EA041546B1 - HETEROAROMATIC COMPOUNDS WITH ACTIVITY AGAINST RSV - Google Patents

Description

The field of technology to which the invention belongs

The present invention relates to compounds having antiviral activity, in particular having inhibitory activity against the replication of respiratory syncytial virus (RSV). In addition, the present invention relates to pharmaceutical compositions containing these compounds, as well as compounds intended for use in the treatment of infection caused by respiratory syncytial virus.

State of the art

Human RSV, or respiratory syncytial virus, is a large RNA virus that belongs to the Pneumoviridae family of the genus Orthopneumovirus together with bovine RSV. Human RSV causes a number of respiratory diseases in people of all ages throughout the world. It is the leading cause of lower respiratory tract disease in infancy and childhood. More than half of all babies experience RSV in their first year of life and nearly all during their first two years. Infection in young children can lead to lung damage that persists for years and may contribute to the development of chronic lung disease later in life (chronic bronchopulmonary obstruction, asthma). Adolescents and adults often suffer from (bad) colds due to RSV infection. Susceptibility increases again in old age, and RSV has been implicated in many outbreaks of pneumonia in the elderly, resulting in significant mortality.

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

So far, only two drugs have been approved for use against RSV infection. The first is ribavirin, a nucleoside analog that provides an aerosolized agent for the treatment of severe RSV infection in hospitalized children. Aerosol route of administration, toxicity (risk of teratogenicity), cost, and highly variable efficacy limit its use. Synagis® (palivizumab) is a monoclonal antibody used for passive immunoprophylaxis. Although the benefit of Synagis® has been demonstrated, the treatment is expensive, requires parenteral administration, and is reserved for children at risk of developing severe disease.

Clearly, there is a need for an effective, non-toxic, and easy-to-administer drug that inhibits RSV replication. Particularly preferred would be the preparation of drugs that inhibit the replication of RSV, which could be administered orally.

Compounds showing activity against RSV are disclosed in WO 2016/174079 and WO 2011/163518.

Detailed description of the invention

The present invention relates to compounds of formula (I)

or its stereochemically isomeric form, where A is

R ⁵ is (b-1)

X ¹ , X ² , X ³ and X ⁴ are selected from the following options:

X ¹ is CH, X ² is CH, X ³ is CH and X ⁴ is CH; or

X ¹ is N, X ² is CH, X ³ is CH and X ⁴ is CH; or

X ¹ is CH, X ² is N, X ³ is CH and X ⁴ is CH; or

- 1 041546

X ¹ is CH, X ² is CH, X ³ is CH and X ⁴ is N; or

X ¹ is N, X ² is N, X ³ is CH and X is CH; or

X ¹ is CH, X ² is N, X ³ is N, and X ⁴ is CH, where _each CH is optionally substituted with halo, C _1-4 alkyl, or C _{1_4} alkyloxy;

each of Y ¹ and Y ² is independently selected from CH;

R ¹ is CH ₃ ;

R ² is hydrogen;

R ³ is halogen;

R ⁴ is C _1-6 alkyl, C _3-6 cycloalkyl or heteroaryl;

R ⁶ is C _3-6 cycloalkyl or heterocycle wherein said C _3-6 cycloalkyl and heterocycle are substituted with one or two substituents each independently selected from -(CO)-OR ⁷ , -(CO)-NR ¹⁰ R ¹¹ ;

R ⁷ is hydrogen;

each of R ¹⁰ and R ¹¹ is independently selected from hydrogen or C _1-4 alkyl;

the heterocycle is pyrrolidinyl;

heteroaryl is pyridinyl;

or to their pharmaceutically acceptable acid addition salts.

When used in the above definitions, halogen is a generic term for fluorine, chlorine, bromine, and iodine;

C _1-4 alkyl denotes straight and branched saturated hydrocarbon radicals containing from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, and the like;

C _1-6 alkyl includes C _1-4 alkyl and its higher homologues containing 5 or 6 carbon atoms, such as, for example, 2-methylbutyl, pentyl, hexyl, and the like;

C _2-6 alkenyl denotes straight or branched divalent 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 their branched isomers;

C ₃ _ ₆ alkenyl denotes straight and branched chain hydrocarbon radicals containing one double bond and having from 3 to 6 carbon atoms, such as, for example, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3- pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 2-hexenyl and the like;

C ₃ - ₆ cycloalkyl is the general term for cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

polyhalo-C ₁ _ ₄ alkyl means polyhalo-substituted C _1-4 alkyl, in particular C _1-4 alkyl (as defined above herein) substituted with 2-6 halogen atoms, such as difluoromethyl, trifluoromethyl, trifluoroethyl, and the like;

-(CO)- or (CO) is carbonyl.

The term compounds of the present invention as used herein is intended to include compounds of formula (I), as well as their salts and solvates.

Any chemical formula used herein in which bonds are shown only as solid lines and not as solid wedge or dashed wedge bonds, or otherwise shown in any particular configuration (e.g., R, S) at one or several atoms, provides for each possible stereoisomer or a mixture of two or more stereoisomers.

Throughout this document, the terms compound of formula (I) and synthetic intermediates of formula (I) are meant to include their stereoisomers and their tautomeric forms.

The terms stereoisomers, stereoisomeric forms, or stereochemically isomeric forms, above or below, are used interchangeably herein.

The present invention includes all stereoisomers of the compounds of the present 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 mirror images of each other. If the compound contains a double bond, then the substituents may be in the E or Z configuration. Substituents on bivalent cyclic (partially) saturated radicals may be in either the cis or trans configuration; for example, if the compound contains a disubstituted cycloalkyl group, then the substituents may be in the cis or trans configuration.

The term stereoisomers also includes any rotamers, also referred to as conformational isomers, which the compounds of formula (I) can form.

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Thus, the present invention includes enantiomers, diastereomers, racemates, E-isomers, Z-isomers, cis-isomers, trans-isomers, rotamers and mixtures thereof, whenever possible from the point of view of chemistry.

The meanings of all these terms, i.e. enantiomers, diastereomers, racemates, E-isomers, Z-isomers, cis-isomers, trans-isomers and mixtures thereof are known to the person skilled in the art.

The absolute configuration is determined in accordance with the Kahn-Ingold-Prelog system. The configuration at an asymmetric atom is indicated as R or as S. Isolated stereoisomers whose absolute configuration is unknown can be designated as (+) or (-) depending on the direction in which they rotate the plane of polarization of light. For example, isolated enantiomers whose absolute configuration is unknown may be designated as (+) or (-) depending on the direction in which they rotate the plane of light polarization.

If a specific stereoisomer is indicated, this means that the specified stereoisomer contains practically no other stereoisomers, i.e. refers to a content of 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 other stereoisomers. Thus, if a compound of formula (I), for example, is indicated as (R), this means that the compound contains essentially no (S)-isomer; if the compound of formula (I), for example, is indicated as E, this means that the compound contains practically no Z-isomer; if the compound of formula (I), for example, is indicated as cis, this means that the compound contains practically no trans isomer.

Some compounds of formula (I) may also exist in their tautomeric form. It is intended that such forms, inasmuch as they may exist, although not explicitly shown in the above formula (I), are included within the scope of the present invention.

It follows that one compound can exist in both stereoisomeric and tautomeric form.

Atropisomers (or atropisomers) are stereoisomers that have a specific spatial configuration resulting from limited rotation around a single bond due to significant 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 set forth herein above are meant to include the therapeutically active non-toxic acid addition salt forms that the compounds of formula (I) are capable of forming. These pharmaceutically acceptable acid addition salts can be easily prepared by treating the base form with such an appropriate acid. Suitable acids include, for example, inorganic acids such as hydrohalic acids, for example 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 to the free base form.

The compounds of formula (I) may exist in both unsolvated and solvated forms. The term solvate is used herein to refer to an association of molecules comprising a compound of the present invention and one or more pharmaceutically acceptable solvent molecules, such as water or ethanol. The term hydrate is used when the indicated solvent is water.

For the avoidance of ambiguity, the compounds of formula (I) may contain these atoms in any of their natural or artificial isotopic forms. In this regard, mention may be made of those embodiments of the present invention in which (a) the compound of formula (I) is not enriched or labeled with isotopes of any atom of the compound, and (b) the compound of formula (I) is enriched or labeled with isotope(s) of any or a compound atom.

Compounds of formula (I) which are isotopically enriched or labeled (in relation to one or more atoms of the compound), i. one or more stable isotopes include, for example, compounds of formula (I) enriched or labeled with isotopes of one or more atoms, such as deuterium, C, C, N, O, and the like.

The first group of compounds are compounds of formula (I) in which X ¹ is CH, X ² is CH, X ³ is CH and X ⁴ is CH.

The second group of compounds are compounds of formula (I) in which X is N, X ² is CH, X ³ is CH and X ⁴ is CH.

A third group of compounds are compounds of formula (I) wherein X ¹ is CH, X ² is N, X ³ is CH and X ⁴ is CH.

The fourth group of compounds are compounds of formula (I), in which X represents

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N, X ² is CH, X ³ is CH and X ⁴ is N.

A fifth group of compounds are compounds of formula (I) wherein X ¹ is N, X ² is N, X ³ is CH and X ⁴ is CH.

A sixth group of compounds are compounds of formula (I) wherein X is CH, X ² is N, X ³ is N and X ⁴ is CH.

The seventh group of compounds are compounds of formula (I), where the radical And corresponds to the formula (a-1).

The eighth group of the compound are compounds of formula (I) wherein R ⁴ is C _3-6 cycloalkyl.

The ninth group of compounds are compounds of formula (I), where R ⁵ corresponds to the formula (b-1), where Y ¹ and Y ² represent CH.

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

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

b) R ¹ is methyl; or

c) R ² is hydrogen; or

d) R ³ is fluorine; or

e) R ⁴ is C _3-6 cycloalkyl, in particular cyclopropyl; or f R ⁴ is C _1-4 alkyl, in particular ethyl; or

g) R ⁴ is heteroaryl, where heteroaryl is pyridinyl; or

h) R ⁵ corresponds to the formula (b-1) where Y ¹ and Y ² are CH and R ³ is halogen, in particular R ³ is fluorine; And

i) R ⁶ is C _3-6 cycloalkyl or pyrrolidinyl, wherein said C _3-6 cycloalkyl or pyrrolidinyl is substituted with one or two substituents each independently selected from -(CO)-OR ⁷ or -(CO)-NR ¹⁰ R ¹¹ .

In general, compounds of formula (I) can be prepared by reacting an intermediate of formula (II) with an alkyl boronate 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, said method optionally further comprising converting a compound of formula (I) to its addition salt. Suitable transition metal coupling reactants and/or suitable ligands for this reaction are, for example, palladium compounds such as tetra(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, 2,2'-bis(diphenylphosphino)-1 ,1 'binaphthyl, etc.

^R4

Compounds of formula (I-a), denoting compounds of formula (I) wherein R ⁵ is of formula (b-1), can be prepared by reacting an intermediate of formula (IV) with either an intermediate of formula (V), (VI) or with (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, said method optionally further comprising converting a compound of formula (I) to its addition salt .

Other synthetic routes for obtaining compounds of formula (I) are described in the experimental part in the form of general preparations and specific working examples.

Compounds of formula (I) can also be prepared by converting compounds of formula (I) into each other according to group transformation reactions known from the prior art.

The starting materials and some of the intermediates are known compounds and can be purchased or prepared according to conventional reaction procedures generally known in the art.

The compounds of formula (I) obtained in the methods described above, can be synthesized as racemic mixtures of enantiomers, which can be separated from each other, following separation procedures known in the art. These compounds of formula (I) obtained in racemic form may be converted to the corresponding diastereomeric salt forms by reaction with an appropriate chiral acid. Said diastereomeric salt forms are then separated, for example by selective or fractional crystallization, and the enantiomers are isolated using alkali. An alternative method for separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms can also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction proceeds stereospecifically. If a specific stereoisomer is desired, then preferably said compound is synthesized using stereospecific preparation methods. These methods advantageously use enantiomerically pure starting materials.

The compounds of formula (I) exhibit antiviral properties. Viral infections that can be treated using the compounds and methods of the present invention include those caused by ortho- and paramyxoviruses, and in particular human and bovine respiratory syncytial virus (RSV). A number of compounds of this invention, in addition, act against mutant strains of RSV. In addition, many of the compounds of this invention exhibit a favorable pharmacokinetic profile and are attractive due to their bioavailability properties, including acceptable half-life, AUC and peak values, and the absence of adverse effects such as insufficiently rapid onset of action and retention in tissues.

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

In addition, the present invention provides pharmaceutical compositions containing at least one pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I). Also contemplated 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 inhibitory compound.

For the purpose of preparing the pharmaceutical compositions of this invention, an effective amount of a particular compound in the form of a base or acid addition salt as an active substance is combined in a homogeneous mixture with at least one pharmaceutically acceptable carrier, and the carrier can take a wide variety of forms depending on the form of the preparation intended for introductions. These pharmaceutical compositions are preferably in unit dosage form, preferably suitable for oral administration, rectal administration, transdermal administration or parenteral injection.

For example, any of the usual liquid pharmaceutical carriers, such as, for example, water, glycols, oils, alcohols, and the like, may be used when preparing compositions in oral dosage form. in the case of oral liquid preparations such as suspensions, syrups, tinctures and solutions; or solid pharmaceutical carriers such as starches, sugars, kaolin, lubricants, binders, disintegrants, and the like. in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules represent the most convenient oral unit dosage form, and in this case, of course, solid pharmaceutical carriers are used. In the case of compositions for parenteral injection, the pharmaceutical carrier will generally contain sterile water, although other ingredients may be included to improve the solubility of the active substance. Injectable solutions can be prepared, for example, using a pharmaceutical carrier containing saline solution, glucose solution or a mixture thereof. Suspensions for injection may also be prepared using suitable liquid carriers, suspending agents, and the like. In compositions suitable for transdermal administration, the pharmaceutical carrier may optionally contain a penetrating agent and/or a suitable wetting agent, optionally combined with acceptable additives in small amounts that do not cause significant adverse effect on the skin. Said additives may be chosen to facilitate the administration of the active substance to the skin and/or to facilitate the preparation of the desired compositions. These topical compositions can be administered in a variety of ways, for example, as a transdermal patch, topical application, or ointment. The addition salts of the compounds of formula (I), due to their increased solubility in water compared to the corresponding base form, are more suitable in the preparation of aqueous compositions.

It is particularly advantageous to formulate the pharmaceutical compositions of this invention in unit dosage form for ease of administration and uniform dosing. Unit dosage form as used herein means physically discrete units suitable as unit doses, each unit containing a predetermined amount of the active substance, calculated to produce the desired therapeutic effect, together with the required pharmaceutical carrier. Examples of such standard medicines

- 5 041546 venous forms are tablets (including divisible or coated tablets), capsules, pills, pouches with a powdered product, plates, solutions or suspensions for injection, teaspoons with a top, tablespoons with a top, etc. ., as well as their individual multiples.

In the case of oral administration, the pharmaceutical compositions of the present invention may take the form of solid dosage forms, for example, tablets (both swallowable and chewable), capsules or gel capsules prepared by conventional methods using pharmaceutically acceptable excipients and carriers such as binders (eg, pregelatinized corn starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose, etc.), bulking agents (eg, lactose, microcrystalline cellulose, calcium phosphate, etc.), lubricants (eg, magnesium stearate, talc , silicon dioxide, and the like), disintegrants (eg, potato starch, sodium starch glycolate, and the like), wetting agents (eg, sodium lauryl sulfate), and the like. Such tablets may also be coated by methods well known in the art.

Liquid preparations for oral administration, for example, may take the form of solutions, syrups or suspensions, or may be formulated as a dry product for mixing with water and/or other suitable liquid carrier before use. Such liquid preparations may be prepared by conventional methods, optionally with other pharmaceutically acceptable additives such as suspending agents (for example, sorbitol syrup, methylcellulose, hydroxypropyl methylcellulose, or hydrogenated edible fats), emulsifiers (for example, lecithin or gum arabic), non-aqueous vehicles (for example, almond oil). oil, fatty esters or ethyl alcohol), sweeteners, flavors, masking agents and preservatives (eg methyl or propyl p-hydroxybenzoates or sorbic acid).

Pharmaceutically acceptable sweeteners useful in the pharmaceutical compositions of the present invention include at least one intense sweetener such as aspartame, acesulfame potassium, sodium cyclamate, alitame, dihydrochalcone sweetener, monellin, stevioside, sucralose (4,1',6' trichloro-4,1',6'-trideoxygalactosucrose) or preferably saccharin, sodium saccharin or calcium saccharin, and optionally at least one bulk sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenated syrup glucose, xylitol, caramel or honey. Intensive sweeteners are usually used in low concentrations. For example, in the case of sodium saccharin, the specified concentration may be from about 0.04 to 0.1% (w/v) of the final composition. The bulk sweetener can be effectively used at higher concentrations of from about 10% to about 35%, preferably from about 10% to 15% (w/v).

Pharmaceutically acceptable flavors that can mask bitter tasting ingredients in low dosage formulations are preferably fruit flavors such as cherry, raspberry, blackcurrant or strawberry flavors. The combination of two flavors can provide very good results. High dosage formulations may require stronger pharmaceutically acceptable flavors such as Caramel Chocolate, Mint Cool, Fantasy, etc. The content of each flavor in the final composition may be from about 0.05 to 1% (w/v). Preferably, combinations of these strong flavors are used. Preferably, a flavoring agent is used which does not undergo any change or loss of taste and/or color under formulation conditions.

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

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

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

The precise dosage and frequency of administration will depend on the particular compound of formula (I) employed.

- 6 041546 the specific condition being treated, the severity of the condition being treated, the age, weight, sex, degree of impairment, and general physical condition of the particular patient, as well as from other drug treatment that the individual may be receiving, which is well known to those skilled in the art technology. Moreover, it is clear that said effective daily amount may be reduced or increased depending on the response of the subject being treated and/or depending on the judgment of the physician prescribing the compounds of the present invention. The effective daily amount ranges given above in this document are therefore only guidelines.

In addition, a combination of another antiviral drug and a compound of formula (I) can be used as a drug. 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 therapy. Various drugs can be combined into one preparation together with pharmaceutically acceptable carriers. For example, the compounds of the present invention can be combined with interferon-beta or tumor necrosis factor alpha 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 infection are RSV fusion inhibitors or RSV polymerase inhibitors. Specific antiviral compounds to be combined with any of the compounds of formula (I) useful in the treatment of RSV infection are RSV inhibitory compounds selected from ribavirin, lumicitabin, presatovir, ALX-0171, MDT-637, BTA-9881, BMS- 433771, YM-543403, A-60444, TMC-353121, RFI-641, CL-387626,

MBX-3 00, 3-({5 -chloro-1 -[3-(methylsulfonyl)propyl] -1 H-benzimidazol-2-yl} methyl)-1 - cyclopropyl-1,3 dihydro-2H-imidazo[4 ,5-c]pyridin-2-one, 3-[[7-chloro-3-(2-ethylsulfonylethyl)imidazo[1,2-a]pyridin-2yl]methyl]-1-cyclopropylimidazo[4,5-c ]pyridin-2-one and 3-({5-chloro-1-[3-(methylsulfonyl)propyl]-1H idol-2-yl}methyl)-1-(2,2,2-trifluoroethyl)-1, 3-dihydro-2H-imidazo[4,5-c]pyridin-2-one.

Experimental part.

A. Abbreviations.

gw or MW ASON lead.

br cataCXium® A d DCE DCM DIPA DIPEA

Microwave DMAP acetic acid aqueous broad di(1-ad-amantyl)-//-butylphospho and n

CAS [321921-71-5] doublet

1,2-dichloroethane dichloromethane diisopropylamine

A.A-diisopropylethylamine

4-(dimethylamino)pyridine

CAS[1122-58-3]

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DME 1,2-dimethoxyethane DMF dimethylformamide DMSO dimethyl sulfoxide _{Et2O Et3N} EtOAc diethyl ether triethylamine ethyl acetate EtOH ethanol

h hour 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- HATU b} pyridinium-3-oxide hexafluorophosphate CAS[148893-10-1] z-PrMgCl KOAc LDA LiHMDS isopropylmagnesium chloride potassium acetate Lithium diisopropylamide Lithium bis(trimethylsilyl)amide m mass/charge MeCN multiplet mass-to-charge ratio acetonitrile MeMgBr MeNH ₂ MeOH methylmagnesium bromide methylamine methanol Me-THF 2-methyltetrahydrofuran CAS [96-47-9] min minute(s) MTVE otreot-butyl methyl ether NMR o/n Nuclear magnetic resonance during the night P(Su)z tricyclohexylphosphine CAS [2622-14-2] Pd(OAc) ₂ palladium(II) acetate CAS [3375-31-3] _PdCl2 palladium(P) chloride CAS[7647-10-1] PdCl ₂ (dppf) [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) CAS[72287-26-4] [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex PdCl ₂ (dppf).DCM with dichloromethane CAS[95464-05-4] PdCl ₂ (dtbpf) [1,1'-bis(di-ot/?eot-butylphosphino)ferrocene]dichloropalladium(II)

- 8 041546 (Ph) ₂ O

RRASA

PPh ₃

ppm

q quin

_Rh2 (OAc)4

k.t.

s

Selectfluor® sext t

Z-BuOK

TFA

TFAA

THF

Xantphos

A

CAS [95408-45-0] diphenyl ether propylphosphonic anhydride CAS [68957-94-8] triphenylphosphine ppm quartet quintuplet rhodium(II) acetate dimer CAS [15956-28-2] room temperature singlet

-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) CAS [140681-55-6] sextuplet triplet from/?et-butoxide potassium trifluoroacetic acid

CAS [76-05-1] trifluoroacetic anhydride CAS [407-25-0] tetrahydrofuran

4,5-bis(diphenylphosphino)-9,9-dimethylxanthene CAS [161265-03-8] heating

The stereochemical configuration for some compounds has been designated as R* or S* (or *R or *S) if absolute stereochemistry is not determined (even if the bonds are shown stereospecifically), although the compound itself was isolated as a single stereoisomer and was enantiomerically pure. This means that the absolute stereochemical configuration of the stereocenter indicated by * is not defined (even if the bonds are shown stereospecifically), although the compound is enantiomerically pure at the indicated center.

B. Synthesis of compounds.

Indolizines.

Synthesis of intermediate compounds.

Synthesis of intermediate compound A3.

Intermediate connection A1.

Methyl 2-bromo-5-ethylindolizine-7-carboxylate.

D1

A mixture of intermediate 4-bromo-1H-pyrrole-2-carbaldehyde [931-33-9] (1.41 g,

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8.10 mmol), methyl 4-bromohex-2-enoate [119226-97-0] (2.26 g, 9.72 mmol, 89% purity) and potassium carbonate (2.46 g, 17.3 mmol ) in DMF (38 ml) was stirred at rt for 16 h. The reaction mixture was poured into water and the aqueous phase was extracted using EtOAc (twice). The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and the solvent was evaporated in vacuo. The crude mixture was purified by preparative LC (SiOH with regular grains, 30 μm, 200 g Interchim®, dry loaded (Celite®), mobile phase gradient: heptane/EtOAc from 100:0 to 50:50) to give Intermediate A1 (0.65 g, 28%).

Intermediate connection A2.

2-Bromo-5-ethylindolizine-7-carboxylic acid.

A mixture of intermediate A1 (0.65 g, 2.30 mmol) and lithium hydroxide monohydrate (193 mg, 4.61 mmol) in THF (15 ml) and H ₂ O (5 ml) was stirred at room temperature for 16 h Additional lithium hydroxide monohydrate (97.0 mg, 2.30 mmol) was added and the reaction mixture was stirred at RT for an additional 2 hours. aqueous solution of HCl. The layers were separated and the aqueous phase was extracted using EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and the solvent was evaporated in vacuo to give Intermediate A2 (617 mg, 95%).

Intermediate connection A3.

(1 R)-2-(2-Bromo-5-ethylindolizine-7-carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline.

To a mixture of intermediate A2 (617 mg, 2.19 mmol) and (1R)-1-methyl-1,2,3,4tetrahydroisoquinoline [84010-66-2] (0.40 ml, 2.62 mmol) in 2 -methyltetrahydrofuran (20 ml) was added HATU (1.66 g, 4.37 mmol) and DIPEA (1.51 ml, 8.76 mmol). The reaction mixture was stirred at rt for 16 h. DCM (5 ml) was added and the reaction mixture was stirred at rt for another 2 h. The precipitate was filtered off and the filtrate was evaporated to dryness. The crude mixture was purified by prep LC (SiOH with regular grains, 30 µm, 40 g Interchim®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc 80:20 to 40:60) to give the intermediate A3 (700 mg, 81%).

Synthesis of intermediate compound I1.

Ethyl (1S,2S)-2-[3-fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropan-1-carboxylate.

Into a sealed tube with a solution of ethyl (1S,2S)-2-(4-bromo-3-fluorophenyl)cyclopropane-1carboxylate [2035422-08-1] (10.0 g, 34.8 mmol) in 1,4-dioxane (170 ml) under a nitrogen atmosphere were added bis(pinacolato)diborone (10.0 g, 39.4 mmol) and potassium acetate (6.80 g, 69.3 mmol). The mixture was purged with nitrogen and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with DCM (2.80 g, 3.42 mmol) was added. The reaction mixture was again purged with nitrogen and stirred at 100° C. for 18 hours. The reaction mixture was diluted with EtOAc. The organic phase was washed with H2O and brine (twice), dried over MgSO4, filtered and concentrated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, Merck 400 g, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc 100:0 to 0:25) to give the intermediate I1 (9.26 g, 80%) as a colorless oil.

- 10 041546

Synthesis of final compounds.

Intermediate connection A4.

Ethyl-(18.28)-2-(4-{5-ethyl-7-[(1H)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]indolizin-2yl}-3- fluorophenyl)cyclopropane-1-carboxylate.

To a degassed mixture of intermediate 3 (250 mg, 0.63 mmol), intermediate II (427 mg, 1.28 mmol) and tribasic potassium phosphate (401 mg, 1.89 mmol) in 1,4-dioxane (6, 3 ml) and H ₂ O (1.6 ml) was added [1,H-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (41.0 mg, 62.9 µmol). The reaction mixture was heated at 100° C. for 30 min using a single mode microwave reactor (Biotage® Initiator EXP 60) with power output from 0 to 400 W. The reaction mixture was diluted with H ₂ O and EtOAc. The layers were separated and the aqueous phase was extracted using EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and the solvent was evaporated in vacuo. The crude mixture was purified by preparative LC (SiOH with regular grains, 30 μm, 40 g Interchim®, liquid phase injection (DCM), mobile phase gradient: heptane/EIAc from 80:20 to 30:70) to give Intermediate A4 (216 mg, 65%).

Connection 1.

(18.28)-2-(4-{5-Ethyl-7-[(1C)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]indolizin-2-yl}-3fluorophenyl) cyclopropane-1-carboxylic acid.

A mixture of intermediate A4 (216 mg, 0.41 mmol) and lithium hydroxide monohydrate (51.7 mg, 1.23 mmol) in THF (5.8 ml) and H ₂ O (2.9 ml) was stirred at room temperature. so within 24 hours the Reaction mixture was diluted with 1 n. aqueous solution of HCl and H ₂ O. The precipitate was filtered off and dried to give compound 1 (124 mg, 61%).

Connection 2.

(1 S,2 8)-2-(4-{5-Ethyl-7-[( 1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7,8-dihydroindolizine2- yl} -3-fluorophenyl)cyclopropane-1-carboxamide.

Mixture of Intermediate 1 (112 mg, 0.23 mmol), HATU (111 mg, 0.29 mmol) and DIPEA

- 11 041546 (116 µl, 0.68 mmol) in DMF (1.3 ml) was stirred at RT for 1 h. Ammonia (28% in H2O, 152 µl, 2.26 mmol) was added and the reaction mixture stirred at RT for 1 h. The reaction mixture was diluted with H2O and EtOAc. The layers were separated and the aqueous phase was extracted using EtOAc. The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and the solvent was evaporated in vacuo. The residue was taken up in MeOH. The solid was filtered off (100 mg) and dissolved in DCM. The organic phase was washed with 1% aqueous NaHCO ₃ solution (twice), dried over MgSO ₄ , filtered and the solvent was evaporated under vacuum. The residue was taken up in MeOH. The solid was filtered off and dried in high vacuum at 60° C. for 5 hours to give compound 2 (34 mg, 30%).

Compound 3

Intermediate connection A5.

Methyl-(3S)-1 -(4-{5-ethyl-7-[(1R-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]indolizin-2yl}-3-fluorophenyl) pyrrolidine-3-carboxylate.

To a degassed mixture of intermediate A3 (170 mg, 0.43 mmol), methyl-(3S)-1-[3fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-3- carboxylate [2035422-46-7] (164 mg, 0.47 mmol) and tribasic potassium phosphate (272 mg, 1.28 mmol) in 1,4-dioxane (4 ml) and H ₂ O (1 ml) were added [ 1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (27.9 mg, 42.8 µmol). The reaction mixture was heated at 80° C. for 30 min using a single mode microwave reactor (Biotage® Initiator EXP 60) with power output from 0 to 400 watts. The reaction mixture was diluted with H ₂ O and EtOAc. The layers were separated and the aqueous phase was extracted using EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and the solvent was evaporated in vacuo. The crude mixture was purified by preparative LC (SiOH with regular grains, 30 μm, 40 g Interchim®, liquid phase injection (DCM), mobile phase gradient: heptan/EtOAc from 80:20 to 30:70) to give Intermediate A5 (100 mg, 43%).

Connection 3.

(3S)-1-(4-{5-Ethyl-7-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]indolizin-2-yl}-3fluorophenyl)pyrrolidine- 3-carboxylic acid.

A mixture of intermediate A5 (100 mg, 185 µmol) and lithium hydroxide monohydrate (23.3 mg, 0.55 mmol) in THF (2.6 ml) and H ₂ O (1.3 ml) was stirred at r.t. for 16 hours. The reaction mixture was diluted with 1N. aqueous solution of HCl and H2O. The mixture was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO4, filtered and the solvent was evaporated in vacuo. The residue was diluted with MeCN and EtOAc and evaporated to dryness to give compound 3 (100 mg, quant. yield) as an orange solid.

- 12 041546

Pyrazolo[1,5-a]pyridines.

Synthesis of intermediate compounds.

Synthesis of intermediate compound 13. o

Br [625446-22-2]

[553-90-2]

LiHMDS

Me-THF -78 to -10 °C, 4 4

MeO

Br nh ₂ nh ₂ h ₂ o AcOH

EUN °C, 7 4

Intermediate 12.

Methyl 4-(4-bromo-2-fluorophenyl)-2-hydroxy-4-oxobut-2-enoate.

Lithium bis(trimethylsilyl)amide (1.5 M in THF, 50 mL, 75.0 mmol) was added to a mixture of 4-bromo-2fluoroacetophenone [625446-22-2] (15.0 g, 69.1 mmol) in 2 -methyltetrahydrofuran (150 ml) at -78°C. The reaction mixture was stirred at this temperature for 15 min and a solution of dimethyl oxalate [553-90-2] (8.33 g, 70.6 mmol) in 2-methyltetrahydrofuran (100 ml) was added. The reaction mixture was stirred at -10°C for 4 h. aqueous HCl solution and the aqueous phase were extracted using EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and the solvent was evaporated in vacuo to give Intermediate 12 (21.9 g, quant. yield) as a yellow solid.

Intermediate 13.

Methyl 3-(4-bromo-2-fluorophenyl)-1H-pyrazole-5-carboxylate.

Mixture of intermediate I2 (21.9 g, 68.6 mmol), hydrazine monohydrate (80% in H ₂ O, 4.2 ml, 70.0 mmol) and acetic acid (0.9 ml, 15.6 mmol) in ethanol (200 ml) was stirred at 80°C for 7 hours the Reaction mixture was cooled, while a precipitate. The precipitate was filtered off, washed with EtOH and dried in vacuo at 50°C for 4 h to give Intermediate I3 (13.2 g, 64%) as a white solid.

Synthesis of intermediates I4 and I5.

14: Ethyl cis-2-(trifluoro-λ ⁴ -boranyl)cyclopropane-1-potassium carboxylate.

15: Ethyl trans-2-(trifluoro-λ ⁴ -boranyl)cyclopropane-1-potassium carboxylate.

Potassium vinyl trifluoroborate [13682-77-4] (2.00 g, 15.0 mmol) was dissolved in THF (20.5 ml). Palladium acetate (33.5 mg, 0.15 mmol) was added and the reaction mixture was stirred at 35°C. Ethyl diazoacetate (85 wt.% in DCM, 2.00 ml, 16.4 mmol) in THF (2 ml) was introduced using a syringe pump over 4 h and the reaction mixture was stirred at 35°C for 18 h. The reaction mixture was diluted heptane at rt and the mixture was stirred for 30 minutes. The suspension was filtered and crystallized from acetone (20 ml) at -18°C. The solid was filtered off to give Intermediate I4 (cis:trans 80:20, 520 mg, 16%) as a gray solid. The filtrate was treated with activated charcoal, filtered and concentrated to dryness. The residue was diluted with EtOH (20 ml) and heated at 50°C. Filtration of the resinous suspension gave intermediate I5 (cis:trans 14:86, 1.83 g, 56%) as a white solid.

- 13 041546

Synthesis of intermediate compound I7.

—+ >Τ°γ%Η --—► N

Ή D mtve / Vnh o >=/ \ K.T., 2 4 O*

[773-64-8] [36016-38-3]16 _rL-O0°C, 34 H ₂ N 8 \=/

Intermediate 16.

tert-Butyl-N-[(2,4,6-trimethylbenzenesulfonyl)oxy]carbamate.

-Vo ₀ -iQV

To a mixture of 2-mesitylenesulfonyl chloride [773-64-8] (5.47 g, 25.0 mmol) and tert-butyl Nhydroxycarbamate [36016-38-3] (3.67 g, 27.5 mmol) in MTBE ( 51 ml) at 0°C was added dropwise Et ₃ N (3.82 ml, 27.5 mmol). The reaction mixture was stirred at RT for 2 hours. The suspension was filtered and the solid was washed using MTBE. The filtrate was dried over MgSO ₄ , filtered and concentrated in vacuo to give Intermediate I6 (8.75 g, quant. yield, 90% purity) as a yellow oil.

Intermediate connection I7.

Amino-2,4,6-trimethylbenzene-1-sulfonate.

O\i nX 8

A solution of intermediate I6 (8.75 g, 25.0 mmol, 90% purity) in TFA (10 ml) was stirred at 0° C. for 3 hours. The reaction mixture was poured into ice water. The precipitate was filtered off, washed with H2O and dried in vacuo to give Intermediate I7 (1 g, 19%) as a white solid.

Synthesis of intermediate compound I8.

Ethyl-3-(4-bromo-3-fluorophenyl)prop-2-inoate.

1) LDA

^-78 C, 30 min

F 2) CICO ₂ EtF /=/ -78 'С to rt, 2 h—Z

In g—4 Λ — --------► In g—G /7 ~—CO ₂ Et

V_J7 THFV-U

[302912-33-0]I8 n-Butyl lithium (1.6 M in hexane, 1.5 ml, 2.40 mmol) was added to a solution of DIPA (0.4 ml, 2.85 mmol) in THF (15 ml) at -78°C. The reaction mixture was stirred for 30 min and a solution of 4-bromo2-fluoroacetylene [302912-33-0] (0.47 g, 2.35 mmol) in THF (5 mL) was added. The reaction mixture was stirred at -78°C for 30 min. Ethyl chloroformate (0.5 ml, 5.23 mmol) was added and the reaction mixture was stirred at -78° C. for 30 min and then at RT for 2 h. The reaction mixture was quenched with 10% aqueous NH ₄ Cl and diluted with EtOAc. The layers were separated and the aqueous phase was extracted using EtOAc. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 40 g GraceResolv™, liquid phase injection (DCM), mobile phase:heptane/EtOAc gradient 100:0 to 85:15) to give an intermediate compound I8 (505 g, 79%).

- 14 041546

Synthesis of pyrazolo[1,5-a]pyridine intermediates.

Synthesis of intermediate B3.

B1 B2

Intermediate I9.

[3-(4-Bromo-2-fluorophenyl)-1H-pyrazol-5-yl]methanol.

I9

Borane tetrahydrofuran complex (1.0 M in THF, 70 ml, 70.0 mmol) was added slowly to a solution of intermediate I3 (7.07 g, 23.6 mmol) in THF (200 ml). The reaction mixture was stirred at RT for 20 hours. The reaction mixture was quenched by carefully adding MeOH. The solution was diluted using EtOAc and brine. The layers were separated and the aqueous phase was extracted using EtOAc. The combined organic extracts were dried over MgSO ₄ , filtered and evaporated in vacuo. The residue was diluted using DCM. The precipitate was filtered off, washed with DCM and dried in vacuo to give Intermediate I9 (3.24 g, 50%) as a white solid.

Intermediate connection I10.

3-(4-Bromo-2-fluorophenyl)-1H-pyrazole-5-carbaldehyde.

110

A mixture of intermediate I9 (6.41 g, 23.6 mmol) and manganese dioxide (20.0 g, 230 mmol) in acetone (300 ml) was stirred at reflux for 2.5 hours. The reaction mixture was filtered through the Celite® layer and the filtrate were evaporated in vacuo to give Intermediate I10 (1.77 g, 28%) as a white solid.

Intermediate B1.

Methyl 2-(4-bromo-2-fluorophenyl)-7-ethylpyrazolo[1,5-a]pyridine-5-carboxylate.

IN 1

A mixture of intermediate I10 (1.77 g, 6.58 mmol), methyl 4-bromohex-2-enoate [119226-97-0] (1.60 g, 7.34 mmol) and potassium carbonate (1.90 g, 13.8 mmol) in DMF (50 mL) was stirred at rt for 18 h. The reaction mixture was diluted with EtOAc and H ₂ O. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried

- 15 041546 over MgSO ₄ , filtered and evaporated under vacuum. The residue was diluted with MeOH and triturated in MeOH. The solid was filtered off and washed with MeOH to give Intermediate B1 (1.4 g, 56%) as a white solid.

Intermediate B2.

Potassium 2-(4-bromo-2-fluorophenyl)-7-ethylpyrazolo[1,5-a]pyridine-5-carboxylate.

Potassium hydroxide (730 mg, 11.1 mmol, 85% purity) was added to a solution of intermediate B1 (1.40 g, 3.71 mmol) in EtOH (35 mL). The reaction mixture was stirred at 80° C. for 18 hours. The reaction mixture was cooled while a precipitate was observed. The precipitate was filtered off to give Intermediate B2 (975 mg, 65%) as a white solid.

Intermediate B3.

(1R)-2-[2-(4-Bromo-2-fluorophenyl)-7-ethylpyrazolo[1,5-a]pyridine-5-carbonyl]-1-methyl-1,2,3,4tetrahydroisoquinoline.

1.25 mmol), (1R)-1-methyl-1,2,3,4tetrahydroisoquinoline [84010-66-2] (220 mg, 1.5 mmol), HATU (640 mg 1.68 mmol) and DIPEA ( 640 μl, 3.71 mmol) in DMF (25 ml) was stirred at RT for 20 h. The reaction mixture was diluted with EtOAc and brine. The layers were separated and the aqueous phase was extracted using EtOAc. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 80 g Grace®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc 90:10 to 0:100) to give an intermediate compound B3 (622 mg, quant. yield) as a white foam.

Synthesis of intermediate B6.

A.. i-PrMgCI

[119226-97-0]

KzCOz

DMF

K.T., 18h

Br

[84010-66NATO, DIPEA

DMF

K.T., 20h

Intermediate connection I11.

3-(4-Bromo-2-fluorophenyl)-N-methoxy-N-methyl-1H-pyrazole-5-carboxamide.

- 16 041546

A mixture of intermediate I3 (500 mg, 1.67 mmol) and N,O-dimethylhydroxylamine hydrochloride (489 mg, 5.02 mmol) in THF (2 ml) was stirred at -30° C. under nitrogen. Isopropylmagnesium chloride (2.0 M in THF, 5.0 ml, 10.0 mmol) was added and the reaction mixture was stirred at -30° C. for 1 h. aqueous HCl solution and diluted with EtOAc. The layers were separated and the aqueous phase was extracted using EtOAc. The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and evaporated in vacuo to give Intermediate I11 (538 mg, 98%) as a white solid.

Intermediate connection I12.

1-[3-(4-Bromo-2-fluorophenyl)-1H-pyrazol-5-yl]ethan-1-one.

Under nitrogen atmosphere, to a solution of intermediate I11 (538 mg, 1.64 mmol) in THF (2 ml) at 0°C was added methylmagnesium bromide (3.0 M in Et ₂ O, 1.1 ml, 3.30 mmol). The reaction mixture was stirred at RT for 3 hours. The reaction was quenched with aqueous NH ₄ Cl and diluted using EtOAc. The layers were separated and the aqueous phase was extracted using EtOAc. The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and evaporated in vacuo to give Intermediate I12 (447 mg, 96%) as a white solid.

Intermediate B4.

Methyl 2-(4-bromo-2-fluorophenyl)-7-ethyl-4-methylpyrazolo[1,5-a]pyridine-5-carboxylate.

mg,

A mixture of intermediate I12 (380

1.34 mmol), methyl 4-bromohex-2-enoate

[119226-97-0] (365 mg, 1.50 mmol, 85% purity) and potassium carbonate (388 mg, 2.81 mmol) in DMF (10 mL) were stirred at rt for 18 h. the mixture was diluted using EtOAc and H ₂ O. The layers were separated and the aqueous phase was extracted using EtOAc. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 40 g Grace®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc 100:0 to 60:40) to give the intermediate compound B4 (182 mg, 35%) as a white solid.

Intermediate B5.

2-(4-bromo-2-fluorophenyl)-7-ethyl-4-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid.

Potassium hydroxide (100 mg, 1.52 mmol, 85% purity) was added to a solution of intermediate B4 (200 mg, 0.51 mmol) in EtOH (5 mL). The reaction mixture was stirred at 80° C. for 6 hours. The reaction mixture was diluted with EtOAc and 10% aqueous KHSO4 was added. The layers were separated and the aqueous phase was extracted using EtOAc. The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and evaporated in vacuo to give Intermediate B5 (180 mg, 93%).

Intermediate B6.

(1R)-2-[2-(4-Bromo-2-fluorophenyl)-7-ethyl-4-methylpyrazolo[1,5-a]pyridine-5-carbonyl]-1-methyl1,2,3,4- tetrahydroisoquinoline.

Mixture of Intermediate B5 (180 mg, 0.48 mmol), (1R)-1-methyl-1,2,3,4tetrahydroisoquinoline [84010-66-2] (83.4 mg, 0.57 mmol), HATU ( 246 mg 0.65 mmol) and DIPEA (246 μl, 1.43 mmol) in DMF (8 ml) were stirred at RT for 20 h. The reaction mixture was diluted with EtOAc and brine. The layers were separated and the aqueous phase was extracted using EtOAc.

- 17 041546

The combined organic extracts were dried over MgSO ₄ , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 40 g Grace®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc 90:10 to 0:100) to give an intermediate compound B6 (232 mg, 96%) as a white foam.

Synthesis of intermediate B10.

About °C TO K.T., 18 4

AT 9

Intermediate B7.

Methyl 2-(4-bromo-2-fluorophenyl)-7-ethyl-4-hydroxypyrazolo[1,5-a]pyridine-5-carboxylate.

AT 7

A mixture of intermediate I3 (5.78 g, 19.3 mmol), methyl 4-bromohex-2-enoate [119226-97-0] (11.0 g, 42.9 mmol) and potassium tert-butoxide (8 .00 g, 71.3 mmol) in DMF (120 ml) was stirred at 80°C for 18 hours. Additional intermediate I2 (1.60 g, 6.30 mmol) and potassium tert-butoxide (2, 00 g, 17.8 mmol) and the reaction mixture was stirred at 80°C for another 4 h. The reaction mixture was diluted using EtOAc and H ₂ O. The layers were separated and the aqueous phase was extracted using EtOAc. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 220 g Grace®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc 100:0 to 65:35) to give intermediate compound B7 (1.85 g, 24%) as a white solid.

Intermediate connection B8.

Methyl 2-(4-bromo-2-fluorophenyl)-7-ethyl-4-methoxypyrazolo[1,5-a]pyridine-5-carboxylate.

wa

A mixture of intermediate B7 (100 mg, 0.25 mmol), methyl iodide (19.0 μl, 305 μmol) and potassium carbonate (70.3 mg, 0.51 mmol) in DMF (2 ml) was stirred at rt. within 18 hours the Reaction mixture was diluted using EtOAc and H ₂ O. The layers were separated and the aqueous phase was extracted using EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 12 g Grace®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc 100:0 to 60:40) to give the intermediate compound B8 (85 mg, 82%) as a white solid.

- 18 041546

Intermediate B9.

2-(4-Bromo-2-fluorophenyl)-7-ethyl-4-methoxypyrazolo[1,5-a]pyridine-5-carboxylic acid.

V$

Potassium hydroxide (41.1 mg, 0.62 mmol, 85% purity) was added to a solution of intermediate B8 (85.0 mg, 0.21 mmol) in EtOH (2 ml). The reaction mixture was stirred at 80° C. for 18 hours. The mixture was diluted with EtOAc and 10% aqueous KHSO4 was added. The layers were separated and the aqueous phase was extracted using EtOAc. The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and evaporated in vacuo to give Intermediate B9 (80 mg, 97%) as a white solid.

Intermediate B10.

(1R)-2-[2-(4-Bromo-2-fluorophenyl)-7-ethyl-4-methoxypyrazolo[1,5-а]pyridine-5-carbonyl]-1-methyl1,2,3,4- tetrahydroisoquinoline.

Mixture of Intermediate B9 (80.0 mg, 0.20 mmol), (1R)-1-methyl-1,2,3,4tetrahydroisoquinoline [84010-66-2] (34.8 mg, 0.24 mmol) and DIPEA (174 μl, 1.01 mmol) in DCM (1 ml) was stirred at 0°C. PPAC (50 wt% in EtOAc, 0.30 ml, 0.51 mmol) was added slowly. The reaction mixture was stirred at 0° C. for 10 min and then at RT for 18 h. The reaction mixture was diluted with EtOAc and 10% aqueous KHSO ₄ was added. The layers were separated and the aqueous phase was extracted using EtOAc. The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and evaporated in vacuo to give Intermediate B10 (83 mg, 78%) as a white foam.

Synthesis of intermediate B13.

- 19 041546

Intermediate I13.

(1 R)-2-(2-Bromo-5-fluoropyridine-4-carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline.

2-Bromo-5-fluoroisonicotinic acid mixture [885588-12-5] (1.00 g, 4.55 mmol), (1R)-1-methyl1,2,3,4-tetrahydroisoquinoline [84010-66-2] (803 mg, 5.45 mmol), HATU (2.34 g 6.14 mmol) and DIPEA (2.34 ml, 13.5 mmol) in DMF (50 ml) were stirred at rt for 20 h The reaction mixture was diluted with EtOAc and brine. The layers were separated and the aqueous phase was extracted using EtOAc. The combined organic extracts were dried over MgSO ₄ , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 80 g Grace®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 90:10 to 0:100) to give intermediate I13 (1.62 g, quant. yield).

Intermediate connection I14.

(1 R)-2-(2-Cyclopropyl-5-fluoropyridine-4-carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline.

To a solution of intermediate I13 (1.50 g, 4.30 mmol) in toluene (30 mL) was added cyclopropylboronic acid [411235-57-9] (738 mg, 8.59 mmol), tribasic potassium phosphate (2.28 g , 10.7 mmol), tricyclohexylphosphine (361 mg, 1.29 mmol) and H ₂ O (4.5 ml). The mixture was purged with nitrogen (3 times) and palladium acetate (145 mg, 644 μmol) was added. The reaction mixture was stirred at 100° C. for 18 hours. The reaction mixture was diluted with EtOAc and H2O. The layers were separated and the aqueous phase was extracted using EtOAc. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 80 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient. teptane/EtOAc from 100:0 to 90:10 and from 50: 50 to 85:15) to give Intermediate I14 (1.15 g, 86%) as a colorless gum.

Intermediate connection I15.

1-Amino-2-cyclopropyl-5-fluoro-4-[(1C)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyridine1 -ia 2,4,6-trimethylbenzene-1 - sulfonate.

A mixture of intermediate I14 (1.24 g, 4.00 mmol) and intermediate I7 (1.00 g, 4.65 mmol) in DCM (10 ml) was stirred at rt for 18 h. The reaction mixture was evaporated under vacuum to give Intermediate I15 (1.88 g, 90%) as a white foam.

Intermediate B11.

Ethyl 2-(4-bromo-2-fluorophenyl)-7-cyclopropyl-4-fluoro-5-[(1C)-1-methyl-1,2,3,4-tetrahydroisoquinoline2-carbonyl]pyrazolo[1,5 -a]pyridine-3-carboxylate.

Mixture of Intermediate I15 (1.00 g, 1.90 mmol), Intermediate I8

- 20 041546 (550 µl, 2.03 mmol) and potassium carbonate (526 mg, 3.81 mmol) in DMF (15 ml) were stirred at rt for 18 h. The reaction mixture was diluted with EtOAc and H2O. The layers were separated and the aqueous phase was extracted using EtOAc. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 80 g Grace®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 100:0 to 50:50) to give intermediate B11 (515 mg, 45%) as a yellow foam.

Intermediate B12.

2-(4-Bromo-2-fluorophenyl)-7-cyclopropyl-4-fluoro-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrazolo[1,5-а ]pyridine-3-carboxylic acid.

To a solution of intermediate B11 (515 mg, 0.87 mmol) in THF (6 ml) and H ₂ O (4 ml) was added lithium hydroxide monohydrate (545 mg, 13.0 mmol). The reaction mixture was stirred at 60°C for 18 hours. Additional lithium hydroxide monohydrate (545 mg, 13.0 mmol) and MeOH (2 ml) were added and the reaction mixture was stirred at 60°C for 5 hours. KHSO4 solution until the pH reached 6 and the aqueous phase was extracted using EtOAc. The combined organic extracts were washed with H ₂ O, dried over MgSO ₄ , filtered and evaporated in vacuo to give Intermediate B12 (520 mg, quant. yield) as a light yellow gum.

Intermediate B13.

(1R)-2-[2-(4-Bromo-2-fluorophenyl)-7-cyclonpropyl-4-fluoropyrazolo[1,5-а]pyridine-5-carbonyl]-1methyl-1,2,3,4- tetrahydroisoquinoline.

A solution of intermediate B12 (520 mg, 0.87 mmol) in diphenyl ether (5 ml) was stirred at 200°C for 5 h. ®, liquid phase injection (DCM), mobile phase:heptane/EtOAc gradient 100:0 to 80:20) to give Intermediate B13 (129 mg, 28%) as an off-white foam.

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Synthesis of final compounds.

<^BF _3K

PdCI ₂ PPh ₃ Cs ₂ CO ₃

THF: _H2O

Et

Compound 4

Pd(OAc) ₂ Cui dce' °C, 18 4

LlOH.H ₂ O THF:H.0

Intermediate B14.

(1R)-2-[2-(4-Ethenyl-2-fluorophenyl)-7-ethylpyrazolo[1,5-a]pyridine-5-carbonyl]-1-methyl-1,2,3,4tetrahydroisoquinoline.

Palladium chloride (7.00 mg, 39.5 µmol) was added to a degassed mixture of intermediate B3 (400 mg, 0.81 mmol), potassium vinyltrifluoroborate [13682-77-4] (325 mg, 2.43 mmol), carbonate cesium (1.20 g, 3.68 mmol) and triphenylphosphine (30.0 mg, 114 μmol) in THF and H ₂ O (9:1, 15 ml). The reaction mixture was heated at 100° C. using a single mode microwave reactor (Biotage® Initiator EXP 60) with power output ranging from 0 to 400 W for 1.5 hours. The reaction mixture was diluted with EtOAc and H ₂ O. The layers were separated and the organic phase was washed with H ₂ O, dried over MgSO ₄ , filtered and concentrated in vacuo. The crude mixture was purified by preparative LC (SiOH with regular grains, 30 μm, 40 g Grace®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc from 100:0 to 60:40) to give Intermediate B14 (249 mg, 70%) as a white foam.

Intermediates B15 and B16.

B15: Ethyl-trans-2-(4-{7-ethyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl] pyrazolo[1,5a] pyridine-2 -yl}-3-fluorophenyl)cyclopropane-1-carboxylate.

B16: Ethyl-cis-2-(4-{7-ethyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-

a] pyridin-2-yl}-3-fluorophenyl)cyclopropane-1-carboxylate.

A mixture of intermediate B14 (249 mg, 567 µmol), copper iodide (43.2 mg, 227 µmol) and palladium acetate (25.4 mg, 113 µmol) in DCE (3 ml) was stirred at 80°C. Ethyl diazoacetate [623-73-4] (purity 85%, 0.42 ml, 3.40 mmol) was added with a syringe pump over 2 h and the reaction mixture was stirred at 80° C. for 18 h. Celite®.

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The filtrate was evaporated under vacuum. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 80 g GraceResolv™, liquid phase injection (DCM), mobile phase:heptane/EtOAc gradient 100:0 to 50:50) to give Intermediate B15 (33 mg, 11%) as a white foam and Intermediate B16 (30 mg, 10%) as a colorless gum.

Connection 4.

Trans-2-(4-{7-ethyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyridin-2-yl}- 3-fluorophenyl)cyclopropane-1-carboxylic acid.

To a solution of intermediate B15 (33.0 mg, 62.8 µmol) in THF (1.8 ml) and H ₂ O (0.75 ml) was added lithium hydroxide monohydrate (13.3 mg, 318 µmol). The reaction mixture was stirred at RT for 18 hours and then at 50° C. for another 18 hours. A 10% aqueous KHSO4 solution was added until pH 6 was reached and the aqueous phase was extracted using EtOAc. The combined organic extracts were washed with H ₂ O, dried over MgSO ₄ , filtered and evaporated in vacuo. The residue was diluted with H ₂ O and MeCN (1:1) and lyophilized to give Compound 4 (23 mg, 74%) as a white solid.

Compound 5

Intermediate B17.

Ethyl-trans-2-(4-{7-ethyl-4-methoxy-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrazolo[1,5-а]pyridine -2-yl}-3-fluorophenyl)cyclopropane-1-carboxylate.

To a mixture of intermediate B10 (68.0 mg, 0.13 mmol), intermediate I5 (cis:trans 14:86, 29.5 mg, 0.13 mmol) and cesium carbonate (118 mg, 0.36 mmol) cataCxium® A (10.8 mg, 30.2 µmol) and palladium acetate (4.92 mg, 2.19 µmol) were added in toluene (1.5 ml) and H ₂ O (0.15 ml). The reaction mixture was purged with nitrogen and stirred at 100° C. for 18 hours. The reaction mixture was diluted with H ₂ O and EtOAc. The layers were separated and the aqueous phase was extracted using EtOAc (twice). The combined organic extracts were dried over MgSO4, filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 40 g Grace®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc 100:0 to 60:40) to give the intermediate compound B17 (43 mg, 60%) as a white foam.

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Compound 5.

trans-2-(4-{7-Ethyl-4-methoxy-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrazolo[1,5-а]pyridine-2 -yl}-3-fluorophenyl)cyclopropane-1-carboxylic acid.

To a solution of intermediate B17 (43.0 mg, 77.4 µmol) in THF (2.4 ml) and H ₂ O (1 ml) was added lithium hydroxide monohydrate (17.9 mg, 0.43 mmol). The reaction mixture was stirred at rt for 24 h. A 10% aqueous solution of KHSO4 was added until pH 6 was reached and the aqueous phase was extracted using EtOAc. The combined organic extracts were washed with H ₂ O, dried over MgSO ₄ , filtered and evaporated in vacuo. The crude mixture was purified with reverse phase (C18 spherical, 25 μm, 40 g YMC-ODS-25, liquid phase injection (MeCN, 2-3 ml), mobile phase gradient: 0.2% aq. NH ₄ HCO ₃ / MeCM from 75:25 to 35:65). Fractions containing product were combined, concentrated and lyophilized to give Compound 5 (27 mg, 66%) as a white solid.

Compound 6

Intermediate I33.

Ethyl trans-2-(4-{7-cyclopropyl-4-fluoro-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrazolo[1,5-а]pyridine -2-yl}-3-fluorophenyl)cyclopropane-1-carboxylate.

To a mixture of intermediate B13 (50.0 mg, 95.7 µmol), intermediate I5 (cis:trans 14:86, 42.1 mg, 0.19 mmol) and cesium carbonate (93.6 mg, 0.29 mmol) in toluene (1 ml) and H ₂ O (0.1 ml) cataCxium® A (8.24 mg, 23.0 μmol) and palladium acetate (3.44 mg, 15.3 μmol) were added. The reaction mixture was purged with nitrogen and stirred at 100° C. for 18 hours. The reaction mixture was diluted with H2O and EtOAc. The layers were separated and the aqueous phase was extracted using EtOAc (twice). The combined organic extracts were dried over MgSO4, filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 40 g Grace®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc 100:0 to 60:40) to give the intermediate compound B18 (36 mg, 68%) as an off-white solid.

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Compound 6.

trans-2-(4-{7-Cyclopropyl-4-fluoro-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrazolo[1,5-а]pyridine-2 -yl}-3-fluorophenyl)cyclopropane-1-carboxylic acid.

To a solution of intermediate B18 (36.0 mg, 64.8 µmol) in THF (2 ml) and H ₂ O (0.9 ml) was added lithium hydroxide monohydrate (15.0 mg, 0.36 mmol). The reaction mixture was stirred at RT for 18 hours. A 10% aqueous solution of KHSO ₄ was added until pH 6 was reached and the aqueous phase was extracted using EtOAc. The combined organic extracts were washed with H ₂ O, dried over MgSO ₄ , filtered and evaporated in vacuo. The residue was dissolved in MeCN and H ₂ O (1:1) and lyophilized to give compound 6 (30 mg, 88%) as a white solid.

Compound 7

Intermediate I34.

Methyl-(3 S)-1 -(4-{7-cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrazolo[1,5-а]pyridine- 2-yl}-3-fluorophenyl)pyrrolidine-3-carboxylate.

Intermediate V3 (36.0 mg, 73.1 µmol), (S)-methylpyrrolidine-3-κcarboxylate hydrochloride [1099646-61-3] (15.0 mg, 90.6 µmol), cesium carbonate was loaded into a sealed tube (70.0 mg, 215 µmol) and XantPhos (5.00 mg, 8.64 µmol) and purged with nitrogen. Added 1,4-dioxane (1.5 ml) and the mixture was again purged with nitrogen. Palladium acetate (2.00 mg, 8.91 µmol) was added. The reaction mixture was purged with nitrogen and stirred at 100° C. for 18 hours. The reaction mixture was diluted with EtOAc and H ₂ O. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 24 g Grace®, liquid injection (DCM), mobile phase gradient: heptane/EtOAc 90:10 to 50:50) to give the intermediate B19 (36 mg, 91%) as a white solid.

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Connection 7.

(3S)-1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyridin-2-yl } -3-fluorophenyl)pyrrolidine-3-carboxylic acid.

To a solution of intermediate B19 (36.0 mg, 66.7 µmol) in THF (2 ml) and H ₂ O (1 ml) was added lithium hydroxide monohydrate (15.0 mg, 0.36 mmol). The reaction mixture was stirred at RT for 18 hours. A 10% aqueous solution of KHSO4 was added until pH 6 was reached and the aqueous phase was extracted using EtOAc. The combined organic extracts were washed with H ₂ O, dried over MgSO ₄ , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (C18 spherical beads, 25 μm, 40 g YMC-ODS-25, liquid phase injection (MeOH, H ₂ O), mobile phase gradient: 0.2% aq. NH4HCO ₃ /MeCN from 90:10 to 50:50). Fractions containing product were combined, concentrated and lyophilized to give Compound 7 (8 mg, 23%) as a pale pink solid.

Connection 8.

(3S)-1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl] pyrazolo[1,5a] pyridin-2-yl }-3-fluorophenyl)pyrrolidine-3-carboxamide.

A mixture of intermediate 7 (100 mg, 0.19 mmol), HATU (108 mg, 0.29 mmol) and DIPEA (98 μl, 0.57 mmol) in DMF (3 ml) was stirred at rt for 1 h.

Ammonia (28% in H ₂ O, 64 μl, 0.95 mmol) was added and the reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with H 2 O and EtOAc. The layers were separated. The organic phase was washed with 1% NaHCO ₃ aqueous solution, dried over MgSO ₄ , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (C18 spherical beads, 25 μm, 40 g YMC-ODS-25, solid phase loading (Celite®), mobile phase gradient: 0.2% aq. NH ₄ HCO ₃ /MeCN from 65:35 to 25:75). Fractions containing product were combined, evaporated in vacuo and lyophilized to give Compound 8 (50 mg, 50%) as a yellow solid.

Compound 9

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Intermediate I35.

Methyl-(3S)-1 -(4-{7-ethyl-4-methyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrazolo[1,5- a]pyridin-2-yl}-3-fluorophenyl)pyrrolidine-3-carboxylate.

A sealed tube was charged with Intermediate B6 (75.0 mg, 148 µmol), (S)-methylpyrrolidine-3-carboxylate hydrochloride [1099646-61-3] (30.4 mg, 183 µmol), cesium carbonate (142 mg, 435 µmol) and XantPhos (10.1 mg, 17.5 µmol) and purged with nitrogen. Added 1,4-dioxane (3 ml) and the mixture was again purged with nitrogen. Palladium acetate (4.05 mg, 18.0 µmol) was added. The reaction mixture was purged with nitrogen and stirred at 100° C. for 18 hours. The reaction mixture was diluted with EtOAc and H2O. The layers were separated and the aqueous phase was extracted using EtOAc (twice). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 50 g Merck, liquid phase injection (DCM), mobile phase gradient: heptαn/EtOAc 100:0 to 50:50) to give the intermediate B20 (59 mg, 72%) as a white solid.

Connection 9.

(3 S)-1 -(4-{7-Ethyl-4-methyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo [ 1.5а] pyridin-2-yl}-3-fluorophenyl)pyrrolidine-3-carboxylic acid.

To a solution of intermediate B20 (59.0 mg, 106 μmol) in THF (3.3 ml) and H ₂ O (1.4 ml) was added lithium hydroxide monohydrate (24.6 mg, 0.59 mmol). The reaction mixture was stirred at RT for 18 hours. A 10% aqueous solution of KHSO4 was added until pH 6 was reached and the aqueous phase was extracted using EtOAc. The combined organic extracts were washed with H ₂ O, dried over MgSO ₄ , filtered and evaporated in vacuo. The crude mixture was purified with reverse phase (C18 spherical, 25 μm, 40 g YMC-ODS-25, liquid phase injection (MeCN, MeOH, H ₂ O), mobile phase gradient: 0.2% aq. NH4HCO ₃ /MeCN from 75:25 to 35:65). Fractions containing product were combined, concentrated in vacuo and lyophilized to give Compound 9 (46 mg, 80%) as a white solid.

Me

LlOH.H ₂ O

PPACA, DIPEA

Compound 10 n _g

THF:H ₂ O KT, 20 4 n •H(

[1099646-61-3]

Pd(OAc) ₂ , XantPhos С S ₂ C ο, dioxane

100°C, 18 4

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Intermediate B21.

Methyl-(3S)-1 -(4-{7-cyclopropyl-4-fluoro-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl] pyrazolo [1,5- a] pyridin-2-yl }-3-fluorophenyl)pyrrolidine-3-carboxylate.

Mixture of intermediate B13 (74.0 mg, 142 µmol), (S)-methylpyrrolidine-3-carboxylate hydrochloride [1099646-61-3] (28.3 mg, 171 µmol) and cesium carbonate (142 mg, 435 µmol) in 1 ,4-dioxane (2.1 ml) was purged with nitrogen. Palladium acetate (3.54 mg, 15.8 µmol) and XantPhos (8.50 mg, 14.7 µmol) were added and the mixture was again purged with nitrogen. The reaction mixture was stirred at 100° C. for 18 hours. The reaction mixture was diluted with EtOAc and H ₂ O. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 20 g Grace®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc 90:10 to 40:60) to give the intermediate compound B21 (47 mg, 58%) as an off-white solid.

Intermediate B22.

(3 S)-1 -(4-{7-Cyclopropyl-4-fluoro-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrazolo [1,5-a] pyridin-2-yl }-3-fluorophenyl)pyrrolidine-3-carboxylic acid.

To a solution of intermediate B21 (45.0 mg, 78.9 µmol) in THF (0.6 ml) and H ₂ O (0.2 ml) was added lithium hydroxide monohydrate (18.3 mg, 437 µmol). The reaction mixture was stirred at RT for 20 h. A 10% aqueous solution of KHSO4 was added until pH 6 was reached and the aqueous phase was extracted using EtOAc. The combined organic extracts were washed with H2O, dried over MgSO ₄ , filtered and evaporated in vacuo to give Intermediate B22 (43 mg, 98%) as a white solid.

Compound 10.

(3 S)-1 -(4-{7-Cyclopropyl-4-fluoro-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl] pyrazolo [1,5-а] pyridin-2-yl }-3-fluorophenyl)pyrrolidine-3-carboxamide.

A mixture of intermediate B22 (43.0 mg, 77.3 µmol) and DIPEA (70 µl, 406 µmol) in DCM (1 ml) was stirred at 0°C. PPAC (50 wt% in EtOAc, 0.12 ml, 202 µmol) was added slowly at 0°C. The reaction mixture was stirred at room temperature for 30 min. Ammonia (28% in H ₂ O, 25 μl, 371 μmol) was added and the mixture was stirred at rt for 3 h. The reaction mixture was diluted with H 2 O and EtOAc. The layers were separated and the aqueous phase was extracted using EtOAc. The combined organic extracts were washed with 10% aqueous KHSO4 and brine, dried over MgSO ₄ , filtered and evaporated in vacuo. The crude mixture was purified with reversed phase (C18 spherical, 25 μm, 40 g YMC-ODS-25, liquid phase injection (MeCN, MeOH, H ₂ O), mobile phase gradient: 0.2% aq. NH ₄ HCO ₃ /MeCN 90:10 to 25:75). Product containing fractions were pooled and diluted with EtOAc. A 10% aqueous solution of KHSO ₄ was added. The layers were separated and the aqueous phase was extracted using EtOAc. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and evaporated in vacuo. The residue was diluted with MeCN and H ₂ O (1:1) and lyophilized to give compound 10 (17 mg, 40%) as a white solid.

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Triazolopyridines.

Synthesis of triazolopyridine intermediates. n

o °C to rt, during the night [| J

Intermediate connection I17.

(1R)-2-(2-Cyclopropylpyridine-4-carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline.

2-cyclopropylpyridine-4-carboxylic acid mixture [1216171-07-1] (730 mg, 4.47 mmol), (1R)-1methyl-1,2,3,4-tetrahydroisoquinoline [84010-66-2] (790 mg, 5.37 mmol), HATU (2.21 g, 5.82 mmol) and DIPEA (2.3 ml, 13.4 mmol) in DMF (26 ml) were stirred at rt for 20 h. the mixture was diluted with H ₂ O and EtOAc. The layers were separated and the aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 40 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 70:30 to 20:80) to give intermediate I17 (1.25 g, 96%) as a colorless oil.

Intermediate connection I18.

-Amino-2-cyclopropyl-4-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyridine-1-ium 2,4,6-trimethylbenzene-1-sulfonate.

A solution of the intermediate compound I17 (1.80 g, 6.16 mmol) in DCM (3.6 ml). The reaction mixture was stirred at RT for 18 hours. The reaction mixture was diluted with Et ₂ O until precipitation was observed. The precipitate was filtered off and washed with Et ₂ O, obtaining the first portion of intermediate compound I18 (2.5 g, 80%). The filtrate was concentrated in vacuo to give a second crop of Intermediate I18 (600 mg, 20%).

Intermediate connection D1.

(1R)-2-[2-(4-Bromo-2-fluorophenyl)-5-cyclopropyl-[1,2,4]triazolo[1,5-а]pyridine-7-carbonyl]-1methyl-1,2 ,3,4-tetrahydroisoquinoline.

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A mixture of intermediate I18 (500 mg, 985 µmol) and 4-bromo-2-fluorobenzonitrile [105942-08-3] (217 mg, 1.08 mmol) in EtOH (10 ml) was cooled to 0°C. Potassium hydroxide (2.0 M in H ₂ O, 542 μl, 1.08 mmol) was added dropwise and the reaction mixture was stirred at RT overnight. The solvent was evaporated under vacuum. The residue was diluted with H ₂ O and DCM. The layers were separated and the aqueous phase was extracted using DCM (3 times). The combined organic extracts were dried over MgSO ₄ , filtered and concentrated in vacuo. The crude mixture was purified by preparative LC (SiOH with regular grains, 30 μm, 40 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc 80:20 to 50:50) to give Intermediate D1 (87 mg, 17%) as a white foam.

Synthesis of final compounds.

Compounds 16 and 17

Intermediate D2.

(1R)-2-[5-Cyclonronyl-2-(4-ethenyl-2-fluorophenyl)-[1,2,4]triazolo[1,5-а]pyridine-7-carbonyl]-1methyl-1,2 ,3,4-tetrahydroisoquinoline.

Palladium chloride (1.82 mg, 10.3 µmol) was added to a degassed mixture of intermediate D1 (116 mg, 0.23 mmol), potassium vinyltrifluoroborate [13682-77-4] (92.2 mg, 0.69 mmol) , cesium carbonate (325 mg, 1.00 mmol) and triphenylphosphine (8.05 mg, 30.7 µmol) in THF and H ₂ O (9:1, 3.5 ml). The reaction mixture was heated at 100° C. using a single mode microwave reactor (Biotage® Initiator EXP 60) with power output ranging from 0 to 400 W for 1.5 hours. The reaction mixture was diluted with EtOAc and H2O. The layers were separated and the organic phase was washed with H2O, dried over MgSO ₄ , filtered and concentrated in vacuo. The crude mixture was purified by preparative LC (SiOH with regular grains, 30 μm, 12 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 90:10 to 40:60) to give the intermediate D2 (83 mg, 80%) as a yellow solid.

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Intermediates D3 and D4.

D3: Ethyl-trans-2-(4-{5-cyclopropyl-7-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl][1,2,4]triazolo[ 1,5-a]pyridin-2-yl}-3-fluorophenyl)cyclopropane-1-carboxylate.

D4: Ethyl-cis-2-(4-{5-cyclopropyl-7-[( 1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl][1,2,4]triazolo[ 1,5-a]pyridin-2-yl}-3-fluorophenyl)cyclopropane-1-carboxylate.

A mixture of intermediate D2 (225 mg, 497 µmol), medif iodide (9.47 mg, 49.7 µmol), palladium acetate (11.2 mg, 49.7 µmol) in DCE (4.0 mL) was stirred at 80 °C and ethyl diazoacetate (0.37 ml, 2.98 mmol, 85% purity) in DCE (1.6 ml) were added with a syringe pump over 4 hours. The reaction mixture was stirred at 80°C for 18 hours. the mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo. The crude mixture (140 mg) was combined with another fraction (81 mg) and purified by preparative LC (irregular SiOH, 15-40 µm, 220 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc from 70:30 to 40:60) to give Intermediate D3 (65 mg, 18%) and Intermediate D4 (45 mg, 12%) as colorless oils.

Compound 16.

trans-2-(4-{5-Cyclopronyl-7-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-

[ 1,2,4]triazolo[1,5-a]pyridin-2-yl}-3-fluorophenyl)cyclopropane-1-carboxylic acid.

To a solution of intermediate D3 (65.0 mg, 0.12 mmol) in THF (1.1 ml) and H ₂ O (0.3 ml) was added lithium hydroxide monohydrate (15.2 mg, 0.36 mmol). The reaction mixture was stirred at rt for 16 h. A 10% aqueous KHSO4 solution was added until pH 6 was reached and the aqueous phase was extracted using EtOAc. The combined organic extracts were washed with H ₂ O, dried over MgSO ₄ , filtered and concentrated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 12 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc/AcOH from 80:19.5:0.5 to 40:58.5:1.5) to give compound 16 (42 mg, 68%).

Compound 17.

cis-2-(4-{5-Cyclopropyl-7-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl] [1,2,4]triazolo[1,5- a] pyridin-2-yl }-3-fluorophenyl)cyclopropane-1-carboxylic acid.

To a solution of intermediate D4 (45.0 mg, 83.5 µmol) in THF (1 ml) and H ₂ O (0.3 ml) was added lithium hydroxide monohydrate (11.0 mg, 0.25 mmol). The reaction mixture was stirred at RT for 16 h. Additional lithium hydroxide monohydrate (11.0 mg, 0.25 mmol) was added and the reaction mixture was stirred at 50°C for 72 h. A 10% aqueous solution was added KHSO ₄ until the pH reached 6 and the aqueous phase was extracted using EtOAc. The combined organic extracts were washed with H2O, dried over MgSO4, filtered and concentrated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 12 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc/AcOH from 80:19.5:0.5 to 40:58.5:1.5) to give compound 17 (33 mg, 77%).

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Compound 18.

trans-2-(4-{5-Cyclonpropyl-7-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl][1,2,4]triazolo[1,5- a]pyridin-2-yl}-3-fluorophenyl)cyclopropan-1-carboxamide.

A mixture of intermediate 16 (18.0 mg, 35.3 µmol), HATU (20.1 mg, 52.9 µmol) and DIPEA (18 µl, 106 µmol) in DMF (1 ml) was stirred at r.t. for 1 h. Ammonia (28% in H ₂ O, 12 μl, 176 μmol) was added and the reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with H ₂ O and EtOAc. The layers were separated and the organic phase was washed with 1% NaHCO ₃ aqueous solution (twice), dried over MgSO ₄ , filtered and evaporated under vacuum. The crude mixture was purified by preparative LC (SiOH with regular grains, 30 μm, 12 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/i-PrOH, 100:0 to 80:20). The residue was lyophilized (MeCN/H ₂ O) to give compound 18 (11 mg, 61%) as a white solid.

Compound 19

Intermediate D5.

Methyl-(3S)-1 -(4-{5-cyclopropyl-7-[( 1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl] [1,2,4]triazolo [1,5-a]pyridin-2-yl}-3-fluorophenyl)pyrrolidine-3-carboxylate.

Intermediate D1 (85 mg, 168 µmol), (S)-methylpyrrolidine-3-carboxylate hydrochloride [1099646-61-3] (33.4 mg, 0.20 mmol), cesium carbonate (164 mg, 505 µmol) and XantPhos (9.73 mg, 16.8 µmol) and purged with nitrogen. Added 1,4-dioxane (2.5 ml) and the mixture was again purged with nitrogen. Palladium acetate (3.78 mg, 16.8 µmol) was added and the mixture was purged with nitrogen. The reaction mixture was stirred at 100° C. for 17 hours. The reaction mixture was diluted with EtOAc and H ₂ O. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and the solvent was evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 12 g Grace®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 90:10 to 20:80) to give intermediate D5 (82 mg, 88%) as a yellow oil.

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Compound 19.

(3 S)-1-(4-{5-Cyclopropyl-7-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl][1,2,4]triazolo[1 ,5-a]pyridin-2-yl}-3-fluorophenyl)pyrrolidin-3-carboxylic acid.

Lithium hydroxide monohydrate (18.6 mg, 0.44 mmol) was added to a solution of intermediate D5 (82.0 mg, 14.8 µmol) in THF (1.86 ml) and H ₂ O (580 µl). The reaction mixture was stirred at rt for 16 h. A 10% aqueous solution of KHSO4 was added until pH 6 was reached and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H ₂ O, dried over MgSO ₄ , filtered and concentrated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 12 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc 80:20:0.5 to 0:97 .5:2.5). The residue was co-evaporated with MeCN and dried under vacuum at 50° C. for 16 h to give an oil (60 mg, 96%). The second purification was performed by preparative LC (C18 spherical beads, 25 μm, 40 g YMC-ODS-25, dry loaded (Celite®), mobile phase gradient: 0.2% aq. NH ₄ HCO ₃ /MeCN from 90 :10 to 50:50). The product was dissolved in MeCN to give compound 19 (48 mg, 60%) as a white solid.

Compound 20.

(3 S)-1-(4-{5-Cyclopropyl-7-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl][1,2,4]triazolo[1 ,5-a]pyridin-2-yl}-3-fluorophenyl)pyrrolidine-3-carboxamide.

A mixture of intermediate 19 (180 mg, 334 µmol), HATU (190 mg, 500 µmol) and DIPEA (107 µl, 1.00 mmol) in DMF (9.2 ml) was stirred at rt for 1 h. Ammonia (28% in H ₂ O, 113 μl, 1.67 mmol) was added and the reaction mixture was stirred at RT for 18 hours. The reaction mixture was diluted with H 2 O and EtOAc. The layers were separated and the organic phase was washed with 1% NaHCO ₃ aqueous solution (twice), dried over MgSO ₄ , filtered and evaporated under vacuum. The crude mixture was purified by preparative LC (irregular SiOH, 30 μm, 12 g GraceResolv™ , liquid phase injection (DCM), mobile phase gradient: DCM/i-PrOH, 100:0 to 80:20). The residue was dissolved in EtOH and dried in vacuo at 50° C. for 16 h to give compound 20 (70 mg, 39%) as a white solid.

Pyrazolo[1,5-c]pyrimidines.

Synthesis of the pyrazolo[1,5-c]pyrimidine core.

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Intermediate I19.

Methyl 2-cyclopropyl-6-methylpyrimidine-4-carboxylate.

In an autoclave, a mixture of 4-chloro-2-cyclopropyl-6-methylpyrimidine [7043-11-0] (1.00 g, 5.93 mmol) and Et ₃ N (1.6 ml, 11.8 mmol) in methanol ( 20 ml) was purged with nitrogen (3 times). [1,G-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (217 mg, 297 μmol) was added. The mixture was purged with CO (3 times). The autoclave was pressurized with CO equal to 8 bar and the reaction mixture was stirred at 70° C. for 24 hours. The reaction mixture was concentrated to dryness. The residue was diluted using DCM and H2O. The layers were separated and the aqueous phase was extracted using DCM (twice). The combined organic extracts were dried over MgSO ₄ , filtered and concentrated to dryness. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 µm, 40 g GraceResolv™, dry-load (SiOH), mobile phase:heptane/EtOAc gradient 90:10 to 40:60) to give intermediate compound I19 (1.07 g, 94%) as a colorless oil.

Intermediate connection I20.

2-Cyclopropyl-6-methylpyrimidine-4-carboxylic acid.

To a solution of intermediate 119 (1.07 g, 5.57 mmol) in THF (36 ml) and H ₂ O (18 ml) was added lithium hydroxide (266 mg, 11.1 mmol). The reaction mixture was stirred at rt for 16 h. A 10% aqueous solution of KHSO4 was added until pH 3 was reached and the mixture was diluted with EtOAc. The layers were separated and the organic phase was washed with brine and H ₂ O (twice), dried over MgSO ₄ , filtered and concentrated to dryness to give Intermediate I20 (678 mg, 68%) as a white solid.

Intermediate I21.

(1R)-2-(2-Cyclopropyl-6-methylpyrimidine-4-carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline.

PPACA [68957-94-8] (50 wt% in DMF, 4.8 ml, 8.11 mmol) was added dropwise to a mixture of intermediate I20 (578 mg, 3.24 mmol) and (1R)-1- methyl-1,2,3,4-tetrahydroisoquinoline [84010-66-2] (554 mg, 3.76 mmol) at 0°C. A solution of DIPEA (2.8 ml, 16.2 mmol) in DCM (16 ml) was added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was combined with another fraction (50 mg, 281 µmol) and diluted, using EtOAc. The layers were separated and the organic phase was washed with 1 M aqueous NaOH solution (twice) and brine (3 times), dried over MgSO ₄ , filtered and concentrated to dryness. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 40 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 80:20 to 30:70) to give intermediate I21 (1.1 g) as a colorless oil.

Intermediate I22.

-(4-Bromo-2-fluorophenyl)-2-{2-cyclopropyl-6-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrimidin-4-yl}ethan-1 -He.

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Lithium bis(trimethylsilyl)amide (1.0 M in THF, 6.1 mL, 6.10 mmol) was added dropwise to a mixture of intermediate I21 (895 mg, 2.91 mmol) and methyl-4-bromo-2- fluorobenzoate [179232-29-2] (714 mg, 3.06 mmol) in 2-methyltetrahydrofuran (7.4 ml) at 0°C. The reaction mixture was allowed to warm to RT and stirred at this temperature for 1.5 hours. The reaction mixture was quenched by adding H ₂ O at 0°C. The layers were separated and the aqueous phase was extracted using EtOAc (twice). The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and concentrated to dryness. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 µm, 40 g GraceResolv™, dry-load (SiOH), mobile phase:heptane/EtOAc gradient 90:10 to 30:70) to give intermediate compound I22 (1.38 g, 93%) as a yellow solid.

Intermediate I23.

N-[1 -(4-Bromo-2-fluorophenyl)-2-{2-cyclopropyl-6-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrimidin-4-yl } ethylidene] hydroxylamine.

Hydroxylamine hydrochloride (957 mg, 13.8 mmol) and sodium acetic acid (1.13 g, 13.8 mmol) were added to a suspension of intermediate I22 (1.40 g, 2.75 mmol) in MeCN (13 ml) and THF (13 ml). The reaction mixture was stirred at RT for 20 hours. The reaction mixture was diluted with H ₂ O and EtOAc. The layers were separated and the organic phase was washed with brine (twice), dried over MgSO ₄ , filtered and concentrated to dryness. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 µm, 40 g GraceResolv™, dry-load (SiOH), mobile phase gradient: heptane/EtOAc, 90:10 to 20:80) to give intermediate I23 (920 mg, 64%) as a yellow solid.

Intermediate connection E1.

(1R)-2-[2-(4-Bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-c]pyrimidine-5-carbonyl]-1-methyl1,2,3,4-tetrahydroisoquinoline.

Trifluoroacetic anhydride (244 μl, 1.76 mmol) was added dropwise to a solution of intermediate I23 (920 mg, 1.76 mmol) in DME (3.8 ml) at 0°C. The reaction mixture was heated to rt and stirred for 20 minutes. The mixture was cooled to 0° C. and Et ₃ N (489 μl, 3.52 mmol) was added dropwise. The reaction mixture was heated to rt and stirred for 30 minutes. The mixture was again cooled to 0° C. and iron(II) chloride (223 mg, 1.76 mmol) was added. The reaction mixture was stirred at 80° C. for 1 h. The reaction was quenched by adding saturated aqueous NaHCO ₃ and diluted using EtOAc. The suspension was filtered through a layer of Celite®. The filtrate was decanted and the organic phase was washed with brine, dried over MgSO ₄ , filtered and concentrated to dryness. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 µm, 40 g GraceResolv™, liquid phase injection (DCM), gradient mobile phase: heptane/EtOAc, 90:10 to 60:40) with obtaining intermediate compound E1 (659 mg, 74%) as a yellow solid.

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Synthesis of final compounds.

Compound 21

Intermediate E2.

Methyl-(3S)-1 -(4-{7-cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrazolo[1,5-c]pyrimidine- 2-yl}-3-fluorophenyl)pyrrolidine-3-carboxylate.

Mixture of Intermediate E1 (659 mg, 1.30 mmol), (S)-methylpyrrolidine-3-carboxylate hydrochloride [1099646-61-3] (316 mg, 1.56 mmol) and cesium carbonate (1.27 g, 3 .91 mmol) in 1,4-dioxane (13.5 ml) in a screw cap vial was purged with nitrogen. XantPhos (75 mg, 130 µmol) and palladium acetate (29.3 mg, 130 µmol) were added and the reaction mixture was again purged with nitrogen. The reaction mixture was stirred at 100° C. for 18 hours. The reaction mixture was filtered through a pad of Celite® and washed using EtOAc and H ₂ O. The filtrate was decanted and the organic phase was washed using H ₂ O (twice), dried over MgSO ₄ , filtered and concentrated to dryness. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 µm, 25 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 90:10 to 60:40) with obtaining intermediate compound E2 (622 mg, 86%) as a yellow solid.

Compound 21.

(3 S)-1 -(4- {7-Cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidine-2- yl}-3-fluorophenyl)pyrrolidine-3-carboxylic acid.

To a solution of intermediate E2 (72.0 mg, 0.13 mmol) in THF (1 ml) and H ₂ O (0.5 ml) was added lithium hydroxide monohydrate (10.9 mg, 0.26 mmol). The reaction mixture was stirred at rt for 16 h. A 10% aqueous KHSO4 solution was added until pH 6 was reached and the aqueous phase was extracted using EtOAc. The combined organic extracts were washed with H ₂ O, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was dried under high vacuum at 60° C. for 2 h to give compound 20 (53 mg, 76%) as a beige solid.

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Compound 22.

(3S)-1-(4-{7-cyclonpropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5c]pyrimidin-2-yl }-3-fluorophenyl)pyrrolidine-3-carboxamide.

To a mixture of compound 21 (150 mg, 256 µmol, 92% purity) and DIPEA (132 µl, 767 µmol) in DMF (1.4 ml) was added HATU (146 mg, 384 µmol). The mixture was stirred at rt for 10 min and ammonia (0.5 M in 1,4-dioxane, 7.6 ml, 3.84 mmol) was added. The reaction mixture was stirred at rt for 16 h. Additional ammonia (0.5 M in 1,4-dioxane, 2.6 ml, 1.28 mmol) was added and the reaction mixture was stirred at rt for 5 h. The reaction mixture was diluted with H ₂ O, brine and EtOAc. The layers were separated and the organic phase was washed with 1 M aqueous NaOH solution (twice) and brine (3 times), dried over MgSO ₄ , filtered and concentrated under vacuum. The residue was diluted with a solution of DCM and MeOH (8:2) and the solid was filtered off, obtaining the first fraction (16 mg). The filtrate was concentrated in vacuo and purified by flash chromatography (irregular SiOH, 15-40 µm, 12 g GraceResolv™, dry-load (SiOH), mobile phase gradient: DCM/MeOH 98:2 to 80:20) to give the second fraction (20 mg). The aqueous layer was acidified with 3M aqueous HCl to pH 1 and then extracted using DCM (twice), dried over MgSO ₄ , filtered and concentrated in vacuo to give a third fraction (40 mg). Fractions were pooled and purified by flash chromatography (irregular SiOH, 15-40 µm, 12 g GraceResolv™, dry-load (SiOH), mobile phase gradient: DCM/MeOH 98:2 to 80:20). The residue (34 mg) was dried under high vacuum at 60° C. for 16 h to give compound 22 (30 mg, 22%) as a beige solid.

Compound 23.

(3S)-1-(4-{7-cyclonpropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5c]pyrimidin-2-yl }-3-fluorophenyl)-N-methylpyrrolidine-3-carboxamide.

To a mixture of compound 21 (150 mg, 256 µmol, 92% purity) and DIPEA (154 µl, 895 µmol) in DMF (1.4 ml) was added HATU (146 mg, 384 µmol). The reaction mixture was stirred at rt for 10 min and methylamine (2.0 M in THF, 448 µl, 895 µmol) was added. The reaction mixture was stirred at rt for 16 h. Additional methylamine (2.0 M in THF, 448 µl, 895 µmol) was added and the reaction mixture was stirred at rt for another 5 h. The reaction mixture was diluted with H2O , brine and EtOAc. The layers were separated and the organic phase was washed with brine (3 times), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 µm, 12 g GraceResolv™, dry-load (SiOH), mobile phase gradient: henthane/EtOAc 70:30 to 0:100). The residue was co-evaporated with MeCN followed by EtOAc and dried under high vacuum at 60° C. for 16 h to give compound 23 (72 mg, 51%) as a yellow solid.

Imidazo[1,2-a]pyrimidines. Synthesis of intermediate compounds. Synthesis of intermediate compound I2. o jCA''ST - [869569-77-7] [109-12-6] NH ₂ NH ₂ .H ₂ O ^F \ _____HN-^y /=\ ------------- ---// ^Br EtOH: dioxane _H y 90 °C, 72 h ² F2 F -----------\ * ^HBr EtOH Δ, 16 4 F1

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Intermediate connection F1.

2-(4-Bromo-2-fluorophenyl)imidazo[1,2-a]pyrimidine hydrobromide.

A mixture of 1-(4-bromo-2-fluorophenyl)-2-bromo-1-ethanone

[869569-77-7] (5.00 g, 16.9 mmol) and

2-aminopyridine [109-12-6] (1.61 g, 16.9 mmol) in EtOH (300 mL) was stirred at reflux for 16 h. The reaction mixture was cooled to rt and the resulting precipitate was filtered off , yielding the first crop of Intermediate F1 (1.2 g, 19%). The filtrate was partially evaporated in vacuo and the precipitate was filtered off to give a second crop of Intermediate F1 (1.4 g, 22%).

Intermediate connection F2.

4-(4-Bromo-2-fluorophenyl)-1 H-imidazole-2-amine.

Mixture of intermediate F1 (2.25 g, 6.03 mmol), Et ₃ N (1.26 ml, 9.05 mmol) and hydrazine monohydrate (2.34 ml, 48.3 mmol) in EtOH (70 ml) and 1,4-dioxane (45 ml) was stirred at 90° C. for 72 hours. The reaction mixture was concentrated to dryness. The residue was diluted with H ₂ O and EtOAc. The layers were separated and the aqueous phase was extracted using EtOAc (once). The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and the solvent was evaporated in vacuo. The residue (1.54 g) was dissolved in DCM. The precipitate was filtered off and dried to give Intermediate F2 (1.01 g, 65%).

Synthesis of intermediate compound I24.

Methyl 4-cyclopropyl-2-hydroxy-4-oxobut-2-enoate.

[765-43-5] [553-90-2] then 0 °C TO RT, AF 124

To a mixture of lithium bis(trimethylsilyl)amide (500 g, 2.99 mol) in 2-methyltetrahydrofuran (3.5 L) in a 6 L mechanically agitated jacketed reactor under nitrogen at -78°C for 30 min. cyclopropyl methyl ketone [765-43-5] (255 ml, 2.73 mol) was added. [During this operation, the temperature was kept below -65°C.] The reaction mixture was stirred at -70°C for 30 min, and then added to the dimethyl oxalate solution over 10 min at 0°C under nitrogen [553-90-2] (321 g, 2.72 mol) in 2-methyltetrahydrofuran (2.5 L) in a 10 L unjacketed reactor equipped with a mechanical stirrer. The resulting reaction mixture was stirred for 3 h and slowly heated to rt. aqueous solution of HCl (2 l). The layers were separated and the aqueous phase was extracted using EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and the solvent was evaporated in vacuo. The crude mixture (620 g) was purified by preparative LC (irregular SiOH, 15-40 µm, 750 g Grace®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 90:10 to 70: 30) to give Intermediate I24 (468 g, 96%) as a colorless oil. The product crystallized upon standing.

Synthesis of intermediate compound F3.

Methyl 2-(4-bromo-2-fluorophenyl)-5-cyclopropylimidazo[1,2-a]pyrimidine-7-carboxylate.

A mixture of intermediate F2 (653 mg, 2.55 mmol) and intermediate I24 (639 mg, 3.57 mmol) in toluene (29 ml) was stirred at 110° C. for 16 hours. The solvent was evaporated to dryness. The residue was triturated in MeOH and the solid was filtered off to give Intermediate F3 (578 mg, 58%).

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Synthesis of intermediate compound F5.

Meo

[84010-66

HATU, D1PEA DMF

K.T, 18 4

Intermediate connection F4.

Potassium 2-(4-bromo-2-fluorophenyl)-5-cyclopropylimidazo[1,2-a]pyrimidine-7-carboxylate.

A mixture of intermediate F3 (528 mg, 1.35 mmol) and potassium hydroxide (152 mg, 2.71 mmol) in EtOH (20 mL) was stirred at rt for 2 h. The reaction mixture was combined with another fraction (50 mg, 128 µmol). The suspension was filtered. The solid was dried and co-evaporated with toluene (twice) to give Intermediate F4 (484 mg, 79%).

Intermediate connection F5.

(1R)-2-[2-(4-Bromo-2-fluorophenyl)-5-cyclopropylimidazo[1,2-a]pyrimidine-7-carbonyl]-1-methyl1,2,3,4-tetrahydroisoquinoline.

To a mixture of intermediate F4 (260 mg, 0.63 mmol), (1R)-1-methyl-1,2,3,4tetrahydroisoquinoline [84010-66-2] (111 mg, 0.75 mmol) and DIPEA (0 .43 ml, 2.52 mmol) in DMF (4 ml) was added HATU (477 mg, 1.26 mmol). The reaction mixture was stirred at RT for 18 hours. The reaction mixture was diluted with H ₂ O, brine and EtOAc. The layers were separated and the aqueous phase was extracted using EtOAc. The combined organic extracts were washed with brine (3 times), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 24 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc 90:10 to 60:40) to give an intermediate compound F5 (306 mg, 96%) as an off-white foam.

Synthesis of intermediate compound F8.

Meo

F3

Ffi

NOH.H ₂ O B g ----------------THF; H ₂ O

K.T., 2 H

Selectfluor®

DMAP B g ------------------CHC^MeOH °C, 5 h

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Intermediate connection F6.

Methyl 2-(4-bromo-2-fluorophenyl)-5-cyclopropyl-3-fluoroimidazo[1,2-a]pyrimidine-7-carboxylate.

YFF ^g

F6

A mixture of intermediate F3 (242 mg, 0.62 mmol), selectfluor® (264 mg, 744 µmol) and DMAP (83.0 mg, 0.68 mmol) in CHCl ₃ (7.5 ml) was placed in a Schlenk tube and MeOH (7.5 ml) was stirred at 70° C. for 5 hours. Additional selectfluor® (132 mg, 372 μmol) and DMAP (45.0 mg, 0.37 mmol) were added and the reaction mixture was stirred at 70° C. for 18 h. The next additional amount of selectfluor® (132 mg, 372 μmol) and DMAP (45.0 mg, 0.37 mmol) was added and the reaction mixture was stirred at 70°C for another 22 h. The reaction mixture was concentrated in vacuo . The crude mixture was combined with another batch (269 mg, 0.69 mmol) and purified by preparative LC (irregular SiOH, 15-40 µm, 40 g GraceResolv™, liquid injection (DCM), mobile phase gradient: DCM/ EtOAc from 90:10 to 70:30). The second purification was performed by preparative LC (irregular SiOH, 15-40 µm, 40 g GraceResolv™, liquid injection (DCM), mobile phase gradient:heptane/(EtOAc/MeOH 9:1) 90:10 to 70 :30) to give Intermediate F6 (153 mg, 29%).

Intermediate connection F7.

Lithium 2-(4-bromo-2-fluorophenyl)-5-cyclopropyl-3-fluoroimidazo[1,2-a]pyrimidine-7-carboxylate.

Y F R

OU

F7

To a solution of intermediate F6 (153 mg, 375 µmol) in THF (11 ml) and H ₂ O (2.5 ml) was added lithium hydroxide monohydrate (47.2 mg, 1.12 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated to dryness and co-evaporated with toluene (twice) to give Intermediate F7 (153 mg, quant. yield) as a yellowish solid.

Intermediate connection F8.

(1R)-2-[2-(4-Bromo-2-fluorophenyl)-5-cyclopropyl-3-fluoroimidazo[1,2-α]pyrimidine-7-carbonyl]-1methyl-1,2,3,4- tetrahydroisoquinoline.

A mixture of intermediate F7 (138 mg, 0.35 mmol), (R)-1-methyl-1,2,3,4tetrahydroisoquinoline [84010-66-2] (62.0 mg, 0.42 mmol) and DIPEA ( 304 μl, 1.76 mmol) in DCM (1 ml) was stirred at 0°C. PPAC (50 wt% in EtOAc, 521 μl, 875 μmol) was added slowly. The reaction mixture was stirred at 0°C for 10 min and then at rt for 18 h. Additional (R)-1-methyl-1,2,3,4-tetrahydroisoquinoline (26.0 mg 0.18 mmol) and PPAC (50 wt.% in EtOAc, 208 μl, 350 μmol) at 0°C and the reaction mixture was stirred at RT for another 22 h. The reaction mixture was diluted with H ₂ O. The layers were separated and the organic phase was extracted. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 12 g GraceResolv™, liquid injection (DCM), mobile phase gradient: heptane/EtOAc 90:10 to 60:40) to give the intermediate F8 (80 mg, 44%) as a yellowish gum.

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Synthesis of final compounds.

LiOH.HjO THF:H ₂ O K.T., 20 h

AND

Compound 24

Intermediate connection F9.

(1R)-2-[5-Cyclopropyl-2-(4-ethenyl-2-fluorophenyl)imidazo[1,2-a]pyrimidine-7-carbonyl]-1-methyl1,2,3,4-tetrahydroisoquinoline.

Palladium(II) chloride (5.00 mg, 28.8 µmol) was added to a degassed mixture of intermediate F5 (324 mg, 641 µmol), potassium vinyltrifluoroborate (258 mg, 1.92 mmol), cesium carbonate (909 mg, 2 .79 mmol) and triphenylphosphine (22.0 mg, 83.8 μmol) in THF and H ₂ O (9:1, 10 ml). The reaction mixture was heated at 100° C. in a single mode microwave reactor (Biotage® Initiator EXP 60) with power output from 0 to 400 W for 1.5 h. Additional palladium(II) chloride (5.00 mg, 28.8 µmol) and triphenylphosphine (22.0 mg, 83.8 µmol) and the reaction mixture was heated at 100°C in a single mode microwave reactor (Biotage® Initiator EXP 60) with power output from 0 to 400 W for 1.5 h. the mixture was diluted with EtOAc and H ₂ O. The layers were separated and the organic phase was washed with H ₂ O, dried over MgSO 4 , filtered and concentrated in vacuo. The crude mixture was purified by preparative LC (SiOH with regular grains, 30 μm, 12 g Interchim®, liquid phase injection (DCM), gradient mobile phase: heptane/EtOAc from 90:10 to 60:40) to give Intermediate F9 (207 mg, 71%) as an off-white solid.

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Intermediate connections F10 and F11.

F10: Ethyl-trans-2-(4-{5-cyclopropyl-7-[( 1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]imidazo[1,2-a]pyrimidine-2 -yl}-3-fluorophenyl)cyclopropane-1-carboxylate.

F11: Ethyl-cis-2-(4-{5-cyclopropyl-7-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]imidazo[1,2-a]pyrimidine-2 -yl}-3-fluorophenyl)cyclopropane-1-carboxylate.

Under nitrogen, a solution of ethyl diazoacetate [623-73-4] (150 µl, 1.21 mmol) in DCM (4 ml) was added to a mixture of intermediate F9 (182 mg, 402 µmol) and dimer under nitrogen using a syringe pump for 40 min. rhodium acetate (9.00 mg, 40.7 µmol) in DCM (9 ml). The reaction mixture was stirred at rt for 3 h. Additional ethyldiazoacetate (150 μl, 1.21 mmol) in DCM (4 ml) was added via syringe pump over 40 min and the reaction mixture was stirred at rt for for 18 hours the Reaction mixture was concentrated under vacuum. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 24 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc 90:10 to 70:30) to give three fractions as a mixture of diastereoisomers (76 mg). Fractions were again purified by preparative LC (irregular SiOH, 15-40 µm, 40 g GraceResolv™, liquid phase injection (DCM), mobile phase:heptane/EtOAc gradient 100:0 to 70:30) to give an intermediate compound F10 (25 mg, 12%), intermediate F11 (11 mg, 5%) and a mixture of intermediates F10 and F11 (7 mg, 3%).

Compound 24.

trans-2-(4-{5-Cyclopropyl-7-[(1K)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]imidazo[1,2a]pyrimidin-2-yl} - 3-fluorophenyl)cyclopropane-1-carboxylic acid.

Lithium hydroxide monohydrate (5.87 mg, 0.14 mmol) was added to a solution of intermediate F10 (25.0 mg, 46.4 µmol) in THF (0.8 ml) and H ₂ O (0.4 ml). The reaction mixture was stirred at RT for 20 hours. The reaction mixture was diluted with brine and 10% aqueous KHSO4 and DCM were added. The layers were separated and the aqueous phase was extracted using DCM (twice). The combined organic extracts were washed with a solution of water and brine (1:1), dried over MgSO ₄ , filtered and evaporated under vacuum. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 4 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH from 100:0 to 96:4). The residue (19 mg) was purified by reverse phase chromatography (C18 spheroids, 25 µm, 40 g YMC-ODS-25, dry-load (Celite®), mobile phase gradient: 0.2% aq. NH ₄ HCO ₃ /MeCN from 85:15 to 45:55). Fractions containing product were pooled and 1N sodium hydroxide was added. aqueous HCl solution to pH 1. The aqueous layer was extracted three times using DCM. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The solid (14 g) was purified by non-chiral SCF chromatography (stationary phase: CHIRALPAK AS-H, 5 μm, 250x20 mm, mobile phase: 70% CO ₂ , 30% MeOH). The residue was solubilized in MeOH (2 ml), diluted with water (10 ml) and lyophilized to give compound 24 (7 mg, 30%) as a fluffy white solid.

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Compounds 25 and 26

Intermediate connection F12.

Ethyl-trans-2-(4-{5-cyclopropyl-3-fluoro-7-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2 carbonyl]imidazo[1,2-a] pyrimidin-2-yl }-3-fluorophenyl)cyclopropane-1-carboxylate.

To a mixture of intermediate F8 (70.0 mg, 134 µmol), intermediate I5 (cis:trans 12:88, 32.4 mg, 147 µmol) and cesium carbonate (121 mg, 372 µmol) in toluene (1.5 ml) and H ₂ O (150 μl) cataCxium A® (11.1 mg, 31.0 μmol) and palladium acetate (5.06 mg, 22.5 μmol) were added under nitrogen atmosphere. The reaction mixture was purged with nitrogen and stirred at 100° C. for 18 hours. The reaction mixture was diluted using EtOAc and H ₂ O. The layers were separated and the aqueous phase was extracted using EtOAc. The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 12 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 100:0 to 70:30) to give intermediate F12 (cis:trans 85:15, 56 mg, 75%) as a colorless gum.

Compounds 25 and 26.

25: trans-2-(4-{5-cyclonronyl-3-fluoro-7-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl] imidazo[ 1,2-a ]pyrimidin-2-yl }-3-fluorophenyl)cyclopropane-1-carboxylic acid.

26: cis-2-(4-{5-cyclopropyl-3-fluoro-7-[(1C)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]imidazo[1,2-a ]pyrimidin-2-yl }-3-fluorophenyl)cyclopropane-1-carboxylic acid.

Lithium hydroxide monohydrate (12.7 mg, 302 µmol) was added to a solution of intermediate F12 (cis:trans 85:15, 56.0 mg, 101 µmol) in THF (1.8 ml) and H ₂ O (0.3 ml). The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with brine and 10% aqueous KHSO4 was added. The aqueous phase was extracted using EtOAc (twice). The combined organic extracts were washed with H2O, dried over MgSO4, filtered and concentrated in vacuo. The mixture was purified using non-chiral supercritical fluid chromatography (stationary phase: diethylaminopropyl 5 μm, 150x30 mm, mobile phase: 50% CO ₂ , 50% MeOH), obtaining 2 fractions: A and B. Fraction A (15 mg) was solubilized in MeCN ( 2 ml), diluted with water (10 ml) and lyophilized to give compound 25 (15 mg, 28%) as a yellowish friable solid. Fraction B (18 mg) was solubilized in MeCN (2 ml), diluted with water (10 ml) and lyophilized to give compound 26 (18 mg, 34%) as a yellowish friable solid.

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Compound 27

Intermediate connection F13.

Methyl (3S)-1-(4-{5-cyclopropyl-7-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]imidazo[1,2-а]pyrimidine-2- yl}-3-fluorophenyl)pyrrolidine-3-carboxylate.

A sealed tube was charged with intermediate F5 (251 mg, 497 µmol), (5)-methylpyrrolidine-3-carboxylate hydrochloride [1099646-61-3] (98.7 mg, 596 µmol), cesium carbonate (485 mg, 1. 49 mmol) and XantPhos (28.7 mg, 49.7 µmol) and purged with nitrogen. 1,4-dioxane (7.5 ml) was added and the mixture was again purged with nitrogen. Palladium acetate (11.2 mg, 49.7 µmol) was added. The reaction mixture was purged with nitrogen and stirred at 100° C. for 17 hours. The reaction mixture was diluted using EtOAc and H ₂ O. The layers were separated and the aqueous phase was extracted using EtOAc (twice). The combined organic extracts were washed with brine, dried over MgSO4, filtered and the solvent was evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 12 g Grace®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 90:10 to 50:50) to give intermediate F13 (187 mg, 68%) as a yellow foam.

Compound 27.

(3S)-1-(4-{5-Cyclopropyl-7-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-carbonyl]imidazo[1,2а]pyrimidin-2-yl } -3-fluorophenyl)pyrrolidine-3-carboxylic acid.

To a solution of intermediate F13 (175 mg, 316 µmol) in THF (4.2 ml) and H ₂ O (1.8 ml) was added lithium hydroxide monohydrate (40.0 mg, 953 µmol). The reaction mixture was stirred at RT for 20 hours. The reaction mixture was diluted with brine and 10% aqueous KHSO4 and DCM were added. The layers were separated and the aqueous phase was extracted using DCM (twice). The combined organic extracts were washed with H ₂ O and brine (1:1), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude mixture was triturated with MeOH. The solid was filtered off and dried in high vacuum at 50° C. for 3 hours to give compound 27 (146 mg, 86%) as a yellow solid.

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Compound 28.

(3 S)-1 -(4- {5-cyclopropyl-7-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]imidazo[1,2а]pyrimidine-2- yl}-3-fluorophenyl)pyrrolidine-3-carboxamide.

A mixture of intermediate I94 (107 mg, 198 µmol), HATU (113 mg, 297 µmol) and DIPEA (107 µl, 0.62 mmol) in DMF (5.4 ml) was stirred at rt for 1 h. Ammonia (28% in H ₂ O, 68 μl, 1.00 mmol) was added and the reaction mixture was stirred at rt for 18 hours. The reaction mixture was diluted with H ₂ O and EtOAc. The layers were separated and the aqueous phase was extracted using EtOAc (twice). The combined organic extracts were washed with brine (3 times), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 12 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH 100:0 to 96:4). The residue was triturated in MeOH. The solid was filtered off and dried in high vacuum at 50° C. for 20 h to give compound 28 (71 mg, 66%) as a yellow solid.

C. Connection identification.

1H NMR.

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

NMR spectra were recorded at ambient temperature unless otherwise noted.

Data are reported as follows: chemical shift given in parts per million (ppm) relative to TMS (δ=0 ppm) used as internal standard, integration, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, quin=quintuplet, sex=sextuplet, m=multiplet, b=broad or a combination thereof), coupling constant(s) J is(are) in hertz (Hz).

Connection 1.

Basic rotamer (80%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 12.37 (br s, 1H), 7.93 (s, 1H), 7.80 (t, J=8.4 Hz, 1H), 7, 54 (s, 1H), 7.16-7.34 (m, 4H), 7.14 (dd, J=12.8, 1.4 Hz, 1H), 7.11 (dd, J=8, 2, 1.6Hz, 1H), 7.05(s, 1H), 6.51(br s, 1H), 5.47-5.61(m, 1H), 3.83-3.98( m, 1H), 3.38-3.59 (m, 1H), 2.98-3.10 (m, 1H), 2.95 (q, J=7.3 Hz, 2H), 2.78 (br d, J=15.8 Hz, 1H), 2.43-2.48 (m, 1H), 1.87-1.93 (m, 1H), 1.52 (br d, J=6 .6 Hz, 3H), 1.40-1.49 (m, 2H), 1.37 (br t, J=6.9 Hz, 3H).

Minor rotamer (20%).

1H NMR (500 MHz, DMSO-d6) δ ppm 12.37 (br s, 1H), 7.93 (s, 1H), 7.80 (t, J=8.4 Hz, 1H), 7.54 (s, 1H), 7.16-7.34 (m, 4H), 7.14 (dd, J=12.8, 1.4 Hz, 1H), 7.11 (dd, J=8.2 , 1.6 Hz, 1H), 7.05 (s, 1H), 6.51 (br s, 1H), 4.94-5.11 (m, 1H), 4.39-4.60 (m , 1H), 3.38-3.59 (m, 1H), 2.98-3.10 (m, 1H), 2.95 (q, J=7.3 Hz, 2H), 2.78 ( br d, J=15.8 Hz, 1H), 2.43-2.48 (m, 1H), 1.87-1.93 (m, 1H), 1.52 (br d, J=6, 6 Hz, 3H), 1.40-1.49 (m, 2H), 1.37 (br t, J=6.9 Hz, 3H).

Connection 2.

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.86 (s, 1H), 7.75 (t, J=8.4 Hz, 1H), 7.48 (s, 1H), 7.27 -7.40 (br s, 1H), 7.13-7.23 (m, 4H), 6.98-7.07 (m, 3H), 6.54-6.85 (br s, 1H) , 6.48 (s, 1H), 5.37 (br s, 1H), 4.10 (br s, 1H), 3.41 (br t, J=ll, 2 Hz, 1H), 2.91 -3.03 (m, 4H), 2.78 (br d, J=16.1 Hz, 1H), 2.27-2.33 (m, 1H), 1.89-1.95 (m, 1H), 1.52 (d, J=6.6 Hz, 3H), 1.37 (t, J=7.4 Hz, 3H), 1.19-1.25 (m, 1H).

Connection 3.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.51 (br s, 1H), 7.79 (s, 1H), 7.67 (t, J=8.8 Hz, 1H), 7, 49 (s, 1H), 7.21-7.34 (m, 1H), 7.17 (br s, 3H), 6.94 (s, 1H), 6.39-6.51 (m, 3H ), 5.48 (s, 1H), 3.94 (s, 1H), 3.41-3.54 (m, 3H), 3.33-3.40 (m, 2H), 3.17- 3.26 (m, 1H), 2.97-3.08 (m, 1H), 2.89-2.97 (m, 2H), 2.77 (br d, J=15.2 Hz, 1H ), 2.12-2.28 (m, 2H), 1.52 (br d, J=6.6 Hz, 3H), 1.36 (br t, J=7.3 Hz, 3H).

Connection 4.

Basic rotamer (70%).

1H NMR (500 MHz, DMSO-d6) δ ppm 12.39 (br s, 1H), 8.07 (t, J=8.0 Hz, 1H), 7.76 (br s, 1H), 7, 32 (br s, 1H), 7.06-7.26 (m, 6H), 6.86 (br s, 1H), 5.58 (br s, 1H), 3.71-3.84 (m , 1H), 3.43-3.54 (m, 1H), 3.16-3.26 (m, 2H), 2.93-3.09 (m, 1H), 2.70-2.87 (m, 1H), 1.90-1.97 (m, 1H), 1.36-1.55 (m, 8H), 1.23 (brs, 1H).

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Minor rotamer (30%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 12.39 (br s, 1H), 8.07 (t, J=8.0 Hz, 1H), 7.76 (br s, 1H), 7.06-7.26 (m, 7H), 6.79 (br s, 1H), 4.90 (br s, 1H), 4.55 (br s, 1H), 3.43-3.54 (m, 1H), 3.16-3.26 (m, 2H), 2.93-3.09 (m, 1H), 2.70-2.87 (m, 1H), 1.90-1 .97 (m, 1H), 1.36-1.55 (m, 8H), 1.23 (brs, 1H).

Compound 5.

Basic rotamer (70%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 12.06 (br s, 1H), 7.97 (t, J=7.9 Hz, 1H), 7.26 (br d, J=7, 6 Hz, 1H), 6.96-7.20 (m, 6H), 6.55-6.70 (m, 1H), 5.58 (q, J=6.5 Hz, 1H), 3, 51-4.08 (m, 4H), 3.34-3.47 (m, 1H), 2.74-3.13 (m, 4H), 2.60-2.70 (m, 1H), 1.80-1.88 (m, 1H), 1.45 (d, J=6.9 Hz, 3H), 1.27-1.42 (m, 5H).

Minor rotamer (30%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 12.06 (br s, 1H), 7.96 (t, J=7.6 Hz, 1H), 6.96-7.20 (m, 7H ), 6.55-6.70 (m, 1H), 4.65-4.79 (m, 1H), 4.52-4.60 (m, 1H), 3.51-4.08 (m , 3H), 3.34-3.47 (m, 1H), 2.74-3.13 (m, 4H), 2.60-2.70 (m, 1H), 1.80-1.88 (m, 1H), 1.27-1.42 (m, 8H).

Compound 6.

Basic rotamer (70%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.39 (br s, 1H), 8.07 (t, J=7.8 Hz, 1H), 7.32 (d, J=7, 6 Hz, 1H), 7.09-7.27 (m, 6H), 6.65 (d, J=6.l Hz, 1H), 5.62 (q, J=6.6 Hz, 1H) , 3.65 (br dd, J=13.9, 3.8 Hz, 1H), 3.44-3.56 (m, 1H), 2.82-2.98 (m, 1H), 2, 68-2.78 (m, 2H), 1.89-2.00 (m, 1H), 1.52 (d, J=7.1 Hz, 3H), 1.39-1.48 (m, 2H), 1.11-1.19 (m, 2H), 0.97-1.08 (m, 2H).

Minor rotamer (30%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 12.39 (br s, 1H), 8.06 (t, J=7.8 Hz, 1H), 7.09-7.27 (m, 7H ), 6.65 (d, J=6.l Hz, 1H), 4.82 (q, J=6.6 Hz, 1H), 4.59 (br d, J=13.6 Hz, 1H) , 3.24-3.29(m, 1H), 2.82-2.98(m, 2H), 2.68-2.78(m, 1H), 1.89-2.00(m, 1H), 1.39-1.49 (m, 5H), 1.11-1.19 (m, 2H), 0.97-1.08 (m, 2H).

Connection 7.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.96 (t, J=8.8 Hz, 1H), 7.67 (br s, 1H), 7.31 (br s, 1H), 7 .14-7.28 (m, 3H), 6.94 (d, J=4.1 Hz, 1H), 6.77 (br s, 1H), 6.51 (dd, J=8.8, 2.2 Hz, 1H), 6.43 (dd, J=14.7, 2.0 Hz, 1H), 5.58 (br s, 1H), 3.78 (br d, J=10.4 Hz, 1H), 3.47 (br d, J=6.9 Hz, 3H), 3.14-3.24 (m, 3H), 3.08-3.15 (m, 1H), 2, 90-3.07 (m, 1H), 2.75 (br d, J=17.3 Hz, 1H), 2.11-2.24 (m, 2H), 1.52 (d, J=6 .6 Hz, 3H), 1.34-1.46 (br s, 3H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.96 (t, J=8.8 Hz, 1H), 7.67 (br s, 1H), 7.14-7.28 (m, 3H), 7.10 (br s, 1H), 6.94 (d, J=4.1 Hz, 1H), 6.70 (br s, 1H), 6.51 (dd, J=8.8 , 2.2 Hz, 1H), 6.43 (dd, J=14.7, 2.0 Hz, 1H), 4.90 (br s, 1H), 4.55 (br s, 1H), 3 .47 (br d, J=6.9 Hz, 3H), 3.14-3.24 (m, 2H), 3.08-3.15 (m, 1H), 2.90-3.07 ( m, 2H), 2.79-2.87 (m, 1H), 2.11-2.24 (m, 2H), 1.52 (d, J=6.6 Hz, 3H), 1.34 -1.46 (brs, 3H).

Connection 8.

Basic rotamer (60%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.97 (t, J=8.8 Hz, 1H), 7.68 (br s, 1H), 7.51 (br s, 1H), 7 .08-7.35 (m, 4H), 7.00 (br s, 1H), 6.95 (d, J=3.8 Hz, 1H), 6.78 (br s, 1H), 6, 51 (dd, J=8.8, 1.9 Hz, 1H), 6.43 (dd, J=14.8, 1.6 Hz, 1H), 5.58 (br s, 1H), 3, 78 (br d, J=8.5 Hz, 1H), 3.44-3.53 (m, 2H), 3.35-3.44 (m, 2H), 3.14-3.24 (m , 2H), 3.08 (br quin, J=7.6 Hz, 1H), 2.92-3.12 (m, 1H), 2.75 (br d, J=14.8 Hz, 1H) , 2.15-2.25 (m, 1H), 2.05-2.14 (m, 1H), 1.52 (d, J=6.6 Hz, 3H), 1.41 (br s, 3H).

Minor rotamer (30%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.97 (t, J=8.8 Hz, 1H), 7.68 (br s, 1H), 7.51 (br s, 1H), 7 .08-7.35 (m, 4H), 7.00 (br s, 1H), 6.95 (d, J=3.8 Hz, 1H), 6.71 (br s, 1H), 6, 51 (dd, J=8.8, 1.9 Hz, 1H), 6.43 (dd, J=14.8, 1.6 Hz, 1H), 4.90 (br s, 1H), 4, 55 (br s, 1H), 3.44-3.53 (m, 1H), 3.35-3.44 (m, 2H), 3.27-3.31 (m, 1H), 3.14 -3.24 (m, 2H), 3.08 (br quin, J=7.6 Hz, 1H), 2.92-3.12 (m, 1H), 2.79-2.88 (br s , 1H), 2.15-2.25 (m, 1H), 2.05-2.14 (m, 1H), 1.52 (d, J=6.6 Hz, 3H), 1.41 ( brs, 3H).

Connection 9.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.91-8.01 (m, 1H), 7.33 (br d, J=7.6 Hz, 1H), 7.23 (br t , J=7.6 Hz, 1H), 7.07-7.21 (m, 2H), 6.84-7.00 (m, 1H), 6.32-6.74 (m, 3H), 5.63-5.72(m, 1H), 4.63-4.72(m, 1H), 3.44-3.55(m, 3H), 3.32-3.38(m, 2H ), 3.13-3.22 (m, 3H), 2.85-3.01 (m, 1H), 2.66-2.78 (m, 1H), 2.37 (br s, 3H) , 2.13-2.27 (m, 2H), 1.54 (br d, J=6.0 Hz, 3H), 1.32-1.45 (m, 3H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.91-8.01 (m, 1H), 7.07-7.21 (m, 4H), 6.84-7.00 (m, 1H ), 6.32-6.74 (m, 3H), 4.74-4.79 (m, 1H), 3.44-3.55 (m, 3H), 3.32-3.38 (m , 3H), 3.13-3.22 (m, 3H), 2.85-3.01 (m, 2H), 2.31 (br s, 3H), 2.13-2.27 (m, 2H), 1.32-1.45 (m, 6H).

Compound 10.

Basic rotamer (70%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.98 (t, J=8.8 Hz, 1H), 7.51 (br s, 1H), 7.32 (br d, J=7 .6 Hz, 1H), 7.23 (br t, J=7.1 Hz, 1H), 7.09-7.21 (m, 2H), 6.96-7.06 (m, 3H), 6.50-6.58 (m, 1H), 6.45 (br dd, J=14.8, 1.9 Hz,

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1H), 5.62 (q, J=6.2 Hz, 1H), 3.65 (br d, J=14.8 Hz, 1H), 3.50 (br t, J=8.8 Hz, 2H), 3.34-3.44 (m, 3H), 3.09 (quin, J=7.5 Hz, 1H), 2.82-2.95 (m, 1H), 2.68-2 .77 (m, 2H), 2.16-2.24 (m, 1H), 2.05-2.15 (m, 1H), 1.52 (d, J=6.6 Hz, 3H), 1.15 (br d, J=8.5 Hz, 2H), 0.96-1.08 (m, 2H).

Minor rotamer (30%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.97 (t, J=8.8 Hz, 1H), 7.51 (br s, 1H), 7.09-7.21 (m, 4H ), 6.96-7.06 (m, 3H), 6.50-6.58 (m, 1H), 6.45 (br dd, J=14.8, 1.9 Hz, 1H), 4 .81 (q, J=6.6 Hz, 1H), 4.55-4.63 (m, 1H), 3.50 (br t, J=8.8 Hz, 2H), 3.34-3 .44 (m, 2H), 3.24-3.30 (m, 1H), 3.09 (quin, J=7.5 Hz, 1H), 2.82-2.95 (m, 2H), 2.68-2.77 (m, 1H), 2.16-2.24 (m, 1H), 2.05-2.15 (m, 1H), 1.42 (br d, J=6, 6 Hz, 3H), 1.15 (br d, J=8.5 Hz, 2H), 0.96-1.08 (m, 2H).

Compound 11.

1H NMR (500 MHz, DMSO-d ₆ , 77°C) δ ppm 12.03 (br s, 1H), 8.32 (d, J=3.5 Hz, 1H), 8.17 (t, J = 8.2 Hz, 1H), 7.50 (s, 1H), 7.12-7.23 (m, 6H), 6.66 (s, 1H), 5.37 (br s, 1H), 4.00 (br s, 1H), 3.42 (br s, 1H), 2.97 (ddd, J=16.7, 11.4, 6.0 Hz, 1H), 2.77 (br d , J=16.1 Hz, 1H), 2.29-2.37 (m, 1H), 1.88-1.94 (m, 1H), 1.52 (d, J=6.6 Hz, 3H), 1.48 (br dt, J=9.3, 4.8 Hz, 1H), 1.38-1.44 (m, 1H), 1.13-1.17 (m, 2H), 0.86-0.92 (m, 2H).

Compound 12.

Basic rotamer (75%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.62 (s, 1H), 8.33 (d, J=4.1 Hz, 1H), 8.19 (t, J=8.0 Hz , 1H), 7.62 (br s, 1H), 7.30 (br s, 1H), 7.09-7.25 (m, 5H), 6.95 (br s, 1H), 6.84 (br s, 1H), 5.54 (br s, 1H), 3.82 (br s, 1H), 3.46 (br s, 1H), 3.03 (br s, 1H), 2.77 (br d, J=15.8 Hz, 1H), 2.53-2.62 (m, 1H), 2.25-2.33 (m, 1H), 1.87-1.98 (m, 1H), 1.51 (br d, J=6.6 Hz, 3H), 1.36-1.42 (m, 1H), 1.27-1.33 (m, 1H), 1.04- 1.17 (m, 4H).

Minor rotamer (25%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.62 (s, 1H), 8.33 (d, J=4.1 Hz, 1H), 8.19 (t, J=8.0 Hz, 1H), 7.62 (br s, 1H), 7.09-7.25 (m, 6H), 6.95 (br s, 1H), 6.84 (br s, 1H), 4.95 ( br s, 1H), 4.51 (br s, 1H), 3.46 (br s, 1H), 3.03 (br s, 1H), 2.77 (br d, J=15.8 Hz, 1H), 2.53-2.62 (m, 1H), 2.25-2.33 (m, 1H), 1.87-1.98 (m, 1H), 1.51 (br d, J =6.6 Hz, 3H), 1.36-1.42(m, 1H), 1.27-1.33(m, 1H), 1.04-1.17(m, 4H).

Compound 13.

Basic rotamer (70%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.17 (br d, J=2.8 Hz, 1H), 8.07 (br t, J=8.8 Hz, 1H), 7.50 (br s, 2H), 7.31 (br s, 1H), 7.04-7.25 (m, 3H), 6.99 (br s, 1H), 6.69 (br s, 1H), 6.50 (br d, J=8.5 Hz, 1H), 6.44 (d, J=14.5 Hz, 1H), 5.57 (br s, 1H), 3.74 (br s, 1H), 3.35-3.56 (m, 4H), 3.20-3.31 (m, 1H), 3.08 (quin, J=7.5 Hz, 1H), 3.00 (br s, 1H), 2.68-2.86 (m, 1H), 2.33 (br s, 1H), 2.15-2.24 (m, 1H), 2.04-2.15 (m , 1H), 1.52 (br d, J=6.6 Hz, 3H), 1.12 (br s, 2H), 0.89 (br s, 2H).

Minor rotamer (30%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.17 (br d, J=2.8 Hz, 1H), 8.07 (br t, J=8.8 Hz, 1H), 7.50 ( br s, 2H), 7.04-7.25 (m, 4H), 6.99 (br s, 1H), 6.62 (br s, 1H), 6.50 (br d, J=8, 5 Hz, 1H), 6.44 (d, J=14.5 Hz, 1H), 4.89 (br s, 1H), 4.54 (br s, 1H), 3.35-3.56 ( m, 4H), 3.20-3.31 (m, 1H), 3.08 (quin, J=7.5 Hz, 1H), 3.00 (br s, 1H), 2.68-2, 86 (m, 1H), 2.33 (br s, 1H), 2.15-2.24 (m, 1H), 2.04-2.15 (m, 1H), 1.52 (br d, J=6.6 Hz, 3H), 1.12(brs, 2H), 0.89(brs, 2H).

Connection 14.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 12.52 (br s, 1H), 8.98 (br s, 1H), 8.80 (br d, J=3.5 Hz, 1H), 8.29 (br s, 1H), 8.06 (t, J=8.8 Hz, 1H), 7.84 (d, J=3.2 Hz, 1H), 7.71 (br s, 1H ), 7.62-7.70 (m, 1H), 7.28-7.36 (m, 1H), 7.09-7.27 (m, 3H), 7.04 (br s, 1H) , 6.52 (dd, J=8.8, 2.2 Hz, 1H), 6.42 (dd, J=14.7, 2.0 Hz, 1H), 5.61 (br d, J= 5.0 Hz, 1H), 3.89 (br d, J=10.4 Hz, 1H), 3.43-3.58 (m, 2H), 3.28-3.40 (m, 3H) , 3.21 (br quin, J=7.1 Hz, 1H), 2.93-3.11 (m, 1H), 2.70-2.87 (m, 1H), 2.12-2, 27 (m, 2H), 1.54 (brs, 3H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 12.52 (br s, 1H), 8.98 (br s, 1H), 8.80 (br d, J=3.5 Hz, 1H), 8.29 (br s, 1H), 8.06 (t, J=8.8 Hz, 1H), 7.84 (d, J=3.2 Hz, 1H), 7.71 (br s, 1H ), 7.62-7.70 (m, 1H), 7.09-7.27 (m, 4H), 6.97 (br s, 1H), 6.52 (dd, J=8.8, 2.2 Hz, 1H), 6.42 (dd, J=14.7, 2.0 Hz, 1H), 5.04 (br s, 1H), 4.57 (br s, 1H), 3, 43-3.58 (m, 2H), 3.28-3.40 (m, 3H), 3.21 (br quin, J=7.1 Hz, 1H), 2.93-3.11 (m , 1H), 2.70-2.87 (m, 1H), 2.12-2.27 (m, 2H), 1.54 (br s, 3H).

Compound 15.

Basic rotamer (70%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.91-9.03 (m, 1H), 8.80 (br d, J=3.2 Hz, 1H), 8.30 (br s, 1H ), 8.06 (t, J=8.8 Hz, 1H), 7.83 (d, J=3.2 Hz, 1H), 7.71 (br s, 1H), 7.62-7, 69 (m, 1H), 7.44-7.56 (m, 1H), 7.31 (br s, 1H), 7.09-7.26 (m, 3H), 7.03 (br s, 1H), 6.94-7.01 (m, 1H), 6.50 (dd, J=8.8, 2.2 Hz, 1H), 6.38 (dd, J=15,l, 1, 9 Hz, 1H), 5.61 (br d, J=4.7 Hz, 1H), 3.89 (br d, J=11.0 Hz, 1H), 3.50-3.59 (m, 1H), 3.47 (br t, J=8.8 Hz, 1H), 3.35-3.41 (m, 2H), 3.25-3.32 (m, 1H), 2.96- 3.12 (m, 2H), 2.70-2.88 (m, 1H), 2.14-2.24 (m, 1H), 2.02-2.14 (m, 1H), 1, 54 (brs, 3H).

Minor rotamer (30%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.91-9.03 (m, 1H), 8.80 (br d, J=3.2 Hz, 1H), 8.30 (br s, 1H), 8.06

- 47 041546 (t, J=8.8 Hz, 1H), 7.83 (d, J=3.2 Hz, 1H), 7.71 (br s, 1H), 7.62-7.69 ( m, 1H), 7.44-7.56 (m, 1H), 7.09-7.26 (m, 4H), 6.94-7.01 (m, 2H), 6.50 (dd, J=8.8, 2.2 Hz, 1H), 6.38 (dd, J=15.1, 1.9 Hz, 1H), 5.04 (br s, 1H), 4.57 (br s , 1H), 3.47 (br t, J=8.8 Hz, 2H), 3.35-3.41 (m, 2H), 3.25-3.32 (m, 1H), 2.96 -3.12(m, 2H), 2.70-2.88(m, 1H), 2.14-2.24(m, 1H), 2.02-2.14(m, 1H), 1 .54 (brs, 3H).

Compound 16.

Basic rotamer (70%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 12.42 (br s, 1H), 8.10 (br t, J=7.9 Hz, 1H), 7.76 (s, 1H), 7 .32 (br d, J=7.6 Hz, 1H), 7.14-7.28 (m, 5H), 6.90 (s, 1H), 5.59 (q, J=6.6 Hz , 1H), 3.65 (br dd, J=13.2, 3.2, 1H), 3.40-3.48 (m, 1H), 2.93-3.04 (m, 1H), 2.73-2.87 (m, 1H), 2.69 (br d, J=16.4 Hz, 1H), 2.53-2.55 (m, 1H), 1.94-2.00 (m, 1H), 1.50-1.55 (m, 3H), 1.44-1.50 (m, 2H), 1.15-1.27 (m, 4H).

Minor rotamer (30%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 12.42 (br s, 1H), 8.10 (br t, J=7.9 Hz, 1H), 7.73 (s, 1H), 7 .14-7.28 (m, 4H), 7.08-7.13 (m, 1H), 7.03-7.07 (m, 1H), 6.84 (s, 1H), 4.79 (q, J=6.9 Hz, 1H), 4.53-4.59 (m, 1H), 3.23-3.29 (m, 1H), 2.93-3.04 (m, 1H ), 2.73-2.87 (m, 2H), 2.53-2.55 (m, 1H), 1.94-2.00 (m, 1H), 1.50-1.55 (m , 3H), 1.44-1.50 (m, 2H), 1.15-1.27 (m, 4H).

Compound 17.

Basic rotamer (70%).

1H NMR (500 MHz, DMSO-d6) δ ppm 12.03 (br s, 1H), 8.03-8.10 (m, 1H), 7.76 (s, 1H), 7.32 (br d , J=7.6 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 7.13-7.26 (m, 4H), 6.91 (s, 1H), 5 .59 (q, J=6.5 Hz, 1H), 3.65 (br dd, J=13.6, 4.1 Hz, 1H), 3.41-3.49 (m, 1H), 2 .93-3.05 (m, 1H), 2.73-2.81 (m, 1H), 2.65-2.73 (m, 2H), 2.08-2.15 (m, lH) , 1.58-1.64 (m, 1H), 1.53 (br d, J=6.9 Hz, 3H), 1.38 (td, J=8.1, 4.9 Hz, 1H) , 1.16-1.27 (m, 4H).

Minor rotamer (30%).

1H NMR (500 MHz, DMSO-d6) δ ppm 12.03 (br s, 1H), 8.03-8.10 (m, 1H), 7.74 (s, 1H), 7.28 (d, J=8.5Hz, 1H), 7.13-7.26(m, 3H), 7.04-7.13(m, 1H), 6.85(s, 1H), 4.79(q , J=6.6 Hz, 1H), 4.56 (br dd, J=12.5, 4.9 Hz, 1H), 3.22-3.29 (m, 1H), 2.93-3 .05 (m, 1H), 2.81-2.87 (m, 1H), 2.73-2.81 (m, 1H), 2.65-2.73 (m, 2H), 2.08 -2.15 (m, 1H), 1.58-1.64 (m, 1H), 1.49 (br d, J=6.6 Hz, 3H), 1.38 (td, J=8, 1, 4.9 Hz, 1H), 1.16-1.27 (m, 4H).

Compound 18.

Basic rotamer (70%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.11 (t, J=7.9 Hz, 1H), 7.75 (s, 1H), 7.64 (br s, 1H), 7, 32 (br d, J=7.3 Hz, 1H), 7.14-7.25 (m, 5H), 6.98 (br s, 1H), 6.90 (s, 1H), 5.59 (q, J=6.7 Hz, 1H), 3.64 (br dd, J=13.9, 3.5 Hz, 1H), 3.40-3.48 (m, 1H), 2.93 -3.04 (m, 1H), 2.74-2.80 (m, 1H), 2.69 (br d, J=16.4 Hz, 1H), 2.31-2.35 (m, 1H), 1.94-1.99 (m, 1H), 1.53 (br d, J=6.9 Hz, 3H), 1.41 (br dt, J=9.5, 4.5 Hz , 1H), 1.32-1.37 (m, 1H), 1.15-1.27 (m, 4H).

Minor rotamer (30%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.11 (t, J=7.9 Hz, 1H), 7.73 (s, 1H), 7.64 (br s, 1H), 7.14 -7.25(m, 4H), 7.08-7.13(m, 1H), 7.03-7.07(m, 1H), 6.98(brs, 1H), 6.84( s, 1H), 4.78 (q, J=6.9 Hz, 1H), 4.53-4.60 (m, 1H), 3.23-3.30 (m, 1H), 2.93 -3.04 (m, 1H), 2.80-2.87 (m, 1H), 2.74-2.80 (m, 1H), 2.31-2.35 (m, 1H), 1 .94-1.99 (m, 1H), 1.48 (br d, J=6.3 Hz, 3H), 1.41 (br dt, J=9.5, 4.5 Hz, 1H), 1.32-1.37(m, 1H), 1.15-1.27(m, 4H).

Compound 19.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 12.63 (br s, 1H), 8.02 (br t, J=8.7 Hz, 1H), 7.66 (s, 1H), 7 .32 (br d, J=7.6 Hz, 1H), 7.21-7.25 (m, 1H), 7.14-7.21 (m, 2H), 6.81 (s, 1H) , 6.54 (dd, J=8.8, 1.9 Hz, 1H), 6.46 (dd, J=14.2, 1.6 Hz, 1H), 5.58 (q, J=6 .3 Hz, 1H), 3.65 (br dd, J=13.4, 3.6 Hz, 1H), 3.48-3.57 (m, 2H), 3.36-3.47 (m , 3H), 3.16-3.24 (m, 1H), 2.93-3.05 (m, 1H), 2.73-2.81 (m, 1H), 2.69 (br d, J=15.8 Hz, 1H), 2.14-2.29 (m, 2H), 1.52 (br d, J=6.6 Hz, 3H), 1.13-1.27 (m, 4H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 12.63 (br s, 1H), 8.02 (br t, J=8.7 Hz, 1H), 7.64 (br s, 1H), 7.14-7.21 (m, 2H), 7.03-7.13 (m, 2H), 6.75 (s, 1H), 6.54 (dd, J=8.8, 1.9 Hz, 1H), 6.46 (dd, J=14.2, 1.6 Hz, 1H), 4.78 (q, J=7.3 Hz, 1H), 4.52-4.60 (m , 1H), 3.48-3.57 (m, 2H), 3.36-3.47 (m, 3H), 3.16-3.24 (m, 1H), 2.93-3.05 (m, 1H), 2.81-2.86 (m, 1H), 2.73-2.81 (m, 1H), 2.14-2.29 (m, 2H), 1.49 (br d, J=6.3 Hz, 3H), 1.13-1.27 (m, 4H).

Compound 20.

Basic rotamer (70%).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.01 (br t, J=8.6 Hz, 1H), 7.66 (s, 1H), 7.51 (br s, 1H), 7, 32 (d, J=7.6 Hz, 1H), 7.14-7.26 (m, 3H), 7.00 (br s, 1H), 6.81 (s, 1H), 6.52 ( dd, J=8.8, 1.3Hz, 1H), 6.43 (br d, J=14.1Hz, 1H), 5.58 (q, J=7.1Hz, 1H), 3 .65 (br d, J=13.6 Hz, 1H), 3.48-3.54 (m, 1H), 3.37-3.48 (m, 3H), 3.34-3.37 ( m, 1H), 3.09 (quin, J=7.6 Hz, 1H), 2.92-3.04 (m, 1H), 2.73-2.87 (m, 1H), 2.69 (br d, J=17.7 Hz, 1H), 2.16-2.26 (m, 1H), 2.05-2.15 (m, 1H), 1.52 (br d, J=6 .6 Hz, 3H), 1.19-1.27 (m, 2H), 1.08-1.18 (m, 2H).

Minor rotamer (30%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.01 (br t, J=8.6 Hz, 1H), 7.63 (br s, 1H), 7.51 (br s, 1H), 7.14-7.26 (m, 2H), 7.04-7.14 (m, 2H), 7.00 (br s, 1H), 6.75 (br s, 1H), 6.52 ( dd, J=8.8, 1.3Hz, 1H), 6.43 (br d, J=14.1Hz, 1H), 4.78 (q, J=5.6Hz, 1H), 4 .51-4.60 (m, 1H), 3.48-3.54 (m, 1H), 3.37-3.48 (m, 3H), 3.21-3.28 (m, 1H) , 3.09

- 48 041546 (quin, J=7.6 Hz, 1H), 2.92-3.04 (m, 1H), 2.73-2.87 (m, 2H), 2.16-2.26 ( m, 1H), 2.05-2.15 (m, 1H), 1.49 (br d, J=6.6 Hz, 3H), 1.19-1.27 (m, 2H), 1, 08-1.18 (m, 2H).

Compound 21.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 12.56 (br s, 1H), 8.02 (t, J=8.8 Hz, 1H), 7.75 (s, 1H), 7, 30 (d, J=7.6 Hz, 1H), 7.17-7.24 (m, 2H), 7.06-7.17 (m, 1H), 7.02 (d, J=3, 8 Hz, 1H), 6.55 (br d, J=8.8 Hz, 1H), 6.49 (br dd, J=14.7, 2.0 Hz, 1H), 5.50 (q, J=6.7 Hz, 1H), 3.94 (br dd, J=13.4, 4.3 Hz, 1H), 3.52-3.58 (m, 1H), 3.46-3, 52 (m, 1H), 3.34-3.43 (m, 3H), 3.19-3.30 (m, 2H), 3.01-3.10 (m, 1H), 2.77 ( br d, J=16.4 Hz, 1H), 2.22-2.29 (m, 1H), 2.14-2.22 (m, 1H), 1.50 (d, J=6.9 Hz, 3H), 1.20-1.38 (m, 4H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 12.56 (br s, 1H), 8.02 (t, J=9.0 Hz, 1H), 7.67 (s, 1H), 7, 17-7.24 (m, 2H), 7.06-7.17 (m, 2H), 6.98 (d, J=3.5 Hz, 1H), 6.55 (br d, J=8 .8 Hz, 1H), 6.49 (br dd, J=14.7, 2.0 Hz, 1H), 5.06 (q, J=6.6 Hz, 1H), 4.50 (br dd , J=12.6, 5.0 Hz, 1H), 3.52-3.58 (m, 1H), 3.46-3.52 (m, 1H), 3.34-3.43 (m , 3H), 3.19-3.30 (m, 2H), 2.86-2.96 (m, 1H), 2.80-2.86 (m, 1H), 2.22-2.29 (m, 1H), 2.14-2.22 (m, 1H), 1.56 (d, J=6.6 Hz, 3H), 1.20-1.38 (m, 4H).

Compound 22.

Basic rotamer (65%).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.02 (t, J=8.8 Hz, 1H), 7.74 (s, 1H), 7.52 (br s, 1H), 7.30 (br d, J=6.8 Hz, 1H), 7.17-7.25 (m, 2H), 7.05-7.16 (m, 1H), 6.96-7.05 (m, 2H), 6.53 (br d, J=8.8 Hz, 1H), 6.46 (br dd, J=15.2, 1.6 Hz, 1H), 5.50 (q, J=6 .4 Hz, 1H), 3.95 (br dd, J=13.9, 4.2 Hz, 1H), 3.50 (br t, J=8.7 Hz, 1H), 3.35-3 .46 (m, 3H), 3.20-3.31 (m, 2H), 3.00-3.14 (m, 2H), 2.73-2.87 (m, 1H), 2.15 -2.25 (m, 1H), 2.05-2.15 (m, 1H), 1.50 (d, J=6.7 Hz, 3H), 1.25-1.39 (m, 4H ).

Minor rotamer (35%).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.02 (t, J=8.8 Hz, 1H), 7.67 (s, 1H), 7.52 (br s, 1H), 7.17 -7.25 (m, 2H), 7.05-7.16 (m, 2H), 6.96-7.05 (m, 2H), 6.53 (br d, J=8.8 Hz, 1H), 6.46 (br dd, J=15.2, 1.6 Hz, 1H), 5.05 (q, J=6.9 Hz, 1H), 4.46-4.54 (m, 1H), 3.50 (br t, J=8.7 Hz, 1H), 3.35-3.46 (m, 3H), 3.20-3.31 (m, 2H), 3.00- 3.14 (m, 1H), 2.73-2.87 (m, 2H), 2.15-2.25 (m, 1H), 2.05-2.15 (m, 1H), 1, 56 (br d, J=6.5 Hz, 3H), 1.25-1.39 (m, 4H).

Compound 23.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.96-8.06 (m, 2H), 7.74 (s, 1H), 7.30 (br d, J=7.3 Hz, 1H ), 7.17-7.26 (m, 2H), 7.06-7.16 (m, 1H), 7.01 (br d, J=2.8 Hz, 1H), 6.53 (br d, J=8.2 Hz, 1H), 6.45 (br d, J=15.1 Hz, 1H), 5.50 (q, J=6.3 Hz, 1H), 3.94 (br d, J=9.5Hz, 1H), 3.51(t, J=8.2Hz, 1H), 3.34-3.47(m, 3H), 3.19-3.29(m , 2H), 3.01-3.13 (m, 2H), 2.73-2.85 (m, 1H), 2.62 (br d, J=4.4 Hz, 3H), 2.05 -2.24 (m, 2H), 1.50 (br d, J=6.6 Hz, 3H), 1.21-1.39 (m, 4H).

Minor rotamer (35%)

1H NMR (500 MHz, DMSO-d6) δ ppm 7.96-8.06 (m, 2H), 7.67 (s, 1H), 7.17-7.26 (m, 2H), 7.06 -7.16 (m, 2H), 6.98 (br d, J=2.8 Hz, 1H), 6.53 (br d, J=8.2 Hz, 1H), 6.45 (br d , J=15.1 Hz, 1H), 5.06 (q, J=6.7 Hz, 1H), 4.46-4.54 (m, 1H), 3.51 (t, J=8, 2 Hz, 1H), 3.34-3.47 (m, 3H), 3.19-3.29 (m, 2H), 3.01-3.13 (m, 1H), 2.73-2 .85 (m, 2H), 2.62 (br d, J=4.4 Hz, 3H), 2.05-2.24 (m, 2H), 1.56 (br d, J=6.3 Hz, 3H), 1.21-1.39 (m, 4H).

Compound 24.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 12.42 (br s, 1H), 8.38-8.43 (m, 1H), 8.19 (br t, J=8.0 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.15-7.26 (m, 5H), 6.98 (s, 1H), 5.60 (q, J=6 .6 Hz, 1H), 3.91 (br dd, J=13.7, 3.9 Hz, 1H), 3.44-3.52 (m, 1H), 2.99-3.08 (m , 1H), 2.73 (br d, J=15.8 Hz, 1H), 2.52-2.59 (m, 2H), 1.87-2.03 (m, 2H), 1.53 (d, J=6.6 Hz, 3H), 1.38-1.50 (m, 2H), 1.02-1.17 (m, 3H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 12.42 (br s, 1H), 8.38-8.43 (m, 1H), 8.19 (br t, J=8.0 Hz, 1H), 7.15-7.26 (m, 4H), 7.10-7.15 (m, 1H), 7.07 (d, J=7.3 Hz, 1H), 6.93 (s , 1H), 5.04 (q, J=6.6 Hz, 1H), 4.57 (br dd, J=12.5, 3.9 Hz, 1H), 3.23-3.30 (m , 1H), 2.83-2.97 (m, 1H), 2.52-2.59 (m, 3H), 1.87-2.03 (m, 2H), 1.59 (d, J =6.9 Hz, 3H), 1.38-1.50 (m, 2H), 1.02-1.17 (m, 3H).

Compound 25.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d6) δ ppm 7.82 (t, J=8.0 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.11-7, 26 (m, 5H), 6.98 (s, 1H), 5.59 (q, J=6.8 Hz, 1H), 3.91 (br dd, J=13.6, 3.8 Hz, 1H), 3.44-3.52 (m, 1H), 2.98-3.07 (m, 1H), 2.83-2.96 (m, 1H), 2.73 (br d, J =16.1 Hz, 1H), 2.57-2.63 (m, 1H), 2.39-2.47 (m, 2H), 1.88-1.94 (m, 1H), 1, 53 (d, J=6.6 Hz, 3H), 1.43-1.49 (m, 1H), 1.39 (brs, 1H), 1.11-1.18 (m, 3H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.82 (t, J=8.0 Hz, 1H), 7.11-7.26 (m, 5H), 7.04 (d, J= 7.3 Hz, 1H), 6.93 (s, 1H), 5.03 (q, J=6.6 Hz, 1H), 4.55 (br dd, J=12.8, 3.9 Hz , 1H), 3.44-3.52 (m, 1H), 2.98-3.07 (m, 1H), 2.83-2.96 (m, 1H), 2.57-2.63 (m, 1H), 2.39-2.47 (m, 3H), 1.88-1.94 (m, 1H), 1.58 (d, J=6.6 Hz, 3H), 1, 43-1.49(m, 1H), 1.39(brs, 1H), 1.11-1.18(m, 3H).

- 49 041546

Compound 26.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.53-7.61 (m, 1H), 7.32 (d, J=7.3 Hz, 1H), 7.05-7.26 ( m, 6H), 5.54-5.63 (m, 1H), 3.84-3.93 (m, 1H), 3.44-3.54 (m, 1H), 2.97-3, 08 (m, 1H), 2.82-2.97 (m, 1H), 2.73 (br dd, J=16.2, 2.4 Hz, 1H), 2.39-2.46 (m , 2H partially hidden by DMSO peak), 1.92 (br s, 1H), 1.67-1.76 (m, 1H), 1.53 (d, J=6.9 Hz, 3H), 1.43 -1.49 (m, 1H), 1.34-1.41 (m, 1H), 0.83-1.06 (m, 3H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.53-7.61 (m, 1H), 7.05-7.26 (m, 7H), 5.04 (quin, J=7.0 Hz, 1H), 4.52-4.58 (m, 1H), 3.44-3.54 (m, 1H), 2.97-3.08 (m, 1H), 2.82-2, 97 (m, 1H), 2.39-2.46 (m, 3n partially hidden by DMSO peak), 1.92 (br s, 1H), 1.67-1.76 (m, 1H), 1.59 (dd, J=10.9, 6.8 Hz, 3H), 1.43-1.49 (m, 1H), 1.34-1.41 (m, 1H), 0.83-1.06 (m, 3H).

Compound 27.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 12.55 (br s, 1H), 8.19-8.24 (m, 1H), 8.09 (t, J=9.0 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.15-7.26 (m, 3H), 6.93 (s, 1H), 6.55 (dt, J=8 .8, 2.7 Hz, 1H), 6.49 (dd, J=14.8, 1.6 Hz, 1H), 5.60 (q, J=6.6 Hz, 1H), 3.93 (br dd, J=13.7, 3.9 Hz, 1H), 3.43-3.57 (m, 3H), 3.34-3.43 (m, 2H), 3.20-3, 26 (m, 1H), 3.01-3.10 (m, 1H), 2.74 (br d, J=15.8 Hz, 1H), 2.14-2.29 (m, 2H), 1.53 (d, J=6.9 Hz, 3H), 1.19-1.26 (m, 2H), 1.02-1.13 (m, 2H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 12.55 (br s, 1H), 8.19-8.24 (m, 1H), 8.09 (t, J=9.0 Hz, 1H ), 7.15-7.26 (m, 2H), 7.10-7.15 (m, 1H), 7.08 (d, J=7.6 Hz, 1H), 6.89 (s, 1H), 6.55 (dt, J=8.8, 2.7 Hz, 1H), 6.49 (dd, J=14.8, 1.6 Hz, 1H), 5.07 (q, J =6.6 Hz, 1H), 4.57 (br dd, J=12.3, 4.4 Hz, 1H), 3.43-3.57 (m, 2H), 3.34-3.43 (m, 2H), 3.26-3.31 (m, 1H), 3.20-3.26 (m, 1H), 2.83-2.97 (m, 2H), 2.14-2 .29 (m, 2H), 1.59 (d, J=6.6 Hz, 3H), 1.19-1.26 (m, 2H), 1.02-1.13 (m, 2H).

Compound 28.

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.20 (br s, 1H), 8.08 (br t, J=8.8 Hz, 1H), 7.50 (br s, 1H) , 7.32 (d, J=7.1 Hz, 1H), 7.05-7.27 (m, 3H), 7.00 (br s, 1H), 6.93 (s, 1H), 6 .53 (br d, J=9.1 Hz, 1H), 6.46 (br d, J=14.7 Hz, 1H), 5.60 (q, J=6.4 Hz, 1H), 3 .93 (br dd, J=13.9, 4.3 Hz, 1H), 3.34-3.55 (m, 4H), 3.22-3.30 (m, 1H partially obscured by the SC peak), 3.02-3.13 (m, 2H), 2.73 (br d, J=16.7 Hz, 1H), 2.15-2.25 (m, 1H), 2.04-2.15 (m, 1H), 1.53 (d, J=7.1 Hz, 3H), 1.17-1.29 (m, 2H), 0.98-1.14 (m, 2H).

Minor rotamer (35%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.20 (br s, 1H), 8.08 (br t, J=8.8 Hz, 1H), 7.50 (br s, 1H) , 7.05-7.27 (m, 4H), 7.00 (br s, 1H), 6.88 (s, 1H), 6.53 (br d, J=9.1 Hz, 1H), 6.46 (br d, J=14.7 Hz, 1H), 5.06 (q, J=6.6 Hz, 1h), 4.53-4.62 (m, 1H), 3.34- 3.55 (m, 4H), 3.22-3.30 (m, 1H partially hidden by the H ₂ O peak), 3.02-3.13 (m, 1H), 2.82-2.97 (m, 2H ), 2.15-2.25 (m, 1H), 2.04-2.15 (m, 1H), 1.59 (d, J=6.6 Hz, 3H), 1.17-1, 29 (m, 2H), 0.98-1.14 (m, 2H).

LC/MS data.

General procedure.

High performance liquid chromatography (HPLC) measurements were performed using an LC pump, diode array detector (DAD) or UV detector and column as described in the respective methods. If necessary, additional detectors were included (see table of methods below).

The flow from the column was sent to a mass spectrometer (MS), which was equipped with an atmospheric pressure ionization source. It is within the skill of the art to set tunable parameters (eg, scan range, minimum measurement time, etc.) to produce ions to determine the nominal monoisotopic molecular weight (MW) of the compound. Data collection was carried out using the appropriate software.

Compounds were described using their experimental retention times (R _t ) and ions. Unless otherwise indicated in the data sheet, the indicated molecular ion corresponds to [M+H]+ (protonated molecule) and/or [M-H]~ (deprotonated molecule). In case the compound was not directly capable of ionization, the type of adduct was indicated (ie [M+NH ₄ ]+, [M+HCOO] ^- etc.). For molecules with complex isotope distributions (Br, Cl, etc.), the indicated value is the value obtained for the smallest mass of the isotope. All results were obtained with experimental errors, which are usually associated with the method used.

Hereinafter, SQD stands for single quadrupole detector, RT stands for room temperature, BH stands for ethylsiloxane/silica bridged hybrid, HSS stands for high strength silicon dioxide, DAD stands for diode array detector.

- 50 041546

Table

LCMS Method Codes

device Column mobile phase Gradient Consumption Run time T columns waters: Acquity UPLC®- DAD and Quattro Micro™ Waters: WEN C18(l.7um, 2.1 x 100mm) A: 95% CH ₃ COONH 4 7 mM/5% CH ₃ CN, B: CH ₃ CN From 84.2% A in 0.49 min to 10.5% A in 2.18 min, hold for 1.94 min, back to 84.2% A in 0.73 min, hold for 0, 73 min 0.343 6.2 40 waters: Acquity® H- class- DAD and SQD2™ Waters: VENTS18 (1.7 microns, 2.1 x 100 mm) A: 95% CH3COO NH ₄ 7 mM/5% CH3CN, B: _CH3CN 84.2% A to 10.5% A in 2.18 min, hold for 1.96 min, back to 84.2% A in 0.73 min, hold for 0.73 min 0.343 6.1 40 waters: Acquity UPLC® H- class- DAD and SQD2™ Waters WEN®C18 (1.7 µm, 2.1x50 mm) A: 95% CH3COO NH ₄ 7 mM/5% CH ₃ CN, B: CH ₃ CN 95% A to 5% A in 1 min, hold for 1.6 min, back to 95% A in 0.2 min, hold for 0.5 min 0.5 3.3 40 conn. no. Rt MW (theor.) BPM1 fM+H]+ Method LC/GC/MS 1 2 3 4 5 6 7 8 9 10 And 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 2.68 3.19 2.71 2.61 2.52 2.69 2.66 3.2 2.7 3.27 1.19 2.98 2.94 2.21 2.56 2.37 2.37 2.83 2.4 2.73 2.69 3.21 3.33 2.34 2.37 2.31 2.39 2.81 496.2 495.2 525.2 497.2 527.2 527.2 526.2 525.3 540.3 555 509.2 508.2 537.2 575.2 574.2 510.2 510.2 509.2 539.2 538.2 539.2 538.2 552.2 510.2 528.2 528.2 539.2 538.2 497.2 496.3 526.3 498.3 528.6 528.3 527.3 526.3 541.4 556.3 510.4 509.3 538.4 576.4 575.5 511.3 511.3 510.3 540.3 539.5 540.4 539.4 553.5 511.2 529.3 529.4 540.3 539.3 A A A A B A A A A A S A A A A A A A A B A A A A A A A A

The flow rate is expressed in ml/min; column temperature (T) - in °C;

run time is in minutes.

- 51 041546

optical rotation.

Optical rotation was measured using a polarimeter with sodium D-line light (589 nm) at 20° C. in DMF as solvent.

conn. no. I«1D ²⁰ Conc. (w/v%) conn. no. Md ²⁰ Conc. (w/v%) 1 +109.29° 0.28 19 +4.44° 0.27 2 +129.07° 0.258 20 -29.74° 0.252 3 +7.69° 0.234 21 +37.88° 0.264 8 -30.77° 0.26 22 +4.96° 0.262 9 -24.07° 0.27 23 -6.08° 0.296 10 -56.43° 0.28 27 +42.19° 0.32 14 +14.16° 0.219 28 -10° 0.25 15 -29.28° 0.222

E. Pharmacological Examples E.1.

Antiviral action.

Black 384-well clear bottom microplates (Corning, Amsterdam, The Netherlands) were filled by sonic droplet ejection using an Echo liquid handler (Labcyte, Sunnyvale, CA). 200 nl of compound stock solutions (100% DMSO) were transferred to assay plates. Performed 9 serial 4-fold dilutions of the compounds, creating the same concentration of compounds per sector. The assay was initiated by adding 10 µl of culture medium to each well (RPMI medium without phenol red, 10% FBS, heat inactivated, 0.04% gentamicin (50 mg/mL). All additional steps were performed using a multichannel dispenser (Thermo Scientific, Erembodegem, Belgium) The rgRSV224 virus (MOI=1) diluted in culture medium was then added to the plates.The rgRSV224 virus is an engineered virus that includes an additional GFP gene (Hallak LK, Spillmann D., Collins PL, Peeples ME, Glycosaminoglycan sulfation requirements for respiratory syncytial virus infection; Journal of virology (2000), 74(22), 10508-13) and licensed from NIH (Bethesda, MD, USA). (3000 cells/well) Media, virus-infected controls, and sham-infection controls were included in each test.The wells contained 0.05% DMSO by volume.Incu cells were tested at 37°C in an atmosphere with 5% CO ₂ . Three days after exposure to the virus, viral replication was quantified by measuring GFP expression in cells using a proprietary MSM laser microscope (Tibotec, Berset, Belgium). EC ₅₀ was defined as 50% inhibitory concentration for GFP expression. Compounds were incubated in parallel for three days in a set of white 384-well microtiter plates (Corning) and the cytotoxicity of the 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. CC ₅₀ was defined as 50% concentration for cytotoxicity.

Table Antivirus data (averaged data of several repeated experiments)

conn. no. RSV HELA ec ₅₀ (µM) TOX. in HELA SS ₅₀ (µM) conn. no. RSV HELA ec ₅₀ (µM) TOX. in HELA SS ₅₀ (µM) 1 0.195 45.10 15 0.480 20.60 2 0.344 52.70 16 0.182 79.40 3 0.218 44.00 17 2.010 >100 4 0.219 57.60 18 0.178 47.90 5 1,700 47.20 19 0.100 60.90 6 0.090 50.20 20 0.102 45.60

-

Claims (9)

7 0.064 48.00 21 0.564 29.80 8 0.054 53.40 22 0.870 >100 9 0.596 50.60 23 0.882 >100 10 0.062 40.40 24 0.105 69.70 AND 0.197 39.90 25 0.112 22.30 12 0.203 59.00 26 3.420 77.20 13 0.294 23.40 27 0.159 40.40 14 1.150 52.80 28 0.112 22.30 F. Examples of Possible Formulations. As used throughout these examples, the term active substance refers to the final compound of formula (I), its pharmaceutically acceptable salts, its solvates and stereochemically isomeric forms and tautomers. The following are typical examples of formulations for the composition of the present invention. F.I. Pills. Active substance 5-50 mg; dicalcium phosphate 20 mg; lactose 30 mg; talc 10 mg; magnesium stearate 5 mg; potato starch up to 200 mg. In this example, the active substance can be replaced by the same amount of any compounds in accordance with the present invention, in particular the same amount of any of the compounds given as an example. F.2. Suspension. An aqueous suspension for oral administration is prepared so that each 1 ml contains from 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 to 1 ml. F.3. injection form. The composition for parenteral administration is obtained by mixing a mass fraction of 1.5% of the active substance of this invention in 10% by volume of propylene glycol in water. F.4. Ointment. Active substance 5-1000 mg; stearyl alcohol 3 g; lanolin 5 g; white vaseline 15 g; water up to 100 g In this example, the active substance can be replaced by the same amount of any compounds in accordance with the present invention, in particular the same amount of any of the compounds given as an example. CLAIM 1. The compound of formula (I), where or its stereochemically isomeric form, where A is R ⁵ is - 53 041546 ^R3 (b-1) X ¹ , X ² , X ³ and X ⁴ are selected from the following options: X ¹ is CH, X ² is CH, X ³ is CH and X ⁴ is CH; or X ¹ is N, X ² is CH, X ³ is CH and X ⁴ is CH, or X ¹ is CH, X ² is N, X ³ is CH and X ⁴ is CH, or X ¹ is CH, X ² is CH, X ³ is CH and X ⁴ is N, or X ¹ is N, X ² is N, X ³ is CH and X ⁴ is CH, or X ¹ is CH, X ² is N, X ³ is N, and X ⁴ is CH, where each CH is optionally substituted with halo, Cmalkyl, or C^dalkyloxy; each of Y ¹ and Y ² is independently selected from CH; R ¹ is CH ₃ ; R ² is hydrogen; R ³ is halogen; R ⁴ is Ciealkyl, C ₃ .bCycloalkyl or heteroaryl; R ⁶ is C ₃ . ₆ cycloalkyl or heterocycle, where indicated With ₃ . ₆ cycloalkyl and heterocycle are substituted with one or two substituents each independently selected from -(CO)-OR ⁷ , -(CO)-NR ¹⁰ R ⁿ ; R ⁷ is hydrogen; each of R ¹⁰ and R ¹¹ is independently selected from hydrogen or C^alkyl; the heterocycle is pyrrolidinyl; heteroaryl is pyridinyl; or a pharmaceutically acceptable acid addition salt thereof. 2. A compound as claimed in claim 1 wherein X ¹ is CH, X ² is N, X ³ is N and X ⁴ is CH. 3. A compound as claimed in claim 1 wherein X ¹ is N, X ² is N, X ³ is CH, and X ⁴ is CH. 4. A compound according to any one of claims 1 to 3, wherein R ³ is fluorine. 5. A compound according to any one of claims 1 to 4, wherein R ⁴ is C ₃ .bCycloalkyl. 6. A pharmaceutical composition containing a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound as claimed in any one of claims 1-5. 7. A process for the preparation of a pharmaceutical composition according to claim 6, wherein the therapeutically active amount of a compound according to any one of claims 1 to 5 is intimately mixed with a pharmaceutically acceptable carrier. 8. Use of a compound according to any one of claims 1 to 5 as a drug for respiratory syncytial virus infection. 9. The use of a pharmaceutical composition according to claim 6 for the treatment of an infection caused by a respiratory syncytial virus. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2