 Hz, 1H), 7.50 (br s, 1H), 7.36 (br s, 1H), 6.99 (br s, 2H), 6.52 (dd, J= 8.8, 2.2 Hz, 1H), 6.44 (dd, J=14.5, 1.9 Hz, 1H), 5.52 (br s, 1H), 4.07 (br s, 1H), 3.48 (t, =8.9 Hz, 1H), 3.35 - 3.43 (m, 2H), 3.34 - 3.55 (m, 1H), 3.27 - 3.30 (m, 1H), 3.08 (quin, J=1.6 Hz, 2H), 2.83 (br d, J=\5A Hz, 1H), 2.15 - 2.24 (m, 1H), 2.05 - 2.14 (m, 1H), 1.50 (br d, J=6.6 Hz, 3H).

Compound 19

Major rotamer (75%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.25 (s, 1H), 8.07 (d, J=4A Hz, 1H), 8.04 (t, J= 9.0 Hz, 1H), 7.50 (br s, 1H), 7.29 (br s, 1H), 7.08 - 7.25 (m, 3H), 6.99 (br s, 1H), 6.50 (dd, J= 8.7, 2.0 Hz, 1H), 6.42 (dd, =14.5, 1.9 Hz, 1H), 6.21 (br s, 1H), 5.53 (br s, 1H), 3.91 (br s, 1H), 3.48 (t, =8.7 Hz, 1H), 3.35 - 3.42 (m, 2H), 3.26 - 3.35 (m, 2H), 3.24 (s, 6H), 3.03 - 3.11 (m, 1H), 2.78 (br d, =16.1 Hz, 1H), 2.51 - 2.53 (m, 1H partially obscured by DMSO peak), 2.15 - 2.23 (m, 1H), 2.05

- 2.14 (m, 1H), 1.52 (br d, J=5.7 Hz, 3H).

Minor rotamer (35%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.25 (s, 1H), 8.07 (d, J=4A Hz, 1H), 8.04 (t, J= 9.0 Hz, 1H), 7.50 (br s, 1H), 7.08 - 7.25 (m, 4H), 6.99 (br s, 1H), 6.50 (dd, J= 8.7, 2.0 Hz, 1H), 6.42 (dd, =14.5, 1.9 Hz, 1H), 6.21 (br s, 1H), 5.05 (br s, 1H), 4.49 (br s, 1H), 3.48 (t, =8.7 Hz, 1H), 3.35

- 3.42 (m, 2H), 3.26 - 3.35 (m, 2H), 3.24 (s, 6H), 3.03 - 3.11 (m, 1H), 2.78 (br d, =16.1 Hz, 1H),

2.51 - 2.53 (m, 1H partially obscured by DMSO peak), 2.15 - 2.23 (m, 1H), 2.05 - 2.14 (m, 1H),

1.52 (br d, J=5J Hz, 3H).

Compound 20

Major rotamer (65%)

Ή NMR (500 MHz, DMSO-de) d ppm 7.97 - 8.10 (m, 3H), 7.50 (br s, 1H), 7.28 (br s, 1H), 7.17 (br s, 3H), 6.99 (br s, 1H), 6.49 (dd, =8.8, 1.9 Hz, 1H), 6.41 (dd, =14.5, 1.6 Hz, 1H), 5.91 (br s, 1H), 5.52 (br s, 1H), 3.93 (br s, 1H), 3.80 (br d, J= 6.0 Hz, 4H), 3.47 (t, =8.7 Hz, 1H), 3.25 -3.44 (m, 4H), 3.07 (quin, J=1.7 Hz, 1H), 2.94 - 3.03 (m, 1H), 2.77 (br d, =15.8 Hz, 1H), 2.14 -2.23 (m, 1H), 2.04 - 2.14 (m, 1H), 1.97 (br s, 4H), 1.52 (br s, 3H).

Minor rotamer (35%)

Ή NMR (500 MHz, DMSO-de) d ppm 7.97 - 8.10 (m, 3H), 7.50 (br s, 1H), 7.17 (br s, 4H), 6.99 (br s, 1H), 6.49 (dd, =8.8, 1.9 Hz, 1H), 6.41 (dd, =14.5, 1.6 Hz, 1H), 5.91 (br s, 1H), 5.05 (br s, 1H), 4.49 (br s, 1H), 3.80 (br d, J= 6.0 Hz, 4H), 3.47 (t, =8.7 Hz, 1H), 3.25 - 3.44 (m, 4H), 3.07 (quin, J=l.l Hz, 1H), 2.94 - 3.03 (m, 1H), 2.77 (br d, =15.8 Hz, 1H), 2.14 - 2.23 (m, 1H), 2.04 -2.14 (m, 1H), 1.97 (br s, 4H), 1.52 (br s, 3H).

Compound 21

Major rotamer (70%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.23 (br s, 1H), 7.51 (br s, 1H), 7.45 (t, =8.7 Hz, 1H), 7.31 (br s, 1H), 7.06 - 7.26 (m, 3H), 7.00 (br s, 1H), 6.79 (br s, 1H), 6.50 (dd, =8.7, 2.1 Hz, 1H), 6.42 (dd, =13.9, 1.9 Hz, 1H), 5.57 (br s, 1H), 3.81 (br s, 1H), 3.48 (t, =8.7 Hz, 1H), 3.26 - 3.42 (m, 4H), 3.09 (quin, J=1.7 Hz, 1H), 3.02 (br s, 1H), 2.76 (br s, 1H), 2.52 - 2.57 (m, 1H), 2.42 (br s, 3H), 2.16 - 2.24 (m, 1H), 2.07 - 2.16 (m, 1H), 1.53 (br d, J=6.6 Hz, 3H), 1.00 - 1.12 (m, 4H).

Minor rotamer (30%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.23 (br s, 1H), 7.51 (br s, 1H), 7.45 (t, =8.7 Hz, 1H), 7.06 - 7.26 (m, 4H), 7.00 (br s, 1H), 6.79 (br s, 1H), 6.50 (dd, =8.7, 2.1 Hz, 1H), 6.42 (dd, =13.9, 1.9 Hz, 1H), 4.96 (br s, 1H), 4.53 (br s, 1H), 3.48 (t, =8.7 Hz, 1H), 3.26 - 3.42 (m, 4H), 3.09 (quin, J=1.7 Hz, 1H), 3.02 (br s, 1H), 2.76 (br s, 1H), 2.52 - 2.57 (m, 1H), 2.42 (br s, 3H), 2.16 - 2.24 (m, 1H), 2.07 - 2.16 (m, 1H), 1.53 (br d, J=6.6 Hz, 3H), 1.00 - 1.12 (m, 4H).

Compound 22

Major rotamer (76%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.58 (s, 1H), 8.42 (dd, =10.2, 8.4 Hz, 1H), 8.16 (d,

J= 4.1 Hz, 1H), 7.50 (br s, 1H), 7.28 (br s, 1H), 7.10 - 7.24 (m, 3H), 6.98 (br s, 1H), 6.80 (br s, 1H), 6.51 (dd, =8.4, 2.0 Hz, 1H), 5.53 (br s, 1H), 3.82 (br s, 1H), 3.59 - 3.69 (m, 1H), 3.52 -3.59 (m, 1H), 3.50 (dd, =10.4, 6.9 Hz, 1H), 3.36 - 3.47 (m, 2H), 3.04 - 3.11 (m, 1H), 2.95 - 3.04 (m, 1H), 2.77 (br d, =16.1 Hz, 1H), 2.53 - 2.59 (m, 1H), 2.15 - 2.23 (m, 1H), 2.05 - 2.15 (m,

1H), 1.51 (d, J= 6.6 Hz, 3H), 1.03 - 1.14 (m, 4H).

Minor rotamer (24%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.58 (s, 1H), 8.42 (dd, =10.2, 8.4 Hz, 1H), 8.16 (d,

J=4.1 Hz, 1H), 7.50 (br s, 1H), 7.10 - 7.24 (m, 4H), 6.98 (br s, 1H), 6.80 (br s, 1H), 6.51 (dd, J=8.4, 2.0 Hz, 1H), 4.96 (br s, 1H), 4.49 (br s, 1H), 3.59 - 3.69 (m, 1H), 3.52 - 3.59 (m, 1H), 3.50 (dd, =10.4, 6.9 Hz, 1H), 3.36 - 3.47 (m, 2H), 3.04 - 3.11 (m, 1H), 2.95 - 3.04 (m, 1H), 2.77 (br d, J=16.1 Hz, 1H), 2.52 - 2.53 (m, 1H), 2.15 - 2.23 (m, 1H), 2.05 - 2.15 (m, 1H), 1.51 (d, J=6.6 Hz, 3H), 1.03 - 1.14 (m, 4H).

Compound 23

Major rotamer (84%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.58 (d, J= 1.3 Hz, 1H), 8.42 (dd, =10.1, 8.5 Hz, 1H), 8.16 (d, J= 3.8 Hz, 1H), 7.50 (br s, 1H), 7.35 (br s, 1H), 6.89 - 7.05 (m, 2H), 6.80 (s, 1H), 6.51 (dd, J=8.5, 1.9 Hz, 1H), 5.45 (br s, 1H), 3.93 (br s, 1H), 3.60 - 3.67 (m, 1H), 3.52 - 3.58 (m, 1H), 3.50 (dd, =10.4, 6.9 Hz, 1H), 3.33 - 3.45 (m, 2H), 3.07 (quin, J= 7.5 Hz, 1H), 2.99 (br s, 1H), 2.80 (br d, =15.1 Hz, 1H), 2.53 - 2.59 (m, 1H), 2.15 - 2.23 (m, 1H), 2.05 - 2.14 (m, 1H), 1.46 (d, J= 6.6 Hz, 3H), 1.04 - 1.14 (m, 4H).

Minor rotamer (16%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.58 (d, J= 1.3 Hz, 1H), 8.42 (dd, =10.1, 8.5 Hz, 1H), 8.16 (d, J= 3.8 Hz, 1H), 7.50 (br s, 1H), 7.35 (br s, 1H), 6.89 - 7.05 (m, 2H), 6.80 (s, 1H), 6.51 (dd, J=8.5, 1.9 Hz, 1H), 4.94 (br s, 1H), 4.57 (br s, 1H), 3.60 - 3.67 (m, 1H), 3.52 - 3.58 (m, 1H), 3.50 (dd, =10.4, 6.9 Hz, 1H), 3.33 - 3.45 (m, 2H), 3.07 (quin, J= 7.5 Hz, 1H), 2.99 (br s, 1H), 2.80 (br d, =15.1 Hz, 1H), 2.52 - 2.53 (m, 1H), 2.15 - 2.23 (m, 1H), 2.05 - 2.14 (m, 1H), 1.46 (d, J= 6.6 Hz, 3H), 1.04 - 1.14 (m, 4H).

Compound 24

Major rotamer (70%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.64 (s, 1H), 8.41 (d, J= 4.1 Hz, 1H), 7.86 (t, J= 7.5 Hz, 1H), 7.78 (br s, 1H), 7.36 (s, 1H), 7.27 - 7.35 (br s, 2H), 7.10 - 7.25 (m, 4H), 6.87 (br s, 1H),

5.54 (br s, 1H), 5.03 (s, 2H), 3.83 (br s, 1H), 3.47 (br s, 1H), 3.04 (br s, 1H), 2.77 (br d, =14.8 Hz, 1H), 2.53 - 2.59 (m, 1H), 1.52 (br d, J=6.6 Hz, 3H), 1.05 - 1.16 (m, 4H).

Minor rotamer (30%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.64 (s, 1H), 8.41 (d, J=4A Hz, 1H), 7.86 (t, J= 7.5 Hz, 1H), 7.78 (br s, 1H), 7.36 (s, 1H), 7.27 - 7.35 (br s, 1H), 7.10 - 7.25 (m, 5H), 6.87 (br s, 1H),

5.03 (s, 2H), 4.84 - 5.00 (m, 1H), 4.50 (br s, 1H), 3.47 (br s, 1H), 3.04 (br s, 1H), 2.77 (br d, J=14.8 Hz, 1H), 2.53 - 2.59 (m, 1H), 1.52 (br d, J=6.6 Hz, 3H), 1.05 - 1.16 (m, 4H).

Compound 25

Major rotamer (75%)

Ή NMR (500 MHz, DMSO-76) d ppm 12.78 (br s, 1H), 9.14 (s, 1H), 8.65 (br s, 1H), 8.38 - 8.56 (m, 2H), 8.14 (s, 1H), 7.99 (d, 7=14.5 Hz, 1H), 7.97 (d, 7= 9.5 Hz, 1H), 7.30 (br s, 1H), 7.06 -7.26 (m, 3H), 6.89 (br s, 1H), 5.55 (br s, 1H), 3.83 (br s, 1H), 3.48 (br s, 1H), 3.04 (br s, 1H), 2.78 (br d, 7=14.2 Hz, 1H), 2.55 - 2.63 (m, 1H), 1.52 (br d, 7=6.3 Hz, 3H), 1.01 - 1.22 (m, 4H).

Minor rotamer (25%)

Ή NMR (500 MHz, DMSO-76) d ppm 12.78 (br s, 1H), 9.14 (s, 1H), 8.65 (br s, 1H), 8.38 - 8.56 (m, 2H), 8.14 (s, 1H), 7.99 (d, 7=14.5 Hz, 1H), 7.97 (d, 7= 9.5 Hz, 1H), 7.06 - 7.26 (m, 4H), 6.89 (br s, 1H), 4.97 (br s, 1H), 4.52 (br s, 1H), 3.48 (br s, 1H), 3.04 (br s, 1H), 2.78 (br d, 7=14.2 Hz, 1H), 2.55 - 2.63 (m, 1H), 1.52 (br d, 7=6.3 Hz, 3H), 1.01 - 1.22 (m, 4H).

Compound 26

Major rotamer (75%)

Ή NMR (500 MHz, DMSO-76) d ppm 9.02 (s, 1H), 8.65 (br s, 1H), 8.37 - 8.50 (m, 2H), 8.19 (s, 1H), 7.90 (d, .7=10.7 Hz, 1H), 7.88 (d, 7=7.3 Hz, 1H), 7.73 (br s, 1H), 7.08 - 7.41 (m, 5H), 6.89 (br s, 1H), 5.55 (br s, 1H), 3.83 (br s, 1H), 3.48 (br s, 1H), 3.05 (br s, 1H), 2.78 (br d, 7=15.1 Hz, 1H), 2.56 - 2.62 (m, 1H), 1.52 (br d, 7=6.6 Hz, 3H), 1.06 - 1.20 (m, 4H).

Minor rotamer (25%)

Ή NMR (500 MHz, DMSO-76) d ppm 9.02 (s, 1H), 8.65 (br s, 1H), 8.37 - 8.50 (m, 2H), 8.19 (s, 1H), 7.90 (d, 7=10.7 Hz, 1H), 7.88 (d, 7=7.3 Hz, 1H), 7.73 (br s, 1H), 7.08 - 7.41 (m, 5H), 6.89 (br s, 1H), 4.97 (br s, 1H), 4.51 (br s, 1H), 3.48 (br s, 1H), 3.05 (br s, 1H), 2.78 (br d, 7=15.1 Hz, 1H), 2.56 - 2.62 (m, 1H), 1.52 (br d, 7=6.6 Hz, 3H), 1.06 - 1.20 (m, 4H).

Compound 27

Major rotamer (80%)

Ή NMR (500 MHz, DMSO-76) d ppm 8.58 (s, 1H), 8.16 (d, 7=4.4 Hz, 1H), 8.07 (t, 7=8.5 Hz, 1H), 7.29 (br s, 1H), 7.17 (br s, 3H), 6.79 (br s, 1H), 6.38 (dd, 7=8.5, 2.2 Hz, 1H), 6.34 (dd, 7=13.6, 2.2 Hz, 1H), 5.68 (d, 7=6.6 Hz, 1H), 5.53 (br s, 1H), 4.55 - 4.64 (m, 1H), 4.13 (t, 7=7.3 Hz, 2H), 3.81 (br s, 1H), 3.60 (dd, 7=8.0, 4.9 Hz, 2H), 3.45 (br s, 1H), 3.04 (br s, 1H), 2.77 (br d, 7=15.8 Hz, 1H), 2.56 (br quin, 7=6.8 Hz, 1H), 1.51 (d, 7=6.6 Hz, 3H), 1.03 - 1.14 (m, 4H).

Minor rotamer (20%)

Ή NMR (500 MHz, DMSO-76) d ppm 8.58 (s, 1H), 8.16 (d, 7=4.4 Hz, 1H), 8.07 (t, 7=8.5 Hz, 1H), 7.29 (br s, 1H), 7.17 (br s, 3H), 6.79 (br s, 1H), 6.38 (dd, 7=8.5, 2.2 Hz, 1H), 6.34 (dd, 7=13.6, 2.2 Hz, 1H), 5.68 (d, 7=6.6 Hz, 1H), 4.95 (br s, 1H), 4.55 - 4.64 (m, 1H), 4.49 (br s, 1H), 4.13 (t, J=1 Hz, 2H), 3.60 (dd, J= 8.0, 4.9 Hz, 2H), 3.45 (br s, 1H), 3.04 (br s, 1H), 2.77 (br d, J=15.8 Hz, 1H), 2.56 (br quin, =6.8 Hz, 1H), 1.51 (d, J=6.6 Hz, 3H), 1.03 - 1.14 (m, 4H).

Compound 28

Major rotamer (75%)

'H NMR (500 MHz, DMSC s) d ppm 11.95 (br s, 1H), 8.58 (s, 1H), 8.18 (d, J=4A Hz, 1H), 8.10 (t, =8.7 Hz, 1H), 7.29 (br s, 1H), 7.18 (br s, 3H), 6.80 (br s, 1H), 6.37 - 6.47 (m, 2H), 5.53 (br s, 1H), 4.05 (br t, =8.0 Hz, 2H), 3.96 (t, J=6.6 Hz, 2H), 3.81 (br s, 1H), 3.58 - 3.66 (m, 1H), 3.46 (br s, 1H), 3.27 (s, 3H), 2.94 - 3.13 (m, 1H), 2.77 (br d, =15.1 Hz, 1H), 2.53 - 2.60 (m,

1H), 1.51 (br d, J= 6.6 Hz, 3H), 1.09 (br s, 4H).

Minor rotamer (25%)

'H NMR (500 MHz, DMSO-de) d ppm 11.95 (br s, 1H), 8.58 (s, 1H), 8.18 (d, =4.1 Hz, 1H), 8.10 (t, =8.7 Hz, 1H), 7.29 (br s, 1H), 7.18 (br s, 3H), 6.80 (br s, 1H), 6.37 - 6.47 (m, 2H), 4.96 (br s, 1H), 4.50 (br s, 1H), 4.05 (br t, =8.0 Hz, 2H), 3.96 (t, J= 6.6 Hz, 2H), 3.58 - 3.66 (m, 1H), 3.46 (br s, 1H), 3.27 (s, 3H), 2.94 - 3.13 (m, 1H), 2.77 (br d, =15.1 Hz, 1H), 2.53 - 2.60 (m,

1H), 1.51 (br d, J= 6.6 Hz, 3H), 1.09 (br s, 4H).

Compound 29

Major rotamer (70%)

Ή NMR (500 MHz, DMSO-de) d ppm 13.11 (br s, 1H), 8.62 (s, 1H), 8.31 (d, J= 4.1 Hz, 1H), 8.18 (t, =8.7 Hz, 1H), 7.53 (s, 1H), 7.05 - 7.41 (m, 4H), 6.90 (d, =8.8 Hz, 1H), 6.84 (br s, 1H), 5.39 - 5.66 (m, 1H), 5.01 (d, J= 1.6 Hz, 2H), 3.41 - 3.55 (m, 1H), 3.03 (br d, J= 2.2 Hz, 1H), 2.77 (br d, J=16.1 Hz, 1H), 2.51 - 2.59 (m, 2H), 1.52 (d, =6.6 Hz, 3H), 1.01 - 1.18 (m, 4H).

Minor rotamer (30%)

'H NMR (500 MHz, DMSO-de) d ppm 13.11 (br s, 1H), 8.62 (s, 1H), 8.31 (d, =4.1 Hz, 1H), 8.18 (t, =8.7 Hz, 1H), 7.53 (s, 1H), 7.05 - 7.41 (m, 4H), 6.90 (d, =8.8 Hz, 1H), 6.84 (br s, 1H), 5.01 (d, J=1.6 Hz, 2H), 3.95 - 4.17 (m, 1H), 3.72 - 3.93 (m, 1H), 3.03 (br d, J=22 Hz, 1H), 2.77 (br d, J=16.1 Hz, 1H), 2.51 - 2.59 (m, 2H), 1.52 (d, =6.6 Hz, 3H), 1.01 - 1.18 (m, 4H)

Compound 30

Major rotamer (80%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.73 (s, 1H), 8.61 (s, 1H), 8.25 (d, J= 4.1 Hz, 1H), 8.14 (t, J= 8.8 Hz, 1H), 7.67 (dd, =14.5, 1.9 Hz, 1H), 7.36 (dd, =8.7, 2.0 Hz, 1H), 7.03 - 7.33 (m, 4H), 6.82 (br s, 1H), 5.65 (d, J= 6.3 Hz, 1H), 5.54 (br s, 1H), 4.42 - 4.48 (m, 1H), 4.16 (t, J=1.7 Hz, 2 H), 3.82 (br s, 1H), 3.74 (dd, J= 8.8, 4.4 Hz, 2H), 3.42 - 3.53 (m, 1H), 3.03 (br s, 1H), 2.58 - 2.79 (m, 1H), 2.54 - 2.57 (m, 1H), 1.51 (d, =6.6, 3H), 1.07 - 1.17 (m, 4H).

Minor rotamer (20%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.73 (s, 1H), 8.61 (s, 1H), 8.25 (d, J= 4.1 Hz, 1H), 8.14 (t, J= 8.8 Hz, 1H), 7.67 (dd, =14.5, 1.9 Hz, 1H), 7.36 (dd, =8.7, 2.0 Hz, 1H), 7.03 - 7.33 (m, 4H), 6.82 (br s, 1H), 5.65 (d, J= 6.3 Hz, 1H), 4.98 (br s, 1H), 4.51 (br s, 1H), 4.42 - 4.48 (m, 1H), 4.16 (t, J=l.l Hz, 2 H), 3.74 (dd, J= 8.8, 4.4 Hz, 2H), 3.42 - 3.53 (m, 1H), 3.03 (br s, 1H), 2.58 - 2.79 (m, 1H), 2.54 - 2.57 (m, 1H), 1.51 (d, =6.6, 3H), 1.07 - 1.17 (m, 4H).

Compound 31

Major rotamer (65%)

Ή NMR (500 MHz, DMSO-de) d ppm 12.44 (br s, 1H), 8.64 (br s, 1H), 8.28 - 8.51 (m, 2H),

7.55 - 7.82 (m, 3H), 7.06 - 7.45 (m, 4H), 6.88 (br s, 1H), 6.65 (br d, =15.8 Hz, 1H), 5.55 (br s, 1H), 3.83 - 4.05 (m, 1H), 3.46 (br s, 1H), 3.04 (br s, 1H), 2.70 - 2.79 (m, 1H), 2.53 - 2.68 (m,

1H), 1.52 (br s, 3H), 1.11 - 1.13 (m, 4H).

Minor rotamer (35%)

Ή NMR (500 MHz, DMSO-de) d ppm 12.44 (br s, 1H), 8.64 (br s, 1H), 8.28 - 8.51 (m, 2H),

7.55 - 7.82 (m, 3H), 7.06 - 7.45 (m, 4H), 6.88 (br s, 1H), 6.65 (br d, =15.8 Hz, 1H), 4.93 - 5.12 (m, 1H), 4.44 - 4.54 (m, 1H), 3.46 (br s, 1H), 3.04 (br s, 1H), 2.70 - 2.79 (m, 1H), 2.53 - 2.68 (m, 1H), 1.52 (br s, 3H), 1.11 - 1.13 (m, 4H)

Compound 32

Major rotamer (65%)

Ή NMR (400 MHz, DMSO-de) d ppm 12.43 (br s, 1H), 8.52 (d, J= 3.8 Hz, 1H), 8.18 (br t, J= 8.1 Hz, 1H), 7.33 (br d, J= 7.2 Hz, 1H), 7.08 - 7.27 (m, 5H), 7.04 (s, 1H), 5.59 (q, J= 6.6 Hz, 1H),

3.84 (br dd, =13.0, 4.2 Hz, 1H), 3.44 - 3.54 (m, 1H), 2.98 - 3.09 (m, 1H), 2.86 - 2.96 (m, 1H), 2.73 (br d, =15.9 Hz, 1H), 2.58 - 2.66 (m, 1H), 1.89 - 1.97 (m, 1H), 1.53 (br d, J=6J Hz, 3H), 1.41 - 1.51 (m, 2H), 1.33 - 1.40 (m, 2H), 1.25 - 1.31 (m, 2H).

Minor rotamer (35%)

Ή NMR (400 MHz, DMSO-de) d ppm 12.43 (br s, 1H), 8.49 (d, J=3J Hz, 1H), 8.18 (br t, J= 8.1 Hz, 1H), 7.08 - 7.27 (m, 6H), 7.00 (s, 1H), 5.00 (q, J=6A Hz, 1H), 4.56 (br d, J=12.6 Hz, 1H), 3.25 - 3.30 (m, 1H), 2.98 - 3.09 (m, 1H), 2.86 - 2.96 (m, 1H), 2.58 - 2.66 (m, 2H), 1.89 - 1.97 (m, 1H), 1.56 (br d, J=6J Hz, 3H), 1.41 - 1.51 (m, 2H), 1.33 - 1.40 (m, 2H), 1.25 - 1.31 (m, 2H).

Compound 33

Major rotamer (60%)

Ή NMR (400 MHz, DMSO-de) d ppm 12.42 (br s, 1H), 8.45 (d, J= 3.9 Hz, 1H), 8.16 (t, =8.2 Hz, 1H), 7.15 - 7.25 (m, 2H), 6.97 (s, 1H), 3.97 (br d, =13.2 Hz, 1H), 3.56 - 3.70 (m, 1H), 2.93 (br t, .7=12.5 Hz, 1H), 2.56 - 2.65 (m, 1H), 2.43 - 2.47 (m, 1H), 1.90 - 1.97 (m, 2H), 1.53 - 1.86 (m, 4H), 1.30 - 1.52 (m, 5H), 1.20 - 1.29 (m, 4H), 1.11 (d, 7=6.4 Hz, 3H).

Minor rotamer (40%)

Ή NMR (400 MHz, DMSO-76) d ppm 12.42 (br s, 1H), 8.48 (d, 7=3.9 Hz, 1H), 8.16 (t, 7=8.2 Hz, 1H), 7.15 - 7.25 (m, 2H), 6.97 (s, 1H), 4.41 (dt, 7=11.9, 6.0 Hz, 1H), 3.46 (br d, 7=15.3 Hz, 1H), 3.07 - 3.17 (m, 1H), 2.56 - 2.65 (m, 2H), 2.00 - 2.10 (m, 1H), 1.90 - 1.97 (m, 1H), 1.53 -1.86 (m, 4H), 1.30 - 1.52 (m, 5H), 1.20 - 1.29 (m, 4H), 1.14 (d, 7=6.5 Hz, 3H).

Compound 34

Major rotamer (60%)

Ή NMR (500 MHz, DMSO-76) d ppm 12.42 (br s, 1 H) 8.45 (d, 7= 3.8 Hz, 1 H) 8.16 (t, 7=8.0 Hz, 1 H) 7.22 (s, 1H) 7.14 - 7.21 (m, 1 H) 6.97 (s, 1 H) 3.97 (br d, 7=13.6 Hz, 1 H) 3.58 - 3.70 (m, 1 H) 2.93 (br t, 7=12.6 Hz, 1 H) 2.56 - 2.62 (m, 1 H) 2.39-2.56 (m, 1H) 2.01 - 2.10 (m, 1 H) 1.89 - 2.01 (m, 1 H) 1.20 - 1.85 (m, 13 H) 1.11 (d, 7=6.3 Hz, 3 H).

Minor rotamer (40%)

'H NMR (500 MHz, DMSO-76) d ppm 12.42 (br s, 1 H) 8.48 (d, 7= 3.8 Hz, 1 H) 8.16 (t, 7=8.0 Hz, 1 H) 7.14 - 7.21 (m, 2 H) 6.97 (s, 1 H) 4.33 - 4.50 (m, 1 H) 3.46 (br d, 7=15.4 Hz, 1 H) 3.05 - 3.18 (m, 1 H) 2.56 - 2.62 (m, 1 H) 2.39-2.56 (m, 1H) 1.89 - 2.01 (m, 2 H) 1.20 - 1.85 (m, 13 H) 1.13 (d, 7=6.3 Hz, 3 H).

Compound 35

Major rotamer (65%)

'H NMR (500 MHz, DMSO-de) d ppm 8.32 (d, 7=4.1 Hz, 1H), 8.07 (t, 7=8.8 Hz, 1H), 7.08 -7.36 (m, 5H), 6.49 (dd, 7=8.8, 2.2 Hz, 1H), 6.42 (dd, 7=14.7, 2.0 Hz, 1H), 5.58 - 5.64 (m, 1H),

5.18 (d, 7=3.5 Hz, 2H), 4.07 (br s, 2H), 3.86 - 3.96 (m, 1H), 3.46 - 3.57 (m, 3H), 3.16 (d, 7=10.4 Hz, 2H), 2.71 - 3.11 (m, 4H), 1.54 (d, 7=6.9 Hz, 3H), 1.35 - 1.41 (m, 3H).

Minor rotamer (35%)

'H NMR (500 MHz, DMSO-de) d ppm 8.30 (d, 7=4.1 Hz, 1H), 8.07 (t, 7=8.8 Hz, 1H), 7.08 -7.36 (m, 5H), 6.49 (dd, 7=8.8, 2.2 Hz, 1H), 6.42 (dd, 7=14.7, 2.0 Hz, 1H), 5.18 (d, 7=3.5 Hz,

2H), 5.01 - 5.09 (m, 1H), 4.53 - 4.61 (m, 1H), 4.07 (br s, 2H), 3.52 (dd, 7=10.6, 3.6 Hz, 2H), 3.26 - 3.35 (m, 1H), 3.16 (d, 7=10.4 Hz, 2H), 2.71 - 3.11 (m, 4H), 1.59 (d, 7=6.6 Hz, 3H), 1.35 -1.41 (m, 3H).

Compound 36

Major rotamer (65%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.31 - 8.36 (m, 1 H) 8.07 (t, =8.7 Hz, 1 H) 7.09 - 7.34 (m, 5 H) 6.33 - 6.42 (m, 2 H) 5.68 (d, J= 6.6 Hz, 1 H) 5.58 - 5.64 (m, 1 H) 4.54 - 4.57 (m, 1 H) 4.14 (t, J= 7.3 Hz, 2 H) 3.90 (br dd, =13.6, 3.8 Hz, 1 H) 3.62 (dd, J=1.7 , 4.9 Hz, 2 H) 3.35 - 3.56 (m, 1 H) 2.72 - 3.13 (m, 4 H) 1.54 (d, J= 6.9 Hz, 3 H) 1.30 (t, J= 7.3 Hz, 3 H).

Minor rotamer (35%)

'H NMR (500 MHz, DMSO-de) d ppm 8.31 - 8.36 (m, 1 H) 8.07 (t, =8.7 Hz, 1 H) 7.09 - 7.34 (m, 5 H) 6.33 - 6.42 (m, 2 H) 5.68 (d, J= 6.6 Hz, 1 H) 5.02 - 5.08 (m, 1 H) 4.54 - 4.64 (m, 2 H) 4.14 (t, =7.3 Hz, 2 H) 3.62 (dd, J=7.7, 4.9 Hz, 2 H) 3.27 - 3.31 (m, 1 H) 2.72 - 3.13 (m, 4 H) 1.58 (d, J= 6.6 Hz, 3 H) 1.36 (t, J=1.6 Hz, 3 H).

Compound 37

Major rotamer (65%)

'H NMR (500 MHz, DMSO-de) d ppm 12.53 (br s, 1H), 8.64 (d, J= 4.1 Hz, 1H), 8.32 (t, =8.0 Hz, 1H), 7.79 (dd, J=12.3, 0.9 Hz, 1H), 7.69 (dd, .7=8.2, 1.3 Hz, 1H), 7.63 (d, J=16.1 Hz, 1H), 7.07 - 7.39 (m, 5H), 6.67 (d, =15.8 Hz, 1H), 5.58 - 5.66 (m, 1H), 3.87 - 3.99 (m, 1H), 3.45 -3.62 (m, 1H), 2.70 - 3.17 (m, 4H), 1.55 (d, J=6.6 Hz, 3H), 1.33 - 1.48 (m, 3H).

Minor rotamer (35%)

'H NMR (500 MHz, DMSO-de) d ppm 12.53 (br s, 1H), 8.62 (d, J=4A Hz, 1H), 8.32 (t, =8.0 Hz, 1H), 7.79 (dd, =12.3, 0.9 Hz, 1H), 7.69 (dd, .7=8.2, 1.3 Hz, 1H), 7.63 (d, =16.1 Hz, 1H), 7.07 - 7.39 (m, 5H), 6.67 (d, =15.8 Hz, 1H),) 5.03 - 5.10 (m, 1H), 4.54 - 4.62 (m, 1H), 3.28 -3.37 (m, 1H), 2.70 - 3.17 (m, 4H), 1.59 (d, J=6.9 Hz, 3H), 1.33 - 1.48 (m, 3H).

Compound 38

Major rotamer (65%)

'H NMR (400 MHz, DMSO-de) d ppm 8.50 (s, 1 H) 8.43 (d, J= 3.9 Hz, 1 H) 8.13 (t, J= 8.5 Hz, 1 H) 7.70 (br d, =14.4 Hz, 1 H) 7.46 (d, J= 8.8 Hz, 1 H) 7.32 (d, J= 7.2 Hz, 1 H) 7.08 - 7.27 (m, 3 H) 7.01 (s, 1 H) 5.59 (q, J=7.3 Hz, 1 H) 4.99 (d, J= 3.6 Hz, 1 H) 4.31 (br s, 1 H) 3.78 - 3.89 (m, 1 H) 3.41 - 3.55 (m, 4 H) 3.25 - 3.35 (m, 1 H) 2.82 - 3.10 (m, 2 H) 2.57 - 2.66 (m, 1 H) 1.87 - 2.00 (m, 1 H) 1.77 - 1.87 (m, 1 H) 1.53 (d, J=6.9 Hz, 3 H) 1.21 - 1.41 (m, 4 H).

Minor rotamer (35%)

'H NMR (400 MHz, DMSO-de) d ppm 8.50 (s, 1 H) 8.41 (d, J= 3.9 Hz, 1 H) 8.13 (t, J= 8.5 Hz, 1 H) 7.70 (br d, =14.4 Hz, 1 H) 7.46 (d, J= 8.8 Hz, 1 H) 7.08 - 7.27 (m, 4 H) 6.97 (s, 1 H) 4.99 (d, J= 3.6 Hz, 1 H) 4.95 - 5.04 (m, 1 H) 4.51 - 4.60 (m, 1 H) 4.31 (br s, 1 H) 3.41 - 3.55 (m, 4 H) 3.25 - 3.35 (m, 1 H) 2.74 (m, 2 H) 2.57 - 2.66 (m, 1 H) 1.87 - 2.00 (m, 1 H) 1.77 - 1.87 (m, 1 H) 1.57 (d, J=6.9 Hz, 3 H) 1.21 - 1.41 (m, 4 H).

Compound 39

Major rotamer (65%)

'H NMR (400 MHz, DMSO-de) d ppm 8.50 (s, 1 H) 8.44 (d, J= 3.9 Hz, 1 H) 8.09 - 8.16 (m, 1 H) 7.70 (d, J=14.4 Hz, 1 H) 7.46 (d, =8.7 Hz, 1 H) 7.39 (d, J= 5.1 Hz, 1 H) 6.97 - 7.04 (m, 2 H)

5.51 - 5.57 (m, 1 H) 4.99 (d, J= 3.6 Hz, 1 H) 4.32 (br s, 1 H) 3.95 (br dd, =13.6, 4.3 Hz, 1 H) 3.39 - 3.52 (m, 4 H) 3.32 - 3.36 (m, 1 H) 2.55 - 3.06 (m, 3 H) 1.88 - 1.99 (m, 1 H) 1.78 - 1.86 (m, 1 H) 1.47 (d, J=6 Hz, 3 H) 1.21 - 1.32 (m, 2 H) 1.32 - 1.40 (m, 2 H).

Minor rotamer (35%)

'H NMR (400 MHz, DMSO-de) d ppm 8.50 (s, 1 H) 8.42 (d, J= 3.9 Hz, 1 H) 8.09 - 8.16 (m, 1 H) 7.70 (d, J=14.4 Hz, 1 H) 7.46 (d, =8.7 Hz, 1 H) 7.30 (d, J= 5.3 Hz, 1 H) 6.97 - 7.04 (m, 1 H)

6.80 (d, J= 5.3 Hz, 1 H) 4.99 (d, J= 3.6 Hz, 1 H) 4.90 - 4.97 (m, 1 H) 4.65 - 4.76 (m, 1 H) 4.32 (br s, 1 H) 3.39 - 3.52 (m, 3 H) 3.18 - 3.36 (m, 2 H) 2.55 - 3.06 (m, 3 H) 1.88 - 1.99 (m, 1 H) 1.78 -1.86 (m, 1 H) 1.51 (d, J=6.5 Hz, 3 H) 1.21 - 1.32 (m, 2 H) 1.32 - 1.40 (m, 2 H).

Compound 39

Major rotamer (65%)

'H NMR (500 MHz, DMSO-de) d ppm 8.49 (s, 1 H) 8.45 (d, J=4A Hz, 1 H) 8.13 (t, =8.7 Hz, 1 H) Ί .11 (dd, J=14.7, 1.7 Hz, 1 H) 7.46 (dd, =8.8, 1.9 Hz, 1 H) 7.08 - 7.35 (m, 5 H) 5.61 (m, 1 H) 4.98 (d, J= 3.5 Hz, 1 H) 4.32 (br s, 1 H) 3.90 (br dd, =13.9, 3.5 Hz, 1 H) 3.32 - 3.56 (m, 5 H) 2.73 - 3.13 (m, 4 H) 1.89 - 1.99 (m, 1 H) 1.78 - 1.86 (m, 1 H) 1.55 (d, =6.9 Hz, 3 H ) 1.40 (t, J=1.6 Hz, 3 H).

Minor rotamer (35%)

'H NMR (500 MHz, DMSO-de) d ppm 8.49 (s, 1 H) 8.43 (d, J= 3.8 Hz, 1 H) 8.13 (t, =8.7 Hz, 1 H) Ί .11 (dd, J=14.7, 1.7 Hz, 1 H) 7.46 (dd, =8.8, 1.9 Hz, 1 H) 7.08 - 7.35 (m, 5 H) 5.06 (m, 1 H) 4.98 (d, J= 3.5 Hz, 1 H) 4.57 (m, 1H) 4.32 (br s, 1 H) 3.32 - 3.56 (m, 5 H) 2.73 - 3.13 (m, 4 H) 1.89 - 1.99 (m, 1 H) 1.78 - 1.86 (m, 1 H) 1.59 (d, J= 6.9 Hz, 3 H ) 1.37 (t, J= 7.6 Hz, 3 H).

Compound 40

Major rotamer (65%)

'H NMR (400 MHz, DMSO-de) d ppm 8.50 (br s, 1H), 8.42 - 8.47 (m, 1H), 8.13 (t, J= 8.8 Hz, 1H), 7.71 (dd, J=14.5, 1.9 Hz, 1H), 7.46 (dd, =8.7, 1.8 Hz, 1H), 7.28 (s, 1H), 6.69 (d, J=2A Hz, 1H), 5.36 - 5.43 (m, 1H), 4.99 (d, =3.5 Hz, 1H), 4.31 (br s, 1H), 4.01 (br dd, =13.6, 5.0 Hz,

1H), 3.42 - 3.53 (m, 4H), 3.31 - 3.36 (m, 1H), 3.03 - 3.13 (m, 2H), 2.60 - 2.99 (m, 2H), 1.88 -1.99 (m, 1H), 1.77 - 1.86 (m, 1H), 1.46 (d, J=6.1 Hz, 3H), 1.35 - 1.42 (m, 3H).

Minor rotamer (35%)

Ή NMR (400 MHz, DMSO-de) d ppm 8.50 (br s, 1H), 8.42 - 8.47 (m, 1H), 8.13 (t, J= 8.8 Hz, 1H), 7.71 (dd, J=14.5, 1.9 Hz, 1H), 7.46 (dd, =8.7, 1.8 Hz, 1H), 7.25 (s, 1H), 6.44 (d, J=1.8 Hz, 1H), 4.99 (d, J= 3.5 Hz, 1H), 4.85 (q, J= 6.9 Hz, 1H), 4.63 - 4.74 (m, 1H), 4.31 (br s, 1H), 3.42 -3.53 (m, 3H), 3.24 - 3.36 (m, 2H), 3.03 - 3.13 (m, 2H), 2.60 - 2.99 (m, 2H), 1.88 - 1.99 (m, 1H), 1.77 - 1.86 (m, 1H), 1.50 (d, J=6J Hz, 3H), 1.35 - 1.42 (m, 3H).

Compound 41

Major rotamer (60%)

Ή NMR (400 MHz, DMSO-de) d ppm 8.50 (s, 1 H) 8.41 - 8.48 (m, 1 H) 8.13 (t, =8.7 Hz, 1 H) 7.71 (dd, =14.6, 1.7 Hz, 1 H) 7.46 (dd, =8.7, 1.7 Hz, 1 H) 7.18 - 7.31 (m, 3 H) 6.98 - 7.10 (m,

1 H) 5.63 (q, J= 6.9 Hz, 1 H) 4.99 (d, J=3A Hz, 1 H) 4.31 (br s, 1 H) 3.92 (br dd, =13.2, 4.0 Hz,

1 H) 3.42 - 3.54 (m, 4 H) 3.33 - 3.35 (m, 1 H) 3.07 (q, J= 7.5 Hz, 2 H) 2.85 - 2.91 (m, 1 H) 2.75 (br d, J=16.6 Hz, 1 H) 1.90 - 1.98 (m, 1 H) 1.79 - 1.87 (m, 1 H) 1.57 (d, J=6J Hz, 1 H) 1.39 (t, J=1.9 Hz, 3 H).

Minor rotamer (40%)

'H NMR (400 MHz, DMSO-de) d ppm 8.50 (s, 1 H) 8.41 - 8.48 (m, 1 H) 8.13 (t, =8.7 Hz, 1 H) 7.71 (dd, J=14.6, 1.7 Hz, 1 H) 7.46 (dd, =8.7, 1.7 Hz, 1 H) 7.18 - 7.31 (m, 2 H) 6.98 - 7.10 (m,

2 H) 5.09 (q, J= 6.5 Hz, 1 H) 4.99 (d, J=3A Hz, 1 H) 4.57 (br dd, =13.0, 3.4 Hz, 1 H) 4.31 (br s, 1 H) 3.42 - 3.54 (m, 4 H) 3.24 - 3.29 (m, 1 H) 3.07 (q, J= 7.5 Hz, 2 H) 2.95 - 3.02 (m, 1H) 2.85 - 2.91 (m, 1 H) 1.90 - 1.98 (m, 1 H) 1.79 - 1.87 (m, 1 H) 1.59 (d, J=6 Hz, 1 H) 1.39 (t, J=1.9 Hz, 3 H).

Compound 42

Major rotamer (60%)

'H NMR (400 MHz, DMSO-de) d ppm 8.49 (s, 1 H) 8.38 (d, J= 3.8 Hz, 1 H) 8.12 (t, =8.7 Hz, 1 H) 7.69 (dd, J=14.5, 1.3 Hz 1 H) 7.45 (dd, =8.7, 1.7 Hz, 1 H) 7.10 (s, 1 H) 4.98 (d, J=3.6 Hz, 1 H) 4.31 (br s, 1 H) 3.40 - 3.60 (m, 4 H) 3.30-3.38 (m, 2 H )3.16 - 3.29 (m, 1 H) 3.07 (q, J= 7.5 Hz, 2 H) 1.75 - 2.16 (m, 3 H) 1.37 (t, J=1.6 Hz, 3 H) 1.18 - 1.27 (m, 6 H) 0.81 (d, =6.6 Hz, 3 H) 0.77 (d, J= 6.5 Hz, 3 H).

Minor rotamer (40%)

'H NMR (400 MHz, DMSO-de) d ppm 8.49 (s, 1 H) 8.42 (d, J= 3.8 Hz, 1 H) 8.12 (t, =8.7 Hz, 1 H) ) 7.69 (dd, J=14.5, 1.3 Hz 1 H) 7.45 (dd, =8.7, 1.7 Hz, 1 H) 7.15 (s, 1 H) 4.98 (d, J= 3.6 Hz, 1 H) 4.31 (br s, 1 H) 3.77 - 3.89 (m, 1 H) 3.30-3.38 (m, 2 H) 3.40 - 3.60 (m, 3 H) 3.16 - 3.29 (m,

1 H) 3.07 (q, J=1.5 Hz, 2 H) 2.46-2.58 (m, 1 H) 1.75-2.00 (m, 2 H) 1.38 (t, J=1.6 Hz, 3 H) 1.31 (d, J= 6.9 Hz, 3 H) 1.07 (t, .7=7.0 Hz, 3 H) 0.97 (d, .7=7.0 Hz, 3 H) 0.95 (d, .7=7.0 Hz, 3 H).

Compound 43

Major rotamer (60%)

'H NMR (400 MHz, DMSO-de) d ppm 8.60 (d, J= 3.9 Hz, 1 H) 8.53 (s, 1 H) 8.36 - 8.46 (m, 2 H) 8.16 (t, .7=8.7 Hz, 1 H) 7.84 (s, 1 H) 7.63 - 7.76 (m, 2 H) 7.41 - 7.51 (m, 2 H) 7.35 (d, J=1.2 Hz,

1 H) 7.09 - 7.27 (m, 3 H) 5.65 (q, J= 6.6 Hz, 1 H) 4.99 (d, .7=3.7 Hz, 1 H) 4.32 (br s, 1 H) 3.97 (br dd, .7=13.8, 3.8 Hz, 1 H) 3.44 - 3.59 (m, 4 H) 3.33 - 3.39 (m, 1 H) 2.87 - 3.14 (m, 1 H) 2.76 (br d, .7=16.1 Hz, 1 H) 1.88 - 2.00 (m, 1 H) 1.78 - 1.87 (m, 1 H) 1.58 (d, J=6.9 Hz, 3 H).

Minor rotamer (40%)

'H NMR (400 MHz, DMSO-de) d ppm 8.58 (d, J= 3.8 Hz, 1 H) 8.53 (s, 1 H) 8.36 - 8.46 (m, 2 H) 8.16 (t, .7=8.7 Hz, 1 H) 7.79 (s, 1 H) 7.63 - 7.76 (m, 2 H) 7.41 - 7.51 (m, 2 H) 7.09 - 7.27 (m, 4 H) 5.14 (q, J= 6.3 Hz, 1 H) 4.99 (d, .7=3.7 Hz, 1 H) 4.58 - 4.64 (m, 1 H) 4.32 (br s, 1 H) 3.44 -3.52 (m, 3 H) 3.33 - 3.39 (m, 1 H) 2.87 - 3.14 (m, 2 H) 2.52 - 2.56 (m, 1 H) 1.88 - 2.00 (m, 1 H) 1.78 - 1.87 (m, 1 H) 1.62 (d, .7=6.7 Hz, 3 H).

Compound 44

Major rotamer (60%)

'H NMR (500 MHz, DMSO-de) d ppm 8.90 (d, J=l 1.4 Hz, 1 H) 8.38 (d, J= 3.5 Hz, 1 H) 7.90-8.04 (m, 1 H) 7.33 (d, J= 7.6 Hz, 1 H) 7.08 - 7.29 (m, 4 H) 6.43 (d, .7=13.9 Hz, 1 H) 5.61 (q,

J= 6.9 Hz, 1 H) 3.89 (dd, .7=13.9, 3.8 Hz, 1 H) 3.69 (t, J= 8.8 Hz, 1 H) 3.54-3.64 (m, 1 H) 3.37 -3.56 (m, 3 H) 3.00 - 3.14 (m, 4 H) 2.76 (m, 1 H) 2.61 (d, 3 H) 2.00 - 2.23 (m, 2 H) 1.54 (d, J= 6.6 Hz, 3 H) 1.38 - 1.41 (m, .7=13.2 Hz, 3 H).

Minor rotamer (40%)

'H NMR (500 MHz, DMSO-de) d ppm 8.90 (d, J=\ 1.4 Hz, 1 H) 8.37 (d, J= 3.5 Hz, 1 H) 7.90-8.04 (m, 1 H) 7.33 (d, J=1.57 Hz, 1 H) 7.08-7.29 (m, 4 H) 6.43 (d, .7=13.9 Hz, 1 H) 5.05 (q,

J= 6.6 Hz, 1 H) 4.56 (dd, .7=13.2, 3.8 Hz, 1 H ) 3.66 (t, J= 8.8 Hz, 1 H) 3.54-3.64 (m, 1 H) 3.37 -3.56 (m, 3 H) 3.00 - 3.14 (m, 4 H) 2.89 (m, 1 H) 2.61 (d, 3 H) 2.00 - 2.23 (m, 2 H) 1.58 (d, J=6.6 Hz, 3 H) 1.36 (t, .7=13.7 Hz, 3 H).

Compound 45

Major rotamer (60%)

'H NMR (500 MHz, DMSO-de) d ppm 8.55 (d, J= 3.2 Hz, 1 H) 8.15 (t, .7=8.4 Hz, 1 H) 7.95 (s, 1 H) 7.57 (s, 1 H) 7.28 - 7.41 (m, 2 H) 7.09-7.27 (m, 4 H) 6.90 (d, .7=8.5 Hz, 1 H) 5.62 (q, .7=6.3 Hz, 1 H) 4.99-5.06 (m, 2 H) 3.89-3.92 (m, 1 H) 3.50-3.55 (m, 1 H) 3.06 - 3.11 (m, 3 H) 2.75 (d, J= 16.1 Hz, 1 H) 1.54 (d, J= 6.6 Hz, 3 H) 1.40 (t, =7.3 Hz, 3 H).

Minor rotamer (40%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.51 (d, J= 2.8 Hz, 1 H) 8.15 (t, =8.4 Hz, 1 H) 7.95 (s, 1 H) 7.57 (s, 1 H) 7.28-7.41 (m, 2 H) 7.09-7.27 (m, 4 H) 6.90 (d, J= 8.5 Hz, 1 H) 5.05 (q, J= 6.3 Hz 1 H) 4.99-5.03 (m, 2 H) 4.56-4.59 (m, 1 H) 3.06 - 3.11 (m, 3 H) 3.01-3.05 (m, 1 H) 2.88 (d, J= 16.4 Hz, 1 H) 1.58 (d, J= 6.6 Hz, 3 H) 1.35 (t, =7.3 Hz, 3 H) .

Compound 46

Major rotamer (60%)

'H NMR (500 MHz, DMSO-de) d ppm 8.61-8.62 (m, J= 3.8 Hz, 1 H) 7.84 (t, J= 7.3 Hz, 1 H)

7.78 (br s, 1 H) 7.30-7.40 (m, 3 H) 7.09-7.27 (m, 5 H) 5.62 (q, J= 6.5 Hz, 1 H) 5.04 (s, 2 H) 3.89-3.95 (m, 1 H) 3.49 - 3.56 (m, 1 H) 3.05-3.12 (m, 3 H) 2.75-2.78 (m, 1 H) 1.54 (d, J=6.9 Hz, 3 H) 1.40 (t, J=1.5 Hz 3 H).

Minor rotamer (40%)

'H NMR (500 MHz, DMSO-de) d ppm 8.59 - 8.60 (m, J=3.8 Hz, 1 H) 7.84 (t, J= 7.3 Hz, 1 H) 7.78 (br s, 1 H) 7.30 - 7.40 (m, 3 H) 7.09 - 7.27 (m, 5 H) 5.06 (q, J= 6.6 Hz, 1 H) 5.04 (s, 2 H) 4.56-4.59 (m, 1 H) 3.05 - 3.12 (m, 3 H) 3.02-3.04 (m, 1 H) 2.85 - 2.98 (m, 1 H) 1.58 (d, J=6.6 Hz, 3 H) 1.36 (t, J= 7.5 Hz 3 H).

Compound 47

Major rotamer (70%)

'H NMR (500 MHz, DMSO-de) d ppm 8.76 - 8.82 (m, 1H), 8.52 (s, 1H), 8.40 - 8.43 (m, 1H),

8.18 (br t, =8.7 Hz, 1H), 7.70 - 7.74 (m, 1H), 7.48 (dd, =8.7, 1.1 Hz, 1H), 7.06 - 7.29 (m, 4H), 5.51 (q, J=6.3 Hz, 1H), 4.99 (d, =3.2 Hz, 1H), 4.32 (br s, 1H), 4.12 (br dd, =13.1, 3.9 Hz, 1H), 3.39 - 3.49 (m, 4H), 2.79 - 3.37 (m, 4H), 1.83 - 1.96 (m, 2H), 1.51 (br d, J=6.6 Hz, 3H), 1.22 - 1.26 (m, 4 H)

Minor rotamer (30%)

'H NMR (500 MHz, DMSO-de) d ppm 8.76 - 8.82 (m, 1H), 8.52 (s, 1H), 8.40 - 8.43 (m, 1 H), 8.18 (br t, =8.7 Hz, 1H), 7.70 - 7.74 (m, 1H), 7.48 (dd, =8.7, 1.1 Hz, 1H), 7.06 - 7.29 (m, 4 H),

5.27 (br d, J= 6.3 Hz, 1H), 4.99 (d, J= 3.2 Hz, 1H), 4.51 (br dd, J=12.0, 4.1 Hz, 1H), 4.32 (br s, 1H), 3.39 - 3.49 (m, 4 H), 2.79 - 3.37 (m, 4 H), 1.83 - 1.96 (m, 2 H), 1.61 (br d, J= 6.6 Hz, 3 H), 1.22 - 1.26 (m, 4 H)

Compound 48

Major rotamer (65%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.72 - 8.77 (m, 1H), 8.29 - 8.31 (m, 1H), 8.10 (t, =8.7 Hz, 1H), 7.07 - 7.30 (m, 4H), 6.41 - 6.51 (m, 2H), 5.51 (br d, =6.3 Hz, 1H), 5.15 (d, J=3.2 Hz, 2H), 4.13 (br d, J= 9.5 Hz, 1H), 4.07 (br s, 2 H), 3.53 (br dd, =10.1, 3.2 Hz, 2H), 3.38 - 3.39 (m, 1H), 2.78 - 3.27 (m, 5H), 1.51 (br d, J=6.6 Hz, 3H), 1.16 - 1.33 (m, 4H)

Minor rotamer (25%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.72 - 8.77 (m, 1H), 8.29 - 8.31 (m, 1H), 8.10 (t, =8.7 Hz, 1H), 7.07 - 7.30 (m, 4H), 6.41 - 6.51 (m, 2H), 5.29 (br d, J= 6.0 Hz, 1H), 5.15 (d, J= 3.2 Hz, 2H), 4.51 (br d, =8.5 Hz, 1H), 4.07 (br s, 2H), 3.53 (br dd, =10.1, 3.2 Hz, 2H), 3.38 - 3.39 (m, 1H), 2.78 - 3.27 (m, 5H), 1.60 (br d, J=5J Hz, 3H), 1.16 - 1.33 (m, 4H).

Compound 49

Major rotamer (65%)

Ή NMR (500 MHz, DMSO-de) d ppm 8.39 (br s, 1 H) 8.22 (br s, 1 H) 7.78 (br t, J= 8.8 Hz, 1 H) 7.64 (br d, =14.8 Hz, 1 H) 7.41 (br d, J= 8.2 Hz, 1 H) 7.31 (br d, J= 7.3 Hz, 1 H) 7.09 - 7.27 (m, 4 H) 6.40 (s, 1 H) 5.58 (br q, J= 6.6 Hz, 1 H) 4.97 (br s, 1 H) 4.31 (br s, 1 H) 3.84 (br d, =10.7 Hz, 1 H) 3.42-3.57 (m, 4 H) 3.24-3.37 (m, 1H) 2.81 - 3.10 (m, 2 H) 2.75 (br d, =16.1 Hz, 1 H) 1.89-1.99 (m, 1 H) 1.78-1.86 (m, 1 H) 1.51 (d, J=6.6 Hz, 3 H) 0.99 - 1.21 (m, 4 H).

Minor rotamer (35%)

'H NMR (500 MHz, DMSO-de) d ppm 8.39 (br s, 1 H) 8.22 (br s, 1 H) 7.78 (br t, J= 8.8 Hz, 1 H) 7.64 (br d, =14.8 Hz, 1 H) 7.41 (br d, J= 8.2 Hz, 1 H) 7.09 - 7.27 (m, 5 H) 6.36 (s, 1 H) 5.01 (br q, J= 7.3 Hz, 1 H) 4.97 (br s, 1 H) 4.54 (br d, J=10J Hz, 1 H) 4.31 (br s, 1 H) 3.42-3.57 (m, 4 H) 3.24-3.37 (m, 1 H) 2.81 - 3.10 (m, 2 H) 2.75 (br d, =16.1 Hz, 1 H) 1.89-1.99 (m, 1 H) 1.78-1.86 (m, 1 H) 1.57 (d, J= 6.6 Hz, 3 H) 0.99 - 1.21 (m, 4 H).

Compound 50

'H NMR (500 MHz, DMSO-de, 350 K) d ppm 8.33 (s, 1 H) 8.17 (br s, 1 H) 7.94 (br s, 1 H) 7.66 (br t, J= 8.8 Hz, 1 H) 7.58 (br d, J=14.5 Hz, 1 H) 7.36 (br d, J= 8.2 Hz, 1 H) 7.12 - 7.22 (m, 4 H) 6.84 (s, 1 H) 6.54 (s, 1 H) 5.32 - 5.42 (m, 1 H) 4.76 (br s, 1 H) 4.31 (br s, 1 H) 4.04 - 4.15 (m, 1 H) 3.44 - 3.51 (m, 3 H) 3.36 - 3.44 (m, 1 H) 3.31 (br d, =11.0 Hz, 1 H) 2.98-3.04 (m, 1 H) 2.73 - 2.83 (m, 3 H) 1.90 - 1.99 (m, 1 H) 1.78-1.85 (m, 1 H) 1.52 (br d, J=6.6 Hz, 3 H) 1.31 (t, =7.6 Hz, 3H).

Compound 51

Major rotamer (65%)

Ή NMR (400 MHz, DMSO-de) d ppm 8.30 (d, J= 3.9 Hz, 1 H) 8.06 (t, J= 8.8 Hz, 1 H) 7.32 (d,

J= 7.3 Hz, 1 H) 7.09 - 7.26 (m, 3 H) 6.96 (s, 1 H) 6.50 (dd, =8.7, 1.6 Hz 1 H) 6.42 (dd, =14.6, 1.6 Hz, 1 H) 5.59 (q, J= 6.6 Hz, 1 H) 5.18 (d, J= 3.2 Hz, 2 H) 4.06-4.09 (m, 2 H) 3.84 (br dd, J=13.8, 4.3 Hz, 1 H) 3.52 (dd, =10.5, 3.7 Hz, 2 H) 3.44 - 3.50 (m, 1 H) 3.16 (br d, =10.4 Hz, 2 H) 2.69 - 3.10 (m, 2 H) 2.55 - 2.66 (m, 1 H) 1.53 (d, J=6.9 Hz, 3 H) 1.21 - 1.38 (m, 4 H).

Minor rotamer (35%)

'H NMR (400 MHz, DMSO-de) d ppm 8.28 (d, J= 3.9 Hz, 1 H) 8.06 (t, J= 8.8 Hz, 1 H) 7.09 -7.26 (m, 4 H) 6.92 (s, 1 H) 6.50 (dd, =8.7, 1.6 Hz 1 H) 6.42 (dd, =14.6, 1.6 Hz, 1 H) 5.18 (d,

J= 3.2 Hz, 2 H) 5.00 (br d, J= 6.8 Hz, 1 H) 4.55 (br dd, =10.8, 3.7 Hz, 1 H) 4.06 - 4.09 (m, 2 H) 3.52 (dd, =10.5, 3.7 Hz, 2 H) 3.22 - 3.31 (m, 1 H) 3.16 (br d, =10.4 Hz, 2 H) 2.69-3.10 (m, 2 H) 2.55 - 2.66 (m, 1 H) 1.56 (d, J=6.9 Hz, 3 H) 1.21 - 1.38 (m, 4 H).

LC-MS data

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

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

Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]+ (protonated molecule) and/or [M-H] (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. [M+N¾]+, [M+HCOO] , etc...). For molecules with multiple isotopic patterns (Br, Cl..), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used.

Hereinafter,“SQD” means Single Quadrupole Detector,“RT” room temperature,“BEH” bridged ethylsiloxane/silica hybrid,“HSS” High Strength Silica,“DAD” Diode Array Detector.

Table: LCMS Method codes (Flow expressed in mL/min; column temperature (T) in°C; Run time in minutes).




Optical rotation

The optical rotation was measured using a polarimeter with light at the wavelength of the D-line of sodium (589 nm) at a temperature of 20°C in DMF as solvent. Specific optical rotation of compounds (20) and (47) was measured at 436 nm in DMF at 20°C as solvent.


E. Pharmacological examples

E.l Antiviral activity

Black 384-well clear-bottom microtiter plates (Coming, Amsterdam, The Netherlands) were filled via acoustic drop ejection using the echo liquid handler (Labcyte, Sunnyvale, California). 200 nL of compound stock solutions (100% DMSO) were transferred to the assay plates. 9 serial 4-fold dilutions of compound were made, creating per quadrant the same compound

concentration. The assay was initiated by adding 10 pL of culture medium to each well (RPMI medium without phenol red, 10% FBS-heat inactivated, 0.04% gentamycin (50 mg/mL). All addition steps are done by using a multidrop dispenser (Thermo Scientific, Erembodegem,

Belgium). Next, rgRSV224 vims (MOI = 1) diluted in culture medium was added to the plates. rgRSV224 vims is an engineered vims that includes an additional GFP gene (Hallak LK, Spillmann D, Collins PL, Peeples ME. Glycosaminoglycan sulfation requirements for respiratory syncytial vims infection; Journal of virology (2000), 74(22), 10508-13) and was in- licensed from the NIH (Bethesda, MD, USA). Finally, 20 pL of a HeLa cell suspension (3,000 cells/well) were plated. Medium, vims- and mock-infected controls were included in each test. The wells contain 0.05% DMSO per volume. Cells were incubated at 37°C in a 5% C02 atmosphere. Three days post-virus exposure, viral replication was quantified by measuring GFP expression in the cells by an in house developed MSM laser microscope (Tibotec, Beerse, Belgium). The EC50 was defined as the 50% inhibitory concentration for GFP expression. In parallel, compounds were incubated for three days in a set of white 384-well microtiter plates (Coming) and the cytotoxicity of compounds in HeLa cells was determined by measuring the ATP content of the cells using the ATPlite kit (Perkin Elmer, Zaventem, Belgium) according to the manufacturer’s instructions.

The CC50 was defined as the 50% concentration for cytotoxicity.

Table : antiviral data (averaged data of several repeat experiments)


F. Prophetic composition examples

“Active ingredient” as used throughout these examples relates to a final compound of Formula (I), the pharmaceutically acceptable salts thereof, the solvates and the stereochemically isomeric forms and the tautomers thereof.

Typical examples of recipes for the formulation of the invention are as follows:

F.l. Tablets

Active ingredient 5 to 50 mg

Di calcium phosphate 20 mg

Lactose 30 mg

Talcum 10 mg

Magnesium stearate 5 mg

Potato starch ad 200 mg

In this Example, active ingredient can be replaced with the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds.

F.2. Suspension

An aqueous suspension is prepared for oral administration so that each 1 milliliter contains 1 to 5 mg of one of the active compounds, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water ad 1 ml.

F.3. Injectable

A parenteral composition is prepared by stirring 1.5 % by weight of active ingredient of the invention in 10% by volume propylene glycol in water.

F.4. Ointment

Active ingredient 5 to 1000 mg

Stearyl alcohol 3 g

Fanoline 5 g

White petroleum 15 g

Water ad 100 g

In this Example, active ingredient can be replaced with the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds.